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Subacromial bursitis | Subacromial bursitis is a condition caused by inflammation of the bursa that separates the superior surface of the supraspinatus tendon (one of the four tendons of the rotator cuff) from the overlying coraco-acromial ligament, acromion, and coracoid (the acromial arch) and from the deep surface of the deltoid muscle. The subacromial bursa helps the motion of the supraspinatus tendon of the rotator cuff in activities such as overhead work.
Musculoskeletal complaints are one of the most common reasons for primary care office visits, and rotator cuff disorders are the most common source of shoulder pain.Primary inflammation of the subacromial bursa is relatively rare and may arise from autoimmune inflammatory conditions such as rheumatoid arthritis, crystal deposition disorders such as gout or pseudogout, calcific loose bodies, and infection. More commonly, subacromial bursitis arises as a result of complex factors, thought to cause shoulder impingement symptoms. These factors are broadly classified as intrinsic (intratendinous) or extrinsic (extratendinous). They are further divided into primary or secondary causes of impingement. Secondary causes are thought to be part of another process such as shoulder instability or nerve injury.In 1983 Neer described three stages of impingement syndrome. He noted that "the symptoms and physical signs in all three stages of impingement are almost identical, including the impingement sign..., arc of pain, crepitus, and varying weakness". The Neer classification did not distinguish between partial-thickness and full-thickness rotator cuff tears in stage III. This has led to some controversy about the ability of physical examination tests to accurately diagnose between bursitis, impingement, impingement with or without rotator cuff tear and impingement with partial versus complete tears.
In 2005, Park et al. published their findings which concluded that a combination of clinical tests were more useful than a single physical examination test. For the diagnosis of impingement disease, the best combination of tests were "any degree (of) a positive Hawkins–Kennedy test, a positive painful arc sign, and weakness in external rotation with the arm at the side", to diagnose a full thickness rotator cuff tear, the best combination of tests, when all three are positive, were the painful arc, the drop-arm sign, and weakness in external rotation.
Signs and symptoms
Subacromial bursitis often presents with a constellation of symptoms called impingement syndrome. Pain along the front and side of the shoulder is the most common symptom and may cause weakness and stiffness. If the pain resolves and weakness persists other causes should be evaluated such as a tear of the rotator cuff or a neurological problem arising from the neck or entrapment of the suprascapular nerve. The onset of pain may be sudden or gradual and may or may not be related to trauma. Night time pain, especially sleeping on the affected shoulder, is often reported. Localized redness or swelling are less common and suggest an infected subacromial bursa. Individuals affected by subacromial bursitis commonly present with concomitant shoulder problems such as arthritis, rotator cuff tendinitis, rotator cuff tears, and cervical radiculopathy (pinched nerve in neck).Impingement may be brought on by sports activities, such as overhead throwing sports and swimming, or overhead work such as painting, carpentry, or plumbing. Activities that involve repetitive overhead activity, or directly in front, may cause shoulder pain. Direct upward pressure on the shoulder, such as leaning on an elbow, may increase pain.
Pathophysiology
The literature on the pathophysiology of bursitis describes inflammation as the primary cause of symptoms. Inflammatory bursitis is usually the result of repetitive injury to the bursa. In the subacromial bursa, this generally occurs due to microtrauma to adjacent structures, particularly the supraspinatus tendon. The inflammatory process causes synovial cells to multiply, increasing collagen formation and fluid production within the bursa and reduction in the outside layer of lubrication.Less frequently observed causes of subacromial bursitis include hemorrhagic conditions, crystal deposition and infection.Many causes have been proposed in the medical literature for subacromial impingement syndrome. The bursa facilitates the motion of the rotator cuff beneath the arch, any disturbance of the relationship of the subacromial structures can lead to impingement. These factors can be broadly classified as intrinsic such as tendon degeneration, rotator cuff muscle weakness and overuse. Extrinsic factors include bone spurs from the acromion or AC joint, shoulder instability and neurologic problems arising outside of the shoulder.
Diagnosis
It is often difficult to distinguish between pain caused by bursitis or that caused by a rotator cuff injury as both exhibit similar pain patterns in the front or side of the shoulder. Subacromial bursitis can be painful with resisted abduction due to the pinching of the bursa as the deltoid contracts. If the therapist performs a treatment direction test and gently applies joint traction or a caudal glide during abduction (MWM), the painful arc may reduce if the problem is bursitis or adhesive capsulitis (as this potentially increases the subacromial space).The following clinical tests, if positive, may indicate bursitis:
The patient actively abducts the arm and a painful arc occurs between 60° and 120°. This is due to the compression of the supraspinatus tendon or subacromial bursa between the anterior acromial arch and humeral head. When lowering from full abduction there is often a painful "catch" at midrange. If the patient can achieve adequate muscle relaxation, passive motion tends to be less painful.
The patient performs an isometric flexion contraction against resistance of the therapist (Speed’s Test). When the therapist’s resistance is removed, a sudden jerking motion results and latent pain indicates a positive test for bursitis.
Neer’s Sign: If pain occurs during forward elevation of the internally rotated arm above 90°. This will identify impingement of the rotator cuff but is also sensitive for subacromial bursitis.Irritation or entrapment of the lower subscapular nerve, which innervates the subscapularis and teres major muscles, will produce muscle guarding at the shoulder that will restrict motion into external rotation, abduction, or flexion. The aforementioned tests will assist in diagnosing bursitis over other conditions. The diagnosis of impingement syndrome should be viewed with caution in people who are less than forty years old, because such individuals may have subtle glenohumeral instability.
Imaging
X-rays may help visualize bone spurs, acromial anatomy and arthritis. Further, calcification in the subacromial space and rotator cuff may be revealed. Osteoarthritis of the acromioclavicular (AC) joint may co-exist and is usually demonstrated on radiographs.MRI imagining can reveal fluid accumulation in the bursa and assess adjacent structures. In chronic cases caused by impingement tendinosis and tears in the rotator cuff may be revealed. At US, an abnormal bursa may show
fluid distension,
synovial proliferation, and/or
thickening of the bursal walls.In any case, the magnitude of pathological findings does not correlate with the magnitude of the symptoms.
Special considerations
In patients with bursitis who have rheumatoid arthritis, short term improvements are not taken as a sign of resolution and may require long term treatment to ensure recurrence is minimized. Joint contracture of the shoulder has also been found to be at a higher incidence in type two diabetics, which may lead to frozen shoulder (Donatelli, 2004).
Treatment
Many non-operative treatments have been advocated, including rest; oral administration of non-steroidal anti-inflammatory drugs; physical therapy; chiropractic; and local modalities such as cryotherapy, ultrasound, electromagnetic radiation, and subacromial injection of corticosteroids.Shoulder bursitis rarely requires surgical intervention and generally responds favorably to conservative treatment. Surgery is reserved for patients who fail to respond to non-operative measures. Minimally invasive surgical procedures such as arthroscopic removal of the bursa allows for direct inspection of the shoulder structures and provides the opportunity for removal of bone spurs and repair of any rotator cuff tears that may be found.
Early / initial
Middle / intermittent
Late / return to function
Prognosis
In 1997 Morrison et al. published a study that reviewed the cases of 616 patients (636 shoulders) with impingement syndrome (painful arc of motion) to assess the outcome of non-surgical care. An attempt was made to exclude patients who were suspected of having additional shoulder conditions such as, full-thickness tears of the rotator cuff, degenerative arthritis of the acromioclavicular joint, instability of the glenohumeral joint, or adhesive capsulitis. All patients were managed with anti-inflammatory medication and a specific, supervised physical-therapy regimen. The patients were followed up from six months to over six years. They found that 67% (413 patients) of the patients improved, while 28% did not improve and went to surgical treatment. 5% did not improve and declined further treatment.Of the 413 patients who improved, 74 had a recurrence of symptoms during the observation period and their symptoms responded to rest or after resumption of the exercise program.The Morrison study shows that the outcome of impingement symptoms varies with patient characteristics. Younger patients (20 years or less) and patients between 41 and 60 years of age, fared better than those who were in the 21 to 40 years age group. This may be related to the peak incidence of work, job requirements, sports and hobby related activities, that may place greater demands on the shoulder. However, patients who were older than sixty years of age had the "poorest results". It is known that the rotator cuff and adjacent structures undergo degenerative changes with ageing.The authors were unable to posit an explanation for the observation of the bimodal distribution of satisfactory results with regard to age. They concluded that it was "unclear why (those) who were twenty-one to forty years old had less satisfactory results". The poorer outcome for patients over 60 years old was thought to be potentially related to "undiagnosed full-thickness tears of the rotator cuff".
References
Anderson, D., M, (2000), Dorland’s Illustrated Medical Dictionary, 29th ed, W.B. Saunders Company, Canada, 965-967.
Buschbacher, R., M, Braddom, R., L. (1994). Sports medicine & rehabilitation: A sport-specific approach. Hanley and Belfus Inc, Philadelphia.
Hartley, A. (1990). Practical joint assessment: A sports medicine manual, St Louis, Sydney.
Further reading
Arend CF. Ultrasound of the Shoulder. Master Medical Books, 2013. Free chapter on bursae around the shoulder joint.
Wilk, Kevin E.; Andrews, James R. (1994). The Athletes shoulder. Edinburgh: Churchill Livingstone. ISBN 978-0-443-08847-6.
Blaine TA, Kim YS, Voloshin I, et al. (2005). "The molecular pathophysiology of subacromial bursitis in rotator cuff disease". J Shoulder Elbow Surg. 14 (1 Suppl S): 84S–89S. doi:10.1016/j.jse.2004.09.022. PMID 15726092.
Brox JI, Gjengedal E, Uppheim G, et al. (1999). "Arthroscopic surgery versus supervised exercises in patients with rotator cuff disease (stage II impingement syndrome): a prospective, randomized, controlled study in 125 patients with a 2 1/2-year follow-up". J Shoulder Elbow Surg. 8 (2): 102–11. doi:10.1016/S1058-2746(99)90001-0. PMID 10226960.
Butcher JD, Salzman KL, Lillegard WA (1996). "Lower extremity bursitis". Am Fam Physician. 53 (7): 2317–24. PMID 8638508.
Donatelli, Robert (2004). Physical therapy of the shoulder. Edinburgh: Churchill Livingstone. ISBN 978-0-443-06614-6.
Handa A, Gotoh M, Hamada K, et al. (2003). "Vascular endothelial growth factor 121 and 165 in the subacromial bursa are involved in shoulder joint contracture in type II diabetics with rotator cuff disease". J. Orthop. Res. 21 (6): 1138–44. doi:10.1016/S0736-0266(03)00102-5. PMID 14554230. S2CID 29665718.
Hartley, Anne (1990). Practical joint assessment: a sports medicine manual. St. Louis, MO: Mosby Year Book. ISBN 978-0-8016-2050-8.
Sports Medicine and Rehabilitation: A Sport-Specific Approach. Hagerstown, MD: Lippincott Williams & Wilkins. 1994. ISBN 978-1-56053-133-3.
Lo IK, Boorman R, Marchuk L, Hollinshead R, Hart DA, Frank CB (2005). "Matrix molecule mRNA levels in the bursa and rotator cuff of patients with full-thickness rotator cuff tears". Arthroscopy. 21 (6): 645–51. doi:10.1016/j.arthro.2005.03.008. PMID 15944617.
Ishii H, Brunet JA, Welsh RP, Uhthoff HK (1997). ""Bursal reactions" in rotator cuff tearing, the impingement syndrome, and calcifying tendinitis". J Shoulder Elbow Surg. 6 (2): 131–6. doi:10.1016/S1058-2746(97)90033-1. PMID 9144600.
McAfee JH, Smith DL (1988). "Olecranon and prepatellar bursitis. Diagnosis and treatment". West. J. Med. 149 (5): 607–10. PMC 1026560. PMID 3074561.
Perry J (1983). "Anatomy and biomechanics of the shoulder in throwing, swimming, gymnastics, and tennis". Clin Sports Med. 2 (2): 247–70. doi:10.1016/S0278-5919(20)31406-X. PMID 9697636.
Reilly JP, Nicholas JA (1987). "The chronically inflamed bursa". Clin Sports Med. 6 (2): 345–70. doi:10.1016/S0278-5919(20)31035-8. PMID 3319205.Trojian T, Stevenson JH, Agrawal N (2005). "What can we expect from nonoperative treatment options for shoulder pain?". J Fam Pract. 54 (3): 216–23. PMID 15755374.
Shamus, Jennifer; Shamus, Eric (2001). Sports injury: prevention & rehabilitation. New York: McGraw-Hill Medical Pub. Div. ISBN 978-0-07-135475-2.
Starr M, Harbhajan K (June 2001). "Recognition and Management of Common Forms of Tendinitis and Bursitis" (PDF). The Canadian Journal of Continuing Medical Education: 155–63. ISSN 0843-994X.
Trojian T, Stevenson JH, Agrawal N (2005). "What can we expect from nonoperative treatment options for shoulder pain?". J Fam Pract. 54 (3): 216–23. PMID 15755374.
van Holsbeeck M, Strouse PJ (1993). "Sonography of the shoulder: evaluation of the subacromial-subdeltoid bursa". AJR Am J Roentgenol. 160 (3): 561–4. doi:10.2214/ajr.160.3.8430553. PMID 8430553.
Yanagisawa K, Hamada K, Gotoh M, et al. (2001). "Vascular endothelial growth factor (VEGF) expression in the subacromial bursa is increased in patients with impingement syndrome". J. Orthop. Res. 19 (3): 448–55. doi:10.1016/S0736-0266(00)90021-4. PMID 11398859. S2CID 20098903.
== External links == |
Microlissencephaly | Microlissencephaly (MLIS) is a rare congenital brain disorder that combines severe microcephaly (small head) with lissencephaly (smooth brain surface due to absent sulci and gyri). Microlissencephaly is a heterogeneous disorder, i.e. it has many different causes and a variable clinical course. Microlissencephaly is a malformation of cortical development (MCD) that occurs due to failure of neuronal migration between the third and fifth month of gestation as well as stem cell population abnormalities. Numerous genes have been found to be associated with microlissencephaly, however, the pathophysiology is still not completely understood.
The combination of lissencephaly with severe congenital microcephaly is designated as microlissencephaly only when the cortex is abnormally thick. If such combination exists with a normal cortical thickness (2.5 to 3 mm), it is known as "microcephaly with simplified gyral pattern" (MSGP). Both MLIS and MSGP have a much more severe clinical course than microcephaly alone. They are inherited in autosomal recessive manner. Prior to 2000, the term "microlissencephaly" was used to designate both MLIS and MSGP.
Types
Microlissencephaly is one of five subtypes of lissencephaly. Microlissencephaly, in turn, can be subclassified based on imaging and clinical picture into 4 types:
MLIS1
Microlissencephaly Type A or Norman-Roberts syndrome (NRS): a microlissencephaly with thick cortex without infratentorial anomalies.Other clinical features may include: a bitemporal narrowing, a broad nasal root. There is postnatal growth retardation, severe mental retardation associated with pyramidal spasticity and epilepsy. This entity could be identical to "lissencephaly with cerebellar hypoplasia type B" (LCHb), and therefore linked to mutations in RELN gene.
MLIS2
Microlissencephaly Type B or Barth microlissencephaly syndrome: is a microlissencephaly with thick cortex, severe cerebellar and brainstem hypoplasia. The Barth-type of MLIS is the most severe of all the known lissencephaly syndromes.This phenotype consists of polyhydramnios (probably due to poor fetal swallowing), severe congenital microcephaly, weak respiratory effort, and survival for only a few hours or days. Barth described two siblings with this type as having a very low brainweight, wide ventricles, a very thin neopallium, absent corpus callosum and absent olfactory nerve.
MLIS3
Microlissencephaly with intermediate cortex and abrupt anteroposterior gradient
MLIS4
Microlissencephaly with mildly to moderately thick (6–8 mm) cortex, callosal agenesis
Presentation
Microlissencephalic patients suffer from spasticity, seizures, severe developmental delay and intellectual disabilities with survival varying from days to years. Patients may also have dysmorphic craniofacial features, abnormal genitalia, and arthrogryposis.Microlissencephaly may arise as a part of Baraitser-Winter syndrome which comprises also ptosis, coloboma, hearing loss and learning disability.
Moreover, it is the distinct developmental brain abnormality in "microcephalic osteodysplastic primordial dwarfism" (MOPD1). Microlissencephaly may be accompanied by micromelia as in Basel-Vanagaite-Sirota syndrome (a.k.a. Microlissencephaly-Micromelia syndrome).
Pathophysiology
The genetic basis and pathophysiology of microlissencephaly are still not completely understood.
Most cases of microlissencephaly are described in consanguineous families suggesting an autosomal recessive inheritance. Mutation of RELN gene or CIT could cause MLIS. Human NDE1 mutations and mouse Nde1 loss lead to cortical lamination deficits, which, together with reduced neuronal production cause microlissencephaly. Homozygous frameshift mutations in NDE1 gene was found to cause microlissencephaly with up to 90% reduction in brain mass and seizures starting early in life. Some other disease-causing genes include: KATNB1 and WDR62. It is hypothesized that the KATNB1-associated microlissencephaly is the result of a combined effect of reduced neural progenitor populations and impaired interaction between the Katanin P80 subunit (encoded by KATNB1) and LIS1 (a.k.a. PAFAH1B1), a protein mutated in type 1 lissencephaly. Missense mutation in ACTG1 gene was identified in three cases of microlissencephaly. ACTG1 is the same gene that, when mutated, causes Baraitser-Winter syndrome. A loss-of-function mutation in the Doublesex- and Mab-3–Related Transcription factor A2 (DMRTA2, also known as DMRT5) gene has been reported in a case of microlissencephaly, implicating DMRTA2 as a critical regulator of cortical neural progenitor cell dynamics.Microlissencepahly is considered a tubulinopathy (tubulin gene defect) i.e. is caused by mutation in tubulin genes, mainly TUBA1A and less commonly TUBB2B, TUBB3, TUBA3E and TUBG1. Central pachygyria, polymicrogyria are more commonly seen in patients with defects in TUBB2B, TUBB3, and TUBB5. This implys the critical role of microtubule cytoskeleton in the pathophysiology of microlissencephaly as well as other neuronal migration disorders.Congenital infections like cytomegalovirus are also known to cause microlissencephaly.Both microlissencephaly and microcephaly with simplified gyral pattern result from either decreased stem cell proliferation or increased apoptosis in the germinal zone of the cerebral cortex.
Diagnosis
Microlissencephaly can be diagnosed by prenatal MRI. MRI is better than ultrasound when it comes to detecting microlissencephaly or MSGP prenatally.
The ideal time for proper prenatal diagnosis is between the 34th and 35th gestational week which is the time when the secondary gyration normally terminates. In microlissencephaly cases, the primary sulci would be unusually wide and flat while secondary sulci would be missing.At birth, lissencephaly with a head circumference of less than minus three standard deviations (< –3 SD) is considered microlissencephaly.Although genetic diagnosis in patients with MLIS is challenging, exome sequencing has been suggested to be a powerful diagnostic tool.
Dobyns-Barkovich classification
In 1999, Dobyns and Barkovich suggested a classification of patients with severe microcephaly combined with gyral abnormalities including: microcephaly with simplified gyral pattern (MSGP), microlissencephaly and polymicrogyria. The classification divided those patients into ten groups in which MSGP represented the first four groups, microlissencephaly referred to the groups from 5-8 and polymicrogyria in the last two groups.In Dobyns-Barkovich classification, Dobyns-Barkovich type 6 is equivalent to Norman-Roberts syndrome (MLIS1) while Dobyns-Barkovich type 8 corresponds to Barth microlissencephaly syndrome (MLIS2).
Differential diagnosis
Microlissencephaly is considered a more severe form than microcephaly with simplified gyral pattern. Microlissencephaly is characterized by a smooth cortical surface (absent sulci and gyri) with a thickened cortex (> 3 mm) and is usually associated with other congenital anomalies. Microcephaly with a simplified gyral pattern has too few sulci and normal cortical thickness (3 mm) and is usually an isolated anomaly.
Prognosis
Many patients will die within the first year of life.
Epidemiology
Microlissencephaly is listed in Orphanet database as a rare disease. There is not much information available about the epidemiology of microlissencepahly in literature. A PhD thesis has estimated the prevalence of microlissencepahly in southeastern Hungary between July 1992 and June 2006 to be a case every 91,000 live births (0.11:10,000).
History
In 1976, the first syndrome with MLIS was reported, now known as Norman–Roberts syndrome (MLIS type A). The Barth type (MLIS type B) was for the first time described in 1982 in two siblings who died soon after birth.
== References == |
Achromatopsia | Achromatopsia, also known as Rod monochromacy, is a medical syndrome that exhibits symptoms relating to five conditions, most notably monochromacy. Historically, the name referred to monochromacy in general, but now typically refers only to an autosomal recessive congenital color vision condition. The term is also used to describe cerebral achromatopsia, though monochromacy is usually the only common symptom. The conditions include: monochromatic color blindness poor visual acuity and day-blindness. The syndrome is also present in an incomplete form that exhibits milder symptoms, including residual color vision. Achromatopsia is estimated to affect 1 in 30,000 live births worldwide.
Signs and symptoms
The five symptoms associated with achromatopsia are:
Color blindness - usually monochromacy
Reduced visual acuity - uncorrectable with lenses
Hemeralopia – with the subject exhibiting photophobia
Nystagmus
Iris operating abnormalitiesThe syndrome is typically first noticed in children around six months of age due to their photophobia or their nystagmus. The nystagmus becomes less noticeable with age but the other symptoms of the syndrome become more relevant as school age approaches. Visual acuity and stability of the eye motions generally improve during the first six to seven years of life – but remain near 20/200. Otherwise the syndrome is considered stationary and does not worsen with age.If the light level during testing is optimized, achromats may achieve corrected visual acuity of 20/100 to 20/150 at lower light levels, regardless of the absence of color. The fundus of the eye appears completely normal.Achromatopsia can be classified as complete or incomplete. In general, symptoms of incomplete achromatopsia are attenuated versions of those of complete achromatopsia. Individuals with incomplete achromatopsia have reduced visual acuity with or without nystagmus or photophobia. Incomplete achromats show only partial impairment of cone cell function.
Cause
Achromatopsia is sometimes called rod monochromacy (as opposed to blue cone monochromacy), as achromats exhibit a complete absence of cone cell activity via electroretinography in photopic lighting. There are at least four genetic causes of achromatopsia, two of which involve cyclic nucleotide-gated ion channels (ACHM2, ACHM3), a third involves the cone photoreceptor transducin (GNAT2, ACHM4), and the last remains unknown.Known genetic causes of this include mutations in the cone cell cyclic nucleotide-gated ion channels CNGA3 (ACHM2) and CNGB3 (ACHM3), the cone cell transducin, GNAT2 (ACHM4), subunits of cone phosphodiesterase PDE6C (ACHM5, OMIM 613093) and PDEH (ACHM6, OMIM 610024), and ATF6 (ACHM7, OMIM 616517).
Pathophysiology
The hemeralopic aspect of achromatopsia can be diagnosed non-invasively using electroretinography. The response at low (scotopic) and median (mesopic) light levels will be normal but the response under high light level (photopic) conditions will be absent. The mesopic level is approximately a hundred times lower than the clinical level used for the typical high level electroretinogram. When as described; the condition is due to a saturation in the neural portion of the retina and not due to the absence of the photoreceptors per se.In general, the molecular pathomechanism of achromatopsia is either the inability to properly control or respond to altered levels of cGMP; particularly important in visual perception as its level controls the opening of cyclic nucleotide-gated ion channels (CNGs). Decreasing the concentration of cGMP results in closure of CNGs and resulting hyperpolarization and cessation of glutamate release. Native retinal CNGs are composed of 2 α- and 2 β-subunits, which are CNGA3 and CNGB3, respectively, in cone cells. When expressed alone, CNGB3 cannot produce functional channels, whereas this is not the case for CNGA3. Coassembly of CNGA3 and CNGB3 produces channels with altered membrane expression, ion permeability (Na+ vs. K+ and Ca2+), relative efficacy of cAMP/cGMP activation, decreased outward rectification, current flickering, and sensitivity to block by L-cis-diltiazem.Mutations tend to result in the loss of CNGB3 function or gain of function—often increased affinity for cGMP—of CNGA3. cGMP levels are controlled by the activity of the cone cell transducin, GNAT2. Mutations in GNAT2 tend to result in a truncated and, presumably, non-functional protein, thereby preventing alteration of cGMP levels by photons. There is a positive correlation between the severity of mutations in these proteins and the completeness of the achromatopsia phenotype.Molecular diagnosis can be established by identification of biallelic variants in the causative genes. Molecular genetic testing approaches used in achromatopsia can include targeted analysis for the common CNGB3 variant c.1148delC (p.Thr383IlefsTer13), use of a multigenerational panel, or comprehensive genomic testing.
ACHM2
While some mutations in CNGA3 result in truncated and, presumably, non-functional channels this is largely not the case. While few mutations have received in-depth study, at least one mutation does result in functional channels. Curiously, this mutation, T369S, produces profound alterations when expressed without CNGB3. One such alteration is decreased affinity for Cyclic guanosine monophosphate. Others include the introduction of a sub-conductance, altered single-channel gating kinetics, and increased calcium permeability.When mutant T369S channels coassemble with CNGB3, however, the only remaining aberration is increased calcium permeability. While it is not immediately clear how this increase in Ca2+ leads to achromatopsia, one hypothesis is that this increased current decreases the signal-to-noise ratio. Other characterized mutations, such as Y181C and the other S1 region mutations, result in decreased current density due to an inability of the channel to traffic to the surface. Such loss of function will undoubtedly negate the cone cells ability to respond to visual input and produce achromatopsia. At least one other missense mutation outside of the S1 region, T224R, also leads to loss of function.
ACHM3
While very few mutations in CNGB3 have been characterized, the vast majority of them result in truncated channels that are presumably non-functional. This will largely result in haploinsufficiency, though in some cases the truncated proteins may be able to coassemble with wild-type channels in a dominant negative fashion. The most prevalent ACHM3 mutation, T383IfsX12, results in a non-functional truncated protein that does not properly traffic to the cell membrane.The three missense mutations that have received further study show a number of aberrant properties, with one underlying theme. The R403Q mutation, which lies in the pore region of the channel, results in an increase in outward current rectification, versus the largely linear current-voltage relationship of wild-type channels, concomitant with an increase in cGMP affinity. The other mutations show either increased (S435F) or decreased (F525N) surface expression but also with increased affinity for cAMP and cGMP. It is the increased affinity for cGMP and cAMP in these mutants that is likely the disorder-causing change. Such increased affinity will result in channels that are insensitive to the slight concentration changes of cGMP due to light input into the retina.
ACHM4
Upon activation by light, cone opsin causes the exchange of GDP for GTP in the guanine nucleotide binding protein (G-protein) α-transducing activity polypeptide 2 (GNAT2). This causes the release of the activated α-subunit from the inhibitory β/γ-subunits. This α-subunit then activates a phosphodiesterase that catalyzes the conversion of cGMP to GMP, thereby reducing current through CNG3 channels. As this process is absolutely vital for proper color processing it is not surprising that mutations in GNAT2 lead to achromatopsia. The known mutations in this gene, all result in truncated proteins. Presumably, then, these proteins are non-functional and, consequently, cone opsin that has been activated by light does not lead to altered cGMP levels or photoreceptor membrane hyperpolarization.
Management
Gene therapy
As achromatopsia is linked to only a few single-gene mutations, it is a good candidate for gene therapy. Gene therapy is a technique for injecting functional genes into the cells that need them, replacing or overruling the original alleles linked to achromatopsia, thereby curing it - at least in part. Achromatopsia has been a focus of gene therapy since 2010, when achromatopsia in dogs was partially cured. Several clinical trials on humans are ongoing with mixed results.
Eyeborg
Since 2003, a cybernetic device called the eyeborg has allowed people to perceive color through sound waves. This form of Sensory substitution maps the hue perceived by a camera worn on the head to a pitch experienced through bone conduction according to a sonochromatic scale. This allows achromats (or even the totally blind) to perceive - or estimate - the color of an object. Achromat and artist Neil Harbisson was the first to use the eyeborg in early 2004, which allowed him to start painting in color. He has since acted as a spokesperson for the technology, namely in a 2012 TED Talk. A 2015 study suggests that achromats who use the Eyeborg for several years exhibit neural plasticity, which indicates the sensory substitution has become intuitive for them.
Other accommodations
While gene therapy and the Eyeborg may currently have low uptake with achromats, there are several more practical ways for achromats to manage their condition:
Some colors can be estimated through the use of colored filters. By comparing the luminosity of a color with and without a filter (or between two different filters), the color can be estimated. This is the premise of monocular lenses and the SeeKey. In some US states, achromats can use a red filter while driving to determine the color of a traffic light.
To alleviate photophobia stemming from hemeralopia, dark red or plum colored filters as either sunglasses or tinted contacts are very helpful at decreasing light sensitivity.
To manage the low visual acuity that is typical of achromatopsia, achromats may use telescopic systems, specifically when driving, to increase the resolution of an object of interest.
Epidemiology
Achromatopsia is a relatively uncommon disorder, with a prevalence of 1 in 30,000 people.However, on the small Micronesian atoll of Pingelap, approximately five percent of the atolls 3,000 inhabitants are affected. This is the result of a population bottleneck caused by a typhoon and ensuing famine in the 1770s, which killed all but about twenty islanders, including one who was heterozygous for achromatopsia.The people of this region have termed achromatopsia "maskun", which literally means "not see" in Pingelapese. This unusual population drew neurologist Oliver Sacks to the island for which he wrote his 1997 book, The Island of the Colorblind.
Blue cone monochromacy
Blue cone monochromacy (BCM) is another genetic condition causing monochromacy. It mimics many of the symptoms of incomplete achromatopsia and before the discovery of its molecular biological basis was commonly referred to as x-linked achromatopsia, sex-linked achromatopsia or atypical achromatopsia. BCM stems from mutations or deletions of the OPN1LW and OPN1MW genes, both on the X chromosome. As a recessive x-linked condition, BCM disproportionately affects males, unlike typical achromatopsia.
Cerebral achromatopsia
Cerebral achromatopsia]is a form of acquired color blindness that is caused by damage to the cerebral cortex. Damage is most commonly localized to visual area V4 of the visual cortex (the major part of the colour center), which receives information from the parvocellular pathway involved in color processing. It is most frequently caused by physical trauma, hemorrhage or tumor tissue growth. If there is unilateral damage, a loss of color perception in only half of the visual field may result; this is known as hemiachromatopsia.. Cerebral achromats usually do not experience the other major symptoms of congenital achromatopsia, since photopic vision is still functions.
Color agnosia involves having difficulty recognizing colors, while still being able to perceive them as measured by a color matching or categorizing task.
Terminology
Monochromacy
Complete lack of the perception of color in a subject, seeing only in black, white, and shades of grey.
Hemeralopia
Reduced visual capacity in bright light, i.e. day-blindness.
Nystagmus
Term to describe both normal and pathological conditions related to the oculomotor system. In the current context, it is a pathological condition involving an uncontrolled oscillatory movement of the eyes during which the amplitude of oscillation is quite noticeable and the frequency of the oscillation tends to be quite low.
Photophobia
Avoidance of bright light by those who have hemeralopia.
References
Footnotes
Sources
External links
Achromatopsia at MedicineNet
Achromatopsia at Merriam-Webster
Achromatopsia at NCBI
The Achromatopsia Network - an archive of information about Achromatopsia and advice on coping with the condition. |
Harlequin syndrome | Harlequin syndrome is a condition characterized by asymmetric sweating and flushing on the upper thoracic region of the chest, neck and face. Harlequin syndrome is considered an injury to the autonomic nervous system (ANS). The ANS controls some of the bodys natural processes such as sweating, skin flushing and pupil response to stimuli. Such individuals with this syndrome have an absence of sweat skin flushing unilaterally; usually on the one side of the face, arms and chest. It is an autonomic disorder that may occur at any age. Harlequin syndrome affects fewer than 200,000 people in the United States.
Symptoms associated with Harlequin syndrome are more likely to appear when a person has been in the following conditions: exercising, warm environment and intense emotional situation. Since one side of the body sweats and flushes appropriately to the condition, the other side of the body will have an absence of such symptoms. This syndrome has also been called the "Harlequin sign" and thought to be one of the spectrum of diseases that may cause Harlequin syndrome.
It can also be the outcome of a one sided endoscopic thoracic sympathectomy (ETS) or endoscopic sympathetic blockade (ESB) surgery.Harlequin syndrome can also be seen as a complication of VA (veno-arterial) extracorporeal membrane oxygenation (ECMO). This involves differential hypoxemia (low oxygen levels in the blood) of the upper body in comparison to the lower body.
Signs and symptoms
The "Harlequin sign" is unilateral flushing and sweating of the face, neck, and upper chest usually after exposure to heat or strenuous exertion. Horner syndrome, another problem associated with the sympathetic nervous system, is often seen in conjunction with harlequin syndrome.Since Harlequin syndrome is associated with a dysfunction in the autonomic nervous system, main symptoms of this dysfunction are in the following: Absence of sweat(anhidrosis) and flushing on one side of the face, neck, or upper thoracic area. In addition, other symptoms include cluster headaches, tearing of the eyes, nasal discharge, abnormal contraction of the pupils, weakness in neck muscles, and drooping of one side of the upper eyelid.
Causes
One possible cause of Harlequin syndrome is a lesion to the preganglionic or postganglionic cervical sympathetic fibers and parasympathetic neurons of the ciliary ganglion. It is also believed that torsion (twisting) of the thoracic spine can cause blockage of the anterior radicular artery leading to Harlequin syndrome. The sympathetic deficit on the denervated side causes the flushing of the opposite side to appear more pronounced. It is unclear whether or not the response of the undamaged side was normal or excessive, but it is believed that it could be a result of the body attempting to compensate for the damaged side and maintain homeostasis.Since the cause and mechanism of Harlequin syndrome is still unknown, there is no way to prevent this syndrome.
Mechanism
Although the exact mechanism for Harlequin syndrome is still unclear, understanding what is affected with this syndrome is important. The majority of cases are thought to occur when nerve bundles in the head and neck are injured. Such bundles are able to send an action potential from the autonomic nervous system to the rest of the body. However, action potentials in this system are not being received by the second or third thoracic vertebrae which innervates the face, neck, and upper chest. Damage or lesions near T2 or T3 could be between the stellate ganglion and superior cervical ganglion. This is where we would observe absence of sweat and skin flushing on one side of the face, neck, and upper chest.
Diagnosis
Diagnosis of Harlequin syndrome is made when the individual has consistent signs and symptoms of the condition, therefore, it is made by clinical observation. In addition, a neurologist or primary care physician may require an MRI test to rule out similar disorders such as Horners syndrome, Adies syndrome, and Ross syndrome. In an MRI, a radiologist may observe areas near brain or spinal cord for lesions, or any damage to the nerve endings. It is also important that the clinician rules out traumatic causes by performing autonomic function tests. Such tests includes the following: tilt table test, orthostatic blood pressure measurement, head-up test, valsalva maneuver, thermoregulatory sweat test, tendon reflex test, and electrocardiography (ECG). CT scan of the heart and lungs may also be performed to rule out a structural underlying lesion. The medical history of the individual should be carefully noted.
Treatment and prognosis
Harlequin syndrome is not debilitating so treatment is not normally necessary. In cases where the individual may feel socially embarrassed, contralateral sympathectomy may be considered, although compensatory flushing and sweating of other parts of the body may occur. In contralateral sympathectomy, the nerve bundles that cause the flushing in the face are interrupted. This procedure causes both sides of the face to no longer flush or sweat. Since symptoms of Harlequin syndrome do not typically impair a persons daily life, this treatment is only recommended if a person is very uncomfortable with the flushing and sweating associated with the syndrome.
Research
In August 2016, researchers at the Instituto de Assistência dos Servidores do Estado do Rio de Janeiro used botulinum toxin as a method to block the acetylcholine release from the presynaptic neurons. Although they have seen a reduction in one sided flushing, sweating still occurs.There have been case studies of individuals who have experienced this syndrome after an operation. Two female patients with metastatic cancer, ages 37-years-old and 58-years-old, were scheduled for placement of an intrathecal pump drug delivery system. After the intrathecal pump was placed, certain medications were given to the patients. Once the medications were administered, both patients had one sided facial flushes, closely resembling Harlequin Syndrome. Patients were given neurological exams to confirm that their nerves were still intact. An MRI was performed and showed no significant evidence of bleeding or nerve compression. After close observation for 16 hours, symptoms of the Harlequin syndrome was diminished and both patients did not have another episode.
Another case study was based on a 6-year-old male visiting an outpatient setting for one sided flushes during or after physical activity or exposed to heat. Vitals, laboratory tests, and CT scans were normal. Along with the flushes, the right pupil was 1.5 mm in size, while the left pupil was 2.5 mm in size; however, no ptosis, miosis, or enophthalmos was noted. The patient also had an MRI scan to rule out any lesion near the brain or spinal cord. No abnormalities were noted and the patient did not receive any treatments. The patient was diagnosed with idiopathic Harlequin syndrome.
Although the mechanism is still unclear, the pathophysiology of this condition, close monitoring, and reassurance are vital factors for successful management.
Eponym
The name for the syndrome is credited to Lance and Drummond who were inspired by resemblance patients half-flushed faces bore to colorful Harlequin masks.
See also
Horners syndrome
References
== External links == |
Analgesic nephropathy | Analgesic nephropathy is injury to the kidneys caused by analgesic medications such as aspirin, bucetin, phenacetin, and paracetamol. The term usually refers to damage induced by excessive use of combinations of these medications, especially combinations that include phenacetin. It may also be used to describe kidney injury from any single analgesic medication.
The specific kidney injuries induced by analgesics are renal papillary necrosis and chronic interstitial nephritis. They appear to result from decreased blood flow to the kidney, rapid consumption of antioxidants, and subsequent oxidative damage to the kidney. This kidney damage may lead to progressive chronic kidney failure, abnormal urinalysis results, high blood pressure, and anemia. A small proportion of individuals with analgesic nephropathy may develop end-stage kidney disease.
Analgesic nephropathy was once a common cause of kidney injury and end-stage kidney disease in parts of Europe, Australia, and the United States. In most areas, its incidence has declined sharply since the use of phenacetin fell in the 1970s and 1980s.
Presentation
Common findings in people with analgesic nephropathy include headache, anemia, high blood pressure (hypertension), and white blood cells in the urine (leucocyturia, pyuria). Some individuals with analgesic nephropathy may also have protein in their urine (proteinuria).
Complications
Complications of analgesic nephropathy include pyelonephritis and end-stage kidney disease. Risk factors for poor prognosis include recurrent urinary tract infection and persistently elevated blood pressure. Analgesic nephropathy also appears to increase the risk of developing cancers of the urinary system.
Pathophysiology
The scarring of the small blood vessels, called capillary sclerosis, is the initial lesion of analgesic nephropathy. Found in the renal pelvis, ureter, and capillaries supplying the nephrons, capillary sclerosis is thought to lead to renal papillary necrosis and, in turn, chronic interstitial nephritis.How phenacetin and other analgesics lead to this damage is incompletely understood. It is currently thought that the kidney toxicities of NSAIDs and the antipyretics phenacetin and paracetamol may combine to give rise to analgesic nephropathy. A committee of investigators reported in 2000 that there was insufficient evidence to suggest that non-phenacetin analgesics by themselves are associated with analgesic nephropathy.
Aspirin and NSAIDs
Proper kidney function depends upon adequate blood flow to the kidney. Kidney blood flow is a complex, tightly regulated process that relies on a number of hormones and other small molecules, such as prostaglandins. Under normal circumstances, prostaglandin E2 (PGE2) produced by the kidney is necessary to support adequate blood flow to the kidney. Like all prostaglandins, PGE2 synthesis depends upon the cyclooxygenases.Aspirin and other NSAIDs are inhibitors of the cyclooxygenases. In the kidney, this inhibition results in decreased PGE2 concentration causing a reduction in blood flow. Because blood flow to the kidney first reaches the renal cortex (outside) and then the renal medulla (inside), the deeper structures of the kidney are most sensitive to decreased blood flow. Thus the innermost structures of the kidney, known as the renal papillae, are especially dependent on prostaglandin synthesis to maintain adequate blood flow. Inhibition of cyclooxygenases therefore rather selectively damages the renal papillae, increasing the risk of renal papillary necrosis.NSAIDs caused no adverse effects on renal function in healthy dogs subjected to anesthesia.
Most healthy kidneys contain enough physiologic reserve to compensate for this NSAID-induced decrease in blood flow. However, those subjected to additional injury from phenacetin or paracetamol may progress to analgesic nephropathy.
Phenacetin and paracetamol
It is unclear how phenacetin induces injury to the kidney. Bach and Hardy have proposed that phenacetins metabolites lead to lipid peroxidation that damages cells of the kidney.Paracetamol is the major metabolite of phenacetin and may contribute to kidney injury through a specific mechanism. In cells of the kidney, cyclooxygenases catalyse the conversion of paracetamol into N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI depletes glutathione via non-enzymatic conjugation with glutathione, a naturally occurring antioxidant. With depletion of glutathione, cells of the kidney become particularly sensitive to oxidative damage.
Diagnosis
Diagnosis is traditionally based on the clinical findings above in combination with excessive analgesic use. It is estimated that between 2 and 3 kg each of phenacetin or aspirin must be consumed before evidence of analgesic nephropathy becomes clinically apparent.Once suspected, analgesic nephropathy can be confirmed with relative accuracy using computed tomography (CT) imaging without contrast. One trial demonstrated that the appearance of papillary calcifications on CT imaging was 92% sensitive and 100% specific for the diagnosis of analgesic nephropathy.
Treatment
Treatment of analgesic nephropathy begins with the discontinuation of analgesics, which often halts the progression of the disease and may even result in normalization of kidney function. In Stage 5 chronic kidney disease patients renal replacement therapy may become necessary.
History
Analgesics are a class of medications widely used in the treatment of pain. They include aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), as well as the antipyretics paracetamol (known as acetaminophen in the United States) and phenacetin. Introduced in the late 19th century, phenacetin was once a common component of mixed analgesics in parts of Europe, Australia, and the United States. These analgesics contained aspirin or other NSAIDs combined with phenacetin, paracetamol, or salicylamide, and caffeine or codeine.In the 1950s, Spühler and Zollinger reported an association between kidney injury and the chronic use of phenacetin. They noted that chronic users of phenacetin had an increased risk of developing specific kidney injuries, namely renal papillary necrosis and chronic interstitial nephritis. This condition was dubbed analgesic nephropathy and was attributed to phenacetin, although no absolute causative role was demonstrated. With further reports of the increased risk of kidney injury with prolonged and excessive phenacetin use, however, phenacetin was banned in several countries between the 1960s and 1980s.As the use of phenacetin declined, so too did the prevalence of analgesic nephropathy as a cause of end-stage kidney disease. Data from Switzerland, for example, demonstrated a decline in the prevalence of analgesic nephropathy among people with end-stage kidney disease, from 28% in 1981 to 12% in 1990. An autopsy study performed in Switzerland suggested that the prevalence of analgesic nephropathy in the general population has likewise decreased; the prevalence was 3% in 1980 and 0.2% in 2000.While these data demonstrate that analgesic nephropathy has been all but eliminated in some regions, in other regions the condition persists. Notably, in Belgium, the prevalence of analgesic nephropathy among people having dialysis was 17.9% in 1984 and 15.6% in 1990. Michielsen and de Schepper suggest that analgesic nephropathy persists among people in Belgium having dialysis not due to non-phenacetin analgesics, but because Belgium accepts a higher proportion of elderly people for dialysis. According to these authors, a greater proportion have analgesic nephropathy because a greater percentage of people in Belgium having dialysis have been exposed to long-term use of phenacetin.
Terminology
The term analgesic nephropathy usually refers to damage induced by excessive use of combinations of these medications, specifically combinations that include phenacetin. For this reason, it is also called analgesic abuse nephropathy. Murray prefers the less judgmental analgesic-associated nephropathy. Both terms are abbreviated to the acronym AAN, by which the condition is also commonly known.
References
== External links == |
Acute cerebellar ataxia of childhood | Acute cerebellar ataxia of childhood is a childhood condition characterized by an unsteady gait, most likely secondary to an autoimmune response to infection, drug induced or paraneoplastic. Most common virus causing acute cerebellar ataxia are chickenpox virus and Epstein–Barr virus, leading to a childhood form of post viral cerebellar ataxia. It is a diagnosis of exclusion.
Signs and symptoms
Acute cerebellar ataxia usually follows 2–3 weeks after an infection. Onset is abrupt. Vomiting may be present at the onset but fever and nuchal rigidity characteristically are absent. Horizontal nystagmus is present in approximately 50% of cases.
Truncal ataxia with deterioration of gait
Slurred speech and nystagmus
Afebrile
Cause
Possible causes of acute cerebellar ataxia include varicella infection, as well as infection with influenza, Epstein–Barr virus, Coxsackie virus, Echo virus or mycoplasma.
Diagnosis
Acute Cerebellar ataxia is a diagnosis of exclusion. Urgent CT scan is necessary to rule out cerebellar tumor or hemorrhage as cause of the ataxia; however in acute cerebellar ataxia, the CT will be normal. CSF studies are normal earlier in the course of disease. Later on CSF shows moderate elevation of proteins.
Differential diagnosis
Brain tumors, including cerebellar astrocytoma, medulloblastoma, neuroblastoma
Cerebellar contusion
Subdural hematoma
Toxins, including ethanol or anticonvulsants
Cerebellar infarction or hemorrhage
Meningitis
Encephalitis
Acute disseminated encephalomyelitis
Multiple sclerosis
Management
Supportive treatment is the only intervention for acute cerebellar ataxia of childhood. Symptoms may last as long as 2 or 3 months.
Epidemiology
Acute cerebellar ataxia is the most common cause of unsteady gait in children. The condition is rare in children older than ten years of age. Most commonly acute cerebellar ataxia affects children between age 2 and 7 years.
See also
Gluten ataxia
References
== External links == |
Autoimmune lymphoproliferative syndrome | Autoimmune lymphoproliferative syndrome (ALPS) is a form of lymphoproliferative disorder (LPDs). It affects lymphocyte apoptosis.It is a rare genetic disorder of abnormal lymphocyte survival caused by defective Fas mediated apoptosis. Normally, after infectious insult, the immune system down-regulates by increasing Fas expression on activated B and T lymphocytes and Fas-ligand on activated T lymphocytes. Fas and Fas-ligand interact to trigger the caspase cascade, leading to cell apoptosis. Patients with ALPS have a defect in this apoptotic pathway, leading to chronic non-malignant lymphoproliferation, autoimmune disease, and secondary cancers.
Signs and symptoms
All people with ALPS have signs of lymphoproliferation, which makes it the most common clinical manifestation of the disease. The increased proliferation of lymphoid cells can cause the size of lymphoid organs such as the lymph nodes and spleen to increase (lymphadenopathy and splenomegaly, present in respectively over 90% and over 80% of patients). The liver is enlarged (hepatomegaly) in 30–40% of patients.Autoimmune disease is the second most common clinical manifestation and one that most often requires treatment. The most common autoimmune presentations include autoimmune cytopenias, which can be mild to very severe and intermittent or chronic. These include autoimmune hemolytic anemia, autoimmune neutropenia, and autoimmune thrombocytopenia. Other autoimmune manifestations can be similar to systemic lupus erythematosus (least common, affecting <5% of patients). Manifestations within the nervous system can include autoimmune cerebellar ataxia, Guillain–Barré syndrome, and transverse myelitis. Manifestations in the gastrointestinal system can include atrophic gastritis, and autoimmune hepatitis, esophagitis, colitis, and pancreatitis. Other manifestations can affect the skin (hives), lungs (bronchiolitis obliterans), or kidneys (autoimmune glomerulonephritis and nephrotic syndrome).
Another sign are cancers such as Hodgkin and non-Hodgkin lymphomas, which appear to be increased, possibly due to Epstein–Barr virus-encoded RNA-positivity. Some carcinomas may occur. Unaffected family members with genetic mutations are also at an increased risk of developing cancer.
Genetics
This condition is usually caused by mutations in the FAS gene. Rarely cases due to mutations in other genes including the
FAS ligand gene have been reported. The disease is inherited in an autosomal dominant manner, but it shows incomplete penetrance with up to 40% of people with a FAS mutation not showing symptoms.
Diagnosis
Diagnostic algorithm
The old diagnostic criteria for the illness included: Chronic non-malignant lymphoproliferation, elevated peripheral blood DNTs and defective in vitro Fas mediated apoptosis.
The new criteria require chronic non-malignant lymphoproliferation (over six months lymphadenopathy and/or splenomegaly), elevated peripheral blood DNTs. A primary accessory in diagnosis is defective in vitro Fas mediated apoptosis and somatic or germline mutation in ALPS causative gene (FAS, FASL, CASP10).
The secondary accessory in diagnosis are elevated biomarkers (plasma sFASL over 200 pg/ml, plasma IL-10 >20 pg/ml, plasma or serum vitamin B12 >1500 ng/L, Plasma IL-18 >500pg/ml) and immunohistochemical findings on biopsy consistent with ALPS as determined by an experienced hematopathologist. Another sign is autoimmune cytopenias and polyclonal hypergammaglobulinemia and a family history of ALPS or non-malignant lymphoproliferation.A definitive diagnosis is chronic non-malignant lymphoproliferation and/or elevated peripheral blood DNTs plus one primary accessory criterion. A probable diagnosis is the same but with one secondary accessory criterion.
Classification
2003 nomenclature
IA - Fas
IB - Fas ligand
IIA - Caspase 10
IIB - Caspase 8
III - unknown
IV - Neuroblastoma RAS viral oncogene homologRevised nomenclature (2010)
ALPS-FAS: Fas. Germline FAS mutations. 70% of patients. Autosomal dominant. Dominant negative and haploinsufficient mutations described.
ALPS-sFAS: Fas. Somatic FAS mutations in DNT compartment. 10% of patients
ALPS-FASL: Fas ligand. Germline FASL mutations. 3 reported cases
ALPS-CASP10: Caspase 10. Germline CASP10 mutation. 2% of patients
ALPS-U: Undefined. 20% of patients
CEDS: Caspase 8 deficiency state. No longer considered a subtype of ALPS but distinct disorder
RALD: NRAS, KRAS. Somatic mutations in NRAS and KRAS in lymphocyte compartment. No longer considered a subtype of ALPS but distinct disease
Treatment
Treatment is most commonly directed at autoimmune disease and may be needed to treat bulky lymphoproliferation. First line therapies include corticosteroids (very active but toxic with chronic use), and IVIgG, which are not as effective as in other immune cytopenia syndromes.Second line therapies include: mycophenolate mofetil (cellcept) which inactivates inosine monophosphate, most studied in clinical trials with responses varying (relapse, resolution, partial response). It does not affect lymphoproliferation or reduce DNTs, with no drug-drug interactions. This treatment is commonly used agent in patients who require chronic treatment based on tolerance and efficacy. It may cause hypogammaglobulinemia (transient) requiring IVIgG replacement.Sirolimus (rapamycin, rapamune) which is a mTOR (mammalian target of rapamycin) inhibitor can be active in most patients and can in some cases lead to complete or near-complete resolution of autoimmune disease (>90%) With this treatment most patients have complete resolution of lymphoproliferation, including lymphadenopathy and splenomegaly (>90%) and have elimination of peripheral blood DNTs. Sirolimus may not be as immune suppressive in normal lymphocytes as other agents. Some patients have had improvement in immune function with transition from cellcept to rapamycin and it has not been reported to cause hypogammaglobulinemia. Hypothetically, Sirolimus may have lower risk of secondary cancers as opposed to other immune suppressants and requires therapeutic drug monitoring. It is the second most commonly used agent in patients that require chronic therapy. It is mostly well tolerated (though side effects include mucositis, diarrhea, hyperlipidemia, delayed wound healing) with drug-drug interactions. It has better activity against autoimmune disease and lymphoproliferation than mycophenolate mofetil and other drugs; however, sirolimus requires therapeutic drug monitoring and can cause mucositis. A risk with any agent in pre-cancerous syndrome as immune suppression can decreased tumor immunosurvellence. Its mTOR inhibitors active against lymphomas, especially EBV+ lymphomas. The Goal serum trough is 5–15 ng/ml and can consider PCP prophylaxis but usually not needed.
Other treatments may include drugs like Fansidar, mercaptopurine: More commonly used in Europe. Another is rituximab but this can cause protracted hypogammaglobulinemia and a splenectomy but there is a >30% risk of pneumococcal sepsis even with vaccination and antibiotic prophylaxis
References
== External links == |
Torus mandibularis | Torus mandibularis is a bony growth in the mandible along the surface nearest to the tongue. Mandibular tori are usually present near the premolars and above the location of the mylohyoid muscles attachment to the mandible. In 90% of cases, there is a torus on both the left and right sides.
The prevalence of mandibular tori ranges from 5-40%. It is less common than bony growths occurring on the palate, known as torus palatinus. Mandibular tori are more common in Asian and Inuit populations, and slightly more common in males. In the United States, the prevalence is 7-10% of the population.
It is believed that mandibular tori are caused by several factors. They are more common in early adulthood and are associated with bruxism. The size of the tori may fluctuate throughout life, and in some cases the tori can be large enough to touch each other in the midline of mouth. Consequently, it is believed that mandibular tori are the result of local stresses and not due solely to genetic influences.
Mandibular tori are usually a clinical finding with no treatment necessary. It is possible for ulcers to form in the area of the tori due to trauma. The tori may also complicate the fabrication of dentures. If removal of the tori is needed, surgery can be done to reduce the amount of bone, but the tori may reform in cases where nearby teeth still receive local stresses.
References
External links
"Oral & Maxiollofacial Pathology Cases: What Could This Be?". Marquette University School of Dentistry. Archived from the original on 2006-10-17.
"What are mandibular tori?". dentagama.com. |
Sclerosteosis | Sclerosteosis is an autosomal recessive disorder characterized by bone overgrowth. It was first described in 1958 but given the current name in 1967. Excessive bone formation is most prominent in the skull, mandible and tubular bones. It can cause facial distortion and syndactyly. Increased intracranial pressure can cause sudden death in patients. It is a rare disorder that is most prominent in the Afrikaner population in South Africa (40 patients), but there have also been cases of American and Brazilian families.
Cause
Sclerosteosis is caused by mutations in the gene that encode for the sclerostin protein. The sclerostin protein is necessary in inhibiting canonical wnt signalling. Wnt signalling results in increased osteoblast activity and RANKL synthesis, sclerostine therefore increases boneformation by indirectly inhibiting RANKL synthesis and thus osteoclast activitation.
References
External links
These Superhumans Are Real and Their DNA Could Be Worth Billions
Sclerostin Inhibition in the Management of Osteoporosis
Effect of bone thickening on the skull area: need of skull removal |
Hemopneumothorax | Hemopneumothorax, or haemopneumothorax, is the condition of having air in the chest cavity (pneumothorax) and blood in the chest cavity (hemothorax). A hemothorax, pneumothorax, or the combination of both can occur due to an injury to the lung or chest.
Cause
The pleural space is located anatomically between the visceral membrane, which is firmly attached to the lungs, and the parietal membrane which is firmly attached to the chest wall (a.k.a. ribcage and intercostal muscles, muscles between the ribs). The pleural space contains pleural fluid. This fluid holds the two membranes together by surface tension, as much as a drop of water between two sheets of glass prevents them from separating. Because of this, when the intercostal muscles move the ribcage outward, the lungs are pulled out as well, dropping the pressure in the lungs and pulling air into the bronchi, when we breathe in. The pleural space is maintained in a constant state of negative pressure (in comparison to atmospheric pressure).
If the chest wall, and thus the pleural space, is punctured, blood, air or both can enter the pleural space. Air and/or blood rushes into the space in order to equalise the pressure with that of the atmosphere. As a result, the fluid is disrupted and the two membranes no longer adhere to each other. When the rib cage moves out, it no longer pulls the lungs with it. Thus the lungs cannot expand, the pressure in the lungs never drops and no air is pulled into the bronchi. Respiration is not possible. The affected lung, which has a great deal of elastic tissue, shrivels in what is referred to as a collapsed lung.
Diagnosis
If you have an injury or trauma to your chest, your doctor may order a chest X-ray to help see if fluid or air is building up within the chest cavity.
Other diagnostic tests may also be performed to further evaluate the fluid in around the lungs, for instance a chest CT scan or an ultrasound. An ultrasound of the chest will show the amount of fluid and its exact location.
Treatment
Treatment for this condition is the same as for hemothorax and pneumothorax independently: by tube thoracostomy, the insertion of a chest drain through an incision made between the ribs, into the intercostal space. A chest tube must be inserted to drain blood and air from the pleural space so it can return to a state of negative pressure and function normally.Commonly, surgery is needed to close off whatever injuries caused the blood and air to enter the cavity (e.g. stabbing, broken ribs).
See also
Catamenial pneumothorax
Tension pneumothorax
Pulmonary contusion
References
== External links == |
Fetus in fetu | Fetus in fetu (or foetus in foetu) is a rare developmental abnormality in which a mass of tissue resembling a fetus forms inside the body of its twin. An early example of the phenomenon was described in 1808 by George William Young.There are two hypotheses for the origin of a "fetus in fetu". One hypothesis is that the mass begins as a normal fetus but becomes enveloped inside its twin. The other hypothesis is that the mass is a highly developed teratoma. "Fetus in fetu" is estimated to occur in 1 in 500,000 live births.
Classification as life
A fetus in fetu can be considered alive, but only in the sense that its component tissues have not yet died or been eliminated. Thus, the life of a fetus in fetu is akin to that of a tumor in that its cells remain viable by way of normal metabolic activity. However, without the gestational conditions in utero with the amnion and placenta, a fetus in fetu can develop into, at best, an especially well differentiated teratoma; or, at worst, a high-grade metastatic teratocarcinoma. In terms of physical maturation, its organs have a working blood supply from the host, but all cases of fetus in fetu present critical defects, such as no functional brain, heart, lungs, gastrointestinal tract, or urinary tract. Accordingly, while a fetus in fetu can share select morphological features with a normal fetus, it has no prospect of any life outside of the host twin. Moreover, it poses clear threats to the life of the host twin on whom its own life depends.
Hypotheses of development
There are two main hypotheses about the development of fetus in fetu.
Teratoma hypothesis
Fetus in fetu may be a very highly differentiated form of dermoid cyst, itself a highly differentiated form of mature teratoma.
Parasitic twin hypothesis
Fetus in fetu may be a parasitic twin fetus growing within its host twin. Very early in a monozygotic twin pregnancy, in which both fetuses share a common placenta, one fetus wraps around and envelops the other. The enveloped twin becomes a parasite, in that its survival depends on the survival of the host twin, by drawing on the host twins blood supply. The parasitic twin is anencephalic (without a brain) and lacks some internal organs, and as such is unable to survive on its own. As the host twin has to "feed" the enveloped twin from the nutrients received over a single umbilical cord, they usually die before birth.
References
External links
Xray of fetus in fetu |
Lipschütz ulcer | Lipschütz ulcer, ulcus vulvae acutum or reactive non-sexually related acute genital ulcers (English: acute ulceration of the vulva) is a rare disease characterized by painful genital ulcers, fever, and lymphadenopathy, occurring most commonly, but not exclusively, in adolescents and young women. Previously, it was described as being more common in virgins. It is not a sexually transmitted disease, and is often misdiagnosed, sometimes as a symptom of Behçets disease.Lipschütz ulcer is named after Benjamin Lipschütz, who first described it in 1912. The cause is still unknown, although it has been associated with several infectious causes, including paratyphoid fever, cytomegalovirus, Mycoplasma pneumoniae and Epstein–Barr virus infection
Signs and symptoms
The most common presentation is a single large, deep ulcer (although several smaller ulcers may occur) in the internal surface of one or both labia minora. The labia majora may be affected, as may the vagina and urethra. The ulcer develops very quickly, and is usually preceded by sudden onset of fever and malaise.
Diagnosis
The diagnosis is mainly clinical and centred in eliminating other more common causes for vulvar ulcers. Nevertheless, it has been proposed that Epstein-Barr detection using polymerase chain reaction for virus genome can help to reach sooner a diagnosis.
Treatment
Treatment is symptomatic, and usually of little value; in most cases, the ulcer heals spontaneously within four to six weeks, sometimes leaving scars. Topical analgesics and anesthetics, as well as topical application of disinfectants/astringents such as potassium permanganate (in sitz baths), is commonly used. In severe cases, a combination of systemic glucocorticoids and broad-spectrum antibiotics has been recommended.
Epidemiology
The disorder typically appears among young girls and adolescents but cases in children as young as 17 months have been reported.
History
The disease was first described in October 1912 by Galician-born Austrian dermatologist and microbiologist Benjamin Lipschütz, who published a series of four cases in girls aged 14 to 17. He initially ascribed the ulcer to infection with "Bacillus crassus" (Lactobacillus acidophilus).
See also
Vulvovaginal health
References
== External links == |
Undifferentiated connective tissue disease | Undifferentiated connective tissue disease (UCTD) is a disease in which the body mistakenly attacks its own tissues. It is diagnosed when there is evidence of an existing autoimmune condition which does not meet the criteria for any specific autoimmune disease, such as systemic lupus erythematosus or scleroderma. Latent lupus and incomplete lupus are alternative terms that have been used to describe this condition.The term is sometimes used interchangeably with mixed connective tissue disease, an overlap syndrome. However, MCTD is thought by some researchers to be a clinically distinct entity and is strongly associated with the presence of high titers of ribonucleoprotein (RNP) antibodies.It is estimated that up to 25 percent of people with systemic autoimmune disease could be considered to have UCTD.
Signs and symptoms
Disease presentation varies widely from patient to patient, as UCTD is by definition nonspecific. Symptoms typically include constitutional complaints that are common to connective tissue diseases such as fatigue, a general sense of feeling unwell, and fever.
Other symptoms associated with UCTD include:
dry eyes
dry mouth
hair loss
joint inflammation
joint pain
oral ulcers
positive ANA test
raynauds phenomenon
sun sensitive rashClinical presentation in some people diagnosed with UCTD may show:
a decrease in white blood cell count in the blood
anemia
abnormal nerve sensations in the extremities
inflammation of the lining of the heart and/or lungs
a decrease in platelet countLung involvement, such as nonspecific interstitial pneumonia, is a possible disease complication.
Diagnosis
There is no official diagnostic criteria for UCTD. Diagnostic testing generally aims to determine whether a patient has a definite or undifferentiated connective tissue disease.
Treatment
Treatment largely depends upon individual disease progression and the nature of presenting symptoms. Antimalarials, corticosteroids, and other drugs may be prescribed, if deemed appropriate by the treating physician.
Prognosis
Most patients will maintain a diagnosis of undifferentiated connective tissue disease. However, about one third of UCTD patients will differentiate to a specific autoimmune disease, like rheumatoid arthritis or systemic sclerosis. About 12 percent of patients will go into remission.Severe vitamin D deficiency has been associated with the progression of UCTD into defined connective tissue diseases. The presence of the autoantibodies anti-dsDNA, anti-Sm, and anti-cardiolipin has been shown to correlate with the development of systemic lupus erythematosus, specifically.
References
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Uterine malformation | A uterine malformation is a type of female genital malformation resulting from an abnormal development of the Müllerian duct(s) during embryogenesis. Symptoms range from amenorrhea, infertility, recurrent pregnancy loss, and pain, to normal functioning depending on the nature of the defect.
Types
The American Fertility Society (now American Society of Reproductive Medicine) Classification distinguishes:
Class I—Müllerian agenesis (absent uterus).
This condition is represented by the hypoplasia or the agenesis (total absence) of the different parts of the uterus:
Vaginal hypoplasia or agenesis
Cervical hypoplasia or agenesis
Fundal hypoplasia or agenesis (absence or hypoplasia of the fundus of the uterus)
Tubal hypoplasia or agenesis (absence or hypoplasia of the Fallopian tubes)
Combined hypoplasia the agenesis of different part of the uterus
This condition is also called Mayer-Rokitansky-Kuster-Hauser syndrome. The patient with MRKH syndrome will have primary amenorrhea.
Class II—Unicornuate uterus (a one-sided uterus).
Rare condition in which a partial or complete lack of one Müllerian duct is present. The uterus has a typical "banana shape" on imaging systems. This condition can be sub-classified in:
Communicating: a rudimentary uterine horn is formed and it presents a cavity that communicates with the body of the uterus
Non-communicating: a rudimentary uterine horn is formed and it presents a cavity that does not communicate with the body of the uterus
No cavity: a rudimentary uterine horn is present without any cavity
No horn: there is no rudimentary uterine horn, just the functioning one is presentClass III—Uterus didelphys, also uterus didelphis (double uterus).
Both Müllerian ducts develop but fail to fuse, thus the patient has a "double uterus". This may be a condition with a double cervix and a vaginal partition (v.i.), or the lower Müllerian system fused into its unpaired condition. See Triplet-birth with Uterus didelphys for a case of a woman having spontaneous birth in both wombs with twins.
Class IV—Bicornuate uterus (uterus with two horns).
Only the upper part of that part of the Müllerian system that forms the uterus fails to fuse, thus the caudal part of the uterus is normal, the cranial part is bifurcated. The uterus is "heart-shaped". This condition can be complete or partial.
Class V—Septated uterus (uterine septum or partition).
The two Müllerian ducts have fused, but the partition between them is still present, splitting the system into two parts. With a complete septum the vagina, cervix and the uterus can be partitioned. Usually the septum affects only the cranial part of the uterus. A uterine septum is the most common uterine malformation and a cause for miscarriages. It is diagnosed by medical image techniques, i.e. ultrasound or an MRI. MRI is considered the preferred modality due to its multiplanar capabilities as well as its ability to evaluate the uterine contour, junctional zone, and other pelvic anatomy. A hysterosalpingogram is not considered as useful due to the inability of the technique to evaluate the exterior contour of the uterus and distinguish between a bicornuate and septate uterus. This condition can be complete or partial
A uterine septum can be corrected by hysteroscopic surgery.
Class VI—DES uterus.
The uterine cavity has a "T-shape" as a result of fetal exposure to diethylstilbestrol.An additional variation is the arcuate uterus where there is a concave dimple in the uterine fundus within the cavity. The distinction between an arcuate uterus and a septate uterus is not standardized.
A rudimentary uterus is a uterine remnant not connected to cervix and vagina and may be found on the other side of a unicornuate uterus.
Patients with uterine abnormalities may have associated renal abnormalities including unilateral renal agenesis.
"Double vagina"
As the vagina is largely derived from the Müllerian ducts, lack of fusion of the two ducts can lead to the formation of a vaginal duplication and lack of absorption of the wall between the two ducts will leave a residual septum, leading to a "double vagina". This condition may be associated with a uterus didelphys or a uterine septum.=
Diagnosis
Besides a physical examination, the physician will need imaging techniques to determine the character of the malformation: gynecologic ultrasonography, pelvic MRI, or hysterosalpingography. A hysterosalpingogram is not considered as useful due to the inability of the technique to evaluate the exterior contour of the uterus and distinguish between a bicornuate and septate uterus.
In addition, laparoscopy and/or hysteroscopy may be indicated.
In some patients the vaginal development may be affected.
Treatment
Surgical intervention depends on the extent of the individual problem. With a didelphic uterus surgery is not usually recommended.
A uterine septum can be resected in a simple out-patient procedure that combines laparoscopy and hysteroscopy. This procedure greatly decreases the rate of miscarriage for women with this anomaly.
Prevalence
The prevalence of uterine malformation is estimated to be 6.7% in the general population, slightly higher (7.3%) in the infertility population, and significantly higher in a population of women with a history of recurrent miscarriages (16%).
See also
Uterus didelphys
Uterus § Other animals – where some malformations in humans are "normal"
References
External links
BBC NEWS - Triplets for woman with two wombs |
Mycotic aneurysm | An infected aneurysm is an aneurysm arising from bacterial infection of the arterial wall. It can be a common complication of the hematogenous spread of bacterial infection.William Osler first used the term "mycotic aneurysm" in 1885 to describe a mushroom-shaped aneurysm in a patient with subacute bacterial endocarditis. This may create considerable confusion, since "mycotic" is typically used to define fungal infections. However, mycotic aneurysm is still used for all extracardiac or intracardiac aneurysms caused by infections, except for syphilitic aortitis.The term "infected aneurysm" proposed by Jarrett and associates is more appropriate, since few infections involve fungi. According to some authors, a more accurate term might have been endovascular infection or infective vasculitis, because mycotic aneurysms are not due to a fungal organism.Mycotic aneurysms account for 2.6% of aortic aneurysms. For the clinician, early diagnosis is the cornerstone of effective treatment. Without medical or surgical management, catastrophic hemorrhage or uncontrolled sepsis may occur. However, symptomatology is frequently nonspecific during the early stages, so a high index of suspicion is required to make the diagnosis.Intracranial mycotic aneurysms (ICMAs) complicate about 2% to 3% of infective endocarditis (IE) cases, although as many as 15% to 29% of patients with IE have neurologic symptoms.Mycotic abdominal aorta aneurysm (MAAA) is a rare and life-threatening condition. Because of its rarity, there is a lack of adequately powered studies and consensus on its treatment and follow up. A management protocol on the management of mycotic abdominal aortic aneurysm was recently published in the Annals of Vascular Surgery by Premnath et al.
== References == |
Moorens ulcer | Moorens ulcer is a rare idiopathic ocular disorder that may lead to blindness due to progressive destruction of the peripheral cornea. Although the etiology of Moorens ulcer is poorly understood, recent evidence suggests that the pathogenesis of this disease appears to be the result of an autoimmune process directed against molecules expressed in the corneal stroma.Moorens ulcer is also defined as a special and the most common type of peripheral ulcerative keratitis (PUK).
Signs and symptoms
Symptoms of Moorens ulcer can include:
Pain in the affected eye(s)
Redness of the affected eye(s)
Progressive ulceration of the cornea
Blurred vision
Photophobia
TearingSome epidemiological studies have noted that men tend to be affected more than women.
Classification
The most commonly used classification was proposed by Watson in 1997. He divided the disease into three types based on the clinical picture:
Unilateral Moorens ulceration is characterized by extremely painful progressive ulceration of the cornea in one eye. This form is more common in elderly patients.
Bilateral aggressive Moorens ulceration which is observed more often in young patients and progresses along the entire circumference, then captures the central area of the cornea.
Bilateral indolent Moorens ulceration (BIM) usually occurs in middle-aged patients and manifested by a progressive peripheral corneal guttering in both eyes.
Risk factors
Several risk factors affecting the development of Moorens ulcer have been suggested.
Corneal trauma
Previous ocular trauma or infection can cause disruption of the corneal integrity resulting in the expression of tissue-specific antigens that are normally hidden from the immune system. It may lead to an increased risk of a sensitization to corneal antigens and an autoimmune reaction against antigens expressed in corneal tissues.
HLA association
Like most autoimmune diseases, Moorens ulcer is thought to be associated with specific HLA haplotypes. In some studies, HLA-DR17 and HLA-DQ2 have been found in increased frequencies in affected patients compared to healthy controls. These results propose a possible association between HLA and Moorens ulcer.
Pathology
The precise pathophysiological mechanism of Moorens ulcer remains unclear, but most data suggest that both cell-mediated immunity and humoral immunity are involved in the pathogenesis of the disease.Reduces numbers of suppressor T cells have been found in peripheral blood from patients with Moorens ulcer. This deficit in systematic immunoregulatory mechanism may lead to loss of a control over autoreactive T and B cells and contributes to disease pathogenesis.Immunohistochemical studies in patients suffered from Moorens ulcer showed massive infiltration of multiple types of inflammatory cells in the conjunctival tissue.
The cell types in the inflammatory lesion includes CD4+ and CD8+ T-lymphocytes, B-lymphocytes, macrophages, a small amount of neutrophils was also observed in the conjunctiva from patients with Moorens ulcer.In addition, circulating IgG antibodies with specificity for corneal and conjunctival antigens have been isolated from patients with Mooren’s ulcer. Gottsch and colleagues have suggested that calgranulin C, a protein expressed in the corneal stroma, may be a possible main target for autoimmune response causing Mooren’s ulcer.Also, significantly increased expression levels of adhesion and co-stimulatory molecules have been found in ocular tissues affected by Moorens ulcer compared to healthy eyes. Upregulation of adhesion molecules allows leukocyte migration into inflamed tissues. Co-stimulatory molecules may contribute to sustained local immune activation. Therefore, blockage of these molecules suppose to be a protentional therapeutic strategy for suppressing the inflammatory progression.Elevated levels of proteases and collagenases which damage the corneal stroma have also been found in affected conjunctival tissues.
Diagnosis
In view of rarity and limited knowledge of the etiology of Mooren’s ulcer, the diagnosis of the disease is complicated.The absence of any systematic disorders which can lead to peripheral corneal ulceration supports the diagnosis of Mooren’s ulcer. To diagnose Mooren’s ulcer, it is necessary to rule out other forms of non-infectious peripheral ulcerative keratitis.
Treatment
Medical treatment
Topical corticosteroids are usually used as first line of therapy. Severe cases require administration of systemic immunosuppressive agents. The more commonly used drugs are cyclosporine A, methotrexate and cyclophosphamide.
Several case reports showed that biological agents, such as anti-tumor necrosis factor alpha (anti-TNF) or monoclonal antibodies against CD20, also can be used as an effective treatment of progressive Mooren’s ulceration.
Surgical treatment
If patients do not respond to medication, surgical intervention must be performed. Conjunctival excision has been shown to be an effective method. The principle of this surgery is based on the removal of unhealthy limbal conjunctiva adjacent to the ulcer. slow down the disease progression due to eliminating the local source of inflammatory cells, mediators and enzymes which cause the tissue damage.Another surgical treatment option which has been successfully used as a treatment for Mooren’s ulcer is amniotic membrane transplantation (AMT). This method consists of applying a piece of amniotic membrane to the ocular surface. Amniotic membrane patches are prepared from placental tissues from women who had a planned cesarean sections. AMT appears to be a useful therapy which results with stabilization of the ulcer progression and corneal epithelial defect healing. It is most likely, that amniotic membrane used as an ocular graft stop the inflammation process because of the expression of immunoregulatory molecules, including Fas ligand and HLA–G antigens. In addition, the amniotic membrane contains a large number of collagens, growth factors and protease inhibitors which can promote healing and reconstruction of the conjunctival epithelium.Other surgical interventions such as lamellar keratectomy, keratoepithelioplasty and corneal transplantation have also been reported as effective treatment options for Mooren’s ulcer.
== References == |
Xanthoma disseminatum | Xanthoma disseminatum is a rare cutaneous condition that preferentially affects males in childhood, characterized by the insidious onset of small, yellow-red to brown papules and nodules that are discrete and disseminated.: 717 It is a histiocytosis syndrome.
See also
Non-X histiocytosis
List of cutaneous conditions
References
== External links == |
Catheter-associated urinary tract infection | Catheter-associated urinary tract Infection, or CAUTI, is a urinary tract infection associated with urinary catheter use.
Core prevention
A number of combined practices such as improved hand hygiene, enhanced barrier protection and reduced catheter use when managing incontinence appear to reduce CAUTI. Urinary catheters should be inserted using aseptic technique and sterile equipment (including sterile gloves, drape, sponges, antiseptic and sterile solution), particularly in an acute care setting. Although catheter use should be minimized in all patients, particularly those at higher risk of CAUTI and mortality (e.g. the elderly or those with impaired immunity), a meta analysis suggests there is insufficient evidence to determine the value of different policies for replacing long term urinary catheters on patient outcomes.
Incidence
Bacteria and yeast, including those naturally occurring as part of the human microbiome, can grow within biofilm that forms along the surface of urinary catheters. This leads to infection in the bladder, kidneys, and other organs connected to the urinary tract.CAUTI can lead to complications such as prostatitis, epididymitis, and orchitis in men, and cystitis, pyelonephritis, gram-negative bacteremia, endocarditis, vertebral osteomyelitis, septic arthritis, endophthalmitis, and meningitis in all patients. Complications associated with CAUTI cause discomfort to the patient, prolonged hospital stay, and increased cost and mortality.
== References == |
Chronic fatigue syndrome | Chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME) or ME/CFS, is a complex, debilitating, long-term medical condition. The causes and mechanisms of the disease are not fully understood. Distinguishing core symptoms are lengthy exacerbations or flare-ups of the illness following ordinary minor physical or mental activity, known as post-exertional malaise (PEM); greatly diminished capacity to accomplish tasks that were routine before the illness; and sleep disturbances.: 7 Orthostatic intolerance (difficulty sitting and standing upright) and cognitive dysfunction are also diagnostic. Frequently and variably, other common symptoms occur involving numerous body systems, and chronic pain is common. The unexplained and often incapacitating fatigue in CFS is different from that caused by normal strenuous ongoing exertion, is not significantly relieved by rest, and is not due to a previous medical condition. Diagnosis is based on the persons symptoms because no confirmed diagnostic test is available.Proposed mechanisms include biological, genetic, epigenetic, infectious, and physical or psychological stress affecting the biochemistry of the body. Persons with CFS may recover or improve over time, but some will become severely affected and disabled for an extended period. No therapies or medications are approved to treat the cause of the illness; treatment is aimed at alleviation of symptoms. The CDC recommends pacing (personal activity management) to keep mental and physical activity from making symptoms worse. Limited evidence suggests that rintatolimod, counseling, and personalized activity management helps improve some patients functional abilities.
About 1% of primary-care patients have CFS; estimates of incidence vary widely because epidemiological studies define the illness dissimilarly. It has been estimated that 836,000 to 2.5 million Americans and 250,000 to 1,250,000 people in the United Kingdom have CFS. CFS occurs 1.5 to 2 times as often in women as in men. It most commonly affects adults between ages 40 and 60 years; it can occur at other ages, including childhood. Other studies suggest that about 0.5% of children have CFS, and that it is more common in adolescents than in younger children.: 182 Chronic fatigue syndrome is a major cause of school absence.: 183 CFS reduces health, happiness, productivity, and can also cause socio-emotional disruptions such as loneliness and alienation. However, there is controversy over many aspects of the disorder. Physicians, researchers, and patient advocates promote different names and diagnostic criteria. Results of studies of proposed causes and treatments are often poor or contradictory.
Signs and symptoms
The United States Centers for Disease Control and Prevention (CDC) recommends these criteria for diagnosis:
Greatly lowered ability to do activities that were usual before the illness. This drop in activity level occurs along with fatigue and must last six months or longer.
Worsening of symptoms after physical or mental activity that would not have caused a problem before the illness. The amount of activity that might aggravate the illness is difficult for a person to predict, and the decline often presents 12 to 48 hours after the activity. The relapse, or crash, may last days, weeks or longer. This is known as post-exertional malaise (PEM).
Sleep problems; people may still feel weary after full nights of sleep, or may struggle to stay awake, fall asleep or stay asleep.Additionally, one of the following symptoms must be present:
Problems with thinking and memory (cognitive dysfunction, sometimes described as "brain fog")
While standing or sitting upright; lightheadedness, dizziness, weakness, fainting or vision changes may occur (orthostatic intolerance)
Other common symptoms
Many, but not all people with ME/CFS report:
Muscle pain, joint pain without swelling or redness, and headache
Tender lymph nodes in the neck or armpits
Sore throat
Irritable bowel syndrome
Chills and night sweats
Allergies and sensitivities to foods, odors, chemicals, lights, or noise
Shortness of breath
Irregular heartbeatIncreased sensitivity to sensory stimuli and pain have also been observed in CFS.The CDC recommends that people with symptoms of CFS consult a physician to rule out other illnesses, which may be treatable.
Onset
The onset of CFS may be gradual or sudden. When it begins suddenly, it often follows a period of infectious-like symptoms or a known infection, and between 20 and 80% of patients report an onset resembling an infection.: 158 When gradual, the illness may begin over the course of months or years. Studies disagree as to which pattern is more common.: 158 : 181 CFS may also occur after physical trauma such as a car accident or surgery.
Physical functioning
The functional capacity of individuals with CFS varies greatly. Some persons with mild CFS lead relatively normal lives with vigilant energy management; persons that are severely ill may be totally bed-ridden and unable to care for themselves. For the majority of persons with CFS, work, school, and family activities are significantly reduced for extended periods of time. The severity of symptoms and disability is the same regardless of gender, and many experience strongly disabling chronic pain. Persons report critical reductions in levels of physical activity. Also, a reduction in the complexity of activity has been observed. Reported impairment is comparable to other fatiguing medical conditions including late-stage AIDS, lupus, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and end-stage kidney disease. CFS affects a persons functional status and well-being more than major medical conditions such as multiple sclerosis, congestive heart failure, or type II diabetes mellitus.Often, courses of remission and relapse of symptoms occur, which make the illness difficult to manage. Persons who feel better for a period may overextend their activities, and the result can be a worsening of their symptoms with a relapse of the illness.About 25% of people with CFS are house-bound or bed-ridden for long periods during their illness, often for decades.: 32 An estimated 75% are unable to work because of their illness. More than half were on disability benefits or temporary sick leave, and less than a fifth worked full-time. Children who become ill with CFS are a major cause of school absence.: 183 People with CFS have decreased scores on the SF-36 quality-of-life questionnaire, especially in the sub scales on vitality, physical functioning, general health, physical role, and social functioning; however, the sub scales for "role emotional" and mental health in CFS patients were consistent with or not substantially lower than healthy controls.
Cognitive functioning
Cognitive dysfunction is one of the more disabling aspects of CFS due to its negative impact on occupational and social functioning. Fifty to eighty percent of persons with CFS are estimated to have serious problems with cognition. Cognitive symptoms are mainly due to deficits in attention, memory, and reaction time. Measured cognitive abilities are found to be below projected normal values and likely to affect day-to-day activities; for example, increases in common mistakes, forgetting scheduled tasks, or having difficulty responding when spoken to are observed.Simple and complex information-processing speed and functions entailing working memory over long time periods are moderately to extensively impaired. These deficits are generally consistent with the patients perceptions. Perceptual abilities, motor speed, language, reasoning, and intelligence do not appear to be significantly altered. When poorer health status was reported, a persons perception of their cognitive problems was frequently greater. Better physical functioning in people with CFS is associated with less visuoperceptual difficulty and fewer language-processing complaints.Inconsistencies of subjective and observed values of cognitive dysfunction reported across multiple studies are likely caused by a number of factors. Differences of research participants cognitive abilities pre- and post-illness onset are naturally variable and are difficult to measure because of a lack of specialized analytical tools that can consistently quantify the specific cognitive difficulties in CFS.The frequency of neuropsychiatric and neuropsychological symptoms is increased in the population of persons with CFS; the understanding of why this occurs is unresolved. Various hypotheses have been advanced to try to explain the relationship between the cognitive symptoms and the illness. Some researchers believe psychiatric causes underlie or contribute to the illness, while other researchers believe the illness causes biochemical and sociological changes in people that produce the symptoms.
Cause
The cause of CFS is unknown. Genetic and physiological factors are thought to work together to precipitate and perpetuate the condition. A 2016 report by the Institute of Medicine states that CFS is a biologically based illness, but that the biologic abnormalities are not sensitive or specific enough to be useful as a diagnosis.Because it may begin as an influenza-like illness with a sudden onset, various infectious causes have been proposed, but evidence is insufficient to support such causation. Infections proposed include mononucleosis, Chlamydophila pneumoniae, human herpesvirus 6, and Lyme disease. Inflammation may be involved. Often, the illness will follow a viral illness such as mononucleosis or gastroenteritis.
Risk factors
All ages, ethnic groups, and income levels are susceptible to the illness. The CDC states that Caucasians may be diagnosed more frequently than other races in America, but the illness is at least as prevalent among African Americans and Hispanics. A 2009 meta-analysis showed that African Americans and Native Americans have a higher risk of CFS, though it specifically excluded other more common ethnicities worldwide, and it acknowledged that studies and data were limited.More women than men get CFS. A large 2020 meta-analysis estimated that between 1.5 and 2.0 times more cases are women. The review acknowledged that different case definitions and diagnostic methods within datasets yielded a wide range of prevalence rates. The CDC estimates CFS occurs up to four times more often in women than in men. The illness can occur at any age, but has the highest prevalence in persons between the ages of 40 and 60. CFS is less prevalent among children and adolescents than among adults.Blood relatives of those who have CFS appear to be more predisposed, implying that genetic factors may increase the risk of susceptibility to the illness.According to the CDC, "CFS is a biological illness, not a psychologic disorder", and those affected "are neither malingering nor seeking secondary gain". The World Health Organization (WHO) classifies CFS as a neurological disease in the ICD-11 for Mortality and Morbidity Statistics (ICD-11).
Viral and other infections
Post-viral fatigue syndrome (PVFS) or post-viral syndrome describes a type of chronic fatigue syndrome that occurs following a viral infection. A recent review found Epstein–Barr virus (EBV) antibody activity to be higher in patients with CFS, and that a subset of patients with CFS were likely to have increased EBV activity compared to controls. Viral infection is a significant risk factor for CFS, with one study finding 22% of people with EBV experience fatigue six months later, and 9% having strictly defined CFS. A systematic review found that fatigue severity was the main predictor of prognosis in CFS, and did not identify psychological factors linked to prognosis.Another review found that risk factors for developing CFS after mononucleosis, dengue fever, or Q-fever included longer bed-rest during the illness, poorer pre-illness physical fitness, attributing symptoms to physical illness, belief that a long recovery time is needed, as well as pre-infection distress and fatigue. The same review found biological factors such as CD4 and CD8 activation and liver inflammation are predictors of sub-acute fatigue but not CFS. However, these findings are not generally accepted due to the use of the Oxford criteria in selecting patients. The CDC does not recognize attribution of symptoms as a risk factor.A study comparing diagnostic labels found that people labelled with ME had the worst prognosis, while those with PVFS had the best. Whether this is due to those with more severe or longer-lasting symptoms results in a label with the description of ME, or if being labelled with ME adversely causes a more severe or prolonged illness is unclear.
Pathophysiology
Neurological
A range of neurological structural and functional abnormalities is found in people with CFS, including lowered metabolism at the brain stem and reduced blood flow to areas of the brain; these differences are consistent with neurological illness, but not depression or psychological illness. The World Health Organization classes chronic fatigue syndrome as a central nervous system disease.Some neuroimaging studies have observed prefrontal and brainstem hypometabolism; however, sample size was limited. Neuroimaging studies in persons with CFS have identified changes in brain structure and correlations with various symptoms. Results were not consistent across the neuroimaging brain structure studies, and more research is needed to resolve the discrepancies found between the disparate studies.Tentative evidence suggests a relationship between autonomic nervous system dysfunction and diseases such as CFS, fibromyalgia, irritable bowel syndrome, and interstitial cystitis. However, it is unknown if this relationship is causative. Reviews of CFS literature have found autonomic abnormalities such as decreased sleep efficiency, increased sleep latency, decreased slow wave sleep, and abnormal heart rate response to tilt table tests, suggesting a role of the autonomic nervous system in CFS. However, these results were limited by inconsistency.Central sensitization, or increased sensitivity to sensory stimuli such as pain have been observed in CFS. Sensitivity to pain increases after exertion, which is opposite to the normal pattern.
Immunological
Immunological abnormalities are frequently observed in those with CFS. Decreased NK cell activity is found more often in people with CFS and this correlates with severity of symptoms. People with CFS have an abnormal response to exercise, including increased production of complement products, increased oxidative stress combined with decreased antioxidant response, and increased Interleukin 10, and TLR4, some of which correlates with symptom severity. Increased levels of cytokines have been proposed to account for the decreased ATP production and increased lactate during exercise; however, the elevations of cytokine levels are inconsistent in specific cytokine, albeit frequently found. Similarities have been drawn between cancer and CFS with regard to abnormal intracellular immunological signaling. Abnormalities observed include hyperactivity of Ribonuclease L, a protein activated by IFN, and hyperactivity of NF-κB.
Endocrine
Evidence points to abnormalities in the hypothalamic-pituitary-adrenal axis (HPA axis) in some, but not all, persons with CFS, which may include slightly low cortisol levels, a decrease in the variation of cortisol levels throughout the day, decreased responsiveness of the HPA axis, and a high serotonergic state, which can be considered to be a "HPA axis phenotype" that is also present in some other conditions, including post-traumatic stress disorder and some autoimmune conditions. It is unclear whether or not decreased cortisol levels of the HPA axis plays a primary role as a cause of CFS, or has a secondary role in the continuation or worsening of symptoms later in the illness. In most healthy adults, the cortisol awakening response shows an increase in cortisol levels averaging 50% in the first half-hour after waking. In people with CFS, this increase apparently is significantly less, but methods of measuring cortisol levels vary, so this is not certain.
Autoimmunity
Autoimmunity has been proposed to be a factor in CFS, but there are only a few relevant findings so far.
There are a subset of patients with increased B cell activity and autoantibodies, possibly as a result of decreased NK cell regulation or viral mimicry. In 2015, a large German study found 29% of ME/CFS patients had elevated autoantibodies to M3 and M4 muscarinic acetylcholine receptors as well as to ß2 adrenergic receptors. A 2016 Australian study found that ME/CFS patients had significantly greater numbers of single nucleotide polymorphisms associated with the gene encoding for M3 muscarinic acetylcholine receptors.
Energy metabolism
Studies have observed mitochondrial abnormalities in cellular energy production, but recent focus has concentrated on secondary effects that may result in aberrant mitochondrial function because inherent problems with the mitochondria structure or genetics have not been replicated.
Diagnosis
No characteristic laboratory abnormalities are approved to diagnose CFS; while physical abnormalities can be found, no single finding is considered sufficient for diagnosis. Blood, urine, and other tests are used to rule out other conditions that could be responsible for the symptoms. The CDC states that a medical history should be taken and a mental and physical examination should be done to aid diagnosis.
Diagnostic tools
The CDC recommends considering the questionnaires and tools described in the 2015 Institute of Medicine report, which include:
The Chalder Fatigue Scale
Multidimensional Fatigue Inventory
Fisk Fatigue Impact Scale
The Krupp Fatigue Severity Scale
DePaul Symptom Questionnaire
CDC Symptom Inventory for CFS
Work and Social Adjustment Scale (WSAS)
SF-36 / RAND-36: 270 A two-day cardiopulmonary exercise test (CPET) is not necessary for diagnosis, although lower readings on the second day may be helpful in supporting a claim for social security disability. A two-day CPET cannot be used to rule out chronic fatigue syndrome.: 216
Definitions
Notable definitions include:
Centers for Disease Control and Prevention (CDC) definition (1994), the most widely used clinical and research description of CFS, is also called the Fukuda definition and is a revision of the Holmes or CDC 1988 scoring system. The 1994 criteria require the presence of four or more symptoms beyond fatigue, while the 1988 criteria require six to eight.
The ME/CFS 2003 Canadian Clinical working definition states: "A patient with ME/CFS will meet the criteria for fatigue, post-exertional malaise and/or fatigue, sleep dysfunction, and pain; have two or more neurological/cognitive manifestations and one or more symptoms from two of the categories of autonomic, neuroendocrine, and immune manifestations; and the illness persists for at least 6 months".
The Myalgic Encephalomyelitis International Consensus Criteria (ICC) published in 2011 is based on the Canadian working definition and has an accompanying primer for clinicians The ICC does not have a six months waiting time for diagnosis. The ICC requires post-exertional neuroimmune exhaustion (PENE) which has similarities with post-exertional malaise, plus at least three neurological symptoms, at least one immune or gastrointestinal or genitourinary symptom, and at least one energy metabolism or ion transportation symptom. Unrefreshing sleep or sleep dysfunction, headaches or other pain, and problems with thinking or memory, and sensory or movement symptoms are all required under the neurological symptoms criterion. According to the ICC, patients with post-exertional neuroimmune exhaustion but only partially meet the criteria should be given the diagnosis of atypical myalgic encephalomyelitis.
The 2015 definition by the National Academy of Medicine (then referred to as the "Institute of Medicine") is not a definition of exclusion (differential diagnosis is still required). "Diagnosis requires that the patient have the following three symptoms: 1) A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities, that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest, and 2) post-exertional malaise* 3) Unrefreshing sleep*; At least one of the two following manifestations is also required: 1) Cognitive impairment* 2) Orthostatic intolerance" and notes that "*Frequency and severity of symptoms should be assessed. The diagnosis of ME/CFS should be questioned if patients do not have these symptoms at least half the time with moderate, substantial, or severe intensity."Clinical practice guidelines are generally based on case descriptions, with the aim of improving diagnosis, management and treatment. An example is the ME/CFS guideline for the National Health Services in England and Wales, updated in 2021. Other guidance can be found at the New York Department of Health.
Differential diagnosis
Certain medical conditions can cause chronic fatigue and must be ruled out before a diagnosis of CFS can be given. Hypothyroidism, anemia, coeliac disease (that can occur without gastrointestinal symptoms), diabetes and certain psychiatric disorders are a few of the diseases that must be ruled out if the patient presents with appropriate symptoms. Other diseases, listed by the Centers for Disease Control and Prevention, include infectious diseases (such as Epstein–Barr virus, influenza, HIV infection, tuberculosis, Lyme disease), neuroendocrine diseases (such as thyroiditis, Addisons disease, adrenal insufficiency, Cushings disease), hematologic diseases (such as occult malignancy, lymphoma), rheumatologic diseases (such as fibromyalgia, polymyalgia rheumatica, Sjögrens syndrome, lupus, giant-cell arteritis, polymyositis, dermatomyositis), psychiatric diseases (such as bipolar disorder, schizophrenia, delusional disorders, dementia, anorexia/bulimia nervosa), neuropsychologic diseases (such as obstructive sleep apnea, parkinsonism, multiple sclerosis), and others (such as nasal obstruction from allergies, sinusitis, anatomic obstruction, autoimmune diseases, cancer, chronic hepatitis, some chronic illness, alcohol or other substance abuse, pharmacologic side effects, heavy metal exposure and toxicity, marked body weight fluctuation). Ehlers–Danlos syndromes (EDS) may also have similar symptoms. Medications can also cause side effects that mimic symptoms of CFS.Persons with fibromyalgia (FM, or fibromyalgia syndrome, FMS), like those with CFS, have muscle pain, severe fatigue and sleep disturbances. The presence of allodynia (abnormal pain responses to mild stimulation) and of extensive tender points in specific locations differentiates FM from CFS, although the two diseases often co-occur.Depressive symptoms, if seen in CFS, may be differentially diagnosed from primary depression by the absence of anhedonia, decreased motivation, and guilt; and the presence of somatic symptoms such as sore throat, swollen lymph nodes, and exercise intolerance with post exertional exacerbation of symptoms.
Management
There is no approved pharmacological treatment, therapy or cure for CFS, although various drugs have been or are being investigated. A 2014 report prepared by the Agency for Healthcare Research and Quality stated that there are wide variations in patient management, that many receive a multifaceted approach to treatment, and that no medications have been approved by the US Food and Drug Administration (FDA) for the treatment of ME/CFS, although several have been used off label. The report concluded that although counseling and graded exercise therapy (GET) have shown some benefits, these interventions have not been studied fully enough to recommend them for all persons affected. The report expressed concern that GET appears to be associated with worsening symptoms in some. The CDC no longer recommends these interventions, and there is some evidence of patient harm.The CDC guide for the management of CFS states that while there is no cure, a number of methods might improve symptoms. Treatment strategies for sleep problems; pain; depression, stress, and anxiety; dizziness and lightheadedness (orthostatic intolerance); and memory and concentration problems are enumerated. Other useful topics that patients and doctors might discuss include carefully monitoring and managing activity to avoid worsening of symptoms, counseling to cope with the impact the illness may have on quality of life, proper nutrition and nutritional supplements that may support better health, and complementary therapies that might help increase energy or decrease pain.The United Kingdoms National Institute for Health and Clinical Excellence (NICE) 2021 guideline directed toward healthcare professionals and patients, specifies the need for shared decision-making between patients and medical care teams and acknowledges the reality and impact of the condition and the symptoms. The NICE guideline covers diagnosis, illness management, and aspects of symptom management: diet, medications, coexisting conditions, flare-ups, and energy management. The guideline recognized symptoms of severe ME/CFS may be misunderstood as neglect or abuse and recommends assessment for safeguarding of persons suspected of having ME/CFS be evaluated by professionals with experience and understanding of the illness. The guideline states that GET is not an appropriate treatment for ME/CFS. CBT might be offered to help a person manage the difficulties of dealing with a chronic illness, not to cure the illness.Prior to publication of the NICE 2021 guideline, Andrew Goddard, president of the Royal College of Physicians, stated there was concern NICE did not adequately consider the experts support and evidence of the benefits of GET and CBT, and urged they be included in the guideline. Various ME/CFS patient groups disputed the benefits of the therapies and stated that GET can make the illness more severe.Comorbid conditions can occur in CFS that may interact with and exacerbate the symptoms of CFS. Appropriate medical intervention for these conditions may be beneficial. The most commonly diagnosed include fibromyalgia, irritable bowel syndrome, depression, anxiety, allergies, and chemical sensitivities.
Pacing
Pacing, or activity management, is an illness management strategy based on the observation that symptoms tend to increase following mental or physical exertion, and was recommended for CFS in the 1980s. It is now commonly used as a management strategy in chronic illnesses and in chronic pain.Its two forms are symptom-contingent pacing, in which the decision to stop (and rest or change an activity) is determined by self-awareness of an exacerbation of symptoms, and time-contingent pacing, which is determined by a set schedule of activities that a patient estimates he or she is able to complete without triggering post-exertional malaise (PEM). Thus, the principle behind pacing for CFS is to avoid overexertion and an exacerbation of symptoms. It is not aimed at treating the illness as a whole. Those whose illness appears stable may gradually increase activity and exercise levels, but according to the principle of pacing, must rest or reduce their activity levels if it becomes clear that they have exceeded their limits. Use of a heart-rate monitor with pacing to monitor and manage activity levels is recommended by a number of patient groups, and the CDC considers it useful for some individuals to help avoid post-exertional malaise.
Energy envelope theory
Energy envelope theory, considered to be consistent with pacing, is a management strategy suggested in the 2011 international consensus criteria for ME, which refers to using an "energy bank budget". Energy envelope theory was devised by psychologist Leonard Jason, who previously had CFS. Energy envelope theory states that patients should stay within, and avoid pushing through, the envelope of energy available to them, so as to reduce the post-exertional malaise "payback" caused by overexertion. This may help them make "modest gains" in physical functioning. Several studies have found energy envelope theory to be a helpful management strategy, noting that it reduces symptoms and may increase the level of functioning in CFS. Energy envelope theory does not recommend unilaterally increasing or decreasing activity and is not intended as a therapy or cure for CFS. It has been promoted by various patient groups. Some patient groups recommend using a heart rate monitor to increase awareness of exertion and enable patients to stay within their aerobic threshold envelope. Despite a number of studies showing positive results for energy envelope theory, randomized controlled trials are lacking.
Exercise
Stretching, movement therapies, and toning exercises are recommended for pain in patients with CFS, and pain medication is also suggested. In many chronic illnesses, aerobic exercise is beneficial, but in chronic fatigue syndrome, the CDC does not recommend it. The CDC states:Any activity or exercise plan for people with ME/CFS needs to be carefully designed with input from each patient. While vigorous aerobic exercise can be beneficial for many chronic illnesses, patients with ME/CFS do not tolerate such exercise routines. Standard exercise recommendations for healthy people can be harmful for patients with ME/CFS. However, it is important that patients with ME/CFS undertake activities that they can tolerate...
Counseling
The CDC states that counseling may help patients cope with pain caused by CFS, and that talking with a professional counselor or therapist may help people to more effectively manage the symptoms that affect their quality of daily life.
Nutrition
A proper diet is a significant contributor to the health of any individual. Medical consultation about diet and supplements is recommended for persons with CFS. Persons with CFS may benefit from a balanced diet and properly supervised administration of nutritional support if deficiencies are detected by medical testing. Risks of nutritional supplements include interactions with prescribed medications.
Treatment
Cognitive behavioral therapy
NICE indicates CBT might be offered to help cope with the difficulty of dealing with the |
Chronic fatigue syndrome | symptoms of ME/CFS, but should not be intended to be curative. The rationale behind the use of CBT to change beliefs about the illness is disputed. The CDC states that speaking with a therapist may help people cope with the illness.A 2015 National Institutes of Health report concluded that while counseling and behavior therapies could produce benefits for some people, they may not yield improvement in quality of life, and because of this limitation such therapies should not be considered as a primary treatment, but rather should be used only as one component of a broader approach. This same report stated that although counseling approaches have shown benefit in some measures of fatigue, function and overall improvement, these approaches have been inadequately studied in subgroups of the wider CFS patient population. Further concern was expressed that reporting of negative effects experienced by patients receiving counseling and behavior therapies had been poor. A report by the Institute of Medicine published in 2015 states that it is unclear whether CBT helps to improve cognitive impairments experienced by patients.: 265 A 2014 systematic review reported that there was only limited evidence that patients increased levels of physical activity after receiving CBT. The authors concluded that, as this finding is contrary to the cognitive behavioural model of CFS, patients receiving CBT were adapting to the illness rather than recovering from it. In a letter published online in the Lancet in 2016, Dr Charles Shepherd, medical advisor to the MEA, expressed the view that the contention between patients and researchers lay in "a flawed model of causation that takes no account of the heterogeneity of both clinical presentations and disease pathways that come under the umbrella diagnosis of ME/CFS".Patient organisations have rebuffed the use of CBT as a treatment for CFS to alter illness beliefs. The ME Association (MEA) recommended in 2015, based on the results of an opinion survey of 493 patients who had received CBT treatment in the UK, CBT in its current form should not be used as a primary intervention for people with CFS. In 2019, a large UK survey of people with ME/CFS reported that CBT was ineffective for more than half of respondents.
Graded exercise therapy
Recommendation for treatment using graded exercise therapy (GET) was removed from NICEs updated Guidelines for Diagnosis and Management of ME/CFS in October 2021. It was removed due to low quality evidence regarding benefit, with the guidelines now stating that clinicians should not prescribe "any programme that... uses fixed incremental increases in physical activity or exercise, for example, graded exercise therapy." Previously, the National Institutes of Health concluded that while GET could produce benefits, it may not yield improvement in quality of life, and because of this limitation GET should not be considered as a primary treatment. It was recommended to be used only as one component of a broader approach. It noted that a focus on exercise programs had discouraged patient participation in other types of physical activity due to concerns of increased symptoms. An addendum stated, if studies based on the Oxford criteria were excluded, there would be insufficient evidence of the effectiveness of GET.A 2019 updated Cochrane review stated that, exercise therapy probably has a positive effect on fatigue in adults, and slightly improves sleep, but the long-term effects are unknown and has limited relevance to current definitions of ME/CFS. Cochrane started re-evaluating the effects of exercise therapies in chronic fatigue syndrome in 2020.Patient organisations have long criticised the use of exercise therapy, most notably GET, as a treatment for CFS. Based on an opinion survey of patients who had received GET, in 2015 the ME Association concluded, GET in its current delivered form should not be recommended as a primary intervention for persons with CFS.
Adaptive pacing therapy
APT, not to be confused with pacing, is a therapy rather than a management strategy. APT is based on the idea that CFS involves a person only having a limited amount of available energy, and using this energy wisely will mean the "limited energy will increase gradually".: 5 A large clinical trial known as the PACE trial found APT was no more effective than usual care or specialized medical care. The PACE trial generated much criticism due to the broad Oxford criteria patient selection, the standards of outcome effectiveness were lowered during the study and that re-analysis of the data did not support the magnitude of improvements initially reported.Unlike pacing, APT is based on the cognitive behavioral model of chronic fatigue syndrome and involves increasing activity levels, which it states may temporarily increase symptoms. In APT, the patient first establishes a baseline level of activity, which can be carried out consistently without any post-exertional malaise ("crashes"). APT states that persons should plan to increase their activity, as able. However, APT also requires patients to restrict their activity level to only 70% of what they feel able to do, while also warning against too much rest. This has been described as contradictory, and Jason states that in comparison with pacing, this 70% limit restricts the activities that patients are capable of and results in a lower level of functioning. Jason and Goudsmit, who first described pacing and the energy envelope theory for CFS, have both criticized APT for being inconsistent with the principles of pacing and highlighted significant differences. APT was promoted by Action for ME, the patient charity involved in the PACE trial, until 2019.
Rintatolimod
Rintatolimod is a double-stranded RNA drug developed to modulate an antiviral immune reaction through activation of toll-like receptor 3. In several clinical trials of CFS, the treatment has shown a reduction in symptoms, but improvements were not sustained after discontinuation. Evidence supporting the use of rintatolimod is deemed low to moderate. The US FDA has denied commercial approval, called a new drug application, citing several deficiencies and gaps in safety data in the trials, and concluded that the available evidence is insufficient to demonstrate its safety or efficacy in CFS. Rintatolimod has been approved for marketing and treatment for persons with CFS in Argentina, and in 2019, FDA regulatory requirements were met for exportation of rintatolimod to the country. Rintatolimod is currently in an experimental trial in the USA to treat both ME/CFS and Long Covid.
Prognosis
Information on the prognosis of CFS is limited, and the course of the illness is variable. According to the NICE guideliene, CFS "varies in long-term outlook from person to person." Complete recovery, partial improvement, and worsening are all possible. Symptoms generally fluctuate over days, weeks, or longer periods, and some people may experience periods of remission. Overall, "many will need to adapt to living with ME/CFS." Some people who improve need to manage their activities in order to stay improved. Children and teenagers are more likely to recover or improve than adults.A 2005 systematic review found that for untreated CFS, "the median full recovery rate was 5% (range 0–31%) and the median proportion of patients who improved during follow-up was 39.5% (range 8–63%)," and that 8 to 30% of patients were able to return to work. Age at onset, a longer duration of follow-up, less fatigue severity at baseline, and other factors were occasionally, but non consistently, related to outcome. Another review found that children have a better prognosis than adults, with 54–94% having recovered by follow-up, compared to less than 10% of adults returning to pre-illness levels of functioning.
Epidemiology
The prevalence rates for CFS/ME vary widely depending on "case definitions and diagnostic methods". Based on the 1994 CDC diagnostic criteria, the global prevalence rate for CFS is 0.89%. In comparison, the prevalence rate for the stricter criteria, such as the 1988 CDC "Holmes" criteria for CFS and the 2003 Canadian criteria for ME (both of which, for example, exclude patients with psychiatric diagnoses), produce an incidence rate of only 0.17%. For an example of how these rates impact a nation: the CDC website notes that between 836,000 and 2.5 million Americans have ME/CFS, "but most remain undiagnosed".Females are diagnosed about 1.5 to 2.0 times more often with CFS than males. An estimated 0.5% of children have CFS, and more adolescents are affected with the illness than younger children.: 182 The incidence rate according to age has two peaks, one at 10–19 and another at 30–39 years. The effect is seen both in female and in male data, but is more pronounce in females. It was suggested that this occurs because these age groups may be more vulnerable to CFS. The rate of prevalence is highest between ages 40 and 60.
History
Myalgic encephalomyelitis
From 1934 onwards, outbreaks of a previously unknown illness began to be recorded by doctors. Initially considered to be occurrences of poliomyelitis, the illness was subsequently referred to as "epidemic neuromyasthenia".
In the 1950s, the term "benign myalgic encephalomyelitis" was used in relation to a comparable outbreak at the Royal Free Hospital in London. The descriptions of each outbreak were varied, but included symptoms of malaise, tender lymph nodes, sore throat, pain, and signs of encephalomyelitis. The cause of the condition was not identified, although it appeared to be infectious, and the term "benign myalgic encephalomyelitis" was chosen to reflect the lack of mortality, the severe muscular pains, symptoms suggesting damage to the nervous system, and to the presumed inflammatory nature of the disorder. Björn Sigurðsson disapproved of the name, stating that the illness is rarely benign, does not always cause muscle pain, and is possibly never encephalomyelitic. The syndrome appeared in sporadic as well as epidemic cases.
In 1969, benign myalgic encephalomyelitis appeared as an entry to the International Classification of Diseases under Diseases of the nervous system.
In 1986, Ramsay published the first diagnostic criteria for ME, in which the condition was characterized by: 1) muscle fatiguability in which, even after minimal physical effort, three or more days elapse before full muscle power is restored; 2) extraordinary variability or fluctuation of symptoms, even in the course of one day; and 3) chronicity.
By 1988, the continued work of Ramsay had demonstrated that, although the disease rarely resulted in mortality, it was often severely disabling.: 28–29 Because of this, Ramsay proposed that the prefix "benign" be dropped.
Chronic fatigue syndrome
In the mid-1980s, two large outbreaks of an illness that resembled mononucleosis drew national attention in the United States. Located in Nevada and New York, the outbreaks involved an illness characterized by "chronic or recurrent debilitating fatigue, and various combinations of other symptoms, including a sore throat, lymph node pain and tenderness, headache, myalgia, and arthralgias". An initial link to the Epstein-Barr virus had the illness acquire the name "chronic Epstein-Barr virus syndrome".: 29
In 1987, the CDC convened a working group to reach a consensus on the clinical features of the illness. The working group concluded that CFS was not new, and that the many different names given to it previously reflected widely differing concepts of the illnesss cause and epidemiology. The CDC working group chose "chronic fatigue syndrome" as a more neutral and inclusive name for the illness, but noted that "myalgic encephalomyelitis" was widely accepted in other parts of the world.
In 1988, the first definition of CFS was published. Although the cause of the illness remained unknown, several attempts were made to update this definition, most notably in 1994.
The most widely referenced diagnostic criteria and definition of CFS for research and clinical purposes were published in 1994 by the CDC.
In 2006, the CDC commenced a national program to educate the American public and health-care professionals about CFS.
Other medical terms
A range of both theorised and confirmed medical entities and naming conventions have appeared historically in the medical literature dealing with ME and CFS. These include:
Epidemic neuromyasthenia was a term used for outbreaks with symptoms resembling poliomyelitis.
Iceland disease and Akureyri disease were synonymous terms used for an outbreak of fatigue symptoms in Iceland.
Low natural killer syndrome, a term used mainly in Japan, reflected research showing diminished in vitro activity of natural killer cells isolated from patients.
Neurasthenia has been proposed as an historical diagnosis that occupied a similar medical and cultural space to CFS.
Royal Free disease was named after the historically significant outbreak in 1955 at the Royal Free Hospital used as an informal synonym for "benign myalgic encephalomyelitis".
Tapanui flu was a term commonly used in New Zealand, deriving from the name of a town, Tapanui, where numerous people had the syndrome.
Society and culture
Naming
Many names have been proposed for the illness. Currently, the most commonly used are "chronic fatigue syndrome", "myalgic encephalomyelitis", and the umbrella term "ME/CFS". Reaching consensus on a name is challenging because the cause and pathology remain unknown.: 29–30 The term "chronic fatigue syndrome" has been criticized by some patients as being both stigmatizing and trivializing, and which in turn prevents the illness from being seen as a serious health problem that deserves appropriate research. While many patients prefer "myalgic encephalomyelitis", which they believe better reflects the medical nature of the illness, there is resistance amongst some clinicians toward the use of myalgic encephalomyelitis on the grounds that the inflammation of the central nervous system (myelitis) implied by the term has not been demonstrated.A 2015 report from the Institute of Medicine recommended the illness be renamed "systemic exertion intolerance disease", (SEID), and suggested new diagnostic criteria, proposing post-exertional malaise, (PEM), impaired function, and sleep problems are core symptoms of ME/CFS. Additionally, they described cognitive impairment and orthostatic intolerance as distinguishing symptoms from other fatiguing illnesses.
Economic impact
Reynolds et al. (2004) estimated that the illness caused about $20,000 per person with CFS in lost productivity, which totals to $9.1 billion per year in the United States.: 29 This is comparable to other chronic illnesses that extract some of the biggest medical and socioeconomic costs. Direct healthcare costs are estimated at between $9 and $14 billion annually in the US alone. A 2008 study calculated that the total annual cost burden of ME/CFS to society in the US was extensive, and could approach $24.0 billion. A 2017 estimate for the annual economic burden in the United Kingdom from ME/CFS was 3.3 billion pounds sterling.
Awareness day
12 May is designated as ME/CFS International Awareness Day. The day is observed so that stakeholders have an occasion to improve the knowledge of "the public, policymakers, and health-care professionals about the symptoms, diagnosis, and treatment of ME/CFS, as well as the need for a better understanding of this complex illness." It was chosen because it is the birthday of Florence Nightingale, who had an illness appearing similar to ME/CFS or fibromyalgia.
Doctor–patient relations
Some in the medical community do not recognize CFS as a real condition, nor does agreement exist on its prevalence. There has been much disagreement over proposed causes, diagnosis, and treatment of the illness. This uncertainty can significantly affect doctor-patient relations. A 2006 survey of GPs in southwest England found that despite more than two-thirds of them accepting CFS/ME as a recognizable clinical entity, nearly half did not feel confident with making the diagnosis and/or treating the disease. Three other key factors that were significantly, positively associated with GPs attitudes were knowing someone socially with CFS/ME, being male, and seeing more patients with the condition in the last year.From the patient perspective, one 1997 study found that 77% of individuals with CFS reported negative experiences with health-care providers. In a more recent metaanalysis of qualitative studies, a major theme identified in patient discourses was that they felt severely ill, yet were blamed and dismissed. A study of themes in patient newsgroup postings noted key themes relating to denial of social recognition of suffering and feelings of being accused of "simply faking it". Another theme that emerged strongly was that achieving diagnosis and acknowledgement requires tremendous amounts of "hard work" by patients.
Blood donation
In 2010, several national blood banks adopted measures to discourage or prohibit individuals diagnosed with CFS from donating blood, based on concern following the 2009 claim of a link, between CFS and a retrovirus which was subsequently shown to be unfounded. Organizations adopting these or similar measures included the Canadian Blood Services, the New Zealand Blood Service, the Australian Red Cross Blood Service and the American Association of Blood Banks, In November 2010, the UK National Blood Service introduced a permanent deferral of donation from ME/CFS patients based on the potential harm to those patients that may result from their giving blood. Donation policy in the UK now states, "The condition is relapsing by nature and donation may make symptoms worse, or provoke a relapse in an affected individual."
Controversy
Much contention has arisen over the cause, pathophysiology, nomenclature, and diagnostic criteria of CFS. Historically, many professionals within the medical community were unfamiliar with CFS, or did not recognize it as a real condition; nor did agreement exist on its prevalence or seriousness. Some people with CFS reject any psychological component.In 1970, two British psychiatrists, McEvedy and Beard, reviewed the case notes of 15 outbreaks of benign myalgic encephalomyelitis and concluded that it was caused by mass hysteria on the part of patients, or altered medical perception of the attending physicians. Their conclusions were based on previous studies that found many normal physical test results, a lack of a discernible cause, and a higher prevalence of the illness in females. Consequently, the authors recommended that the disease should be renamed "myalgia nervosa". This perspective was rejected in a series of case studies by Dr. Melvin Ramsay and other staff of the Royal Free Hospital, the center of a significant outbreak. The psychological hypothesis posed by McEvedy and Beard created great controversy, and convinced a generation of health professionals in the UK that this could be a plausible explanation for the condition, resulting in neglect by many medical specialties. The specialty that did take a major interest in the illness was psychiatry.Because of the controversy, sociologists hypothesized that stresses of modern living might be a cause of the illness, while some in the media used the term "Yuppie flu" and called it a disease of the middle class. People with disabilities from CFS were often not believed and were accused of being malingerers. The November 1990 issue of Newsweek ran a cover story on CFS, which although supportive of an organic cause of the illness, also featured the term yuppie flu, reflecting the stereotype that CFS mainly affected yuppies. The implication was that CFS is a form of burnout. The term yuppie flu is considered offensive by both patients and clinicians.In 2009, the journal Science published a study that identified the XMRV retrovirus in a population of people with CFS. Other studies failed to reproduce this finding, and in 2011, the editor of Science formally retracted its XMRV paper while the Proceedings of the National Academy of Sciences similarly retracted a 2010 paper which had appeared to support the finding of a connection between XMRV and CFS.
Research funding
United Kingdom
The lack of research funding and the funding bias towards biopsychosocial studies and against biomedical studies has been highlighted a number of times by patient groups and a number of UK politicians. A parliamentary inquiry by an ad hoc group of parliamentarians in the United Kingdom, set up and chaired by former MP, Dr Ian Gibson, called the Group on Scientific Research into CFS/ME,: 169–86 was addressed by a government minister claiming that few good biomedical research proposals have been submitted to the Medical Research Council (MRC) in contrast to those for psychosocial research. They were also told by other scientists of proposals that have been rejected, with claims of bias against biomedical research. The MRC confirmed to the group that from April 2003 to November 2006, it has turned down 10 biomedical applications relating to CFS/ME and funded five applications relating to CFS/ME, mostly in the psychiatric/psychosocial domain.In 2008, the MRC set up an expert group to consider how the MRC might encourage new high-quality research into CFS/ME and partnerships between researchers already working on CFS/ME and those in associated areas. It currently lists CFS/ME with a highlight notice, inviting researchers to develop high-quality research proposals for funding. In February 2010, the All-Party Parliamentary Group on ME (APPG on ME) produced a legacy paper, which welcomed the recent MRC initiative, but felt that far too much emphasis in the past had been on psychological research, with insufficient attention to biomedical research, and that further biomedical research must be undertaken to help discover a cause and more effective forms of management for this disease.Controversy surrounds psychologically oriented models of the disease and behavioral treatments conducted in the UK.
United States
In 1998, $13 million for CFS research was found to have been redirected or improperly accounted for by the United States CDC, and officials at the agency misled Congress about the irregularities. The agency stated that they needed the funds to respond to other public-health emergencies. The director of a US national patient advocacy group charged the CDC had a bias against studying the disease. The CDC pledged to improve their practices and to restore the $13 million to CFS research over three years.On 29 October 2015, the National Institutes of Health declared its intent to increase research on ME/CFS. The NIH Clinical Center was to study individuals with ME/CFS, and the National Institute of Neurological Disorders and Stroke would lead the Trans-NIH ME/CFS Research Working Group as part of a multi-institute research effort.
Notable cases
In 1989, The Golden Girls (1985–1992) featured chronic fatigue syndrome in a two-episode arc, "Sick and Tired: Part 1" and "Part 2", in which protagonist Dorothy Zbornak, portrayed by Bea Arthur, after a lengthy battle with her doctors in an effort to find a diagnosis for her symptoms, is finally diagnosed with CFS. American author Ann Bannon had CFS. Laura Hillenbrand, author of the popular book Seabiscuit, has struggled with CFS since age 19.
Research
The different case definitions used to research the illness influence the types of patients selected for studies, and research also suggests subtypes of patients may exist within a heterogeneous population. In one of the definitions, symptoms are accepted that may suggest a psychiatric disorder, while others specifically exclude primary psychiatric disorders. The lack of a single, unifying case definition was criticized in the Institute of Medicines 2015 report for "creating an unclear picture of the symptoms and signs of the disorder" and "complicating comparisons of the results" (study results).: 72 More robust diagnostic methods are being investigated with the aim of identifying unique biomarkers that may be used in clinical testing. In 2019, two different papers were published proposing blood-based biomarkers for CFS. One found that blood cells of CFS patients could be distinguished from healthy controls by their response to hyperosmotic stress. Another found that the red blood cells of CFS patients were stiffer, and thus less able to deform in order to pass through capilliaries.
See also
Long COVID
Unrest (2017 film)
References
External links
"CDC – Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)". Centers for Disease Control. Retrieved 20 May 2020. |
Senile osteoporosis | Senile osteoporosis has been recently recognized as a geriatric syndrome with a particular pathophysiology. There are different classification of osteoporosis: primary, in which bone loss is a result of aging and secondary, in which bone loss occurs from various clinical and lifestyle factors. Primary, or involuntary osteoporosis, can further be classified into Type I or Type II. Type I refers to postmenopausal osteoporosis and is caused by the deficiency of estrogen. While senile osteoporosis is categorized as an involuntary, Type II, and primary osteoporosis, which affects both men and women over the age of 70 years. It is accompanied by vitamin D deficiency, bodys failure to absorb calcium, and increased parathyroid hormone.Research over the years has shown that senile osteoporosis is the product of a skeleton in an advanced stage of life and can be caused by a deficiency caused by calcium. However, physicians are also coming to the conclusion that multiple mechanisms in the development stages of the disease interact together resulting in an osteoporotic bone, regardless of age. Still, elderly people make up the fastest growing population in the world. As bone mass declines with age, the risk of fractures increases. Annual incidence of osteoporotic fractures is more than 1.5 million in the US and notably 20% of people die during the first year after a hip fracture.It costs the US health system around $17 billion annually, with the cost projecting to $50 billion by 2040. These costs represent a higher burden compared to other disease states, such as breast cancer, stroke, diabetes, or chronic lung disease. Although there are cost effective and well-tolerated treatments, 23% of the diagnosed are women over 67 have received either bone mineral density (BMD) tests or prescription for treatment after fracture. The clinical and economic burdens indicate there should be more effort in assessment of risk, prevention, and early intervention when it comes to osteoporosis.
Presentation
Complications
Because senile osteoporosis is caused by the loss of bone mass due to aging, the bones are more fragile and thus more prone to fractures and fracture-related complications. These complications can include a more than doubled risk increase for future fractures and a lower quality of life resulting from chronic pain or disability, sometimes needing long-term nursing care. Depending on the site, pathologic fractures can also increase relative mortality risk. Hip fractures alone are particularly debilitating and have a nearly 20% higher mortality rate within one year of the fracture. Other fractures are more subtle and can go undetected for some time. For example, vertebral compression fractures in the spine, often noticeable by a loss of vertical height, can occur even during routine motions like twisting, coughing, and reaching.In addition to decreased bone mineral density, there are other factors that contribute to fracture risk such as advanced age, lower body mass index, fracture history, smoking, steroid use, high alcohol intake, and fall history. Studies linking alcohol and fracture risk define high intake as three or more drinks per day. High caffeine intake may also play a role in fracture risk. Many healthcare organizations also utilize a Fracture Risk Assessment Tool (FRAX) that can estimate a 10-year probability of having an osteoporotic fracture based on an individuals health information and the criteria listed above.
Cause
Bone remodeling, or the absorption and resorption of bone, is a natural mechanism that occurs to repair and strengthen bones in the body. However, an imbalance between the resorption and formation of bone occurs as people age, contributing to the development of senile osteoporosis. The aging of cortical and trabecular bones in particular cause the decrease in bone density in the elderly population. Although most of the etiologic considerations regarding senile osteoporosis are not very clear for physicians yet, risk factors of osteoporosis have been identified. These factors include gender, age, hormone imbalances, reduced bone quality, and compromised integrity of bone microarchitecture.Based on the current evidence attached to clinical experimentation, there is some evidence that the pathogenesis of the disease is related to a deficiency of zinc. Such deficiency is known to lead to an increment of endogenous heparin, which is most likely caused by mast cell degranulation, and an increase in the bone resorption (calcium discharge in the bones) reaction of prostaglandin E2, which constrain the formation of more bone mass, making bones more fragile. These co-factors are shown to play an important role in the pathogenetic process attached to senile osteoporosis as they enhance the action of the parathyroid hormone.The intake of calcium in elder people is quite low, and this problem is worsened by a reduced capability to ingest it. This, attached to a decrease in the absorption of vitamin D concerning metabolism, are also factors that contributes to a diagnosis of osteoporosis type II.
Risk factors
While senile osteoporosis (type II) is mainly attributed to age, other risks include medical, pharmacological, genetic, and environmental factors. Peak bone mass is a major determinant of bone density, which starts in utero and is typically complete by the age 40.
Medical
Though secondary osteoporosis is a separate category when it comes to osteoporosis diagnosis, it can still be a contributing factor to primary osteoporosis. Secondary osteoporosis can be present in pre- and post-menopausal women and in men and have found to be factors contributing to osteoporosis in both sexes (50-80% of men and 30% of post-menopausal women). Therefore, when treating people over 70, it is important to exclude secondary causes of osteoporosis which include endocrine disorders (e.g. hyperthyroidism and diabetes mellitus), gastrointestinal, hepatic and nutritional disorders (e.g. celiac disease and inflammatory bowel disease), hematological disorders (e.g. systemic mastocytosis), renal disorders (e.g. chronic kidney disease), and autoimmune disorders (e.g. rheumatoid arthritis and systemic lupus erythematosus).
Medications
Medications that can contribute to bone loss include aluminum (found in antacids), aromatase inhibitors, cyclosporine, depo-medroxyprogesterone (premenopausal), glucocorticoids, lithium, proton pump inhibitors, serotonin reuptake inhibitors, tacrolimus, and tamoxifen (premenopausal). These medications can contribute to bone loss and can increase risk for osteoporotic fractures.
Genetic
Maternal body build, lifestyle, and vitamin D status are some of the genetic and epigenetic effects that have been found to affect the BMD, specifically the developmental plasticity.Additionally, other studies have found that race (e.g. Black women have the lowest risk), age (i.e. older age), body mass (i.e. lower weight), and gender (female) play a role in contributing to the risk of osteoporosis. Although the incidence of developing osteoporosis and hip fractures vary between population groups, older age is consistently associated with a higher incidence of fractures due to osteoporosis.
Social and nutritional factors
There are several environmental and social factors that can contribute to the risk of developing osteoporosis. Smoking tobacco can increase the risk by decreasing the ability of the intestine to absorb calcium. Caffeine intake and heavy alcohol were also correlated with the decrease in bone density in the elderly population.Without proper intake of vitamin D and calcium, it can increase the risk of osteoporosis in the elderly. These vitamin deficiencies pose as a risk factor, as it can decrease bone mass, decrease calcium absorption, and increase in bone turnover. There are also various medications can that interfere with the absorption of calcium, such as anticonvulsants, diuretics, corticosteroids, immunosuppressive medications, some antibiotics, and NSAIDS.
Diagnosis
Because the diagnosis of osteoporosis is made only after a pathologic fracture has occurred, it is best to take serial bone density (also known as bone mineral density or BMD) measurement scans for high risk individuals (elderly). The World Health Organization (WHO) has established a diagnostic criteria for osteoporosis using BMD T-scores which describes an individuals BMD in terms of the number of SDs by which is differs from the mean peak value in young, healthy persons of the same sex—currently more than 2.5 SDs below the mean as the criterion for osteoporosis. For osteopenia (low bone mass) the range is 1.0 SD to less than 2.5 SDs below the mean. However, T-scores were initially used as an estimation of the prevalence of osteoporosis across populations not to assess osteoporosis prevalence in specific individuals which lead to the National Osteoporosis Foundation and the International Society for Clinical Densitometry to consider using dual-energy X-ray absorptiometry (DXA) of the hip and/or spine as the preferred measurement diagnosis of osteoporosis.
Prevention
Of the risks listed above, falls contribute most significantly to the incidence of osteoporotic fractures. Regular exercise has the strongest correlation in decreasing fall risk. Back and posture exercises such as tai chi as well as weight-bearing exercises such as walking can slow bone loss, improve balance, and strengthen muscles. There are also precautions that can be taken at home to reduce the risk of falling. These include anchoring rugs to the floor, minimizing clutter, improving overall lighting and visibility, and installing handrails in stairways and hallways.
Treatment
Calcium and vitamin D3 intake from diet or supplementation are crucial in the ethiopathogenesis of this disease; therefore, the effective treatments should consist of non pharmacological methods (such as a modified diet with more calcium 1000–1500 mg/day and vitamin D3 intake of 600-800 IU/day, exercising, smoking cessation, and alcohol restriction), fall prevention, and individually chosen pharmacological intervention (antiresorptive agent like bisphosphonate or estrogen replacement therapy in women). Given bone fracture (hip, vertebrae, and colles) is a devastating complication of osteoporosis, vitamin D3 combined with calcium are used as primary prevention, along with alendronate, residronate, strontium and zoledronic acid which have proven efficacy in primary and secondary hip fracture prevention. The Institute of Medicine recommends a daily allowance of 800 IU of Vitamin D for people 70 and over, to get to a level of serum 25-hydroxyvitamin D (25OHD) of at least 20 ng/ml (50 nmol/liter) in addition to a daily allowance of 1,200 mg of calcium.One systematic review of pharmacological agents from 2008 on postmenopausal woman age 65 found bisphosphonates to be more efficacious in improvement of bone marrow density and reduction of vertebral fractures compared to placebo. This systematic review also found that parathyroid hormone and estrogen/progesterone therapy had significant improvements in bone marrow density compared to placebo. In addition to bisphosphonates, pharmacological treatments for osteoporosis can include calcitonin, parathyroid hormone 1-34, hormone replacement therapy, and monoclonal antibody therapy. Another systematic review published in the Journal of American Geriatrics Society from 2017 showed that among men with risk of osteoporotic fracture, bisphosphonates had significant reduction in fracture compared to placebo, while calcitonin and monoclonal antibody therapy did not show efficacy compared to placebo.In post-menopausal older women, estrogen therapy (but not low-dose conjugated estrogens or ultra-low-dose estradiol) may reduce the incidence of new vertebral, non-vertebral, and hip fractures. Selective estrogen-receptor modulators such as raloxifene have been FDA approved to treat osteoporosis as it inhibits bone resorption, slightly increases spine BMD but have not been proved efficacious in antifracture properties.Even though more studies are necessary for an efficient evaluation of the role played by zinc in senile osteoporosis, some doctors may recommend a proper supplementation of dietary zinc in addition to calcium and vitamin D3.
References
== Further reading == |
Nathalie syndrome | Nathalie syndrome is a rare genetic developmental defect during embryogenesis disorder and is thought to be hereditary.In 1975 a physician described four siblings in a Dutch family with symptoms of the condition; the condition was named after the oldest sibling.According to Orphanet, the condition occurs in 1 in 1 million people.Children with this condition appear younger than their age. Nathalie syndrome can cause disability and death around early or mid adulthood. Sudden death, cardiomyopathy, and heart failure have been reported in some cases.
== References == |
Urachal diverticulum | A urachal diverticulum (also vesicourachal diverticulum) is a congenital disorder caused by the partial persistence of the allantois. The allantois, which later becomes the urachus, connects an embryos bladder to the yolk sac. Normally, the urachus closes off to become the median umbilical ligament; however, if it does not seal close to the bladder, a blind pouch connected to the bladder remains. This is usually asymptomatic but can lead to recurrent urinary tract infections. If the urachus is wholly patent, urine can drain from the bladder to an opening by the umbilicus, a condition known as urachal fistula.
== References == |
Microstomia | Microstomia is a small mouth (micro- a combining form meaning small + -stomia a combining form meaning mouth = (abnormally) "small mouth" in Greek.)
Congenital
It is a feature of many craniofacial syndromes, including Freeman–Sheldon syndrome and Sheldon-Hall syndromes (or distal arthrogryposis multiplex congenita). It may present with whistling-face feature, as well, as in Freeman-Sheldon syndrome. In this syndrome, it impairs alimentation and may require repeated oral surgeries (called commissurotomy) to improve function.
Acquired
Microstomia can occur as a result of scarring due to many conditions. It is seen as complication of facial burns.
It can also be a feature of systemic scleroderma.
References
== External links == |
Sclerodactyly | Sclerodactyly is a localized thickening and tightness of the skin of the fingers or toes that yields a characteristic claw-like appearance and spindle shape of the affected digits, and renders them immobile or of limited mobility. The thickened, discolored patches of skin are called morphea, and may involve connective tissue below the skin, as well as muscle and other tissues. Sclerodactyly is often preceded by months or even years by Raynauds phenomenon when it is part of systemic scleroderma.The term "sclerodactyly" comes from the combination of the Greek words "skleros" meaning hard and "daktylos" meaning a finger or toe – "hard fingers or toes".
It is generally associated with systemic scleroderma and mixed connective tissue disease, and auto-immune disorders.
Sclerodactyly is one component of the limited cutaneous form of systemic sclerosis (lcSSc), also known as CREST syndrome (CREST is an acronym that stands for calcinosis, Raynauds phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia.) Sclerodactyly is also one component of Huriez Syndrome, along with palmoplantar keratoderma and skin cancer. Sclerodactyly sometimes arises as a complication of the microvascular changes seen in diabetes mellitus, and is in this case referred to as diabetic sclerodactyly.Treatment of sclerodactyly is by physical therapy, phototherapy, surgery, topical corticosteroids or vitamin D analogues, and systemic immunosuppressive drugs when the condition is part of systemic scleroderma. Localized treatment wont halt systemic disease, but can restore function and cosmetic aspects of the affected digits. The mild to moderate proximal interphalangeal (PIP) joint flexion and extension contractures and stiff distal interphalangeal (DIP) joints in slight flexion often seen in sclerodactyly can be addressed somewhat with physical therapy. In a few cases when immune involvement isnt apparent (in these cases environmental causes are suspected), the condition may gradually clear up by itself If the trigger is avoided. In other cases, early treatment while the disease is in the inflammatory stage is much more likely to be successful than on established lesions.
See also
Hand eczema
Atopic dermatitis
== References == |
Convergence insufficiency | Convergence insufficiency is a sensory and neuromuscular anomaly of the binocular vision system, characterized by a reduced ability of the eyes to turn towards each other, or sustain convergence.
Symptoms
The symptoms and signs associated with convergence insufficiency are related to prolonged, visually demanding, near-centered tasks. They may include, but are not limited to, diplopia (double vision), asthenopia (eye strain), transient blurred vision, difficulty sustaining near-visual function, abnormal fatigue, headache, and abnormal postural adaptation, among others. In some cases, difficulty with making eye contact have been noted as a complaint amongst those affected. Note that some Internet resources confuse convergence and divergence dysfunction, reversing them.
Diagnosis
Diagnosis of convergence insufficiency is made by an eye care professional skilled in binocular vision dysfunctions, such as an orthoptist, to rule out any organic disease. Convergence insufficiency is characterized by one or more of the following diagnostic findings: patient symptoms, high exophoria at near, reduced accommodative convergence/accommodation ratio, receded near point of convergence, and low fusional vergence ranges and/or facility. Some patients with convergence insufficiency have concurrent accommodative insufficiency—accommodative amplitudes should therefore also be measured in symptomatic patients.
Convergence insufficiency can cause difficulty learning to read.
Treatment
Convergence insufficiency may be treated with convergence exercises prescribed by an eyecare specialist trained in orthoptics or binocular vision anomalies (see: vision therapy). Some cases of convergence insufficiency are successfully managed by prescription of eyeglasses, sometimes with therapeutic prisms.
Pencil push-ups therapy is performed at home. The patient brings a pencil slowly to within 2–3 cm (0.79–1.18 in) of the eye just above the nose about fifteen minutes per day five times per week. Patients should record the closest distance that they could maintain fusion (keep the pencil from going double as long as possible) after each five minutes of therapy. Computer software may be used at home or in an orthoptists/vision therapists office to treat convergence insufficiency. A weekly 60-minute in-office therapy visit may be prescribed. This is generally accompanied with additional in-home therapy.In 2005, the Convergence Insufficiency Treatment Trial (CITT) published two randomized clinical studies. The first, published in Archives of Ophthalmology, demonstrated that computer exercises when combined with office/based vision therapy/orthoptics were more effective than "pencil pushups" or computer exercises alone for convergency insufficiency in nine- to eighteen-year-old children. The second found similar results for adults 19 to 30 years of age. In a bibliographic review of 2010, the CITT confirmed their view that office-based accommodative/vergence therapy is the most effective treatment of convergence insufficiency, and that substituting it in entirety or in part with other eye training approaches such as home-based therapy may offer advantages in cost but not in outcome. A later study of 2012 confirmed that orthoptic exercises led to longstanding improvements of the asthenopic symptoms of convergence sufficiency both in adults and in children. A 2020 Cochrane Review concludes that office-based vergence/accommodative therapy with home reinforcement is more effective than home-based pencil/target push-ups or home-based computer vergence/accommodative therapy for children. In adults, evidence of the effectiveness of various non-surgical interventions is less clear.Both positive fusional vergence (PFV) and negative fusional vergence (NFV) can be trained, and vergence training should normally include both.
Surgical correction options are also available, but the decision to proceed with surgery should be made with caution as convergence insufficiency generally does not improve with surgery. Bilateral medial rectus resection is the preferred type of surgery. However, the patient should be warned about the possibility of uncrossed diplopia at distance fixation after surgery. This typically resolves within one to three months postoperatively. The exophoria at near often recurs after several years, although most patients remain asymptomatic.
Reading difficulty
In some cases, convergence Insufficiency can be the underlying cause of difficulty learning to read. As a result of the eyes not converging on the same point for sustained periods of time when reading, words can appear blurry or double because the brain is receiving two different images. Convergence insufficiency is not a learning disability. However, some children with the condition who are struggling to learn to read can be confused for having dyslexia due to difficulty learning to read. Children struggling with symptoms such as letters appearing blurry or double and experience tiredness or headaches when reading should consult an optometrist.
Prevalence
Among fifth and sixth grade children convergence insufficiency is 13%. In studies that used standardized definitions of convergence insufficiency, investigators have reported a prevalence of 4.2% to 6% in school and clinic settings. The standard definition of convergence insufficiency is exophoria greater at near than at distance, a receded near point of convergence, and reduced convergence amplitudes at near.
See also
References
== External links == |
Atypical anorexia nervosa | Atypical anorexia nervosa is an eating disorder in which individuals meet all the qualifications for anorexia nervosa, including a body image disturbance and a history of restrictive eating and weight loss, except that they are not currently underweight. Atypical anorexia qualifies as a mental health disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), under the category Other Specified Feeding and Eating Disorders (OSFED). The characteristics of people with atypical anorexia generally do not differ significantly from anorexia nervosa patients except for their current weight.Atypical anorexia was not described in earlier editions of the DSM, which included a requirement that person to have a body weight no higher than 85% of normal. Patients with atypical anorexia were diagnosed with the DSM-4 qualification "eating disorder not otherwise specified" (EDNOS) until the DSM-5 was released in 2013. Prior to DSM-5, EDNOS made up the majority of eating disorders diagnoses, making it difficult to estimate the prevalence of atypical anorexia during this period.The term atypical anorexia was historically used to describe the restrictive eating habits of some people with autism. The DSM-5 superseded this term with the avoidant restrictive food intake disorder (ARFID) diagnosis.
Signs and symptoms
Current consensus is that atypical anorexia patients are at risk for the same medical complications of anorexia nervosa.Evidence from a study conducted at the University of California San Francisco Eating Disorders Program suggests that atypical anorexia patients are equally likely as anorexia nervosa patients to develop secondary side effects, including bradycardia (decreased heart rate), amenorrhea (stopping of the menstrual period), and electrolyte imbalances.
Treatment
Treatment for atypical anorexia is very similar to treatment for anorexia nervosa. Increasing calorie intake to a healthy amount is a crucial part of treatment, but patients with severe atypical anorexia are at risk for refeeding syndrome during early recovery, so it is recommended that they are treated in an inpatient facility and slowly adjusted to increased calorie intake by 100-200 additional calories per day. Treatment may also include a variety of therapies that help a patient deal with the depression, anxiety, and other mental symptoms that arise from the eating disorder.In the US, treatment may be complicated by the need to get health insurance plans to pay. Medical coding may be incorrect on requests or may be rejected because payers incorrectly evaluated it under the separate criteria for anorexia nervosa.
Epidemiology
It is difficult to gauge the true prevalence of atypical anorexia pre-2013 because patients were lumped together under the EDNOS diagnosis. Evidence suggests that atypical anorexia is more prevalent than anorexia nervosa, but individuals experiencing it are less likely to receive care. For example, one prospective study of 196 women found a prevalence of 2.8% for atypical anorexia, compared to only 0.8% for anorexia nervosa by the age of 20.
== References == |
Gillespie syndrome | Gillespie syndrome, also called aniridia, cerebellar ataxia and mental deficiency, is a rare genetic disorder. The disorder is characterized by partial aniridia (meaning that part of the iris is missing), ataxia (motor and coordination problems), and, in most cases, intellectual disability. It is heterogeneous, inherited in either an autosomal dominant or autosomal recessive manner. Gillespie syndrome was first described by American ophthalmologist Fredrick Gillespie in 1965.
Presentation
The combination of muscular hypotonia and fixed dilated pupils in infancy is suspicious of Gillespie syndrome. Early onset partial aniridia, cerebellar ataxia, and mental retardation are hallmark of syndrome. The iris abnormality is specific and seems pathognomonic of Gillespie syndrome. The aniridia consisting of a superior coloboma and inferior iris hypoplasia, foveomacular dysplasia.Atypical Gillespie syndrome associated with bilateral ptosis, exotropia, correctopia, iris hypoplasia, anterior capsular lens opacities, foveal hypoplasia, retinal vascular tortuosity, and retinal hypopigmentation.Neurological signs are nystagmus, mild craniofacial asymmetry, axial hypotonia, developmental delay, and mild mental retardation. Mariën P did not support the prevailing view of a global mental retardation as a cardinal feature of Gillespie syndrome but primarily reflect cerebellar induced neurobehavioral dysfunctions following disruption of the cerebrocerebellar anatomical circuitry that closely resembles the "cerebellar cognitive and affective syndrome" (CeCAS).Congenital pulmonary stenosis and helix dysplasia can be associated.
Genetics
Gillespie syndrome is a heterogeneous disorder, and can be inherited in either an autosomal dominant or recessive manner. Autosomal dominant inheritance indicates that the defective gene responsible for a disorder is located on an autosome, and only one copy of the gene is sufficient to cause the disorder, when inherited from a parent who has the disorder.Autosomal recessive inheritance means the defective gene responsible for the disorder is located on an autosome, but two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.PAX6 gene analysis can also be helpful to distinguish between autosomal dominant aniridia and Gillespie syndrome. However atypical Gillespie syndrome is associated mutation with PAX6 gene.To elucidate the underlying genetic defects karyotyping and the search for de novo translocations especially of chromosome X and 11 should be performed.This condition is caused by mutations in the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) gene. This gene is located on the short arm of chromosome 3 (3p26.1). Mutations in this gene have also been associated with spinocerebellar ataxia type 15 and 29.
Diagnosis
Brain MRI shows vermis atrophy or hypoplasic. Cerebral and cerebellar atrophy with white matter changes in some cases.
Treatment
History
1964 – GILLESPIE FD first described in two siblings with aniridia, cerebellar ataxia, and mental retardation.
1971 – Sarsfield, J. K. described more cases in a family with normal NCV and muscle biopsy.
1997 – Nelson J reported diffuse MRI abnormality in Cerebral and cerebellar atrophy with white matter changes suggested more diffuse disease.
1998 – Dollfus H reported a patient with a phenotype suggestive of a chromosomal abnormality.
2008 – Mariën P found limited cognitive deficit that closely resembles the "cerebellar cognitive and affective syndrome" (CeCAS).
References
External links
Gillespie syndrome at MedlinePlus |
Peptic ulcer disease | Peptic ulcer disease (PUD) is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines is a duodenal ulcer. The most common symptoms of a duodenal ulcer are waking at night with upper abdominal pain and upper abdominal pain that improves with eating. With a gastric ulcer, the pain may worsen with eating. The pain is often described as a burning or dull ache. Other symptoms include belching, vomiting, weight loss, or poor appetite. About a third of older people have no symptoms. Complications may include bleeding, perforation, and blockage of the stomach. Bleeding occurs in as many as 15% of cases.Common causes include the bacteria Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs). Other, less common causes include tobacco smoking, stress as a result of other serious health conditions, Behçets disease, Zollinger–Ellison syndrome, Crohns disease, and liver cirrhosis. Older people are more sensitive to the ulcer-causing effects of NSAIDs. The diagnosis is typically suspected due to the presenting symptoms with confirmation by either endoscopy or barium swallow. H. pylori can be diagnosed by testing the blood for antibodies, a urea breath test, testing the stool for signs of the bacteria, or a biopsy of the stomach. Other conditions that produce similar symptoms include stomach cancer, coronary heart disease, and inflammation of the stomach lining or gallbladder inflammation.Diet does not play an important role in either causing or preventing ulcers. Treatment includes stopping smoking, stopping use of NSAIDs, stopping alcohol, and taking medications to decrease stomach acid. The medication used to decrease acid is usually either a proton pump inhibitor (PPI) or an H2 blocker, with four weeks of treatment initially recommended. Ulcers due to H. pylori are treated with a combination of medications, such as amoxicillin, clarithromycin, and a PPI. Antibiotic resistance is increasing and thus treatment may not always be effective. Bleeding ulcers may be treated by endoscopy, with open surgery typically only used in cases in which it is not successful.Peptic ulcers are present in around 4% of the population. New ulcers were found in around 87.4 million people worldwide during 2015. About 10% of people develop a peptic ulcer at some point in their life. Peptic ulcers resulted in 267,500 deaths in 2015, down from 327,000 in 1990. The first description of a perforated peptic ulcer was in 1670, in Princess Henrietta of England. H. pylori was first identified as causing peptic ulcers by Barry Marshall and Robin Warren in the late 20th century, a discovery for which they received the Nobel Prize in 2005.
Signs and symptoms
Signs and symptoms of a peptic ulcer can include one or more of the following:
abdominal pain, classically epigastric, strongly correlated with mealtimes. In case of duodenal ulcers, the pain appears about three hours after taking a meal and wakes the person from sleep;
bloating and abdominal fullness;
waterbrash (a rush of saliva after an episode of regurgitation to dilute the acid in esophagus, although this is more associated with gastroesophageal reflux disease);
nausea and copious vomiting;
loss of appetite and weight loss, in gastric ulcer;
weight gain, in duodenal ulcer, as the pain is relieved by eating;
hematemesis (vomiting of blood); this can occur due to bleeding directly from a gastric ulcer or from damage to the esophagus from severe/continuing vomiting.
melena (tarry, foul-smelling feces due to presence of oxidized iron from hemoglobin);
rarely, an ulcer can lead to a gastric or duodenal perforation, which leads to acute peritonitis and extreme, stabbing pain, and requires immediate surgery.A history of heartburn or gastroesophageal reflux disease (GERD) and use of certain medications can raise the suspicion for peptic ulcer. Medicines associated with peptic ulcer include NSAIDs (non-steroid anti-inflammatory drugs) that inhibit cyclooxygenase and most glucocorticoids (e.g., dexamethasone and prednisolone).In people over the age of 45 with more than two weeks of the above symptoms, the odds for peptic ulceration are high enough to warrant rapid investigation by esophagogastroduodenoscopy.The timing of symptoms in relation to the meal may differentiate between gastric and duodenal ulcers. A gastric ulcer would give epigastric pain during the meal, associated with nausea and vomiting, as gastric acid production is increased as food enters the stomach. Pain in duodenal ulcers would be aggravated by hunger and relieved by a meal and is associated with night pain.Also, the symptoms of peptic ulcers may vary with the location of the ulcer and the persons age. Furthermore, typical ulcers tend to heal and recur, and as a result the pain may occur for few days and weeks and then wane or disappear. Usually, children and the elderly do not develop any symptoms unless complications have arisen.
A burning or gnawing feeling in the stomach area lasting between 30 minutes and 3 hours commonly accompanies ulcers. This pain can be misinterpreted as hunger, indigestion, or heartburn. Pain is usually caused by the ulcer, but it may be aggravated by the stomach acid when it comes into contact with the ulcerated area. The pain caused by peptic ulcers can be felt anywhere from the navel up to the sternum, it may last from few minutes to several hours, and it may be worse when the stomach is empty. Also, sometimes the pain may flare at night, and it can commonly be temporarily relieved by eating foods that buffer stomach acid or by taking anti-acid medication. However, peptic ulcer disease symptoms may be different for everyone.
Complications
Gastrointestinal bleeding is the most common complication. Sudden large bleeding can be life-threatening. It is associated with 5% to 10% death rate.
Perforation (a hole in the wall of the gastrointestinal tract) following a gastric ulcer often leads to catastrophic consequences if left untreated. Erosion of the gastrointestinal wall by the ulcer leads to spillage of the stomach or intestinal contents into the abdominal cavity, leading to an acute chemical peritonitis. The first sign is often sudden intense abdominal pain, as seen in Valentinos syndrome. Posterior gastric wall perforation may lead to bleeding due to the involvement of gastroduodenal artery that lies posterior to the first part of the duodenum. The death rate in this case is 20%.
Penetration is a form of perforation in which the hole leads to and the ulcer continues into adjacent organs such as the liver and pancreas.
Gastric outlet obstruction (stenosis) is a narrowing of the pyloric canal by scarring and swelling of the gastric antrum and duodenum due to peptic ulcers. The person often presents with severe vomiting.
Cancer is included in the differential diagnosis (elucidated by biopsy), Helicobacter pylori as the etiological factor making it 3 to 6 times more likely to develop stomach cancer from the ulcer. The risk for developing gastrointestinal cancer also appears to be slightly higher with gastric ulcers
Cause
H. pylori
Helicobacter pylori is one of the major causative factors of peptic ulcer disease. It secretes urease to create an alkaline environment, which is suitable for its survival. It expresses blood group antigen adhesin (BabA) and outer inflammatory protein adhesin (OipA), which enables it to attach to the gastric epithelium. The bacterium also expresses virulence factors such as CagA and PicB, which cause stomach mucosal inflammation. The VacA gene encodes for vacuolating cytotoxin, but its mechanism of causing peptic ulcers is unclear. Such stomach mucosal inflammation can be associated with hyperchlorhydria (increased stomach acid secretion) or hypochlorhydria (reduced stomach acid secretion). Inflammatory cytokines inhibit the parietal cell acid secretion. H. pylori also secretes certain products that inhibit hydrogen potassium ATPase; activate calcitonin gene-related peptide sensory neurons, which increases somatostatin secretion to inhibit acid production by parietal cells; and inhibit gastrin secretion. This reduction in acid production causes gastric ulcers. On the other hand, increased acid production at the pyloric antrum is associated with duodenal ulcers in 10% to 15% of H. pylori infection cases. In this case, somatostatin production is reduced and gastrin production is increased, leading to increased histamine secretion from the enterochromaffin cells, thus increasing acid production. An acidic environment at the antrum causes metaplasia of the duodenal cells, causing duodenal ulcers.Human immune response toward the bacteria also determines the emergence of peptic ulcer disease. The human IL1B gene encodes for Interleukin 1 beta, and other genes that encode for tumour necrosis factor (TNF) and Lymphotoxin alpha also play a role in gastric inflammation.
NSAIDs
Taking nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin can increase the risk of peptic ulcer disease by four times compared to non-users. The risk of getting a peptic ulcer is two times for aspirin users. Risk of bleeding increases if NSAIDs are combined with selective serotonin reuptake inhibitor (SSRI), corticosteroids, antimineralocorticoids, and anticoagulants. The gastric mucosa protects itself from gastric acid with a layer of mucus, the secretion of which is stimulated by certain prostaglandins. NSAIDs block the function of cyclooxygenase 1 (COX-1), which is essential for the production of these prostaglandins. Besides this, NSAIDs also inhibit stomach mucosa cells proliferation and mucosal blood flow, reducing bicarbonate and mucus secretion, which reduces the integrity of the mucosa. Another type of NSAIDs, called COX-2 selective anti-inflammatory drugs (such as celecoxib), preferentially inhibit COX-2, which is less essential in the gastric mucosa. This reduces the probability of getting peptic ulcers; however, it can still delay ulcer healing for those who already have a peptic ulcer. Peptic ulcers caused by NSAIDs differ from those caused by H. pylori as the latters appear as a consequence of inflammation of the mucosa (presence of neutrophil and submucosal edema), the former instead as a consequence of a direct damage of the NSAID molecule against COX enzymes, altering the hydrophobic state of the mucus, the permeability of the lining epithelium and mitochondrial machinery of the cell itself. In this way NSAIDs ulcers tend to complicate faster and dig deeper in the tissue causing more complications, often asymptomatically until a great portion of the tissue is involved.
Stress
Stress due to serious health problems, such as those requiring treatment in an intensive care unit, is well described as a cause of peptic ulcers, which are also known as stress ulcers.While chronic life stress was once believed to be the main cause of ulcers, this is no longer the case. It is, however, still occasionally believed to play a role. This may be due to the well-documented effects of stress on gastric physiology, increasing the risk in those with other causes, such as H. pylori or NSAID use.
Diet
Dietary factors, such as spice consumption, were hypothesized to cause ulcers until the late 20th century, but have been shown to be of relatively minor importance. Caffeine and coffee, also commonly thought to cause or exacerbate ulcers, appear to have little effect. Similarly, while studies have found that alcohol consumption increases risk when associated with H. pylori infection, it does not seem to independently increase risk. Even when coupled with H. pylori infection, the increase is modest in comparison to the primary risk factor.
Other
Other causes of peptic ulcer disease include gastric ischaemia, drugs, metabolic disturbances, cytomegalovirus (CMV), upper abdominal radiotherapy, Crohns disease, and vasculitis. Gastrinomas (Zollinger–Ellison syndrome), or rare gastrin-secreting tumors, also cause multiple and difficult-to-heal ulcers.It is still unclear if smoking increases the risk of getting peptic ulcers.
Diagnosis
The diagnosis is mainly established based on the characteristic symptoms. Stomach pain is usually the first signal of a peptic ulcer. In some cases, doctors may treat ulcers without diagnosing them with specific tests and observe whether the symptoms resolve, thus indicating that their primary diagnosis was accurate.More specifically, peptic ulcers erode the muscularis mucosae, at minimum reaching to the level of the submucosa (contrast with erosions, which do not involve the muscularis mucosae).Confirmation of the diagnosis is made with the help of tests such as endoscopies or barium contrast x-rays. The tests are typically ordered if the symptoms do not resolve after a few weeks of treatment, or when they first appear in a person who is over age 45 or who has other symptoms such as weight loss, because stomach cancer can cause similar symptoms. Also, when severe ulcers resist treatment, particularly if a person has several ulcers or the ulcers are in unusual places, a doctor may suspect an underlying condition that causes the stomach to overproduce acid.An esophagogastroduodenoscopy (EGD), a form of endoscopy, also known as a gastroscopy, is carried out on people in whom a peptic ulcer is suspected. It is also the gold standard of diagnosis for peptic ulcer disease. By direct visual identification, the location and severity of an ulcer can be described. Moreover, if no ulcer is present, EGD can often provide an alternative diagnosis.
One of the reasons that blood tests are not reliable for accurate peptic ulcer diagnosis on their own is their inability to differentiate between past exposure to the bacteria and current infection. Additionally, a false negative result is possible with a blood test if the person has recently been taking certain drugs, such as antibiotics or proton-pump inhibitors.The diagnosis of Helicobacter pylori can be made by:
Urea breath test (noninvasive and does not require EGD);
Direct culture from an EGD biopsy specimen; this is difficult and can be expensive. Most labs are not set up to perform H. pylori cultures;
Direct detection of urease activity in a biopsy specimen by rapid urease test;
Measurement of antibody levels in the blood (does not require EGD). It is still somewhat controversial whether a positive antibody without EGD is enough to warrant eradication therapy;
Stool antigen test;
Histological examination and staining of an EGD biopsy.The breath test uses radioactive carbon to detect H. pylori. To perform this exam, the person is asked to drink a tasteless liquid that contains the carbon as part of the substance that the bacteria breaks down. After an hour, the person is asked to blow into a sealed bag. If the person is infected with H. pylori, the breath sample will contain radioactive carbon dioxide. This test provides the advantage of being able to monitor the response to treatment used to kill the bacteria.
The possibility of other causes of ulcers, notably malignancy (gastric cancer), needs to be kept in mind. This is especially true in ulcers of the greater (large) curvature of the stomach; most are also a consequence of chronic H. pylori infection.
If a peptic ulcer perforates, air will leak from inside the gastrointestinal tract (which always contains some air) to the peritoneal cavity (which normally never contains air). This leads to "free gas" within the peritoneal cavity. If the person stands, as when having a chest X-ray, the gas will float to a position underneath the diaphragm. Therefore, gas in the peritoneal cavity, shown on an erect chest X-ray or supine lateral abdominal X-ray, is an omen of perforated peptic ulcer disease.
Classification
Peptic ulcers are a form of acid–peptic disorder. Peptic ulcers can be classified according to their location and other factors.
By location
Duodenum (called duodenal ulcer)
Esophagus (called esophageal ulcer)
Stomach (called gastric ulcer)
Meckels diverticulum (called Meckels diverticulum ulcer; is very tender with palpation)
Modified Johnson
Type I: Ulcer along the body of the stomach, most often along the lesser curve at incisura angularis along the locus minoris resistantiae. Not associated with acid hypersecretion.
Type II: Ulcer in the body in combination with duodenal ulcers. Associated with acid oversecretion.
Type III: In the pyloric channel within 3 cm of pylorus. Associated with acid oversecretion.
Type IV: Proximal gastroesophageal ulcer.
Type V: Can occur throughout the stomach. Associated with the chronic use of NSAIDs (such as ibuprofen).
Macroscopic appearance
Gastric ulcers are most often localized on the lesser curvature of the stomach. The ulcer is a round to oval parietal defect ("hole"), 2–4 cm diameter, with a smooth base and perpendicular borders. These borders are not elevated or irregular in the acute form of peptic ulcer, and regular but with elevated borders and inflammatory surrounding in the chronic form. In the ulcerative form of gastric cancer, the borders are irregular. Surrounding mucosa may present radial folds, as a consequence of the parietal scarring.
Microscopic appearance
A gastric peptic ulcer is a mucosal perforation that penetrates the muscularis mucosae and lamina propria, usually produced by acid-pepsin aggression. Ulcer margins are perpendicular and present chronic gastritis. During the active phase, the base of the ulcer shows 4 zones: fibrinoid necrosis, inflammatory exudate, granulation tissue and fibrous tissue. The fibrous base of the ulcer may contain vessels with thickened wall or with thrombosis.
Differential diagnosis
Conditions that may appear similar include:
Prevention
Prevention of peptic ulcer disease for those who are taking NSAIDs (with low cardiovascular risk) can be achieved by adding a proton pump inhibitor (PPI), an H2 antagonist, or misoprostol. NSAIDs of the COX-2 inhibitors type may reduce the rate of ulcers when compared to non-selective NSAIDs. PPI is the most popular agent in peptic ulcer prevention. However, there is no evidence that H2 antagonists can prevent stomach bleeding for those taking NSAIDs. Although misoprostol is effective in preventing peptic ulcer, its properties of promoting abortion and causing gastrointestinal distress limit its use. For those with high cardiovascular risk, naproxen with PPI can be a useful choice. Otherwise, low-dose aspirin, celecoxib, and PPI can also be used.
Management
Eradication therapy
Once the diagnosis of H. pylori is confirmed, the first-line treatment would be a triple regimen in which pantoprazole and clarithromycin are combined with either amoxicillin or metronidazole. This treatment regimen can be given for 7–14 days. However, its effectiveness in eradicating H. pylori has been reducing from 90% to 70%. However, the rate of eradication can be increased by doubling the dosage of pantoprazole or increasing the duration of treatment to 14 days. Quadruple therapy (pantoprazole, clarithromycin, amoxicillin, and metronidazole) can also be used. The quadruple therapy can achieve an eradication rate of 90%. If the clarithromycin resistance rate is higher than 15% in an area, the usage of clarithromycin should be abandoned. Instead, bismuth-containing quadruple therapy can be used (pantoprazole, bismuth citrate, tetracycline, and metronidazole) for 14 days. The bismuth therapy can also achieve an eradication rate of 90% and can be used as second-line therapy when the first-line triple-regimen therapy has failed
NSAIDs induced ulcers
NSAID-associated ulcers heal in 6 to 8 weeks provided the NSAIDs are withdrawn with the introduction of proton pump inhibitors (PPI).
Bleeding
For those with bleeding peptic ulcers, fluid replacement with crystalloids is sometimes given to maintain volume in the blood vessels. Maintaining haemoglobin at greater than 7 g/dL (70 g/L) through restrictive blood transfusion has been associated with reduced rate of death. Glasgow-Blatchford score is used to determine whether a person should be treated inside a hospital or as an outpatient. Intravenous PPIs can suppress stomach bleeding more quickly than oral ones. A neutral stomach pH is required to keep platelets in place and prevent clot lysis. Tranexamic acid and antifibrinolytic agents are not useful in treating peptic ulcer disease.Early endoscopic therapy can help to stop bleeding by using cautery, endoclip, or epinephrine injection. Treatment is indicated if there is active bleeding in the stomach, visible vessels, or an adherent clot. Endoscopy is also helpful in identifying people who are suitable for hospital discharge. Prokinetic agents such as erythromycin and metoclopramide can be given before endoscopy to improve endoscopic view. Either high- or low-dose PPIs are equally effective in reducing bleeding after endoscopy. High-dose intravenous PPI is defined as a bolus dose of 80 mg followed by an infusion of 8 mg per hour for 72 hours—in other words, the continuous infusion of PPI of greater than 192 mg per day. Intravenous PPI can be changed to oral once there is no high risk of rebleeding from peptic ulcer.For those with hypovolemic shock and ulcer size of greater than 2 cm, there is a high chance that the endoscopic treatment would fail. Therefore, surgery and angiographic embolism are reserved for these complicated cases. However, there is a higher rate of complication for those who underwent surgery to patch the stomach bleeding site when compared to repeated endoscopy. Angiographic embolisation has a higher rebleeding rate but a similar rate of death to surgery.
Anticoagulants
According to expert opinion, for those who are already on anticoagulants, the international normalized ratio (INR) should be kept at 1.5. For aspirin users who required endoscopic treatment for bleeding peptic ulcer, there is two times increased risk of rebleeding but with 10 times reduced risk of death at 8 weeks following the resumption of aspirin. For those who were on double antiplatelet agents for indwelling stent in blood vessels, both antiplatelet agents should not be stopped because there is a high risk of stent thrombosis. For those who were under warfarin treatment, fresh frozen plasma (FFP), vitamin K, prothrombin complex concentrates, or recombinant factor VIIa can be given to reverse the effect of warfarin. High doses of vitamin K should be avoided to reduce the time for rewarfarinisation once the stomach bleeding has stopped. Prothrombin complex concentrates are preferred for severe bleeding. Recombinant factor VIIa is reserved for life-threatening bleeding because of its high risk of thromboembolism. Direct oral anticoagulants (DOAC) are recommended instead of warfarin as they are more effective in preventing thromboembolism. In case of bleeding caused by DOAC, activated charcoal within 4 hours is the antidote of choice.
Epidemiology
The lifetime risk for developing a peptic ulcer is approximately 5% to 10% with the rate of 0.1% to 0.3% per year. Peptic ulcers resulted in 301,000 deaths in 2013, down from 327,000 in 1990.In Western countries, the percentage of people with H. pylori infections roughly matches age (i.e., 20% at age 20, 30% at age 30, 80% at age 80, etc.). Prevalence is higher in third world countries, where it is estimated at 70% of the population, whereas developed countries show a maximum of a 40% ratio. Overall, H. pylori infections show a worldwide decrease, more so in developed countries. Transmission occurs via food, contaminated groundwater, or human saliva (such as from kissing or sharing food utensils).Peptic ulcer disease had a tremendous effect on morbidity and mortality until the last decades of the 20th century when epidemiological trends started to point to an impressive fall in its incidence. The reason that the rates of peptic ulcer disease decreased is thought to be the development of new effective medication and acid suppressants and the rational use of nonsteroidal anti-inflammatory drugs (NSAIDs).
History
John Lykoudis, a general practitioner in Greece, treated people for peptic ulcer disease with antibiotics beginning in 1958, long before it was commonly recognized that bacteria were a dominant cause for the disease.Helicobacter pylori was identified in 1982 by two Australian scientists, Robin Warren and Barry J. Marshall, as a causative factor for ulcers. In their original paper, Warren and Marshall contended that most gastric ulcers and gastritis were caused by colonization with this bacterium, not by stress or spicy food, as had been assumed before.The H. pylori hypothesis was still poorly received, so in an act of self-experimentation Marshall drank a Petri dish containing a culture of organisms extracted from a person with an ulcer and five days later developed gastritis. His symptoms disappeared after two weeks, but he took antibiotics to kill the remaining bacteria at the urging of his wife, since halitosis is one of the symptoms of infection. This experiment was published in 1984 in the Australian Medical Journal and is among the most cited articles from the journal.
In 1997, the Centers for Disease Control and Prevention, with other government agencies, academic institutions, and industry, launched a national education campaign to inform health care providers and consumers about the link between H. pylori and ulcers. This campaign reinforced the news that ulcers are a curable infection and that health can be greatly improved and money saved by disseminating information about H. pylori.In 2005, the Karolinska Institute in Stockholm awarded the Nobel Prize in Physiology or Medicine to Marshall and his long-time collaborator Dr. Warren "for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease." Marshall continues research related to H. pylori and runs a molecular biology lab at UWA in Perth, Western Australia.
Some believed that mastic gum, a tree resin extract, actively eliminates the H. pylori bacteria. However, multiple subsequent studies have found no effect of using mastic gum on reducing H. pylori levels.
Notes
References
External links
Gastric ulcer images
"Peptic Ulcer". MedlinePlus. U.S. National Library of Medicine. Archived from the original on 16 April 2020. Retrieved 20 May 2020. |
Mesangial proliferative glomerulonephritis | Mesangial proliferative glomerulonephritis (MesPGN) is a morphological pattern characterized by a numerical increase in mesangial cells and expansion of the extracellular matrix within the mesangium of the glomerulus. The increase in the number of mesangial cells can be diffuse or local and immunoglobulin and/or complement deposition can also occur. MesPGN is associated with a variety of disease processes affecting the glomerulus, though can be idiopathic. The clinical presentation of MesPGN usually consists of hematuria or nephrotic syndrome. Treatment is often consistent with the histologic pattern of and/or disease process contributing to mesangial proliferative glomerulonephritis, and usually involves some form of immunosuppressant.
Mechanism
MesPGN often occurs as a result of glomerular injury, though can be idiopathic. MesPGN has been associated with disease processes such as: IgA nephropathy, IgM nephropathy, systemic lupus erythematous, Alports syndrome, resolving post-infectious glomerulonephritis, and complement nephropathy, such as C1Q nephropathy.IgA nephropathy is the most common cause of MesPGN. It is thought abnormally glycosylated IgA form polymers and deposit in the mesangium. Subsequently, IgA immune complexes bind to IgA receptors on mesangial cells and induce injury to mesangial cells through release of cytokines and growth factors that promote infiltration of leukocytes, mesangial cell proliferation, and mesangial matrix expansion.In the context of resolving post-infectious glomerulonephritis, MesPGN can be seen after an infection with a nephritogenic strain of group A streptococci. Pathogenesis of post-streptococcal glomerulonephritis includes injury to the glomerulus by immune complexes (IgG) passively trapped in the glomerulus, which leads to an inflammatory response from recruited immune cells, cytokines, chemical mediators, and complement and coagulation cascade activation. The inflammatory response includes endothelial and mesangial cell proliferation.Mesangial proliferative glomerulonephritis of Lupus nephritis, Class II is also noted by mesangial hypercellularity and matrix expansion. Microscopic haematuria with or without proteinuria may be seen in Class II Lupus nephritis. Hypertension, nephrotic syndrome, and acute kidney injury are very rare at this stage.Idiopathic mesangial proliferative glomerulonephritis is less established in the literature. Idiopathic mesangial proliferative glomerulonephritis does not involve the deposition of either IgA or IgG immune complexes, though there can be focal or diffuse IgM deposits in the mesangium. The relationship of IgM and mesangial proliferative glomerulonephritis is hypothesized to involve either formed or deposited IgM complexes in the mesangium leading to T-cell mediated inflammatory response, mesangial proliferation, and glomerular injury or, as a result of mesangial proliferation, decreased clearance of monocytic IgM complexes.
Diagnosis
Most glomerulonephritis classification and prognosis are aided by histological evaluation by renal biopsy. The renal biopsy is classically evaluated with light microscopy, electron microscopy, and immunohistology to diagnose a histological pattern, which is then compared to clinical evaluation through history, physical, and laboratory evaluation. The laboratory evaluation usually follows that of a standard nephrology work up and will likely be targeted to a differential diagnosis. Studies focusing on mesangial proliferative glomerulonephritis often use defined clinical criteria and histological criteria to select patients for research. For example, one study used the following histological criteria: "Glomeruli with mesangial hypercellularity (four or more cells/mesangium with or without mesangial matrix expansion and immune complex deposits)". The histologic pattern of injury can also provide insight into the prognosis of the glomerular disorder. Mesangial proliferation indicates a mild, though active, lesion. Overall, a kidney biopsy should address the following:
Primary diagnosis, with clinical modifiers
Pattern of injury
Established score/class/grade of disease entities (i.e., lupus nephritis, IgA nephropathy)
Secondary diagnosis (i.e., ATN, interstitial nephritis, thrombotic microangiopathy)
Ancillary studies, if done (i.e., IgG sub typing)
Chronicity grade and scoreThe kidney biopsy is foundational to informing the diagnosis of mesangial proliferative glomerulonephritis, as it is a morphological pattern.
Clinical Presentation
Mesangial proliferative glomerulonephritis often presents with hematuria (gross or microscopic) or nephrotic syndrome. Presentation can also include asymptomatic proteinuria. These presenting symptoms are relatively non-specific and are often seen in other glomerular disorders. Preceding upper respiratory tract infection or post-streptococcal glomerulonephritis may contribute to hematuria, as both have been identified in patients presenting with hematuria in the context of mesangial proliferative glomerulonephritis. Preceding infection was not as readily identified in patients presenting with either asymptomatic proteinuria or nephrotic syndrome. However, it has been shown patients presenting with nephrotic syndrome have some histo- and clinic-pathologic similarities to minimal change disease.
Treatment
Treatment for glomerular disorders is often established for specific histological patterns. Presentations of hematuria in the context of mesangial proliferative glomerulonephritis often resolve spontaneously, with a relatively benign course. Presentation of nephrotic syndrome in the context of mesangial proliferative glomerulonephritis have been treated with immunosuppressants, such as steroids and cyclophosphamide. Presentation with nephrotic syndrome can resolve with treatment, but can also progress. Patients can become resistant to steroids or specific immunosuppressive agents, in which case it may be necessary to use different immunosuppressive agents.
References
== External links == |
Rhinoscleroma | Rhinoscleroma, is a chronic granulomatous bacterial disease of the nose that can sometimes infect the upper respiratory tract. It most commonly affects the nasal cavity—the nose is involved in 95–100 per cent of cases—however, it can also affect the nasopharynx, larynx, trachea, and bronchi. Slightly more females than males are affected and patients are usually 10 to 30 years of age. Rhinoscleroma is considered a tropical disease and is mostly endemic to North Africa, South Asia and Central America, less common in the United States.
Signs and symptoms
Rhinoscleroma has been divided into 3 stages: catarrhal/atrophic, granulomatous, and sclerotic stages. The catarrhal stage begins with a nonspecific rhinitis, which progresses into purulent, fetid rhinorrhea, and crusting, which can last for weeks or even months. The granulomatous stage results in the development of a bluish red nasal mucosa and the development of intranasal rubbery nodules or polyps. Nose bleeds, nasal deformity, and destruction of the nasal cartilage are also noted (Hebra nose). The damage may result in anesthesia of the soft palate, enlargement of the uvula, dysphonia, and various degrees of airway obstruction. The fibrotic stage is characterized by sclerosis and fibrosis. Lymphadenitis is absent.
Causes
It is caused by Klebsiella rhinoscleromatis—subspecies of
Klebsiella pneumoniae— a gram-negative, encapsulated, nonmotile, rod-shaped bacillus (diplobacillus), member of the family Enterobacteriaceae. It is sometimes referred to as the "Frisch bacillus," named for Anton von Frisch who identified the organism in 1882. It is contracted directly by droplets or by contamination of material that is subsequently inhaled.
Diagnosis
A positive culture in MacConkey agar is diagnostic, but cultures are only positive in 50–60% of cases. Diagnostic characteristics are most commonly found in the granulomatous stage and are described as being plasma cells with birefringent inclusions, Russell bodies, pseudoepitheliomatous hyperplasia, and groups of large vacuolated histiocytes containing Klebsiella rhinoscleromatis (Mikulicz cells).
Treatment
It is not lethal in nature and is responsive to tetracycline or ciprofloxacin. Surgical treatment include rhinoplasty. However, if left untreated the disease can lead to sepsis, bleeding, or other chronic conditions that can be fatal.
History
Hans von Hebra (1847–1902) wrote the classical description of the disease in a paper published in the January 1870 issue of the Wiener Medizinische Wochenschrift. Hans von Hebra was the son of Czech born dermatologist Ferdinand Ritter von Hebra (1816–1880), founder of the New Vienna School of Dermatology. He was assisted by M. Kohn who provided much of the histology for the paper. M. Kohn is the birth name of Moritz Kaposi (1837–1902). In 1876, Mikulicz contributed to the microscopic histology. In 1882, Anton Von Frisch (1849–1917) discovered the gram-negative bacillus which causes the disease.
Terminology
Hebra nose. Scleroma. Fr: Sclérome. Sp: Rinoscleroma. Ger: Sklerom. Nasen-Rachenrauminduration.Archaic terms include: Syphilis of the nose. Nasal leprosy. Scleroma neonatorum. Scleroma respiratorum. Scrofulous lupus.
See also
Erythrasma
List of cutaneous conditions
List of inclusion bodies that aid in diagnosis of cutaneous conditions
Notes
References
DiBartolomeo, Joseph R. (1976), Scleroma of the nose and pharynx. Journal: West. J. Med., vol. 124., pp. 13–17.
Frisch, Anton von (1882), Zur Aetiologie des Rhinoskleroms. Journal: Wiener Medizinische Wochenschrift; vol. 32, pp. 969–972.
Hebra, Hans von (1870), Ueber ein eigenthümliches Neugebilde an der Nase; Rhinosclerom; nebst histologischem Befunde vom Dr. M. Kohn. Journal: Wiener Medizinische Wochenschrift; vol. 20, pp. 1–5.
Morton, Leslie T. (1970), A medical bibliography (Garrison and Morton). Philadelphia & Toronto: J. B. Lippincott Company, p. 388.
Palmer, P. E. S. & Reeder, M. M. (2000), The imaging of tropical diseases. Heidelberg: Springer Verlach; vols. 1 & 2 (ISBN 3-540-66219-7).
External links
DiBartolomeo, Scleroma of the nose and pharynx. |
Chronic sclerosing sialadenitis | Chronic sclerosing sialadenitis is a chronic (long-lasting) inflammatory condition affecting the salivary gland. Relatively rare in occurrence, this condition is benign, but presents as hard, indurated and enlarged masses that are clinically indistinguishable from salivary gland neoplasms or tumors. It is now regarded as a manifestation of IgG4-related disease.Involvement of the submandibular glands is also known as Küttners tumor, named after Hermann Küttner (1870–1932), a German Oral and Maxillofacial Surgeon, who reported four cases of submandibular gland lesions for the first time in 1896.
Presentation
The inflammatory lesions in Küttners tumor may occur on one side (unilateral) or both sides (bilateral), predominantly involving the submandibular gland, but is also known to occur in other major and minor salivary glands, including the parotid gland.
Overall, salivary gland tumors are relatively rare, with approximately 2.5–3 cases per 100,000 people per year seen in the Western world; however, salivary gland malignancies account for 3–5% of all head and neck cancers. However, salivary tumors show a great deal of morphological diversity, as well as variations in the nature of the lesion (malignant vs. benign): approximately 20% to 25% of parotid tumors, 35% to 40% of submandibular tumors, and more than 90% of sublingual gland tumors are malignant. This situation underscores the diagnostic challenges in respect of Küttners tumor; despite being benign, this condition mimics the clinical appearance of malignancy in the salivary gland.
The swollen masses of Küttners tumor are generally painful, and patients are advised surgical resection (known as sialadenectomy) of a part or whole of the glandular tissue upon suspicion of possible malignancy. It is only upon post-surgical histopathology of the excised mass that the diagnosis of Küttners tumor is definitively made.
Histological features
The histopathological features that characterize Küttners tumor include:
Heavy infiltration of the glandular tissue by lymphocytes (predominantly activated B-cells and helper T-cells) as well as plasma cells (collectively known as Lymphoplasmacytic Infiltrate).
Presence of reactive lymphoid follicles in the infiltrate, marked by a lack of atypical lymphoid cells (this is in sharp contrast to the presentations in lymphoma).
Atrophy and loss of acini (groups of secretory cells found in the salivary glands).
Encasement of the glandular ducts in thick fibrous tissues, as a result of chronic presence of inflammatory infiltrate in that area - a condition known as periductal fibrosis.
Eventual periductal and interlobular (inside the gland) sclerosis (replacement of regular tissue with hard connective tissue).
Pathogenesis
The cause and pathogenesis of this chronic condition are not very well understood. Several factors have been postulated:
Formation of a hard salivary calculus or sialolith by accumulation of calcium salts in the duct of the salivary gland (a process known as Sialolithiasis). This has been proposed as the most common cause for Küttners tumor of the submandibular gland, with sialoliths observed in an appreciable proportion of cases. However, sialolith involvement may not be found in many cases.
Abnormalities of the salivary gland ducts leading to excessive accumulation or retention of ductal secretions, which can excite chronic inflammations.
Immune, especially autoimmune, cause - which has gained steam, given the observation that the tissue of the glands is overrun with lymphoid immune cells and fibrous connective tissue, as well as corroboration from markedly similar lesions (with histologic and immunohistochemical findings) seen elsewhere in the body. The presence of abundant Immunoglobulin G4 (IgG4) associated with Plasma cells infiltrating into the salivary glands, as well as increased serum IgG4 concentration, has been noted with patients with Küttners tumor.This chronic condition is primarily observed in adult (40–70 years) patients. However, Küttners tumor, with prominent immunopathological features, has been described in an 11-year-old boy in Brazil in 2012.
Diagnosis
Given the difficulties of a definitive pre-operative diagnosis, the clinical entity of Küttners tumor has so far remained significantly under-reported and under-recognized. In recent times, armed with a better understanding of the occurrences and observable features of this condition, surgeons are increasingly depending upon pre-operative ultrasonography along with Fine-needle aspiration cytological (FNAC) examinations to make an accurate presumptive diagnosis, and according to one estimate, about 44% of patients undergoing submandibular resection are found to have this condition. In the ultrasonogram, Küttners tumor is characterized by a diffuse, heterogeneous zone of echo-shadows. The FNAC finds cells greatly reduced in number (called paucicellularity) along with scattered tubular ducts against a backdrop of lymphoplasmacytic infiltration and fibrous depositions. There may be a reduced but moderate number of cells and ducts enveloped in fibrous sheaths, as well as fibrous proliferation of the glands septa. The cytologic findings by themselves may not be specific, and the diagnosis requires adjunct consideration of both the ultrasonogram and clinical presentation. Application of magnetic resonance imaging (MRI) has been tried to non-invasively examine the morphological variations in Küttners tumor and differentiate them from those seen in malignant tumors; while MRI findings of the affected tissue and the pattern of cellular infiltration may offer some diagnostic clues for this condition, so far the results have been inconclusive.
Existing treatment
Standard, and most effective, therapy to date is glandular sialadenectomy, which is associated with fairly low operative morbidity; however, in recent times, the administration of steroid (which can shrink the inflammatory lesion and is known to reduce serum IgG4 values) has been considered favorably, and may be useful in younger patients or those who refuse surgery.
See also
Sialadenitis
References
== External links == |
Q fever | Q fever or query fever is a disease caused by infection with Coxiella burnetii, a bacterium that affects humans and other animals. This organism is uncommon, but may be found in cattle, sheep, goats, and other domestic mammals, including cats and dogs. The infection results from inhalation of a spore-like small-cell variant, and from contact with the milk, urine, feces, vaginal mucus, or semen of infected animals. Rarely, the disease is tick-borne. The incubation period is 9–40 days. Humans are vulnerable to Q fever, and infection can result from even a few organisms. The bacterium is an obligate intracellular pathogenic parasite.
Signs and symptoms
Incubation period is usually two to three weeks. The most common manifestation is flu-like symptoms: abrupt onset of fever, malaise, profuse perspiration, severe headache, muscle pain, joint pain, loss of appetite, upper respiratory problems, dry cough, pleuritic pain, chills, confusion, and gastrointestinal symptoms, such as nausea, vomiting, and diarrhea. About half of infected individuals exhibit no symptoms.During its course, the disease can progress to an atypical pneumonia, which can result in a life-threatening acute respiratory distress syndrome, whereby such symptoms usually occur during the first four to five days of infection.Less often, Q fever causes (granulomatous) hepatitis, which may be asymptomatic or become symptomatic with malaise, fever, liver enlargement, and pain in the right upper quadrant of the abdomen. Whereas transaminase values are often elevated, jaundice is uncommon. Retinal vasculitis is a rare manifestation of Q fever.The chronic form of Q fever is virtually identical to endocarditis (i.e. inflammation of the inner lining of the heart), which can occur months or decades following the infection. It is usually fatal if untreated. However, with appropriate treatment, the mortality falls to around 10%.
Diagnosis
Diagnosis is usually based on serology (looking for an antibody response) rather than looking for the organism itself. Serology allows the detection of chronic infection by the appearance of high levels of the antibody against the virulent form of the bacterium. Molecular detection of bacterial DNA is increasingly used. Contrary to most obligate intracellular parasites, Coxiella burnetii can be grown in an axenic culture, but its culture is technically difficult and not routinely available in most microbiology laboratories.Q fever can cause endocarditis (infection of the heart valves) which may require transoesophageal echocardiography to diagnose. Q fever hepatitis manifests as an elevation of alanine transaminase and aspartate transaminase, but a definitive diagnosis is only possible on liver biopsy, which shows the characteristic fibrin ring granulomas.
Prevention
Research done in the 1960s–1970s by French Canadian-American microbiologist and virologist Paul Fiset was instrumental in the development of the first successful Q fever vaccine.Protection is offered by Q-Vax, a whole-cell, inactivated vaccine developed by an Australian vaccine manufacturing company, CSL Limited. The intradermal vaccination is composed of killed C. burnetii organisms. Skin and blood tests should be done before vaccination to identify pre-existing immunity, because vaccinating people who already have immunity can result in a severe local reaction. After a single dose of vaccine, protective immunity lasts for many years. Revaccination is not generally required. Annual screening is typically recommended.In 2001, Australia introduced a national Q fever vaccination program for people working in "at risk" occupations. Vaccinated or previously exposed people may have their status recorded on the Australian Q Fever Register, which may be a condition of employment in the meat processing industry or in veterinary research. An earlier killed vaccine had been developed in the Soviet Union, but its side effects prevented its licensing abroad.Preliminary results suggest vaccination of animals may be a method of control. Published trials proved that use of a registered phase vaccine (Coxevac) on infected farms is a tool of major interest to manage or prevent early or late abortion, repeat breeding, anoestrus, silent oestrus, metritis, and decreases in milk yield when C. burnetii is the major cause of these problems.
Treatment
Treatment of acute Q fever with antibiotics is very effective and should be given in consultation with an infectious diseases specialist. Commonly used antibiotics include doxycycline, tetracycline, chloramphenicol, ciprofloxacin, ofloxacin, and hydroxychloroquine. Chronic Q fever is more difficult to treat and can require up to four years of treatment with doxycycline and quinolones or doxycycline with hydroxychloroquine. If a person has Chronic Q fever, doxycycline and hydroxychloroquine will be prescribed for at least eighteen months. Q fever in pregnancy is especially difficult to treat because doxycycline and ciprofloxacin are contraindicated in pregnancy. The preferred treatment for pregnancy and children under the age of eight is co-trimoxazole.
Epidemiology
The pathogenic agent is found worldwide, with the exception of New Zealand. The bacterium is extremely sustainable and virulent: a single organism is able to cause an infection. The common source of infection is the inhalation of contaminated dust, contact with contaminated milk, meat, or wool, and particularly birthing products. Ticks can transfer the pathogenic agent to other animals. Transfer between humans seems extremely rare and has so far been described in very few cases.Some studies have shown more men to be affected than women, which may be attributed to different employment rates in typical professions.
"At risk" occupations include:
Veterinary personnel;
Stockyard workers;
Farmers;
Sheep shearers;
Animal transporters;
Laboratory workers handling potentially infected veterinary samples or visiting abattoirs;
People who cull and process kangaroos; and
Hide (tannery) workers.
History
Q fever was first described in 1935 by Edward Holbrook Derrick in slaughterhouse workers in Brisbane, Queensland. The "Q" stands for "query" and was applied at a time when the causative agent was unknown; it was chosen over suggestions of abattoir fever and Queensland rickettsial fever, to avoid directing negative connotations at either the cattle industry or the state of Queensland.The pathogen of Q fever was discovered in 1937, when Frank Macfarlane Burnet and Mavis Freeman isolated the bacterium from one of Derricks patients. It was originally identified as a species of Rickettsia. H.R. Cox and Gordon Davis elucidated the transmission when they isolated it from ticks found in the US state of Montana in 1938. It is a zoonotic disease whose most common animal reservoirs are cattle, sheep, and goats. Coxiella burnetii – named for Cox and Burnet – is no longer regarded as closely related to the Rickettsiae, but as similar to Legionella and Francisella, and is a Gammaproteobacterium.
Society and culture
An early mention of Q fever was important in one of the early Dr. Kildare films (1939, Calling Dr. Kildare). Kildares mentor Dr. Gillespie (Lionel Barrymore) tires of his protégé working fruitlessly on "exotic diagnoses" ("I think its Q fever!") and sends him to work in a neighborhood clinic, instead.Q fever was also highlighted in an episode of the U.S. television medical drama House ("The Dig", season seven, episode 18).
Biological warfare
C. burnetii has been used to develop biological weapons.The United States investigated it as a potential biological warfare agent in the 1950s, with eventual standardization as agent OU. At Fort Detrick and Dugway Proving Ground, human trials were conducted on Whitecoat volunteers to determine the median infective dose (18 MICLD50/person i.h.) and course of infection. The Deseret Test Center dispensed biological Agent OU with ships and aircraft, during Project 112 and Project SHAD. As a standardized biological, it was manufactured in large quantities at Pine Bluff Arsenal, with 5,098 gallons in the arsenal in bulk at the time of demilitarization in 1970.
C. burnetii is currently ranked as a "category B" bioterrorism agent by the CDC. It can be contagious, and is very stable in aerosols in a wide range of temperatures. Q fever microorganisms may survive on surfaces up to 60 days. It is considered a good agent in part because its ID50 (number of bacilli needed to infect 50% of individuals) is considered to be one, making it the lowest known.
In animals
Q fever can affect many species of domestic and wild animals, including ruminants (cattle, sheep, goats, bison, deers...), carnivores (dogs, cats, seals...), rodents, reptiles and birds.
However, ruminants (cattle, goats and sheep) are the most frequently affected animals, and can serve as a reservoir for the bacteria.
Clinical signs
In contrast to humans, even though a respiratory and cardiac infection could be experimentally reproduced in cattle, the clinical signs mainly affect the reproductive system. Q fever in ruminants is therefore mainly responsible for abortions, metritis, retained placenta and infertility.
The clinical signs vary between species. In small ruminants (sheep and goats), it is dominated by abortions, premature births, stillbirths and the birth of weak lambs or kids. One of the characteristics of abortions in goats is that they are very frequent and clustered in the first year or two after contamination of the farm. This is known as an abortion storm.In cattle, although abortions also occur, they are less frequent and more sporadic. The clinical picture is rather dominated by non-specific signs such as placental retentions, metritis and, consequently, fertility disorders.
Epidemiology
With the exception of New Zealand, which is currently free of Q fever, the disease is present throughout the world. Numerous epidemiological surveys have been carried out. They have shown that approximately 1 in 3 cattle farms and 1 in 4 sheep or goat farms are infected. However, there are wide variations between studies and countries. In China, Iran, Great Britain, Germany, Hungary, the Netherlands, Spain, the US, Belgium, Denmark, Croatia, Slovakia, the Czech Republic, Serbia, Slovenia and Jordan, for example, it has been shown that more than 50% of cattle herds were infected with Q fever.Infected animals shed the bacteria by three routes: genital discharge, faeces and milk. Excretion is greatest at the time of parturition or abortion and placentas and aborted fetuses are the main sources of bacteria, particularly in goats.
As Coxiella burnetii is small and resistant in the environment, it is easily airborne and can be transmitted from one farm to another, even if it is several kilometres away.
Control
Biosecurity measures
Based on the epidemiological data, biosecurity measures can be derived:
The spread of manure from infected farm should be avoided in windy conditions
The level of hygiene must be very high during parturition and fetal annexes and fetuses must be collected and destroyed as soon as possible
Medical measures
A vaccine for cattle and goats exists. It reduces clinical expression such as abortions and decreases excretion of the bacteria by the animals leading to control of Q fever in herds.In addition, vaccination of herds against Q fever has been shown to reduce the risk of human infection.
References
External links
Q fever at the CDC
Coxiella burnetii genomes and related information at PATRIC, a Bioinformatics Resource Center funded by NIAID |
Psychosis | Psychosis is an abnormal condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior that is inappropriate for a given situation. There may also be sleep problems, social withdrawal, lack of motivation, and difficulties carrying out daily activities. Psychosis can have serious adverse outcomes.As with many psychiatric phenomena, psychosis has several different causes. These include mental illness, such as schizophrenia or schizoaffective disorder, bipolar disorder, sensory deprivation and in rare cases, major depression (psychotic depression). Other causes include: trauma, sleep deprivation, some medical conditions, certain medications, and drugs such as cannabis, hallucinogens, and stimulants. One type, known as postpartum psychosis, can occur after giving birth. The neurotransmitter dopamine is believed to play an important role. Acute psychosis is considered primary if it results from a psychiatric condition and secondary if it is caused by a medical condition or drugs. The diagnosis of a mental health condition requires excluding other potential causes. Testing may be done to check for central nervous system diseases, toxins, or other health problems as a cause.Treatment may include antipsychotic medication, psychotherapy, and social support. Early treatment appears to improve outcomes. Medications appear to have a moderate effect. Outcomes depend on the underlying cause. In the United States about 3% of people develop psychosis at some point in their lives. The condition has been described since at least the 4th century BCE by Hippocrates and possibly as early as 1500 BCE in the Egyptian Ebers Papyrus.
Signs and symptoms
Hallucinations
A hallucination is defined as sensory perception in the absence of external stimuli. Hallucinations are different from illusions and perceptual distortions, which are the misperception of external stimuli. Hallucinations may occur in any of the senses and take on almost any form. They may consist of simple sensations (such as lights, colors, sounds, tastes, or smells) or more detailed experiences (such as seeing and interacting with animals and people, hearing voices, and having complex tactile sensations). Hallucinations are generally characterized as being vivid and uncontrollable. Auditory hallucinations, particularly experiences of hearing voices, are the most common and often prominent feature of psychosis.
Up to 15% of the general population may experience auditory hallucinations (though not all are due to psychosis). The prevalence of auditory hallucinations in patients with schizophrenia is generally put around 70%, but may go as high as 98%. Reported prevalence in bipolar disorder ranges between 11% and 68%. During the early 20th century, auditory hallucinations were second to visual hallucinations in frequency, but they are now the most common manifestation of schizophrenia, although rates vary between cultures and regions. Auditory hallucinations are most commonly intelligible voices. When voices are present, the average number has been estimated at three. Content, like frequency, differs significantly, especially across cultures and demographics. People who experience auditory hallucinations can frequently identify the loudness, location of origin, and may settle on identities for voices. Western cultures are associated with auditory experiences concerning religious content, frequently related to sin. Hallucinations may command a person to do something potentially dangerous when combined with delusions.So-called "minor hallucinations", such as extracampine hallucinations, or false perceptions of people or movement occurring outside of ones visual field, frequently occur in neurocognitive disorders, such as Parkinsons disease.Visual hallucinations occur in roughly a third of people with schizophrenia, although rates as high as 55% are reported. The prevalence in bipolar disorder is around 15%. Content commonly involves animate objects, although perceptual abnormalities such as changes in lighting, shading, streaks, or lines may be seen. Visual abnormalities may conflict with proprioceptive information, and visions may include experiences such as the ground tilting. Lilliputian hallucinations are less common in schizophrenia, and are more common in various types of encephalopathy, such as peduncular hallucinosis.A visceral hallucination, also called a cenesthetic hallucination, is characterized by visceral sensations in the absence of stimuli. Cenesthetic hallucinations may include sensations of burning, or re-arrangement of internal organs.
Delusions
Psychosis may involve delusional beliefs. A delusion is a fixed, false idiosyncratic belief, which does not change even when presented with incontrovertible evidence to the contrary. Delusions are context- and culture-dependent: a belief which inhibits critical functioning and is widely considered delusional in one population may be common (and even adaptive) in another, or in the same population at a later time. Since normative views may contradict available evidence, a belief need not contravene cultural standards in order to be considered delusional.
Prevalence in schizophrenia is generally considered at least 90%, and around 50% in bipolar disorder.
The DSM-5 characterizes certain delusions as "bizarre" if they are clearly implausible, or are incompatible with the surrounding cultural context. The concept of bizarre delusions has many criticisms, the most prominent being judging its presence is not highly reliable even among trained individuals.A delusion may involve diverse thematic content. The most common type is a persecutory delusion, in which a person believes that an entity seeks to harm them. Others include delusions of reference (the belief that some element of ones experience represents a deliberate and specific act by or message from some other entity), delusions of grandeur (the belief that one possesses special power or influence beyond ones actual limits), thought broadcasting (the belief that ones thoughts are audible) and thought insertion (the belief that ones thoughts are not ones own). A delusion may also involve misidentification of objects, persons, or environs that the afflicted should reasonably be able to recognize; such examples include Cotards syndrome (the belief that oneself is partly or wholly dead) and clinical lycanthropy (the belief that oneself is or has transformed into an animal).
The subject matter of delusions seems to reflect the current culture in a particular time and location. For example, in the US, during the early 1900s syphilis was a common topic, during the second world war Germany, during the cold war communists, and in recent years technology has been a focus. Some psychologists, such as those who practice the Open Dialogue method, believe that the content of psychosis represents an underlying thought process that may, in part, be responsible for psychosis, though the accepted medical position is that psychosis is due to a brain disorder.
Historically, Karl Jaspers classified psychotic delusions into primary and secondary types. Primary delusions are defined as arising suddenly and not being comprehensible in terms of normal mental processes, whereas secondary delusions are typically understood as being influenced by the persons background or current situation (e.g., ethnicity; also religious, superstitious, or political beliefs).
Disorganization of speech/thought or behavior
Disorganization is split into disorganized speech (or thought), and grossly disorganized motor behavior. Disorganized speech or thought, also called formal thought disorder, is disorganization of thinking that is inferred from speech. Characteristics of disorganized speech include rapidly switching topics, called derailment or loose association; switching to topics that are unrelated, called tangential thinking; incomprehensible speech, called word salad or incoherence. Disorganized motor behavior includes repetitive, odd, or sometimes purposeless movement. Disorganized motor behavior rarely includes catatonia, and although it was a historically prominent symptom, it is rarely seen today. Whether this is due to historically used treatments or the lack thereof is unknown.Catatonia describes a profoundly agitated state in which the experience of reality is generally considered impaired. There are two primary manifestations of catatonic behavior. The classic presentation is a person who does not move or interact with the world in any way while awake. This type of catatonia presents with waxy flexibility. Waxy flexibility is when someone physically moves part of a catatonic persons body and the person stays in the position even if it is bizarre and otherwise nonfunctional (such as moving a persons arm straight up in the air and the arm staying there).
The other type of catatonia is more of an outward presentation of the profoundly agitated state described above. It involves excessive and purposeless motor behaviour, as well as an extreme mental preoccupation that prevents an intact experience of reality. An example is someone walking very fast in circles to the exclusion of anything else with a level of mental preoccupation (meaning not focused on anything relevant to the situation) that was not typical of the person prior to the symptom onset. In both types of catatonia, there is generally no reaction to anything that happens outside of them. It is important to distinguish catatonic agitation from severe bipolar mania, although someone could have both.
Negative symptoms
Negative symptoms include reduced emotional expression (flat affect), decreased motivation (avolition), and reduced spontaneous speech (poverty of speech, alogia). Individuals with this condition lack interest and spontaneity, and have the inability to feel pleasure (anhedonia).
Psychosis in adolescents
Psychosis is rare in adolescents. Young people who have psychosis may have trouble connecting with the world around them and may experience hallucinations and/or delusions. Adolescents with psychosis may also have cognitive deficits that may make it harder for the youth to socialize and work. Potential impairments include the speed of mental processing, ability to focus without getting distracted (limited attention span), and deficits in verbal memory. If an adolescent is experiencing psychosis, they most likely have comorbidity meaning they could have multiple mental illnesses. Because of this, it can be difficult to determine if it is psychosis or autism spectrum disorder, social or generalized anxiety disorder, or obsessive-compulsive disorder.
History
Etymology
The word psychosis was introduced to the psychiatric literature in 1841 by Karl Friedrich Canstatt in his work Handbuch der Medizinischen Klinik. He used it as a shorthand for psychic neurosis. At that time neurosis meant any disease of the nervous system, and Canstatt was thus referring to what was considered a psychological manifestation of brain disease. Ernst von Feuchtersleben is also widely credited as introducing the term in 1845, as an alternative to insanity and mania.
The term stems from Modern Latin psychosis, "a giving soul or life to, animating, quickening" and that from Ancient Greek ψυχή (psyche), "soul" and the suffix -ωσις (-osis), in this case "abnormal condition".In its adjective form "psychotic", references to psychosis can be found in both clinical and non-clinical discussions. However, in a non-clinical context, "psychotic" is a nonspecific colloquialism used to mean "insane".
Classification
The word was also used to distinguish a condition considered a disorder of the mind, as opposed to neurosis, which was considered a disorder of the nervous system. The psychoses thus became the modern equivalent of the old notion of madness, and hence there was much debate on whether there was only one (unitary) or many forms of the new disease. One type of broad usage would later be narrowed down by Koch in 1891 to the psychopathic inferiorities—later renamed abnormal personalities by Schneider.The division of the major psychoses into manic depressive illness (now called bipolar disorder) and dementia praecox (now called schizophrenia) was made by Emil Kraepelin, who attempted to create a synthesis of the various mental disorders identified by 19th-century psychiatrists, by grouping diseases together based on classification of common symptoms. Kraepelin used the term manic depressive insanity to describe the whole spectrum of mood disorders, in a far wider sense than it is usually used today.
In Kraepelins classification this would include unipolar clinical depression, as well as bipolar disorder and other mood disorders such as cyclothymia. These are characterised by problems with mood control and the psychotic episodes appear associated with disturbances in mood, and patients often have periods of normal functioning between psychotic episodes even without medication. Schizophrenia is characterized by psychotic episodes that appear unrelated to disturbances in mood, and most non-medicated patients show signs of disturbance between psychotic episodes.
Treatment
Early civilizations considered madness a supernaturally inflicted phenomenon. Archaeologists have unearthed skulls with clearly visible drillings, some datable back to 5000 BC suggesting that trepanning was a common treatment for psychosis in ancient times. Written record of supernatural causes and resultant treatments can be traced back to the New Testament. Mark 5:8–13 describes a man displaying what would today be described as psychotic symptoms. Christ cured this "demonic madness" by casting out the demons and hurling them into a herd of swine. Exorcism is still utilized in some religious circles as a treatment for psychosis presumed to be demonic possession. A research study of out-patients in psychiatric clinics found that 30 percent of religious patients attributed the cause of their psychotic symptoms to evil spirits. Many of these patients underwent exorcistic healing rituals that, though largely regarded as positive experiences by the patients, had no effect on symptomology. Results did, however, show a significant worsening of psychotic symptoms associated with exclusion of medical treatment for coercive forms of exorcism.
The medical teachings of the fourth-century philosopher and physician Hippocrates of Cos proposed a natural, rather than supernatural, cause of human illness. In Hippocrates work, the Hippocratic corpus, a holistic explanation for health and disease was developed to include madness and other "diseases of the mind." Hippocrates writes:
Men ought to know that from the brain, and from the brain only, arise our pleasures, joys, laughter, and jests, as well as our sorrows, pains, griefs and tears. Through it, in particular, we think, see, hear, and distinguish the ugly from the beautiful, the bad from the good, the pleasant from the unpleasant…. It is the same thing which makes us mad or delirious, inspires us with dread and fear, whether by night or by day, brings sleeplessness, inopportune mistakes, aimless anxieties, absentmindedness, and acts that are contrary to habit.
Hippocrates espoused a theory of humoralism wherein disease is resultant of a shifting balance in bodily fluids including blood, phlegm, black bile, and yellow bile. According to humoralism, each fluid or "humour" has temperamental or behavioral correlates. In the case of psychosis, symptoms are thought to be caused by an excess of both blood and yellow bile. Thus, the proposed surgical intervention for psychotic or manic behavior was bloodletting.18th-century physician, educator, and widely considered "founder of American psychiatry", Benjamin Rush, also prescribed bloodletting as a first-line treatment for psychosis. Although not a proponent of humoralism, Rush believed that active purging and bloodletting were efficacious corrections for disruptions in the circulatory system, a complication he believed was the primary cause of "insanity". Although Rushs treatment modalities are now considered antiquated and brutish, his contributions to psychiatry, namely the biological underpinnings of psychiatric phenomenon including psychosis, have been invaluable to the field. In honor of such contributions, Benjamin Rushs image is in the official seal of the American Psychiatric Association.
Early 20th-century treatments for severe and persisting psychosis were characterized by an emphasis on shocking the nervous system. Such therapies include insulin shock therapy, cardiazol shock therapy, and electroconvulsive therapy. Despite considerable risk, shock therapy was considered highly efficacious in the treatment of psychosis including schizophrenia. The acceptance of high-risk treatments led to more invasive medical interventions including psychosurgery.
In 1888, Swiss psychiatrist Gottlieb Burckhardt performed the first medically sanctioned psychosurgery in which the cerebral cortex was excised. Although some patients showed improvement of symptoms and became more subdued, one patient died and several developed aphasia or seizure disorders. Burckhardt would go on to publish his clinical outcomes in a scholarly paper. This procedure was met with criticism from the medical community and his academic and surgical endeavors were largely ignored. In the late 1930s, Egas Moniz conceived the leucotomy (AKA prefrontal lobotomy) in which the fibers connecting the frontal lobes to the rest of the brain were severed. Monizs primary inspiration stemmed from a demonstration by neuroscientists John Fulton and Carlyles 1935 experiment in which two chimpanzees were given leucotomies and pre- and post-surgical behavior was compared. Prior to the leucotomy, the chimps engaged in typical behavior including throwing feces and fighting. After the procedure, both chimps were pacified and less violent. During the Q&A, Moniz asked if such a procedure could be extended to human subjects, a question that Fulton admitted was quite startling. Moniz would go on to extend the controversial practice to humans with various psychotic disorders, an endeavor for which he received a Nobel Prize in 1949. Between the late 1930s and early 1970s, the leucotomy was a widely accepted practice, often performed in non-sterile environments such as small outpatient clinics and patient homes. Psychosurgery remained standard practice until the discovery of antipsychotic pharmacology in the 1950s.The first clinical trial of antipsychotics (also commonly known as neuroleptics) for the treatment of psychosis took place in 1952. Chlorpromazine (brand name: Thorazine) passed clinical trials and became the first antipsychotic medication approved for the treatment of both acute and chronic psychosis. Although the mechanism of action was not discovered until 1963, the administration of chlorpromazine marked the advent of the dopamine antagonist, or first generation antipsychotic. While clinical trials showed a high response rate for both acute psychosis and disorders with psychotic features, the side effects were particularly harsh, which included high rates of often irreversible Parkinsonian symptoms such as tardive dyskinesia. With the advent of atypical antipsychotics (also known as second generation antipsychotics) came a dopamine antagonist with a comparable response rate but a far different, though still extensive, side-effect profile that included a lower risk of Parkinsonian symptoms but a higher risk of cardiovascular disease. Atypical antipsychotics remain the first-line treatment for psychosis associated with various psychiatric and neurological disorders including schizophrenia, bipolar disorder, major depressive disorder, anxiety disorders, dementia, and some autism spectrum disorders.Dopamine is now one of the primary neurotransmitters implicated in psychotic symptomology. Blocking dopamine receptors (namely, the dopamine D2 receptors) and decreasing dopaminergic activity continues to be an effective but highly unrefined effect of antipsychotics, which are commonly used to treat psychosis. Recent pharmacological research suggests that the decrease in dopaminergic activity does not eradicate psychotic delusions or hallucinations, but rather attenuates the reward mechanisms involved in the development of delusional thinking; that is, connecting or finding meaningful relationships between unrelated stimuli or ideas. The author of this research paper acknowledges the importance of future investigation:
The model presented here is based on incomplete knowledge related to dopamine, schizophrenia, and antipsychotics—and as such will need to evolve as more is known about these.
Freuds former student Wilhelm Reich explored independent insights into the physical effects of neurotic and traumatic upbringing, and published his holistic psychoanalytic treatment with a schizophrenic. With his incorporation of breathwork and insight with the patient, a young woman, she achieved sufficient self-management skills to end the therapy.Lacan extended Freuds ideas to create a psychoanalytic model of psychosis based upon the concept of "foreclosure", the rejection of the symbolic concept of the father.
Society
Psychiatrist David Healy has criticised pharmaceutical companies for promoting simplified biological theories of mental illness that seem to imply the primacy of pharmaceutical treatments while ignoring social and developmental factors that are known important influences in the etiology of psychosis.
Disability
The classification of psychosis as a social disability is a common occurrence.
Psychosis is considered to be among the top 10 causes of social disability among adult men and women in developed countries. And the traditional, negative narrative around disability has been shown to strongly and adversely influence the pathways through employment and education for people experiencing psychosis.Social disability by way of social disconnection is a significant public health concern and is associated with a broad range of negative outcomes, including premature mortality. Social disconnection refers to the ongoing absence of family or social relationships with marginal participation in social activities.
N. Myers (2019), N. A. L. Myers (2012) and Brown (2011) found that reduced participation in social networks, not only negatively effects the individual on a physical and mental level, it has been shown that failure to be included in social networks influences the individuals ability to participate in the wider community through employment and education opportunities.
N. Myers (2019) discuss how equal opportunity to participate in meaningful relationships with friends, family and partners, as well as engaging in social constructs such as employment, can provide significant physical and mental value to peoples lives. And how breaking the disability mindset around people experiencing psychosis is imperative for their overall, long-term health and wellbeing as well as the contributions they are able to make to their immediate social connections and the wider community.
Causes
The symptoms of psychosis may be caused by serious psychiatric disorders such as schizophrenia, a number of medical illnesses, and trauma. Psychosis may also be temporary or transient, and be caused by medications or substance use disorder (substance-induced psychosis).
Normal states
Brief hallucinations are not uncommon in those without any psychiatric disease, including healthy children. Causes or triggers include:
Falling asleep and waking: hypnagogic and hypnopompic hallucinations
Bereavement, in which hallucinations of a deceased loved one are common
Severe sleep deprivation
Extreme stress (see below)
Trauma and Stress
Traumatic life events have been linked with an elevated risk of developing psychotic symptoms. Childhood trauma has specifically been shown to be a predictor of adolescent and adult psychosis. Individuals with psychotic symptoms are three times more likely to have experienced childhood trauma (e.g., physical or sexual abuse, physical or emotional neglect) than those in the general population. Increased individual vulnerability toward psychosis may interact with traumatic experiences promoting an onset of future psychotic symptoms, particularly during sensitive developmental periods. Importantly, the relationship between traumatic life events and psychotic symptoms appears to be dose-dependent in which multiple traumatic life events accumulate, compounding symptom expression and severity. However, acute, stressful events can also trigger brief psychotic episodes. Trauma prevention and early intervention may be an important target for decreasing the incidence of psychotic disorders and ameliorating its effects.A healthy person could become psychotic if he is placed in an empty room with no light and sound after 15 minutes a phenomenon known as sensory deprivation.Neuroticism, a personality trait associated with vulnerability to stressors, is an independent predictor of the development of psychosis.
Psychiatric disorders
From a diagnostic standpoint, organic disorders were believed to be caused by physical illness affecting the brain (that is, psychiatric disorders secondary to other conditions) while functional disorders were considered disorders of the functioning of the mind in the absence of physical disorders (that is, primary psychological or psychiatric disorders). Subtle physical abnormalities have been found in illnesses traditionally considered functional, such as schizophrenia. The DSM-IV-TR avoids the functional/organic distinction, and instead lists traditional psychotic illnesses, psychosis due to general medical conditions, and substance-induced psychosis.
Primary psychiatric causes of psychosis include the following:
schizophrenia
affective (mood) disorders, including major depression, and severe depression or mania in bipolar disorder (manic depression). People experiencing a psychotic episode in the context of depression may experience persecutory or self-blaming delusions or hallucinations, while people experiencing a psychotic episode in the context of mania may form grandiose delusions.
schizoaffective disorder, involving symptoms of both schizophrenia and mood disorders
delusional disorder (persistent delusional disorder)Psychotic symptoms may also be seen in:
Schizotypal personality disorder
Certain personality disorders in times of stress (including paranoid personality disorder, schizoid personality disorder, and borderline personality disorder)
Major depressive disorder in its severe form, although it is possible and more likely to have severe depression without psychosis
Bipolar disorder in the manic and mixed episodes of bipolar I disorder and depressive episodes of both bipolar I and bipolar II; however, it is possible to experience such states without psychotic symptoms.
Post-traumatic stress disorder
Chronic hallucinatory psychosis
Shared delusional disorder
Sometimes in obsessive–compulsive disorder (OCD)
Dissociative disorders, due to many overlapping symptoms, careful differential diagnosis includes especially dissociative identity disorder.
Subtypes
Subtypes of psychosis include:
Postpartum psychosis, occurring shortly after giving birth, primarily associated with maternal bipolar disorder
Monothematic delusions
Myxedematous psychosis
Stimulant psychosis
Tardive psychosis
Shared psychosis (folie à deux)
Cycloid psychosis
Cycloid psychosis is typically an acute, self-limiting form of psychosis with psychotic and mood symptoms that progress from normal to full-blown, usually between a few hours to days, and not related to drug intake or brain injury. While proposed as a distinct entity, clinically separate from schizophrenia and affective disorders, cycloid psychosis is not formally acknowledged by current ICD or DSM criteria. Its unclear place in psychiatric nosology has likely contributed to the limited scientific investigation and literature on the topic.
Postpartum psychosis
Postpartum psychosis is a rare yet serious and debilitating form of psychosis. Symptoms range from fluctuating moods and insomnia to mood-incongruent delusions related to the individual or the infant. Women experiencing postpartum psychosis are at increased risk for suicide or infanticide. Many women who experience first-time psychosis from postpartum often have bipolar disorder, meaning they could experience an increase of psychotic episodes even after postpartum.
Medical conditions
A very large number of medical conditions can cause psychosis, sometimes called secondary psychosis. Examples include:
disorders causing delirium (toxic psychosis), in which consciousness is disturbed
neurodevelopmental disorders and chromosomal abnormalities, including velocardiofacial syndrome
neurodegenerative disorders, such as Alzheimers disease, dementia with Lewy bodies, and Parkinsons disease
focal neurological disease, such as stroke, brain tumors, multiple sclerosis, and some forms of epilepsy
malignancy (typically via masses in the brain, paraneoplastic syndromes)
infectious and postinfectious syndromes, including infections causing delirium, viral encephalitis, HIV/AIDS, malaria, syphilis
endocrine disease, such as hypothyroidism, hyperthyroidism, Cushings syndrome, hypoparathyroidism and hyperparathyroidism; sex hormones also affect psychotic symptoms and sometimes giving birth can provoke psychosis, termed postpartum psychosis
inborn errors of metabolism, such as Wilsons disease, porphyria, and homocysteinemia.
nutritional deficiency, such as vitamin B12 deficiency
other acquired metabolic disorders, including electrolyte disturbances such as hypocalcemia, hypernatremia, hyponatremia, hypokalemia, hypomagnesemia, hypermagnesemia, hypercalcemia, and hypophosphatemia, but also hypoglycemia, hypoxia, and failure of the liver or kidneys
autoimmune and related disorders, such as systemic lupus erythematosus (lupus, SLE), sarcoidosis, Hashimotos encephalopathy, anti-NMDA-receptor encephalitis, and non-celiac gluten sensitivity
poisoning, by therapeutic drugs (see below), recreational drugs (see below), and a range of plants, fungi, metals, organic compounds, and a few animal toxins
sleep disorders, such as in narcolepsy (in which REM sleep intrudes into wakefulness)
parasitic diseases, such as neurocysticercosis
huntington disease
Psychoactive drugs
Various psychoactive substances (both legal and illegal) have been implicated in causing, exacerbating, or precipitating psychotic states or disorders in users, with varying levels of evidence. This may be upon intoxication for a more prolonged period after use, or upon withdrawal. Individuals who experience substance-induced psychosis tend to have a greater awareness of their psychosis and tend to have higher levels of suicidal thinking compared to those who have a primary psychotic illness. Drugs commonly alleged to induce psychotic symptoms include alcohol, cannabis, cocaine, amphetamines, cathinones, psychedelic drugs (such as LSD and psilocybin), κ-opioid receptor agonists (such as enadoline and salvinorin A) and NMDA receptor antagonists (such as phencyclidine and ketamine). |
Psychosis | Caffeine may worsen symptoms in those with schizophrenia and cause psychosis at very high doses in people without the condition. Cannabis and other illicit recreational drugs are often associated with psychosis in adolescents and cannabis use before 15 years old may increase the risk of psychosis in adulthood.
Alcohol
Approximately three percent of people with alcoholism experience psychosis during acute intoxication or withdrawal. Alcohol related psychosis may manifest itself through a kindling mechanism. The mechanism of alcohol-related psychosis is due to the long-term effects of alcohol consumption resulting in distortions to neuronal membranes, gene expression, as well as thiamin deficiency. It is possible that hazardous alcohol use via a kindling mechanism can cause the development of a chronic substance-induced psychotic disorder, i.e. schizophrenia. The effects of an alcohol-related psychosis include an increased risk of depression and suicide as well as causing psychosocial impairments. Delirium Tremens, a symptom of chronic alcoholism which can appear in the acute withdraw phase, shares many symptoms with alcohol-related psychosis suggesting a common mechanism.
Cannabis
According to current studies, cannabis use is associated with increased risk of psychotic disorders, and the more often cannabis is used the more likely a person is to develop a psychotic illness. Furthermore, people with a history of cannabis use develop psychotic symptoms earlier than those who have never used cannabis. Some debate exists regarding the causal relationship between cannabis use and psychosis with some studies suggesting that cannabis use hastens the onset of psychosis primarily in those with pre-existing vulnerability. Indeed, cannabis use plays an important role in the development of psychosis in vulnerable individuals, and cannabis use in adolescence should be discouraged. Some studies indicate that the effects of two active compounds in cannabis, tetrahydrocannabinol (THC) and cannabidiol (CBD), have opposite effects with respect to psychosis. While THC can induce psychotic symptoms in healthy individuals, limited evidence suggests that CBD may have antipsychotic effects.
Methamphetamine
Methamphetamine induces a psychosis in 26–46 percent of heavy users. Some of these people develop a long-lasting psychosis that can persist for longer than six months. Those who have had a short-lived psychosis from methamphetamine can have a relapse of the methamphetamine psychosis years later after a stressful event such as severe insomnia or a period of hazardous alcohol use despite not relapsing back to methamphetamine. Individuals who have a long history of methamphetamine use and who have experienced psychosis in the past from methamphetamine use are highly likely to re-experience methamphetamine psychosis if drug use is recommenced. Methamphetamine-induced psychosis is likely gated by genetic vulnerability, which can produce long-term changes in brain neurochemistry following repetitive use.
Medication
Administration, or sometimes withdrawal, of a large number of medications may provoke psychotic symptoms. Drugs that can induce psychosis experimentally or in a significant proportion of people include stimulants, such as amphetamine and other sympathomimetics, dopamine agonists, ketamine, corticosteroids (often with mood changes in addition), and some anticonvulsants such as vigabatrin.
Pathophysiology
Neuroimaging
The first brain image of an individual with psychosis was completed as far back as 1935 using a technique called pneumoencephalography (a painful and now obsolete procedure where cerebrospinal fluid is drained from around the brain and replaced with air to allow the structure of the brain to show up more clearly on an X-ray picture).
Both first episode psychosis, and high risk status is associated with reductions in grey matter volume (GMV). First episode psychotic and high risk populations are associated with similar but distinct abnormalities in GMV. Reductions in the right middle temporal gyrus, right superior temporal gyrus (STG), right parahippocampus, right hippocampus, right middle frontal gyrus, and left anterior cingulate cortex (ACC) are observed in high risk populations. Reductions in first episode psychosis span a region from the right STG to the right insula, left insula, and cerebellum, and are more severe in the right ACC, right STG, insula and cerebellum.Another meta analysis reported bilateral reductions in insula, operculum, STG, medial frontal cortex, and ACC, but also reported increased GMV in the right lingual gyrus and left precentral gyrus. The Kraepelinian dichotomy is made questionable by grey matter abnormalities in bipolar and schizophrenia; schizophrenia is distinguishable from bipolar in that regions of grey matter reduction are generally larger in magnitude, although adjusting for gender differences reduces the difference to the left dorsomedial prefrontal cortex, and right dorsolateral prefrontal cortex.During attentional tasks, first episode psychosis is associated with hypoactivation in the right middle frontal gyrus, a region generally described as encompassing the dorsolateral prefrontal cortex (dlPFC). In congruence with studies on grey matter volume, hypoactivity in the right insula, and right inferior parietal lobe is also reported. During cognitive tasks, hypoactivities in the right insula, dACC, and the left precuneus, as well as reduced deactivations in the right basal ganglia, right thalamus, right inferior frontal and left precentral gyri are observed. These results are highly consistent and replicable possibly except the abnormalities of the right inferior frontal gyrus. Decreased grey matter volume in conjunction with bilateral hypoactivity is observed in anterior insula, dorsal medial frontal cortex, and dorsal ACC. Decreased grey matter volume and bilateral hyperactivity is reported in posterior insula, ventral medial frontal cortex, and ventral ACC.
Hallucinations
Studies during acute experiences of hallucinations demonstrate increased activity in primary or secondary sensory cortices. As auditory hallucinations are most common in psychosis, most robust evidence exists for increased activity in the left middle temporal gyrus, left superior temporal gyrus, and left inferior frontal gyrus (i.e. Brocas area). Activity in the ventral striatum, hippocampus, and ACC are related to the lucidity of hallucinations, and indicate that activation or involvement of emotional circuitry are key to the impact of abnormal activity in sensory cortices. Together, these findings indicate abnormal processing of internally generated sensory experiences, coupled with abnormal emotional processing, results in hallucinations. One proposed model involves a failure of feedforward networks from sensory cortices to the inferior frontal cortex, which normally cancel out sensory cortex activity during internally generated speech. The resulting disruption in expected and perceived speech is thought to produce lucid hallucinatory experiences.
Delusions
The two-factor model of delusions posits that dysfunction in both belief formation systems and belief evaluation systems are necessary for delusions. Dysfunction in evaluations systems localized to the right lateral prefrontal cortex, regardless of delusion content, is supported by neuroimaging studies and is congruent with its role in conflict monitoring in healthy persons. Abnormal activation and reduced volume is seen in people with delusions, as well as in disorders associated with delusions such as frontotemporal dementia, psychosis and Lewy body dementia. Furthermore, lesions to this region are associated with "jumping to conclusions", damage to this region is associated with post-stroke delusions, and hypometabolism this region associated with caudate strokes presenting with delusions.
The aberrant salience model suggests that delusions are a result of people assigning excessive importance to irrelevant stimuli. In support of this hypothesis, regions normally associated with the salience network demonstrate reduced grey matter in people with delusions, and the neurotransmitter dopamine, which is widely implicated in salience processing, is also widely implicated in psychotic disorders.
Specific regions have been associated with specific types of delusions. The volume of the hippocampus and parahippocampus is related to paranoid delusions in Alzheimers disease, and has been reported to be abnormal post mortem in one person with delusions. Capgras delusions have been associated with occipito-temporal damage, and may be related to failure to elicit normal emotions or memories in response to faces.
Negative symptoms
Psychosis is associated with ventral striatal (VS) which is the part of the brain that is involved with the desire to naturally satisfy the bodys needs. When high reports of negative symptoms were recorded, there were significant irregularities in the left VS. Anhedonia, the inability to feel pleasure, is a commonly reported symptom in psychosis; experiences are present in most people with schizophrenia. The impairment that may present itself as anhedonia derives from the inability to not only identify goals, but to also identify and engage in the behaviors necessary to achieve goals. Studies support a deficiency in the neural representation of goals and goal directed behavior by demonstrating that when the reward is not anticipated, there is a strong correlation of high reaction in the ventral striatum; reinforcement learning is intact when contingencies about stimulus-reward are implicit, but not when they require explicit neural processing; reward prediction errors are what the actual reward is versus what the reward was predicted to be. In most cases positive prediction errors are considered an abnormal occurrence. A positive prediction error response occurs when there is an increased activation in a brain region, typically the striatum, in response to unexpected rewards. A negative prediction error response occurs when there is a decreased activation in a region when predicted rewards do not occur. Anterior Cingulate Cortex (ACC) response, taken as an indicator of effort allocation, does not increase with reward or reward probability increase, and is associated with negative symptoms; deficits in Dorsolateral Prefrontal Cortex (dlPFC) activity and failure to improve performance on cognitive tasks when offered monetary incentives are present; and dopamine mediated functions are abnormal.
Neurobiology
Psychosis has been traditionally linked to the overactivity of the neurotransmitter dopamine. In particular to its effect in the mesolimbic pathway. The two major sources of evidence given to support this theory are that dopamine receptor D2 blocking drugs (i.e., antipsychotics) tend to reduce the intensity of psychotic symptoms, and that drugs that accentuate dopamine release, or inhibit its reuptake (such as amphetamines and cocaine) can trigger psychosis in some people (see stimulant psychosis).NMDA receptor dysfunction has been proposed as a mechanism in psychosis. This theory is reinforced by the fact that dissociative NMDA receptor antagonists such as ketamine, PCP and dextromethorphan (at large overdoses) induce a psychotic state. The symptoms of dissociative intoxication are also considered to mirror the symptoms of schizophrenia, including negative symptoms. NMDA receptor antagonism, in addition to producing symptoms reminiscent of psychosis, mimics the neurophysiological aspects, such as reduction in the amplitude of P50, P300, and MMN evoked potentials. Hierarchical Bayesian neurocomputational models of sensory feedback, in agreement with neuroimaging literature, link NMDA receptor hypofunction to delusional or hallucinatory symptoms via proposing a failure of NMDA mediated top down predictions to adequately cancel out enhanced bottom up AMPA mediated predictions errors. Excessive prediction errors in response to stimuli that would normally not produce such a response is thought to root from conferring excessive salience to otherwise mundane events. Dysfunction higher up in the hierarchy, where representation is more abstract, could result in delusions. The common finding of reduced GAD67 expression in psychotic disorders may explain enhanced AMPA mediated signaling, caused by reduced GABAergic inhibition.The connection between dopamine and psychosis is generally believed to be complex. While dopamine receptor D2 suppresses adenylate cyclase activity, the D1 receptor increases it. If D2-blocking drugs are administered, the blocked dopamine spills over to the D1 receptors. The increased adenylate cyclase activity affects genetic expression in the nerve cell, which takes time. Hence antipsychotic drugs take a week or two to reduce the symptoms of psychosis. Moreover, newer and equally effective antipsychotic drugs actually block slightly less dopamine in the brain than older drugs whilst also blocking 5-HT2A receptors, suggesting the dopamine hypothesis may be oversimplified. Soyka and colleagues found no evidence of dopaminergic dysfunction in people with alcohol-induced psychosis and Zoldan et al. reported moderately successful use of ondansetron, a 5-HT3 receptor antagonist, in the treatment of levodopa psychosis in Parkinsons disease patients.A review found an association between a first-episode of psychosis and prediabetes.Prolonged or high dose use of psychostimulants can alter normal functioning, making it similar to the manic phase of bipolar disorder. NMDA antagonists replicate some of the so-called "negative" symptoms like thought disorder in subanesthetic doses (doses insufficient to induce anesthesia), and catatonia in high doses). Psychostimulants, especially in one already prone to psychotic thinking, can cause some "positive" symptoms, such as delusional beliefs, particularly those persecutory in nature.
Culture
Cross-cultural studies into schizophrenia have found that individual experiences of psychosis and ‘hearing voices’ vary across cultures. In countries such as the United States where there exists a predominantly biomedical understanding of the body, the mind and in turn, mental health, subjects were found to report their hallucinations as having ‘violent content’ and self-describing as ‘crazy’. This lived experience is at odds with the lived experience of subjects in Accra, Ghana, who describe the voices they hear as having ‘spiritual meaning’ and are often reported as positive in nature; or subjects in Chennai, India, who describe their hallucinations as kin, family members or close friends, and offering guidance.These differences are attributed to ‘social kindling’ or how ones social context shapes how an individual interprets and experiences sensations such as hallucinations. This concept aligns with pre-existing cognitive theory such as reality modelling and is supported by recent research that demonstrates that individuals with psychosis can be taught to attend to their hallucinations differently, which in turn alters the hallucinations themselves. Such research creates pathways for social or community-based treatment, such as reality monitoring, for individuals with schizophrenia and other psychotic disorders, providing alternatives to, or supplementing traditional pharmacologic management.
Cross-cultural studies explore the way in which psychosis varies in different cultures, countries and religions. The cultural differences are based on the individual or shared illness narratives surrounding cultural meanings of illness experience. In countries such as India, Cambodia and Muslim majority countries, they each share alternative epistemologies. These are known as knowledge systems that focus on the connections between mind, body, culture, nature, and society. Cultural perceptions of mental disorders such as psychosis or schizophrenia are believed to be caused by jinn (spirits) in Muslim majority countries. Furthermore, those in Arab-Muslim societies perceive those who act differently than the social norm as “crazy” or as abnormal behaviour. This differs from the lived experience of individuals in India and how they attain their perspectives on mental health issues through a variety of spiritual and healing traditions. In Cambodia, hallucinations are linked with spirit visitation, a term they call “cultural kindling”. These examples of differences are attributed to culture and the way it shapes conceptions of mental disorders. These cultural differences can be useful in bridging the gap of cultural understanding and psychiatric signs and symptoms.
Diagnosis
To make a diagnosis of a mental illness in someone with psychosis other potential causes must be excluded. An initial assessment includes a comprehensive history and physical examination by a health care provider. Tests may be done to exclude substance use, medication, toxins, surgical complications, or other medical illnesses. A person with psychosis is referred to as psychotic.
Delirium should be ruled out, which can be distinguished by visual hallucinations, acute onset and fluctuating level of consciousness, indicating other underlying factors, including medical illnesses. Excluding medical illnesses associated with psychosis is performed by using blood tests to measure:
Thyroid-stimulating hormone to exclude hypo- or hyperthyroidism,
Basic electrolytes and serum calcium to rule out a metabolic disturbance,
Full blood count including ESR to rule out a systemic infection or chronic disease, and
Serology to exclude syphilis or HIV infection.Other investigations include:
EEG to exclude epilepsy, and an
MRI or CT scan of the head to exclude brain lesions.Because psychosis may be precipitated or exacerbated by common classes of medications, medication-induced psychosis should be ruled out, particularly for first-episode psychosis. Both substance- and medication-induced psychosis can be excluded to a high level of certainty, using toxicology screening.
Because some dietary supplements may also induce psychosis or mania, but cannot be ruled out with laboratory tests, a psychotic individuals family, partner, or friends should be asked whether the patient is currently taking any dietary supplements.Common mistakes made when diagnosing people who are psychotic include:
Not properly excluding delirium,
Not appreciating medical abnormalities (e.g., vital signs),
Not obtaining a medical history and family history,
Indiscriminate screening without an organizing framework,
Missing a toxic psychosis by not screening for substances and medications,
Not asking their family or others about dietary supplements,
Premature diagnostic closure, and
Not revisiting or questioning the initial diagnostic impression of primary psychiatric disorder.Only after relevant and known causes of psychosis are excluded, a mental health clinician may make a psychiatric differential diagnosis using a persons family history, incorporating information from the person with psychosis, and information from family, friends, or significant others.
Types of psychosis in psychiatric disorders may be established by formal rating scales. The Brief Psychiatric Rating Scale (BPRS) assesses the level of 18 symptom constructs of psychosis such as hostility, suspicion, hallucination, and grandiosity. It is based on the clinicians interview with the patient and observations of the patients behavior over the previous 2–3 days. The patients family can also answer questions on the behavior report. During the initial assessment and the follow-up, both positive and negative symptoms of psychosis can be assessed using the 30 item Positive and Negative Symptom Scale (PANSS).The DSM-5 characterizes disorders as psychotic or on the schizophrenia spectrum if they involve hallucinations, delusions, disorganized thinking, grossly disorganized motor behavior, or negative symptoms. The DSM-5 does not include psychosis as a definition in the glossary, although it defines "psychotic features", as well as "psychoticism" with respect to personality disorder. The ICD-10 has no specific definition of psychosis.Factor analysis of symptoms generally regarded as psychosis frequently yields a five factor solution, albeit five factors that are distinct from the five domains defined by the DSM-5 to encompass psychotic or schizophrenia spectrum disorders. The five factors are frequently labeled as hallucinations, delusions, disorganization, excitement, and emotional distress. The DSM-5 emphasizes a psychotic spectrum, wherein the low end is characterized by schizoid personality disorder, and the high end is characterized by schizophrenia.
Prevention
The evidence for the effectiveness of early interventions to prevent psychosis appeared inconclusive. But psychosis caused by drugs can be prevented. Whilst early intervention in those with a psychotic episode might improve short-term outcomes, little benefit was seen from these measures after five years. However, there is evidence that cognitive behavioral therapy (CBT) may reduce the risk of becoming psychotic in those at high risk, and in 2014 the UK National Institute for Health and Care Excellence (NICE) recommended preventive CBT for people at risk of psychosis.
Treatment
The treatment of psychosis depends on the specific diagnosis (such as schizophrenia, bipolar disorder or substance intoxication). The first-line treatment for many psychotic disorders is antipsychotic medication,
which can reduce the positive symptoms of psychosis in about 7 to 14 days. For youth or adolescents, treatment options include medications, psychological interventions, and social interventions.
Medication
The choice of which antipsychotic to use is based on benefits, risks, and costs. It is debatable whether, as a class, typical or atypical antipsychotics are better. Tentative evidence supports that amisulpride, olanzapine, risperidone and clozapine may be more effective for positive symptoms but result in more side effects. Typical antipsychotics have equal drop-out and symptom relapse rates to atypicals when used at low to moderate dosages. There is a good response in 40–50%, a partial response in 30–40%, and treatment resistance (failure of symptoms to respond satisfactorily after six weeks to two or three different antipsychotics) in 20% of people. Clozapine is an effective treatment for those who respond poorly to other drugs ("treatment-resistant" or "refractory" schizophrenia), but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people.Most people on antipsychotics get side effects. People on typical antipsychotics tend to have a higher rate of extrapyramidal side effects while some atypicals are associated with considerable weight gain, diabetes and risk of metabolic syndrome; this is most pronounced with olanzapine, while risperidone and quetiapine are also associated with weight gain. Risperidone has a similar rate of extrapyramidal symptoms to haloperidol.
Psychotherapy
Psychological treatments such as acceptance and commitment therapy (ACT) are possibly useful in the treatment of psychosis, helping people to focus more on what they can do in terms of valued life directions despite challenging symptomology. Metacognitive training (MCT) is associated with reduced delusions, hallucinations and negative symptoms as well as improved self-esteem and functioning in individuals with schizophrenia spectrum disorders.There are many psychosocial interventions that seek to treat the symptoms of psychosis: need adapted treatment, open dialogue, psychoanalysis/psychodynamic psychotherapy, major role therapy, soteria, psychosocial outpatient and inpatient treatment, milieu therapy, and cognitive behavioral therapy (CBT). When these are used without antipsychotic medications, they may be somewhat effective for some people, especially for CBT, need-adapted treatment, and soteria.
Early intervention
Early intervention in psychosis is based on the observation that identifying and treating someone in the early stages of a psychosis can improve their longer term outcome. This approach advocates the use of an intensive multi-disciplinary approach during what is known as the critical period, where intervention is the most effective, and prevents the long-term morbidity associated with chronic psychotic illness.
Systematic reform
Addressing systematic reform is essential to creating effective prevention as well as supporting treatments and recovery for those with psychosis.
Waghorn et al. suggest that education interventions can be a building block to support those with psychosis to successfully participate in society. In their study they analyse the relationship between successful education attainment and psychosis. Findings suggest proportionately more school aged persons with psychosis discontinued their education, compared to those without psychosis.Waghorn et al. finds that specialised supported education for those with psychotic disorders can help lead to successful education attainment. Additionally, future employment outcomes are relative to such education attainment. Established approaches to supported education in the US include three basic models, self-contained classrooms, onsite support model and the mobile support model. Each model includes the participation of mental health service staff or educational facility staff in the students education arrangements.Potential benefits of specialised supported education found from this study include coordination with other service providers (e.g. income support, housing, etc.) to prevent disrupting education, providing specialised career counselling, development of coping skills in the academic environment. These examples provide beneficial ways for people with psychosis to finish studies successfully as well as counter future experiences of psychosis.
Research
Further research in the form of randomized controlled trials is needed to determine the effectiveness of treatment approaches for helping adolescents with psychosis. Through 10 randomized clinical trials, studies showed that Early Intervention Services (EIS) for patients with early-phase schizophrenia spectrum disorders have generated promising outcomes. EIS are specifically intended to fulfill the needs of patients with early-phase psychosis. In addition, one meta-analysis that consisted of four randomized clinical trials has examined the efficacy of EIS to Therapy as Usual (TAU) for early-phase psychosis, revealing that EIS techniques are superior to TAU.A study suggests that combining cognitive behavioral therapy (CBT) with SlowMo, an app that helps notice their "unhelpful fast-thinking" might be more effective for treating paranoia in people with psychosis than CBT alone.
See also
Open Dialogue
Metacognitive training
References
Bibliography
Badcock JC, Paulik G, eds. (2019). A Clinical Introduction to Psychosis: Foundations for Clinical Psychologists and Neuropsychologists (1st ed.). Cambridge, Massachusetts: Academic Press, imprint of Elsevier. doi:10.1016/C2017-0-01829-3. ISBN 978-0-12-815012-2. S2CID 243510002.
Lewandowski KE, Moustafa A, eds. (2019). Social Cognition in Psychosis (1st ed.). Cambridge, Massachusetts: Academic Press, imprint of Elsevier. doi:10.1016/C2017-0-03061-6. ISBN 978-0-12-815315-4. S2CID 239126550.
Semple D, Smyth R (2019). "Schizophrenia and related psychoses". In Semple D, Smyth R (eds.). Oxford Handbook of Psychiatry (4th ed.). Oxford: Oxford University Press. pp. 179–240. doi:10.1093/med/9780198795551.003.0005. ISBN 978-0-19-879555-1.
Tamminga CA, van Os J, Reininghaus U, Ivleva E, eds. (2020). Psychotic Disorders: Comprehensive Conceptualization and Treatments (1st ed.). Oxford: Oxford University Press. doi:10.1093/med/9780190653279.001.0001 (inactive 31 July 2022). ISBN 978-0-19-065327-9.{{cite book}}: CS1 maint: DOI inactive as of July 2022 (link)
Thompson AD, Broome MR, eds. (2020). Risk Factors for Psychosis: Paradigms, Mechanisms, and Prevention (1st ed.). Cambridge, Massachusetts: Academic Press, imprint of Elsevier. doi:10.1016/B978-0-12-813201-2.00001-6. ISBN 978-0-12-813201-2. S2CID 213499429.
Further reading
Personal accounts
External links
National Institute of Mental Health |
Arthrogryposis | Arthrogryposis (AMC) describes congenital joint contracture in two or more areas of the body. It derives its name from Greek, literally meaning "curving of joints" (arthron, "joint"; grȳpōsis, late Latin form of late Greek grūpōsis, "hooking").Children born with one or more joint contractures have abnormal fibrosis of the muscle tissue causing muscle shortening, and therefore are unable to perform active extension and flexion in the affected joint or joints.AMC has been divided into three groups: amyoplasia, distal arthrogryposis, and syndromic. Amyoplasia is characterized by severe joint contractures and muscle weakness. Distal arthrogryposis mainly involves the hands and feet. Types of arthrogryposis with a primary neurological or muscle disease belong to the syndromic group.
Signs and symptoms
Often, every joint in a patient with arthrogryposis is affected; in 84% all limbs are involved, in 11% only the legs, and in 4% only the arms are involved. Every joint in the body, when affected, displays typical signs and symptoms: for example, the shoulder (internal rotation); wrist (volar and ulnar); hand (fingers in fixed flexion and thumb in palm); hip (flexed, abducted and externally rotated, frequently dislocated); elbow (extension and pronation) and foot clubfoot and less commonly congenital vertical talus.Range of motion can be different between joints because of the different deviations. Some types of arthrogryposis like amyoplasia have a symmetrical joint/limb involvement, with normal sensations. The contractures in the joints can result in delayed walking development in the first five years, but severity of contractures do not necessarily predict eventual walking ability or inability.Intelligence is normal to above normal in children with amyoplasia, but it is not known how many of these children have an above normal intelligence, and there is no literature available about the cause of this syndrome. There are a few syndromes like the Freeman–Sheldon and Gordon syndrome, which have craniofacial involvement. The amyoplasia form of arthrogryposis is sometimes accompanied with a midline facial hemangioma.
Arthrogryposis is not a diagnosis but a clinical finding, so this disease is often accompanied with other syndromes or diseases. These other diagnoses could affect any organ in a patient. There are a few slightly more common diagnoses such as pulmonary hypoplasia, cryptorchidism, congenital heart defects, tracheoesophageal fistulas, inguinal hernias, cleft palate, and eye abnormalities.
Causes
Research of arthrogryposis has shown that anything that inhibits normal joint movement before birth can result in joint contractures. Arthrogryposis could be caused by genetic and environmental factors. In principle: any factor that curtails fetal movement can result in congenital contractures. The exact causes of arthrogryposis are unknown.
Extrinsic factors
The malformations of arthrogryposis can be secondary to environmental factors such as: decreased intrauterine movement, oligohydramnios (low volume or abnormal distribution of intrauterine fluid), and defects in the fetal blood supply. Other causes could be: hyperthermia, limb immobilization and viral infections. A specific virus that may cause arthrogryposis is contraction of the Zika virus during pregnancy. Congenital Zika syndrome (CZS), may occur when there is vertical transmission of the Zika virus to the fetus. Myasthenia gravis of the mother leads also in rare cases to arthrogryposis. The major cause in humans is fetal akinesia, however, this is disputed lately.
Intrinsic factors
Arthrogryposis could also be caused by intrinsic factors. This includes molecular, muscle- and connective tissue development disorders or neurological abnormalities.
Molecular basis
Research has shown that there are more than 35 specific genetic disorders associated with arthrogryposis. Most of those mutations are missense, which means the mutation results in a different amino acid. Other mutations that could cause arthrogryposis are: single gene defects (X-linked recessive, autosomal recessive and autosomal dominant), mitochondrial defects and chromosomal disorders (for example: trisomy 18). This is mostly seen in distal arthrogryposis. Mutations in at least five genes (TNN12, TNNT3, TPM2, MYH3 and MYH8) could cause distal arthrogryposis. There could be also connective tissue, neurological or muscle development disorders.
Muscle and connective tissue development disorders
Loss of muscle mass with an imbalance of muscle power at the joint can lead to connective tissue abnormality. This leads to joint fixation and reduced fetal movement. Also muscle abnormalities could lead to a reduction of fetal movement.
Those could be: dystrophy, myopathy and mitochondrial disorders. This is mostly the result of abnormal function of the dystrophin-glycoprotein-associated complex in the sarcolemma of skeletal muscles.
Neurological abnormalities
Seventy to eighty percent of cases of the most severe forms of arthrogryposis are caused by neurological abnormalities, which can be either genetic or environmental.The underlying aetiology and pathogenesis of congenital contractures, particularly arthrogryposis and the mechanism of the mutations remains an active area of investigation, because identifying these factors could help to develop treatment and congenital finding of arthrogryposis.
Diagnosis
Research on prenatal diagnosis has shown that a diagnosis can be made prenatally in approximately 50% of fetuses presenting arthrogryposis. It could be found during routine ultrasound scanning showing a lack of mobility and abnormal position of the foetus. There are other options for visualization of details and structures using techniques such as 4D ultrasound. In clinic a child can be diagnosed with arthrogryposis with physical examination, confirmed by ultrasound, MRI, or muscle biopsy.
Classification
Some of the different types of AMC include:
Arthrogryposis multiplex due to muscular dystrophy.
Arthrogryposis ectodermal dysplasia other anomalies, also known as Cote Adamopoulos Pantelakis syndrome, Trichooculodermovertebral syndrome, TODV syndrome and Alves syndrome.
Arthrogryposis epileptic seizures migrational brain disorder.
Arthrogryposis IUGR thoracic dystrophy, also known as Van Bervliet syndrome.
Arthrogryposis-like disorder, also known as Kuskokwim disease.
Arthrogryposis-like hand anomaly and sensorineural deafness.
Arthrogryposis multiplex congenita CNS calcification.
Arthrogryposis multiplex congenita distal (AMCD), also known as X-linked spinal muscular atrophy type 2.
Gordon syndrome, also known as distal arthrogryposis type 3.
Arthrogryposis multiplex congenita, distal type 2A, also known as Freeman–Sheldon syndrome.
Arthrogryposis multiplex congenita, distal type 2B, also known as Sheldon–Hall syndrome.
Arthrogryposis multiplex congenita neurogenic type (AMCN). This particular type of AMC has been linked to the AMCN gene on locus 5q35.
Arthrogryposis multiplex congenita pulmonary hypoplasia, also with a large number of synonyms.
Arthrogryposis multiplex congenita whistling face, also known as Illum syndrome.
Arthrogryposis multiplex congenita, distal type 1 (AMCD1).
Arthrogryposis multiplex with deafness, inguinal hernias, and early death. This syndrome is suspected to be inherited in an X-linked or autosomal recessive fashion. There were only three reported cases with all three patients dead.
Arthrogryposis ophthalmoplegia retinopathy, also known as Oculomelic amyoplasia.
Arthrogryposis renal dysfunction cholestasis syndrome, also known as ARC Syndrome.Another form has been related to mutations in the leucine-rich glioma-inactivated 4 (LGI4) gene.
Treatment
The treatment of arthrogryposis includes occupational therapy, physical therapy, splinting and surgery. An approach that occupational therapists use is orthopedic management. Using casts in order to correct joint deformities can be very effective since the joints can be misaligned and present with deformities. Another vital intervention that occupational therapists use to treat arthrogryposis, is range of motion exercises. This is in order to increase joint mobility. The primary long-term goals of these treatments are increasing joint mobility and muscle strength and the development of adaptive use patterns that allow for walking and independence with activities of daily living. Since arthrogryposis has many different types, the treatment varies between patients depending on the symptoms.
Only a few good articles exist in which a surgical technique that is used to treat arthrogryposis is described. These surgeries are explained below.
Passive enhancement
There are a number of passive devices for enhancing limb movement, intended to be worn to aid movement and encourage muscular development. For example, the Wilmington Robotic Exoskeleton is a potential assistive device built on a back brace, shadowing the upper arm and forearm. It can be difficult to fit and heavy and awkward to wear.Researchers at the University of Delaware are developing a light and unobtrusive therapeutic garment, suitable for babies and children, called the Playskin Lift. The garment looks like normal clothing but contains bundled steel wires under the arms, which help to push the arms toward a lifted position while allowing the wearer to move freely from that position.
Wrist surgery
Children with the amyoplasia type of arthrogryposis usually have flexion and ulnar deviation of the wrists. Dorsal carpal wedge osteotomy is indicated for wrists with excessive flexion contracture deformity when non-surgical interventions such as occupational therapy and splinting have failed to improve function. On the dorsal side, at the level of the midcarpus, a wedge osteotomy is made. Sufficient bone is resected to at least be able to put the wrist in a neutral position. If the wrist also has ulnar deviation, more bone can be taken from the radial side to correct this abnormality. This position is held into place with two cross K-wires. In addition, a tendon transfer of the extensor carpi ulnaris to the extensor carpi radialis brevis may be performed to correct ulnar deviation or wrist extension weakness, or both. This tendon transfer is only used if the extensor carpi ulnaris appears to be functional enough.
Thumb surgery
The soft tissue envelope in congenital contractual conditions such as clasped or arthrogrypotic thumbs is often deficient in two planes, the thumb-index web and the flexor aspect of the thumb. There is often an appearance of increased skin at the base of the index finger that is part of the deformity. This tissue can be used to resurface the thumb-index web after a comprehensive release of all the tight structures to allow for a larger range of motion of the thumb. This technique is called the index rotation flap.The flap is taken from the radial side of the index finger. It is proximally based at the distal edge of the thumb-index web. The flap is made as wide as possible, but still small enough to close with the excessive skin on the palmar side of the index finger. The flap is rotated around the tightest part of the thumb to the metacarpophalangeal joint of the thumb, allowing for a larger range of motion.
Foot surgeries
Generally, foot surgery is usually reserved for patients with a walking or ambulatory potential. Foot surgery may also be indicated to assist brace and orthosis fitting and hence promote supported standing. The most common foot deformity in arthrogryposis is club feet or talipes equinovarus. In the early years of life the serial casting according to the Ponseti method usually yields good results. The Ponseti method can also be used as a first line treatment in older and more resistant cases. In such severe and neglected cases bony surgery in the form of foot osteotomies and arthrodesis is usually indicated. It is usually accompanied by soft tissue surgery in the form of release of contracted tendon and capsular structures. In older patients near skeletal maturity joint fusion or arthrodesis may be indicated as well. Less frequent patients with arthrogryposis may develop congenital vertical talus also known as rocker bottom foot. Similarly, congenital vertical talus is classically managed by serial casting according to the reversed Ponseti method. Resistant or recurrent cases may be offered an extensive soft tissue release. However this is fraught with risk of foot stiffness and pain in the long term. Talectomy or excision of the talus to give room for creation of plantigrade foot has been practiced. Naviculectomy or midtarsal resection arthroplasty represents a less invasive option with satisfactory short-term results.
Prognosis
AMC is considered non-progressive, so with proper medical treatment things can improve. The joint contractures will not get worse than they are at the time of birth. There is no way to resolve or cure AMC completely but with proper treatment most children make significant improvements in their range of motion and ability to move their limbs, which enables them to carry out daily activities and live relatively normal lives.Therapeutic interventions that are cornerstones in the treatment of AMC include: stretching and range of motion exercises, physical, occupational and speech therapy, splinting and serial casting. Surgical intervention may also improve joint mobility and function. Other positive prognostic factors for independent walking are active hips and knees, hip flexion contractures of less than 20 degrees and knee flexion contractures of less than 15 degrees without severe scoliosis.
Epidemiology
Arthrogryposis is a rare condition. Some authors say the overall prevalence is one in 3,000 and others say it is one in 11,000–12,000 among European live births. Congenital clubfoot is the most common single contracture and its prevalence is one in 500 live births.
See also
X-linked spinal muscular atrophy type 2
References
== External links == |
Heart-hand syndrome, Spanish type | Heart-hand syndrome, Spanish type, also known as heart-hand syndrome type 3 or III, is a very rare genetic disorder which is characterized by heart, hand, and sometimes feet abnormalities. It is a type of heart-hand syndrome, a class of genetic disorders characterized by cardiac malformations and hand malformations. Only one family with the disorder has been reported in medical literature.
Description
People with this disorder have symptoms that affect the heart, hands and feet. These include:
Heart
Sick sinus
Bundle branch block
Hands
Brachydactyly which resembles brachydactyly type C
Abnormal development of the middle phalanges of the fingers
Accessory ossicle on the proximal phalange of the index finger.
Feet
Subtle feet anomalies such as syndactyly
Etimology
This condition was first discovered by Ruiz de la Fuente et al., when they described a 3-generation family from Spain with the symptoms mentioned above. The cardiac defects varied between family members; 3 members had intraventicular conduction defects and 1 had a sick sinus. In this family, the 2nd and 5th fingers were the most severely affected out of all the fingers. Autosomal dominant inheritance was suspected.
== References == |
Craniomandibular osteopathy | Craniomandibular osteopathy, also known as lions jaw, is a developmental disease in dogs causing extensive bony changes in the mandible and skull. In this disease, a cyclical resorption of normal bone and replacement by immature bone occurs along the inner and outer surfaces of the affected bones. It usually occurs between the ages of 3 and 8 months. Breeds most commonly affected include the West Highland White Terrier, Scottish Terrier, Cairn Terrier, and Boston Terrier. It is rare in large-breed dogs, but it has been reported. Symptoms include firm swelling of the jaw, drooling, pain, and difficulty eating.
It is an inherited disease, especially in Westies, in which it has been recognized as an autosomal recessive trait. Canine distemper has also been indicated as a possible cause, as has E. coli infection, which could be why it is seen occasionally in large-breed dogs. Growth of lesions will usually stop around the age of one year, and possibly regress. This timing coincides with the normal completion of endochondral bone growth and ossification. If the disease is extensive, especially around the tympanic bulla (middle ear), then the prognosis is guarded.
A similar disease seen in young Bullmastiffs is known as calvarial hyperostotic syndrome. It is also similar to human infantile cortical hyperostosis. It is characterized by irregular, progressive bony proliferation and thickening of the cortical bone of the calvaria, which is part of the skull. Asymmetry of the lesions may occur, which makes it different from craniomandibular osteopathy. Symptoms include painful swelling of the skull, fever, and lymph node swelling. In most cases it is self-limiting.
== References == |
Tracheobronchomalacia | Tracheobronchomalacia or TBM is a condition characterized by flaccidity of the tracheal support cartilage which leads to tracheal collapse. This condition can also affect the bronchi. There are two forms of this condition: primary TBM and secondary TBM. Primary TBM is congenital and starts as early as birth. It is mainly linked to genetic causes. Secondary TBM is acquired and starts in adulthood. It is mainly developed after an accident or chronic inflammation.Tracheobronchomalacia may also occur in people who have normal cartliginous structure of the trachea, but significant atrophy of the posterior wall, causing significant invagination of the trachea on expiration. In these cases it is more commonly known as Excessive Dynamic Airway Collapse (EDAC).
Signs and symptoms
Initially TBM may be asymptomatic or some patients do not experience symptoms at all. In a progressive TBM case symptoms include:
shortness of breath
a cough
mucus build up
stridor (a wheeze-like sound on breathing out)
difficulty in breathing
bluish coloration to skin around the nose and mouth
Chronic coughSymptoms may become worse if the patient is stressed, sick, lying down, or forcing a cough.
Cause
Congenital TBM is present from birth. Acquired TBM often has no clear cause but is frequently found together with other pulmonary diseases like asthma and Chronic obstructive pulmonary disease, as well as Gastroesophageal reflux disease. TBM can be caused by damage to the support cartilage or membranous wall of the trachea, this can be the result of physical trauma (such as from prolonged Tracheal intubation) or pathological changes caused by inflammatory diseases like Relapsing polychondritis. In patients with TBM in one study, the number of longitudinal elastic fibers in the pars of membranacea was reduced throughout the whole trachea.People with heritable connective tissue disorders like Ehlers–Danlos syndrome seem to have at an increased risk of both congenital and acquired TBM, although the extent of that risk is unknown. There have been studies linking long-term use of inhaled Corticosteroids to Tracheobronchomalacia.
Diagnosis
Diagnosis is conducted according to the severity of the symptoms. Initially pulmonary function tests are administered. These tests include the lungs capability of air intake and outtake, and gas flow of oxygen and carbon dioxide between the body and environment. Following these function tests a special type of Chest CT scan or a bronchoscopy will be ordered. The results of the scan and bronchoscopy will display the status of the condition. A mild case of tracheobronchomalacia would be if the patients trachea condenses 50% of its normal space when exhaling. Moderate tracheobronchomalacia would be 25% of the normal trachea space constricting and a severe case would be if the walls touch each other.Tracheobronchomalacia is thought to be underdiagnosed as mild cases may be asymptomatic and symptoms are often mistaken for more common respiratory conditions like Athsma and Chronic obstructive pulmonary disease.
Treatment
To properly treat a patient with tracheobronchomalacia, the subtype must be determined (primary or secondary). After the type is named, the cause must be identified, whether it is from genetics, a trauma accident, or chronic tracheal illness. If a trauma case or chronic tracheal illnesses were the cause, the first steps of treatment would be to address these underlying issues. If the cause is genetic or the previous underlying issues could not be fixed, other treatments would be assessed. More severe treatments include silicone stenting to prevent tracheal constriction, surgery to strengthen or attempt to rebuild the walls, continuous positive airway pressure that has a machine blow small amounts of air into the trachea to keep it open (mainly at night), or a tracheostomy, which is surgically inserted into the patients neck that leads to the trachea to help with breathing. Another form of treatment may include a tracheobronchoplasty which is a specific surgical procedure that helps control the airway by splinting the trachea. The splint helps strengthen the trachea with the hopes that the symptoms improve. People with tracheobronchomalacia who do not experience symptoms do not need treatment and are often undiagnosed.On 28 May 2013, it was reported that a cure had been developed via a 3D printed windpipe. This cure has currently saved the lives of at least 3 infants.
See also
Bronchomalacia
Tracheomalacia
References
External links
Tracheobronchomalacia in Children on Medscape
Tracheobronchomalacia on Genetic and Rare Diseases Information Center (GARD)
CureTBM Foundation on CureTBM.org |
Cyclic neutropenia | Cyclic neutropenia (CyN) is a rare hematologic disorder and form of congenital neutropenia that tends to occur approximately every three weeks and lasting for few days at a time due to changing rates of neutrophil production by the bone marrow. It causes a temporary condition with a low absolute neutrophil count and because the neutrophils make up the majority of circulating white blood cells it places the body at severe risk of inflammation and infection. In comparison to severe congenital neutropenia, it responds well to treatment with granulocyte colony-stimulating factor (filgrastim), which increases the neutrophil count, shortens the cycle length, as well decreases the severity and frequency of infections.
Signs and symptoms
The common symptoms of neutropenia are recurrent fever, malaise, inflammation of the tissues surrounding the teeth, mouth ulcers, inflammation and bacterial infection of the respiratory tract, digestive tract, skin, and abdominal pain. It is considered that the greatest risk for death is from developing necrotizing enterocolitis (NEC), peritonitis, bacteremia or Clostridium and Escherichia coli sepsis and septic shock, and pneumonia.
Causes
Cyclic neutropenia (CyN), like severe congenital neutropenia (SCN), is a rare disorder. It is considered that in the general population, CyN has a frequency of one in one million. It is the result of autosomal dominant mutation in ELANE gene located on the short arm (p) of chromosome 19 (19p13.3), the gene encoding neutrophil elastase, which is also the most common cause of the SCN. It sporadically occurs as a de novo mutation variant or can be present among members of the same family. In the case of CyN, the mutation variants have been found to mostly cluster in intron 4 and exon 4 and 5, but were also located in intron 3, and exon 2 and 3. Some mutation variants have been found in both Cyn and SCN, which indicates they are phenotypes of the same disease with different severity.It is considered that the mutation causes a decrease in the "neutrophil production or excessive apoptosis (shorter half-life)" which results in a deficiency of mature neutrophils in the blood. The exact pathological mechanism is still researched, with the main hypotheses being mislocalization of ELANE or unfolded protein response (UPR) induced by mutant ELANE, however according to Mehta et al. (2016), the "UPR induction by mutant ELANE is not strong enough to promote cell death and that mutant ELANE causes SCN through an alternative mechanism". According to Garg et al. (2020), new "findings challenge the currently prevailing model that SCN results from mutant ELANE, which triggers endoplasmic reticulum stress, UPR, and apoptosis". The expression of the ELANE gene has been linked to GFI1 gene, and some considered that interaction with other genes causes the emergence and severity of one or the other phenotypic disorder. It is unclear what causes the cyclic aspect in CyN. According to Donadieu et al. (2011), the "cyclic aspect ... suggests the existence of a cryptic biological clock that regulates granulopoiesis. This putative clock might be revealed by particular mutations". Michael Mackey "postulates that the production of neutrophils is governed by long‐range stimulatory factors in a long feedback loop that has a built‐in time delay in the maturation of promyelocytes to fully differentiated neutrophils". It is also not clear what causes that the levels of secretory leucocyte protease inhibitor (SLPI), which influences the induction of the unfolded protein response (UPR), are not diminished and as such activation of UPR is absent in CyN compared to SCN, in other words, different ELANE mutations "have different effects on UPR activation, and SLPI regulates the extent of ELANE‐triggered UPR".
A 2020 study published in Annals of the New York Academy of Sciences about the pathomechanism of CyN revealed that "some HSPCs escape the UPR‐induced endoplasmic reticulum (ER) stress and proliferate in response to granulocyte colony‐stimulating factor (G‐CSF) to a certain threshold at which UPR again affects the majority of HSPCs. There is a cyclic balance between ER stress-induced apoptosis of HSPCs and compensatory G‐CSF–stimulated HSPC proliferation followed by granulocytic differentiation"; in other words, CyN is "characterized by cycling UPR activities and cycling UPR‐escaping cells". Also, the most probable reason that from the same mutation variant develops SCN and not CyN is due to more severe damage caused by UPR stress in SCN.
Diagnosis
A diagnosis is usually confirmed by monitoring absolute neutrophil (ANC) count three times per week for at least six weeks. The confirmation can be assisted with Lomb periodogram. During the condition, which lasts for three to six days and tends to occur approximately every three weeks (but can range from 14 to 36 days), the absolute neutrophil count (ANC) is less than 200-500 cells/microL (<0.2-0.5x109/L), with increase of monocyte counts, and mild oscillations of other cells, including a mild anemia. Between cycles the neutrophil count mostly peaks at subnormal or normal values.Genetic testing is advised for mutations in the ELANE and other neutropenia related genes (like HAX1, G6PC3, GFI1 etc.) to differentiate it from other secondary causes and forms of neutropenia. In some cases intervals and oscillations can be lower, making the ANC analysis insufficient, and since both disorders can have the same mutation variants in ELANE it is preferable to have both ANC and genetic analysis to confirm in the diagnosis whether it is severe congenital or cyclic neutropenia.
Treatment
Although individuals between cycles are generally healthy and symptoms tend to improve in adulthood, it is advised avoiding activities prone to injuries, to have regular oral and dental care, and BCG vaccine to be avoided. It is advised monitoring white blood cells several times a year. The treatment following the symptoms should be immediate to prevent infections, especially during a fever when it requires broad-spectrum antibiotic therapy (see febrile neutropenia). The most important and often life-saving treatment is the preventive therapy of granulocyte colony-stimulating factor (G-CSF), in the form of filgrastim, which regulates the production of neutrophils within the bone marrow, but shortens the neutropenic cycle to about 7-14 days and the duration of the severe condition. The subcutaneous injections, with median dosage of 1.5 μg/kg/day, can be given daily, intermittently once every three days, or timed to just treat the neutropenic period. The therapy is considered to be "safe and effective", with no significant adverse effects, besides a possibility of development of osteopenia.The granulocyte-macrophage colony-stimulating factor (GM-CSF) is less effective with more adverse effects. Another alternative is hematopoietic stem cell transplantation (HSCT), but is usually practiced in SCN, and in one case between two sibling donors, one of which was undergoing HSCT treatment for acute myeloid leukemia (AML) while the second had CyN and whose marrow was transferred, was also transferred CyN through allogeneic marrow grafting. It shows that CyN is a stem cell disorder. Yearly bone marrow examinations are not recommended.
Prognosis
There is a very high risk of life-threatening infections and death at an early age. The quality of life and survival greatly improves with G-CSF treatment, which is practiced since the late 1980s. Unlike severe congenital neutropenia, individuals with cyclic neutropenia have a better response to G-CSF and do not have a risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, in long-term observation of over 300 patients with CyN, there has been one case of developing chronic myelogenous leukemia (CML) and one of AML, indicating it is also a pre-leukemic condition, but the risk is "very low" (1%), and the risk is "correlated with disease severity rather than with occurrence of an ELANE mutation". According to Donadieu et al. (2011), "the cumulative risk of experiencing at least one serious (potentially life-threatening) infection by age 20 years is similar in patients with permanent and cyclic neutropenia, although the former patients tend to have earlier manifestations".
History
First described in 1910, it was suggested and confirmed to have an autosomal dominant (AD) inheritance in the 1940s and 1960s, but was differentiated from congenital neutropenias until the 1990s when were analyzed pedigrees and identified genetic mutations shared by patients with severe congenital neutropenia.
See also
Leukopenia
Agranulocytosis
References
External links
Severe Chronic Neutropenia International Registry
"Understanding Neutropenia: The 20 Year Experience of the Severe Chronic Neutropenia International Registry (SCNIR)" (2014) |
Zar | Zar may refer to:
Places
Zar, Armenia
Zar, Azerbaijan
Žár, Czech Republic
Zar, Iran, in Markazi Province
Zeraq, or Zar, Hamadan Province, Iran
Żar, Łódź Voivodeship, Poland
Żar (mountain), in Poland
Žar Mountain, a mountain range in Kosovo
South African Republic (Dutch: Zuid-Afrikaanse Republiek)
People
Surname
Chet Zar (born 1967), American artist; son of James Zar
Heather Zar (born ?), South African pediatrician, respiratory specialist, writer, and professor
Ibn Abi Zar (died between 1310 and 1320), Moroccan historian and poet; presumed author of the medieval history of Morocco, Rawd al-Qirtas
James Zar (1941–2015), American artist; father of Chet Zar
Jerrold Zar (born 1941), American biologist and professor
Lwi Zar (born 1976), Burmese politician
Mordechai Zar (1914–1982), Israeli politician
Moshe Zar (born 1938), Israeli settlement leader and religious Zionist
Paul Zar (born 1967), American bobsledder and Olympic competitor
Pe Thein Zar (1943–2018), Burmese-born Australian student leader, lawyer, revolutionary and freedom fighter, and writer
Rose Zar (1922–2001), a Polish Holocaust survivor, human rights activist, and author
Sarah Zar (born ?), American visual and performance artist, musician, songwriter, and writer
Given name
Zar Wali Khan (born 1953), Pakistani Islamic scholar
Zar Gul Khan (fl. 2017), Pakistani politician
Zar Lawrence (born 1982), New Zealand rugby player
Zar Randeri (pen name of Bharucha Hasim bin Yusuf; 1887–?), Indian Gujarati poet and translator
Zar Zar Myint (born 1993), Burmese footballer
Zar Zari Zar Baksh (fl.c. AD 1400), Indian Sufi saint
Zarsanga (or Zar Sanga, born 1946), Pakistani Pashto folk singer
Other uses
Zār, or Zaar, a demon or spirit in the Horn of Africa and adjacent regions of the Middle East
Zar, a band featuring John Lawton
Zar, a fictional land in "The White Ship" by H. P. Lovecraft
Zar Points, a statistical method for evaluating hands in contract bridge
Rincón Zapotec, a language of Mexico, ISO 639-3 code zar
South African rand, the currency of South Africa, ISO 4217 code ZAR
See also
All pages with titles beginning with Zar
All pages with titles containing Zar
Zaar (disambiguation)
Żar (disambiguation)
Tsar (disambiguation)
Zar und Zimmermann, a comic opera |
Nocturnal sleep-related eating disorder | Nocturnal sleep-related eating disorder (NSRED) is a combination of a parasomnia and an eating disorder. It is a NREM parasomnia. It is described as being in a specific category within somnambulism or a state of sleepwalking that includes behaviors connected to a persons conscious wishes or wants. Thus many times NSRED is a persons fulfilling of their conscious wants that they suppress; however, this disorder is difficult to distinguish from other similar types of disorders.
Comparison with night eating syndrome
NSRED is closely related to night eating syndrome (NES) except for the fact that those with NES are completely awake and aware of their eating and bingeing at night while those with NSRED are sleeping and unaware of what they are doing. NES is primarily considered an eating disorder while NSRED is primarily considered a parasomnia; however, both are a combination of parasomnia and eating disorders since those with NES usually have insomnia or difficulty sleeping and those with NSRED experience symptoms similar to binge eating. Some even argue over whether NES and NSRED are the same or distinct disorders. Even though there have been debates over these two disorders, specialists have examined them to try to determine the differences. Dr. J. Winkelman noted several features of the two disorders that were similar, but he gave one important factor that make these disorders different. In his article "Sleep-Related Eating Disorder and Night Eating Syndrome: Sleep Disorders, Eating Disorders, Or both", Winkelman said, "Both [disorders] involve nearly nightly binging at multiple nocturnal awakenings, defined as excess calorie intake or loss of control over consumption." He also reported that both disorders have a common occurrence of approximately one to five percent of adults, have been predominantly found in women, with a young adult onset, have a chronic course, have a primary morbidity of weight gain, sleep disruption, and shame over loss of control over food intake, have familial bases, and have been observed to have comorbid depression and daytime eating disorders. However, Winkelman said, "The most prominent cited distinction between NES and SRED is the level of consciousness during nighttime eating episodes." Therefore, these two disorders are extremely similar with only one distinction between them. Doctors and psychologists have difficulty differentiating between NES and NSRED, but the distinction of a persons level of consciousness is what doctors chiefly rely on to make a diagnosis. One mistake that is often made is the misdiagnosis of NSRED for NES. However, even though NSRED is not a commonly known and diagnosed disease, many people with it in differing ways while doctors work to find a treatment that works for everyone; several studies have been done on NSRED, such as the one conducted by Schenck and Mahowald. These studies, in turn, provide the basic information on this disorder including the symptoms, behaviors, and possible treatments that doctors are using today.
Signs and symptoms
Over the past 30 years, several studies have found that those affected by NSRED all have different symptoms and behaviors specific to them, yet they also all have similar characteristics that doctors and psychologists have identified to distinguish NSRED from other combinations of sleep and eating disorders such as night eating syndrome. Winkelman says that typical behaviors for patients with NSRED include: "Partial arousals from sleep, usually within 2 to 3 hours of sleep onset, and subsequent ingestion of food in a rapid or out of control manner." They also will attempt to eat bizarre amalgamations of foods and even potentially harmful substances such as glue, wood, or other toxic materials. In addition, Schenck and Mahowald noted that their patients mainly ate sweets, pastas, both hot and cold meals, improper substances such as "raw, frozen, or spoiled foods; salt or sugar sandwiches; buttered cigarettes; and odd mixtures prepared in a blender."During the handling of this food, patients with NSRED distinguish themselves, as they are usually messy or harmful to themselves. Some eat their food with their bare hands while others attempt to eat it with utensils. This occasionally results in injuries to the person as well as other injuries. After completing their studies, Schenck and Mahowald said, "Injuries resulted from the careless cutting of food or opening of cans; consumption of scalding fluids (coffee) or solids (hot oatmeal); and frenzied running into walls, kitchen counters, and furniture." A few of the more notable symptoms of this disorder include large amounts of weight gain over short periods of time, particularly in women; irritability during the day, due to lack of restful sleep; and vivid dreams at night. It is easily distinguished from regular sleepwalking by the typical behavioral sequence consisting of "rapid, automatic arising from bed, and immediate entry into the kitchen." In addition, throughout all of the studies done, doctors and psychiatrists discovered that these symptoms are invariant across weekdays, weekends, and vacations as well as the eating excursions being erratically spread throughout a sleep cycle. Most people with this disease retain no control over when they arise and consume food in their sleep. Although some have been able to restrain themselves from indulging in their unconscious appetites, some have not and must turn to alternative methods of stopping this disorder. It is important for trained physicians to recognize these symptoms in their patients as quickly as possible, so those with NSRED may be treated before they injure themselves.
Diagnosis
Criteria
The diagnostic criteria utilized by the International Classification of Sleep Disorders-Third Edition (ICSD-3) include some dysfunctional eating when the person wake up during the main sleep period, eating unusual or toxic food, negative health consequences. The patient could be injured during these episodes and he might not be conscious and wont remember them. This criterion differentiates SRED from Night eating syndrome(NES). Patients with NES are conscious during the episode.
Treatment
For those patients who have not been able to stop this disorder on their own, doctors have been working to discover a treatment that will work for everyone. One treatment that Schenck and Mahowald studied consisted of psychotherapy combined with "environmental manipulation". This was usually done separately from the weight-reducing diets. However, during this study only 10 percent of the patients were able to lose more than one third of their initial excess weight, which was not a viable percentage. In addition, they reported that many of the patients experienced "major depression" and "severe anxiety" during the attempted treatments. This was not one of the most successful attempts to help those with NSRED.
However, Dr. R. Auger reported on another trial treatment where patients were treated utilizing pramipexole. Those conducting the treatment noticed how the nocturnal median motor activity was decreased, as was assessed by actigraphy, and individual progress of sleep quality was reported. Nevertheless, Augur also said, "27 percent of subjects had RLS (restless legs syndrome, a condition known to respond to this medication), and number and duration of waking episodes related to eating behaviors were unchanged." Encouraged by the positive response verified in the above-mentioned trial treatment, doctors and psychiatrists conducted a more recent study described by Auger as "efficacy of topiramate [an antiepileptic drug associated with weight loss] in 17 consecutive patients with NSRED." Out of the 65 percent of patients who continued to take the medication on a regular basis, all confirmed either considerable development or absolute remission of "night-eating" in addition to "significant weight loss" being achieved. This has been one of the most effective treatments discovered so far, but many patients still had NSRED. Therefore, other treatments were sought after.
Such treatments include those targeted to associated sleep disorders with the hope that it would play an essential part of the treatment process of NSRED. In Schenck and Mahowalds series, combinations of cardibopa/L-dopa, codeine, and clonazepam were used to treat five patients with RLS and one patient with somnambulism and PLMS (periodic limb movements in sleep). These patients all were with NSRED as well as these other disorders, and they all experienced a remission of their NSRED as a result of taking these drugs. Two patients with OSA (obstructive sleep apnea) and NSRED also reported as having a "resolution of their symptoms with nasal continuous positive airway pressure (nCPAP) therapy." Clonazepam monotherapy was also found to be successful in 50 percent of patients with simultaneous somnambulism. Dopaminergic agents such as monotherapy were effective in 25 percent of the NSRED subgroup. Success with combinations of dopaminergic and opioid drugs, with the occasional addition of sedatives, also was found in seven patients without associated sleep disorders. In those for whom opioids and sedatives are relatively contraindicated (e.g., in those with histories of substance abuse), two case reports were described as meeting with success with a combination of bupropion, levodopa, and trazodone. Notably, hypnotherapy, psychotherapy, and various behavioral techniques, including environmental manipulation, were not effective on the majority of the patients studied. Nevertheless, Auger argue that behavioral strategies should complement the overall treatment plan and should include deliberate placement of food to avoid indiscriminate wandering, maintenance of a safe sleep environment, and education regarding proper sleep hygiene and stress management. Even with their extensive studies, Schenck and Mahowald did not find the success as Auger found by treating his patients with topiramate.
History
The first case of NSRED was reported in 1955, but over the next 36 years, only nine more reports were made of this syndrome. Seven of these reports were single-case studies and the other two instances were seen during objective sleep studies, all done by psychiatrists and doctors. Schenck and Mahowald were the first to a major study on this disorder. They started their study of NSRED in 1985 and continued until 1993 with several cases among a total of 38 other various sleep-related disorders. Many of the cases they observed had symptoms that overlapped with those of NES, but this study was the first to discover that NSRED was different from NES in the fact that those with NSRED were either partially or completely unaware of their actions at night while those with NES were aware. Schenck and Mahowald also discovered that none of the patients had any eating instability before their problems at night while sleeping. In their 1993 report, they summarized the major findings with the idea that women encompass at least two thirds of the patients and that the majority of these patients had become overweight. They also discovered that while the patients night-eating normally started during early adulthood, this wasnt always the case as it started as early as childhood to as late as middle adulthood. These patients not only had NSRED, but many of them had also had other nighttime behaviors such as sleep terrors for several years. This revolutionized the way people saw NSRED.
With the technological age growing and more people becoming obese, Schenck and Mahowalds discovery of NSRED causing a large weight increase helped doctors more easily identify this disorder. As seen in Table 1 below, almost half of Schenck and Mahowalds patients were significantly obese. According to body mass indexs criteria, no patient was emaciated. Schenck and Mahowald said, "virtually all patients had accurate non-distorted appraisals of their body size, shape, and weight. Furthermore, unlike the patients in Stunkards series, none of our patients had problematic eating in the evening between dinner and bedtime; sleep onset insomnia was not present; and sleep latency was usually brief, apart from several patients with RLS." After realizing what was wrong with them, many of Schenck and Mahowalds patients with NSRED restricted their day eating and over exercised. This table summary identifies the first initial findings concerning NSRED, and it shows how NSRED is a random malady that affects many different types of people in individual ways.
See also
Night eating syndrome
References
== External links == |
Accessory auricle | An accessory auricle is considered a developmental anomaly resulting from the persistence of a structure which variably recapitulates the normal external ear.
Signs and symptoms
The general presentation is of a skin-covered nodule, papule, or nodule of the skin surface, usually immediately anterior to the auricle. However, it may be anywhere within the periauricular tissues. Bilateral presentation can be seen.
Genetics
A study of a family with 11 affected showed the accessory auricle were inherited in an autosomal dominant manner.
Diagnosis
The lesions presents as a nodule or papule, either sessile or pedunculated. They may be soft or have a cartilaginous structure. By histologic examination, it is a recapitulation of normal external auricle. There will be skin, cartilaginous structures, and cartilage (although the later is not seen in all variants of this disorder). Some investigators believe that the tragus is the only hillock which is derived from the first branchial arch. This is clearly suggestive that true cases of Accessory Auricle represent a true duplication of the hillocks that were part of the second branchial arch. The second ear appears as a mirror image folded forward and lying on the posterior cheek.
Differential diagnosis
These structures are distinctly different from squamous papilloma and benign teratoma.
Classification
The several components or degrees of development range from an ear tag, preauricular appendage, preauricular tag, or accessory tragus, to supernumerary ears or polyotia. It is a relatively common congenital anomaly of the first branchial arch or second branchial arches. Other anomalies may be present concurrently, including cleft palate, cleft lip, or mandibular hypoplasia. There is a known association with Goldenhar syndrome (oculo-auriculo-vertebral syndrome) and with Wildervanck syndrome. There may also be an association with congenital cartilaginous rest of the neck.
Management
Simple surgical excision is curative. The recommended treatment is that the skin is peeled off the extra-auricular tissue and protruding cartilage remnants are trimmed. Normal appearance is achieved in majority of cases. The reconstruction successful in true cases of accessory auricle, as it also is in individuals with auricular appendages.
Epidemiology
These lesions usually present in neonates, although they may not come to clinical attention until adulthood (for cosmetic reasons). There is no gender predilection. They are present in approximately 3-6 per 1000 live births.
References
Further reading
Lester D. R. Thompson; Bruce M. Wenig (2011). Diagnostic Pathology: Head and Neck. Hagerstown, MD: Lippincott Williams & Wilkins. pp. 7:2–3. ISBN 978-1-931884-61-7.
== External links == |
Chronic lymphocytic leukemia | Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on there are typically no symptoms. Later non-painful lymph node swelling, feeling tired, fever, night sweats, or weight loss for no clear reason may occur. Enlargement of the spleen and low red blood cells (anemia) may also occur. It typically worsens gradually over years.Risk factors include having a family history of the disease, with 10% of those who develop CLL having a family history of the disease. Exposure to Agent Orange, certain insecticides, sun exposure, exposure to hepatitis C virus, and common infections are also considered risk factors. CLL results in the buildup of B cell lymphocytes in the bone marrow, lymph nodes, and blood. These cells do not function well and crowd out healthy blood cells. CLL is divided into two main types: those with a mutated IGHV gene and those without. Diagnosis is typically based on blood tests finding high numbers of mature lymphocytes and smudge cells.Early-stage CLL in asymptomatic cases responds better to careful observation, as there is no evidence that early intervention treatment can alter the course of the disease. Immune defects occur early in the course of CLL and these increase the risk of developing serious infection, which should be treated appropriately with antibiotics. In those with significant symptoms, chemotherapy, immunotherapy, or chemoimmunotherapy may be used. Depending on the individual’s age, physical condition, and whether they have the del(17p) or TP53 mutation, different first line treatments may be offered. As of 2021, BTK inhibitors such as ibrutinib and acalabrutinib are often recommended for first line treatment of CLL. The medications fludarabine, cyclophosphamide, and rituximab were previously the initial treatment in those who are otherwise healthy.CLL affected about 904,000 people globally in 2015 and resulted in 60,700 deaths. In 2021, the estimated incidence of CLL in the United States is 21, 250 new cases and 4,320 deaths. The disease most commonly occurs in people over the age of 65 due to the accumulation of genetic mutations that occurs over time. Men are diagnosed around twice as often as women (6.8 to 3.5 ratio). It is much less common in people from Asia. Five-year survival following diagnosis is approximately 83% in the United States. It represents less than 1% of deaths from cancer.
Signs and symptoms
Most people are diagnosed as having CLL based on the result of a routine blood test that shows a high white blood cell count, specifically a large increase in the number of circulating lymphocytes. These people generally have no symptoms. Less commonly, CLL may present with enlarged lymph nodes. If enlarged lymph nodes are caused by infiltrating CLL-type cells, a diagnosis of small lymphocytic lymphoma (SLL) is made. Less commonly the disease comes to light only after the cancerous cells overwhelm the bone marrow resulting in low red blood cells, neutrophils, or platelets. Or there is fever, night sweats, weight loss, and the person feels tired.CLL can be grouped with small lymphocytic lymphoma (SLL) as one disease with two clinical presentations. Wherein, with CLL, diseased cells propagate from within the bone marrow, in SLL they propagate from within the lymphatic tissue. CLLs are, in virtually all cases, preceded by a particular subtype of monoclonal B-cell lymphocytosis (MBL). This subtype, termed chronic lymphocytic leukemia-type MBL (CLL-type MBL) is an asymptomatic, indolent, and chronic disorder in which people exhibit a mild increase in the number of circulating B-cell lymphocytes. These B-cells are abnormal: they are monoclonal, i.e. produced by a single ancestral B-cell, and have some of the same cell marker proteins, chromosome abnormalities, and gene mutations found in CLL. CLL/SLL MBL consist of two groups: low-count CLL/SLL MBL has monoclonal B-cell blood counts of <0.5x9 cells/liter (i.e. 0.5x9/L) while high-count CLL/SLL MBL has blood monoclonal B-cell counts ≥0.5x9/L but <5x109/L. Individuals with blood counts of these monoclonal B-cells >5x9/L are diagnosed as having CLL. Low-count CLL/SLL MBL rarely if ever progresses to CLL while high-count CLL/SLL MBL does so at a rate of 1-2% per year. Thus, CLL may present in individuals with a long history of having high-count CLL/SLL MBL. There is no established treatment for these individuals except monitoring for development of the disorders various complications (see treatment of MBL complications) and for their progression to CLL.
Complications
Complications include a low level of antibodies in the bloodstream (hypogammaglobulinemia) leading to recurrent infection, warm autoimmune hemolytic anemia in 10–15% of patients, and bone marrow failure. Chronic lymphocytic leukemia may also transform into Richters syndrome, the development of fast-growing diffuse large B cell lymphoma, prolymphocytic leukemia, Hodgkins lymphoma, or acute leukemia in some patients. Its incidence is estimated to be around 5% in people with CLL.Gastrointestinal (GI) involvement can rarely occur with chronic lymphocytic leukemia. Some of the reported manifestations include intussusception, small intestinal bacterial contamination, colitis, and others. Usually, GI complications with CLL occur after Richter transformation. Two cases to date have been reported of GI involvement in chronic lymphocytic leukemia without Richters transformation.
Cause
CLL can also be caused by a number of epigenetic changes, which are adaptations that add a tag to specific DNA sequences, rather than altering the sequence itself. In CLL, these changes can be classified into the addition of 3 different methyl subgroups (naïve B-cell-like, memory B-cell-like, and intermediate), which impact how much that DNA sequence is transcribed. Some relevant genetic mutations may be inherited. Since there is no one single mutation that is associated with CLL in all cases, an individual’s susceptibility may be impacted when multiple mutations that are associated with an increase in the risk of CLL are co-inherited. Up until 2020, 45 susceptibility loci have been identified. 93% of these loci are linked to the alteration of 30 gene expressions involved in immune response, cell survival, or Wnt signaling. Exposure to Agent Orange increases the risk of CLL, and exposure to hepatitis C virus may increase the risk. There is no clear association between ionizing radiation exposure and the risk of developing CLL. Blood transfusions have been ruled out as a risk factor.
Diagnosis
The diagnosis of CLL is based on the demonstration of an abnormal population of B lymphocytes in the blood, bone marrow, or tissues that display an unusual but characteristic pattern of molecules on the cell surface. CLL is usually first suspected by a diagnosis of lymphocytosis, an increase in a type of white blood cell, on a complete blood count test. This frequently is an incidental finding on a routine physician visit. Most often the lymphocyte count is greater than 5000 cells per microliter (µl) of blood but can be much higher. The presence of lymphocytosis in a person who is elderly should raise strong suspicion for CLL, and a confirmatory diagnostic test, in particular flow cytometry, should be performed unless clinically unnecessary.
Molecular examination of peripheral blood and flow cytometry
The combination of the microscopic examination of the peripheral blood and analysis of the lymphocytes by flow cytometry to confirm clonality and marker molecule expression is needed to establish the diagnosis of CLL. Both are easily accomplished on a small amount of blood. A flow cytometer instrument can examine the expression of molecules on individual cells in fluids. This requires the use of specific antibodies to marker molecules, with fluorescent tags recognized by the instrument.
In CLL, the lymphocytes are all genetically identical since they are derived from the same B cell lineage, expressing common B-cell markers CD19 and CD20, with abnormal expression of surface markers CD5 and CD23. These B cells resemble normal lymphocytes under the microscope, although slightly smaller, and are fragile when smeared onto a glass slide, giving rise to many broken cells, which are called "smudge" or "smear" cells and can indicate the presence of the disease. Smudge cells are due to cancer cells lacking in vimentin, a type of cytoskeleton proteins which is a structural component in a cell which maintains the cells internal shape and mechanical resilience).: 1899
Surface markers
The atypical molecular pattern on the surface of the cell includes the coexpression of cell surface markers clusters of differentiation 5 (CD5) and 23. In addition, all the CLL cells within one individual are clonal, that is, genetically identical. In practice, this is inferred by the detection of only one of the mutually exclusive antibody light chains, kappa or lambda, on the entire population of the abnormal B cells. Normal B lymphocytes consist of a stew of different antibody-producing cells, resulting in a mixture of both kappa- and lambda-expressing cells. The lack of the normal distribution of these B cells is one basis for demonstrating clonality, the key element for establishing a diagnosis of any B cell malignancy (B cell non-Hodgkin lymphoma).The Matutess CLL score allows the identification of a homogeneous subgroup of classical CLL, that differs from atypical/mixed CLL for the five markers expression (CD5, CD23, FMC7, CD22, and immunoglobulin light chain)
Matutess CLL scoring system is very helpful for the differential diagnosis between classical CLL and the other B cell chronic lymphoproliferative disorders, but not for the immunological distinction between mixed/atypical CLL and mantle cell lymphoma (MCL malignant B cells). Discrimination between CLL and MCL can be improved by adding non-routine markers such as CD54 and CD200. Among routine markers, the most discriminating feature is the CD20/CD23 mean fluorescence intensity ratio. In contrast, FMC7 expression can surprisingly be misleading for borderline cases.
Clinical staging
Staging, determining the extent of the disease, is done with the Rai staging system or the Binet classification (see details) and is based primarily on the presence of a low platelet or red cell count. Early-stage disease does not need to be treated. CLL and SLL are considered the same underlying disease, just with different appearances.: 1441 Rai staging system (most commonly used in the United States)
Stage 0: characterized by absolute lymphocytosis (>15,000/mm3) without lymphadenopathy, hepatosplenomegaly, anemia, or thrombocytopenia
Stage I: characterized by absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia
Stage II: characterized by absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy
Stage III: characterized by absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or splenomegaly
Stage IV: characterized by absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemiaBinet classification (most commonly used in Europe)
Clinical stage A: characterized by no anemia or thrombocytopenia and fewer than three areas of lymphoid involvement (Rai stages 0, I, and II)
Clinical stage B: characterized by no anemia or thrombocytopenia with three or more areas of lymphoid involvement (Rai stages I and II)
Clinical stage C: characterized by anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement (Rai stages III and IV)
Array-based karyotyping
Array-based karyotyping is a cost-effective alternative to FISH for detecting chromosomal abnormalities in CLL. Several clinical validation studies have shown >95% concordance with the standard CLL FISH panel.
Related diseases
In the past, cases with similar microscopic appearance in the blood but with a T cell phenotype were referred to as T-cell CLL. However, these are now recognized as a separate disease group and are currently classified as T-cell prolymphocytic leukemias (T-PLL). An accurate diagnosis of T-PLL is important as it is a rare and aggressive disease.CLL should not be confused with acute lymphoblastic leukemia, a highly aggressive leukemia most commonly diagnosed in children, and highly treatable in the pediatric setting.
Differential diagnosis
Hematologic disorders that may resemble CLL in their clinical presentation, behavior, and microscopic appearance include mantle cell lymphoma, marginal zone lymphoma, B cell prolymphocytic leukemia, and lymphoplasmacytic lymphoma.
B cell prolymphocytic leukemia, a related, but more aggressive disorder, has cells with similar phenotype, but are significantly larger than normal lymphocytes and have a prominent nucleolus. The distinction is important as the prognosis and therapy differ from CLL.
Hairy cell leukemia is also a neoplasm of B lymphocytes, but the neoplastic cells have a distinct morphology under the microscope (hairy cell leukemia cells have delicate, hair-like projections on their surfaces) and unique marker molecule expression.All the B cell malignancies of the blood and bone marrow can be differentiated from one another by the combination of cellular microscopic morphology, marker molecule expression, and specific tumor-associated gene defects. This is best accomplished by evaluation of the patients blood, bone marrow, and occasionally lymph node cells by a pathologist with specific training in blood disorders. A flow cytometer is necessary for cell marker analysis, and the detection of genetic problems in the cells may require visualizing the DNA changes with fluorescent probes by FISH.
Treatment
CLL treatment focuses on controlling the disease and its symptoms rather than on an outright cure. In those without or only minimal symptoms watchful waiting is generally appropriate.CLL is treated by chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation. Symptoms are sometimes treated surgically (splenectomy – removal of enlarged spleen) or by radiation therapy ("de-bulking" swollen lymph nodes).Initial CLL treatments vary depending on the exact diagnosis and the progression of the disease, and even with the preference and experience of the health care practitioner. Any of dozens of agents may be used for CLL therapy.
Decision to treat
While it is generally considered incurable, CLL progresses slowly in most cases. Many people with CLL lead normal and active lives for many years—in some cases for decades. Because of its slow onset, asymptomatic early-stage CLL (Rai 0, Binet A) is, in general, not treated since it is believed that early-stage CLL intervention does not improve survival time or quality of life. Instead, the condition is monitored over time to detect any change in the disease pattern.The decision to start CLL treatment is taken when there is evidence for progressive symptomatic disease (summarized as "active disease").Clinical "staging systems" such as the Rai four-stage system and the Binet classification can help to determine when and how to treat the patient.Determining when to start treatment and by what means is often difficult; no survival advantage is seen in treating people with asymptomatic early-stage CLL. The International Workshop on CLL (iwCLL) has issued guidelines with specific markers that should be met to initiate treatment.
Chemotherapy
Combination chemotherapy regimens are effective in both newly diagnosed and relapsed CLL. Combinations of fludarabine with alkylating agents (cyclophosphamide) produce higher response rates and longer progression-free survival than single agents:
FC (fludarabine with cyclophosphamide)
FR (fludarabine with rituximab)
FCR (fludarabine, cyclophosphamide, and rituximab)
CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)Although the purine analogue fludarabine was shown to give superior response rates to chlorambucil as primary therapy, no evidence shows early use of fludarabine improves overall survival, and some clinicians prefer to reserve fludarabine for relapsed disease.
Chemoimmunotherapy with FCR has shown to improve response rates, progression-free survival, and overall survival in a large randomized trial in CLL patients selected for good physical fitness. This has been the first clinical trial demonstrating that the choice of a first-line therapy can improve the overall survival of people with CLL.Alkylating agents approved for CLL include bendamustine and cyclophosphamide.
Targeted therapy
Targeted therapy attacks cancer cells at a specific target, with the aim of not harming normal cells. Targeted drugs used in CLL include venetoclax (a Bcl-2 inhibitor), ibrutinib (a Brutons tyrosine kinase inhibitor), idelalisib and duvelisib (inhibitors of some forms of the enzyme phosphoinositide 3-kinase), as well as monoclonal antibodies against CD20 (rituximab, ofatumumab and obinutuzumab) and CD52 (alemtuzumab). Notably, some of the effects of the targeted therapies such as BCR inhibitors can be attributed to disrupting the interaction of CLL cells with tumour promoting T cells.
Stem cell transplantation
Autologous stem cell transplantation, using the recipients own cells, is not curative.: 1458 Younger individuals, if at high risk for dying from CLL, may consider allogeneic hematopoietic stem cell transplantation (HSCT). Myeloablative (bone marrow killing) forms of allogeneic stem cell transplantation, a high-risk treatment using blood cells from a healthy donor, may be curative, but treatment-related toxicity is significant.: 1458 An intermediate level, called reduced-intensity conditioning allogeneic stem cell transplantation, may be better tolerated by older or frail patients.
Refractory CLL
"Refractory" CLL is a disease that no longer responds favorably to treatment within 6 months following the last cancer therapy. In this case, more aggressive targeted therapies, such as BCR or BCL2 pathway inhibitors, have been associated with increased survival.
During pregnancy
Leukemia is rarely associated with pregnancy, affecting only about one in 10,000 pregnant women. Treatment for chronic lymphocytic leukemias can often be postponed until after the end of the pregnancy. If treatment is necessary, then giving chemotherapy during the second or third trimesters is less likely to result in pregnancy loss or birth defects than treatment during the first trimester.
Prognosis
Prognosis can be affected by the type of genetic mutation that the person with CLL has. Some examples of genetic mutations and their prognoses are: mutations in the IGHV region are associated with a median overall survival (OS) of more than 20–25 years, while no mutations in this region is associated with a median OS of 8–10 years; deletion of chromosome 13q is associated with a median OS of 17 years; and trisomy of chromosome 12, as well as deletion of chromosome 11q, is associated with a median OS of 9–11 years. While prognosis is highly variable and dependent on various factors including these mutations, the average 5-year relative survival is 86.1%. Telomere length has been suggested to be a valuable prognostic indicator of survival. In addition, a persons sex has been found to have an impact on CLL prognosis and treatment efficacy. More specifically, females have been found to survive longer (without disease progression) than males, when treated with certain medications.
Epidemiology
CLL is the most common type of leukaemia in the Western world compared to non-Western regions such as Asia, Latin America, and Africa. It is observed globally males are twice as likely than females to acquire CLL. CLL is primarily a disease of older adults, with 9 out of 10 cases occurring after the age of 50 years. The median age of diagnosis is 70 years. In young people, new cases of CLL are twice as likely to be diagnosed in men than in women. In older people, however, this difference becomes less pronounced: after the age of 80 years, new cases of CLL are diagnosed equally between men and women.According to the American Cancer Society, in the United States, 13,040 males and 8,210 females (total of 21,250 people) are expected to be newly diagnosed with CLL in 2021. In that same year, 2,620 males and 1,700 females (total of 4,320 people) are expected to die from CLL. Because of the prolonged survival, which was typically about 10 years in past decades, but which can extend to a normal life expectancy, the prevalence (number of people living with the disease) is much higher than the incidence (new diagnoses). CLL is the most common type of leukemia in the UK, accounting for 38% of all leukemia cases. Approximately 3,200 people were diagnosed with the disease in 2011.In Western populations, subclinical "disease" can be identified in 3.5% of normal adults, and in up to 8% of individuals over the age of 70. That is, small clones of B cells with the characteristic CLL phenotype can be identified in many healthy elderly persons. The clinical significance of these cells is unknown.
In contrast, CLL is rare in Asian countries, such as Japan, China, and Korea, accounting for less than 10% of all leukemias in those regions.: 1432 A low incidence is seen in Japanese immigrants to the US, and in African and Asian immigrants to Israel.Of all cancers involving the same class of blood cell, 7% of cases are CLL/SLL.People who live near areas with considerable industrial pollution have an elevated risk of developing leukemia, particularly CLL.
Research directions
In light of new therapies such as targeted agents, the role of bone marrow transplants is decreasing. Bone marrow transplants are not recommended as a front-line therapy, and only recommended in specific cases where front-line therapies have either failed or there is a lack of response to BCL-2 inhibitors.
Researchers at the Abramson Cancer Center of the University of Pennsylvania School of Medicine reported preliminary success in the use of gene therapy, through genetically modified T cells, to treat CLL. The findings, which were published in August 2011, were based on data from three patients who had modified T cells injected into their blood. The T cells had been modified to express genes that would allow the cells to proliferate in the body and destroy B cells including those causing the leukemia. Two patients went into remission, while the presence of leukemia in the third patient reduced by 70%.One of the patients had been diagnosed with CLL for 13 years, and his treatment was failing before he participated in the clinical trial. One week after the T cells were injected, the leukemia cells in his blood had disappeared. The T cells were still found in the bloodstream of the patients six months after the procedure, meaning they would be able to fight the disease should leukemia cells return. This was the first time scientists "have used gene therapy to successfully destroy cancer tumors in patients with advanced disease".Research is also investigating therapies targeting B cell receptor signalling. Syk inhibitors fostamatinib and entospletinib are currently in trials. The trial of a combination of ibrutinib and venetoclax had encouraging results in a small number of people.People with CLL undergoing immunotherapy with chimeric antigen receptor T cells have been found to have a high response rate.
See also
Monoclonal B-cell lymphocytosis
Virtual karyotype
B-cell CLL/lymphoma
References
External links
Chronic Lymphocytic Leukemia Archived 2008-12-21 at the Wayback Machine at American Cancer Society
General information about CLL Archived 2004-10-19 at the Wayback Machine from the US National Cancer Institute
Cancer.Net: Chronic Lymphocytic Leukemia |
Hypertelorism | Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits (eyes), or orbital hypertelorism. In this condition the distance between the inner eye corners as well as the distance between the pupils is greater than normal. Hypertelorism should not be confused with telecanthus, in which the distance between the inner eye corners is increased but the distances between the outer eye corners and the pupils remain unchanged.Hypertelorism is a symptom in a variety of syndromes, including Edwards syndrome (trisomy 18), 1q21.1 duplication syndrome, basal cell nevus syndrome, DiGeorge syndrome and Loeys–Dietz syndrome.
Hypertelorism can also be seen in Apert syndrome, Autism spectrum disorder, craniofrontonasal dysplasia, Noonan syndrome, neurofibromatosis, LEOPARD syndrome, Crouzon syndrome, Wolf–Hirschhorn syndrome, Andersen–Tawil syndrome, Waardenburg syndrome and cri du chat syndrome, along with piebaldism, prominent inner third of the eyebrows, irises of different color, spondyloepiphyseal dysplasia, mucopolysaccharide metabolism disorders (Morquio syndrome and Hurlers syndrome), deafness and also in hypothyroidism. Some links have been found between hypertelorism and attention deficit hyperactivity disorder.
Embryology
Because hypertelorism is an anatomic condition associated with a heterogeneous group of congenital disorders, it is believed that the underlying mechanism of hypertelorism is also heterogeneous. Theories include too early ossification of the lower wings of the sphenoid, an increased space between the orbita, due to increasing width of the ethmoid sinuses, field defects during the development, a nasal capsule that fails to form, leading to a failure in normal medial orbital migration and also a disturbance in the formation of the cranial base, which can be seen in syndromes like Apert and Crouzon.
Treatment
The craniofacial surgery to correct hypertelorism is usually done between five and eight years of age. This aesthetic-focused procedure addresses the psychosocial aspects in the childs early school years. Another reason for a correction age of five years or older is that the surgery should be delayed until the tooth buds have grown out low enough into the maxilla, thus preventing damage to them. Also, before age five the craniofacial bones are thin and fragile, which can make surgical correction difficult. In addition, it is possible that orbital surgery during infancy may inhibit midface growth.For the treatment of hypertelorism there are two main operative options: The box osteotomy and the facial bipartition (also referred to as median fasciotomy).
Box osteotomy
This treatment of orbital hypertelorism was first performed by Paul Tessier. The surgery starts off by various osteotomies that separate the entire bony part of the orbit from the skull and surrounding facial bones. One of the osteotomies consists of removing the bone between the orbits. The orbits are then mobilized and brought towards each other. Because this often creates excessive skin between the orbits a midline excision of skin is frequently necessary. This approximates the eyebrows and eye corners and provides a more pleasing look.
Facial bipartition
The standard procedure (box osteotomy) was modified by Jacques van der Meulen and resulted in the development of the facial bipartition (or median faciotomy).
Facial bipartition first involves splitting the frontal bone from the supraorbital rim. Then the orbits and the midface are released from the skull-base using monoblock osteotomy. Then a triangular shaped piece of bone is removed from the midline of the midface. The base of this triangular segment lies above the orbita and the apex lies between the upper incisor teeth. After removing this segment it is possible to rotate the two halves of the midface towards each other, thus resulting in reduction of the distance between the orbits. It also results in leveling out the V-shaped maxilla and therefore widening of it.
Because hypertelorism is often associated with syndromes like Apert, hypertelorism is often seen in combination with midface dysplasia. If this is the case, facial bipartition can be combined with distraction osteogenesis. The aim of distraction osteogenesis of the midface is to normalize the relationship between orbital rim to eye and also normalize the position of zygomas, nose and maxilla in relation to the mandible.
Soft tissue reconstruction
To create an acceptable aesthetic result in the correction of orbital hypertelorism, it is also important to take soft-tissue reconstruction in consideration. In this context, correction of the nasal deformities is one of the more difficult procedures. Bone and cartilage grafts may be necessary to create a nasal frame and local rotation with for example forehead flaps, or advancement flaps can be used to cover the nose.
Complications from surgery
As with almost every kind of surgery, the main complications in both treatments of hypertelorism include excessive bleeding, risk of infection and CSF leaks and dural fistulas. Infections and leaks can be prevented by giving perioperative antibiotics and identifying and closing of any dural tears. The risk of significant bleeding can be prevented by meticulous technique and blood loss is compensated by transfusions. Blood loss can also be reduced by giving hypotensive anesthesia. Major eye injuries, including blindness, are rarely seen. Visual disturbances can occur due to the eye muscle imbalance after orbital mobilization. Ptosis and diplopia can also occur postoperatively, but this usually self-corrects. A quite difficult problem to correct postoperatively is canthal drift, which can be managed best by carefully preserving the canthal tendon attachments as much as possible. Despite the extensiveness in these procedures, mortality is rarely seen in operative correction of hypertelorism.
See also
Hypotelorism
Telecanthus
References
== External links == |
Nail clubbing | Nail clubbing, also known as digital clubbing or clubbing, is a deformity of the finger or toe nails associated with a number of diseases, mostly of the heart and lungs. When it occurs together with joint effusions, joint pains, and abnormal skin and bone growth it is known as hypertrophic osteoarthropathy.Clubbing is associated with lung cancer, lung infections, interstitial lung disease, cystic fibrosis, or cardiovascular disease. Clubbing may also run in families, and occur unassociated with other medical problems.The incidence of clubbing is unknown; it was present in about 1% of people admitted to an internal medicine unit of a hospital. Clubbing has been recognized as a sign of disease since the time of Hippocrates.
Causes
Clubbing is associated with
Lung disease:
Lung cancer
Interstitial lung disease most commonly idiopathic pulmonary fibrosis
Complicated tuberculosis
Suppurative lung disease: lung abscess, empyema, bronchiectasis, cystic fibrosis
Mesothelioma of the pleura
Arteriovenous fistula or malformation
Sarcoidosis
Heart disease:
Any disease featuring chronic hypoxia
Congenital cyanotic heart disease (most common cardiac cause)
Subacute bacterial endocarditis
Atrial myxoma (benign tumor)
Tetralogy of Fallot
Gastrointestinal and hepatobiliary:
Malabsorption
Crohns disease and ulcerative colitis
Cirrhosis, especially in primary biliary cholangitis
Hepatopulmonary syndrome, a complication of cirrhosis
Others:
Graves disease (autoimmune hyperthyroidism) – in this case it is known as thyroid acropachy
Familial and hereditary clubbing and "pseudoclubbing" (people of African descent often have what appears to be clubbing)
Vascular anomalies of the affected arm such as an axillary artery aneurysm (in unilateral clubbing)Nail clubbing is not specific to chronic obstructive pulmonary disease (COPD). Therefore, in patients with COPD and significant degrees of clubbing, a search for signs of bronchogenic carcinoma (or other causes of clubbing) might still be indicated. A congenital form has also been recognized.
Hypertrophic pulmonary osteoarthropathy
A special form of clubbing is hypertrophic pulmonary osteoarthropathy (HPOA), known in continental Europe as Pierre Marie-Bamberger syndrome. This is the combination of clubbing and thickening of periosteum (connective tissue lining of the bones) and synovium (lining of joints), and is often initially diagnosed as arthritis. It is commonly associated with lung cancer.
Primary hypertrophic osteoarthropathy
Primary hypertrophic osteoarthropathy is HPOA without signs of pulmonary disease. This form has a hereditary component, although subtle cardiac abnormalities can occasionally be found. It is known eponymously as the Touraine–Solente–Golé syndrome. This condition has been linked to mutations in the gene on the fourth chromosome (4q33-q34) coding for the enzyme 15-hydroxyprostaglandin dehydrogenase (HPGD); this leads to decreased breakdown of prostaglandin E2 and elevated levels of this substance.
Pathogenesis
The exact cause for sporadic clubbing is unknown. Theories as to its cause include:
Vasodilation (i.e., distended blood vessels).
Secretion of growth factors (e.g., platelet-derived growth factor and hepatocyte growth factor) from the lungs.
Overproduction of prostaglandin E2 by other tissues.
Increased entry of megakaryocytes into the systemic circulation. Under normal circumstances in healthy individuals, megakaryocytes that arise from the bone marrow are trapped in the pulmonary capillary bed and broken down before they enter the systemic circulation. It is thought that in disorders where there is right-to-left shunting or lung malignancy, the megakaryocytes can bypass the breakdown within the pulmonary circulation and enter the systemic circulation. They are then trapped within the capillary beds within the extremities, such as the digits, and release platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). PDGF and VEGF have growth promoting properties and cause connective tissue hypertrophy and capillary permeability.
Diagnosis
When clubbing is observed, pseudoclubbing should be excluded before making the diagnosis. Associated conditions may be identified by taking a detailed medical history—particular attention is paid to lung, heart, and gastrointestinal conditions—and conducting a thorough clinical examination, which may disclose associated features relevant to the underlying diagnosis. Additional studies such as a chest X-ray and a chest CT-scan may reveal otherwise asymptomatic cardiopulmonary disease.
Stages
Clubbing is present in one of five stages:
No visible clubbing - Fluctuation (increased ballotability) and softening of the nail bed only. No visible changes of nails.
Mild clubbing - Loss of the normal <165° angle (Lovibond angle) between the nailbed and the fold (cuticula). Schamroths window (see below) is obliterated. Clubbing is not obvious at a glance.
Moderate clubbing - Increased convexity of the nail fold. Clubbing is apparent at a glance.
Gross clubbing - Thickening of the whole distal (end part of the) finger (resembling a drumstick)
Hypertrophic osteoarthropathy - Shiny aspect and striation of the nail and skinSchamroths sign or Schamroths window test (originally demonstrated by South African cardiologist Leo Schamroth on himself) is a popular test for clubbing. When the distal phalanges (bones nearest the fingertips) of corresponding fingers of opposite hands are directly opposed (place fingernails of same finger on opposite hands against each other, nail to nail), a small diamond-shaped "window" is normally apparent between the nailbeds. If this window is obliterated, the test is positive and clubbing is present.
Epidemiology
The exact frequency of clubbing in the population is not known. A 2008 study found clubbing in 1%, or 15 patients, of 1511 patients admitted to a department of internal medicine in Belgium. Of these, 40%, or 6 patients, turned out to have significant underlying disease of various causes, while 60%, or 9 patients, had no medical problems on further investigations and remained well over the subsequent year.
History
At least since the time of Hippocrates, clubbing has been recognized as a sign of disease. The phenomenon has been called "Hippocratic fingers".
See also
Clubbed thumb (unrelated congenital deformity)
== References == |
Ogden syndrome | Ogden syndrome, also known as N-terminal acetyltransferase deficiency (NATD), is an X-linked disorder of infancy comprising a distinct combination of distinctive craniofacial features producing an aged appearance, growth failure, hypotonia, global developmental delays, cryptorchidism, and spontaneous cardiac arrhythmias. The first family was identified in Ogden, Utah, with five affected boys in two generations of family members. A mutation was identified as a c.109T>C (p.Ser37Pro) variant in NAA10, a gene encoding the catalytic subunit of the major human N-terminal acetyltransferase enzyme system (NatA). This same mutation was identified in a second unrelated family, with three affected boys in two generations. This severe genetic disorder has provisionally been named Ogden syndrome, as this is the city where the first affected family resides.
Signs and symptoms
This is an X-linked condition affecting males more than females and is characterized by postnatal growth failure with developmental delays and dysmorphic features characterized by wrinkled forehead, anterior and posterior fontanels, prominent eyes, large down-slanting palpebral fissures, thickened or hooded eyelids, large ears, flared nares, hypoplastic alae nasi, short columella, protruding upper lip, and microretrognathia. There is also delayed closing of fontanelle, and the boys also have broad great toes. Skin is characterized by redundancy or laxity with minimal subcutaneous fat, cutaneous capillary malformations, and very fine hair and eyebrows. Death resulted from cardiogenic shock following arrhythmia, which was noted in all affected individuals. The boys had heart rhythm abnormalities and craniofacial abnormalities, which accounted for their similar appearance. The boys were never able to sit up on their own, and none learned how to talk. They all had a characteristically aged appearance, earning them the family nickname of "little old men." Several of the boys had structural anomalies of their hearts including ventricular septal defect, atrial septal defect, and pulmonary artery stenosis. Events recorded on electrocardiogram before death included torsades de pointes, premature ventricular contraction (PVC), premature atrial contraction (PAC), supraventricular tachycardia (SVtach), and ventricular tachycardia (Vtach). Most of the children had inguinal hernias, and the majority had, at least, unilateral cryptorchidism. All had neonatal hypotonia progressing to hypertonia, and cerebral atrophy on MRI; several, but not all, had neurogenic scoliosis. Death occurred prior to two years in all cases and prior to one year in the majority. There are extensive clinical details for each child reported in the original publication
Biochemistry
Ogden syndrome is a lethal X-linked recessive condition. Because the affected gene is on the X-chromosome, it affects males far more severely due to the fact that males only carry one copy of the X chromosome so the mutation is in every cell but females carry two and therefore some cells may use the non mutated copy and others use the mutated copy. It was the first reported human genetic disorder linked with a mutation in an N-terminal acetyltransferase (NAT) gene. The original Ogden family males have the Ser37Pro (S37P) mutation in the gene encoding NAA10, the catalytic subunit of NatA, the major human enzyme heterodimer involved in the post-translational acetylation of proteins. The S37P mutation swaps one amino acid for another, a serine for a proline, in just one part at the end of the resulting NatA protein subunit. Other mutations have since been discovered in very small number of cases worldwide with the most prevalent being Arg83Cys mutation. Mutations to this gene changes the structure of the protein, which makes it less effective at N-terminal acetylation than the normal protein, causing a multitude of effects for the baby, as N-terminal acetylation is one of the most common protein modifications in humans, occurring on approximately 80% of all human proteins.
Diagnosis
Whole exome sequencing is the definitive diagnostic method used to confirm OS.
History
Halena Black had her first son, Kenny Rae, in 1979. Being that he was her first born child, Black did not notice that something was wrong. Kenny Rae Black passed in 1980, right before his first birthday and was the first known infant to die from Ogden syndrome. However, it did not end there. Halena Black continued to have children and in 1987 she had her next boy, Hyrum. From the start, Black noticed that Hyrum had the same characteristics as Kenny Rae but thought it was due to the fact that they were brothers. Like Kenny Rae, Hyrum passed before his first birthday. It was only until Blacks daughters began having children of their own that she realized something was not right. The sons born to Blacks daughters looked identical to her own sons and that was when Halena sought medical help.Answers came thirty years after Kenny Raes death. Ogden syndrome was discovered in 2011 by a team of researchers led by Gholson J. Lyon, consisting of: Alan F. Rope, Kai Wang, Rune Evjenth, Jinchuan Xing, Jennifer J. Johnston, Jeffrey J. Swensen, W. Evan Johnson, Barry Moore, Chad D. Huff, Lynne M. Bird, John C. Carey, John M. Opitz, Cathy A. Stevens, Tao Jiang, Christa Schank, Heidi Deborah Fain, Reid J. Robison, and 10 others. Just before Lyon was about to publish his findings, another team researching a family living mainly in California contacted him. The newly found family had also lost three infant boys all with similar characteristics. This new family shared the same rare mutation as the Black family. The existence of another family made this mutation a syndrome, and not something isolated.
References
External links
NAA10 Families Together |
Cytochrome c oxidase | The enzyme cytochrome c oxidase or Complex IV, (was EC 1.9.3.1, now reclassified as a translocase EC 7.1.1.9) is a large transmembrane protein complex found in bacteria, archaea, and mitochondria of eukaryotes.It is the last enzyme in the respiratory electron transport chain of cells located in the membrane. It receives an electron from each of four cytochrome c molecules and transfers them to one oxygen molecule and four protons, producing two molecules of water. In addition to binding the four protons from the inner aqueous phase, it transports another four protons across the membrane, increasing the transmembrane difference of proton electrochemical potential, which the ATP synthase then uses to synthesize ATP.
Structure
The complex
The complex is a large integral membrane protein composed of several metal prosthetic sites and 14 protein subunits in mammals. In mammals, eleven subunits are nuclear in origin, and three are synthesized in the mitochondria. The complex contains two hemes, a cytochrome a and cytochrome a3, and two copper centers, the CuA and CuB centers. In fact, the cytochrome a3 and CuB form a binuclear center that is the site of oxygen reduction. Cytochrome c, which is reduced by the preceding component of the respiratory chain (cytochrome bc1 complex, Complex III), docks near the CuA binuclear center and passes an electron to it, being oxidized back to cytochrome c containing Fe3+. The reduced CuA binuclear center now passes an electron on to cytochrome a, which in turn passes an electron on to the cytochrome a3>-CuB binuclear center. The two metal ions in this binuclear center are 4.5 Å apart and coordinate a hydroxide ion in the fully oxidized state.
Crystallographic studies of cytochrome c oxidase show an unusual post-translational modification, linking C6 of Tyr(244) and the ε-N of His(240) (bovine enzyme numbering). It plays a vital role in enabling the cytochrome a3- CuB binuclear center to accept four electrons in reducing molecular oxygen and four protons to water. The mechanism of reduction was formerly thought to involve a peroxide intermediate, which was believed to lead to superoxide production. However, the currently accepted mechanism involves a rapid four-electron reduction involving immediate oxygen-oxygen bond cleavage, avoiding any intermediate likely to form superoxide.: 865–866
The conserved subunits
Assembly
COX assembly in yeast is a complex process that is not entirely understood due to the rapid and irreversible aggregation of hydrophobic subunits that form the holoenzyme complex, as well as aggregation of mutant subunits with exposed hydrophobic patches. COX subunits are encoded in both the nuclear and mitochondrial genomes. The three subunits that form the COX catalytic core are encoded in the mitochondrial genome.
Hemes and cofactors are inserted into subunits I & II. The two heme molecules reside in subunit I, helping with transport to subunit II where two copper molecules aid with the continued transfer of electrons. Subunits I and IV initiate assembly. Different subunits may associate to form sub-complex intermediates that later bind to other subunits to form the COX complex. In post-assembly modifications, COX will form a homodimer. This is required for activity. Dimers are connected by a cardiolipin molecule, which has been found to play a key role in stabilization of the holoenzyme complex. The dissociation of subunits VIIa and III in conjunction with the removal of cardiolipin results in total loss of enzyme activity. Subunits encoded in the nuclear genome are known to play a role in enzyme dimerization and stability. Mutations to these subunits eliminate COX function.Assembly is known to occur in at least three distinct rate-determining steps. The products of these steps have been found, though specific subunit compositions have not been determined.Synthesis and assembly of COX subunits I, II, and III are facilitated by translational activators, which interact with the 5’ untranslated regions of mitochondrial mRNA transcripts. Translational activators are encoded in the nucleus. They can operate through either direct or indirect interaction with other components of translation machinery, but exact molecular mechanisms are unclear due to difficulties associated with synthesizing translation machinery in-vitro. Though the interactions between subunits I, II, and III encoded within the mitochondrial genome make a lesser contribution to enzyme stability than interactions between bigenomic subunits, these subunits are more conserved, indicating potential unexplored roles for enzyme activity.
Biochemistry
The overall reaction is
4 Fe2+ – cytochrome c + 4 H+ + O2 → 4 Fe3+ – cytochrome c + 2 H2O ΔfGo = - 218 kJ/molTwo electrons are passed from two cytochrome cs, through the CuA and cytochrome a sites to the cytochrome a3–CuB binuclear center, reducing the metals to the Fe2+ form and Cu+. The hydroxide ligand is protonated and lost as water, creating a void between the metals that is filled by O2. The oxygen is rapidly reduced, with two electrons coming from the Fe2+-cytochrome a3, which is converted to the ferryl oxo form (Fe4+=O). The oxygen atom close to CuB picks up one electron from Cu+, and a second electron and a proton from the hydroxyl of Tyr(244), which becomes a tyrosyl radical. The second oxygen is converted to a hydroxide ion by picking up two electrons and a proton. A third electron from another cytochrome c is passed through the first two electron carriers to the cytochrome a3–CuB binuclear center, and this electron and two protons convert the tyrosyl radical back to Tyr, and the hydroxide bound to CuB2+ to a water molecule. The fourth electron from another cytochrome c flows through CuA and cytochrome a to the cytochrome a3–CuB binuclear center, reducing the Fe4+=O to Fe3+, with the oxygen atom picking up a proton simultaneously, regenerating this oxygen as a hydroxide ion coordinated in the middle of the cytochrome a3–CuB center as it was at the start of this cycle. Overall, four reduced cytochrome cs are oxidized while O2 and four protons are reduced to two water molecules.: 841–5
Inhibition
COX exists in three conformational states: fully oxidized (pulsed), partially reduced, and fully reduced. Each inhibitor has a high affinity to a different state. In the pulsed state, both the heme a3 and the CuB nuclear centers are oxidized; this is the conformation of the enzyme that has the highest activity. A two-electron reduction initiates a conformational change that allows oxygen to bind at the active site to the partially-reduced enzyme. Four electrons bind to COX to fully reduce the enzyme. Its fully reduced state, which consists of a reduced Fe2+ at the cytochrome a3 heme group and a reduced CuB+ binuclear center, is considered the inactive or resting state of the enzyme.Cyanide, azide, and carbon monoxide all bind to cytochrome c oxidase, inhibiting the protein from functioning and leading to the chemical asphyxiation of cells. Higher concentrations of molecular oxygen are needed to compensate for increasing inhibitor concentrations, leading to an overall reduction in metabolic activity in the cell in the presence of an inhibitor. Other ligands, such as nitric oxide and hydrogen sulfide, can also inhibit COX by binding to regulatory sites on the enzyme, reducing the rate of cellular respiration.Cyanide is a non-competitive inhibitor for COX, binding with high affinity to the partially-reduced state of the enzyme and hindering further reduction of the enzyme. In the pulsed state, cyanide binds slowly, but with high affinity. The ligand is posited to electrostatically stabilize both metals at once by positioning itself between them. A high nitric oxide concentration, such as one added exogenously to the enzyme, reverses cyanide inhibition of COX.Nitric oxide can reversibly bind to either metal ion in the binuclear center to be oxidized to nitrite. NO and CN− will compete with oxygen to bind at the site, reducing the rate of cellular respiration. Endogenous NO, however, which is produced at lower levels, augments CN− inhibition. Higher levels of NO, which correlate with the existence of more enzyme in the reduced state, lead to a greater inhibition of cyanide. At these basal concentrations, NO inhibition of Complex IV is known to have beneficial effects, such as increasing oxygen levels in blood vessel tissues. The inability of the enzyme to reduce oxygen to water results in a buildup of oxygen, which can diffuse deeper into surrounding tissues. NO inhibition of Complex IV has a larger effect at lower oxygen concentrations, increasing its utility as a vasodilator in tissues of need.Hydrogen sulfide will bind COX in a noncompetitive fashion at a regulatory site on the enzyme, similar to carbon monoxide. Sulfide has the highest affinity to either the pulsed or partially reduced states of the enzyme, and is capable of partially reducing the enzyme at the heme a3 center. It is unclear whether endogenous H2S levels are sufficient to inhibit the enzyme. There is no interaction between hydrogen sulfide and the fully reduced conformation of COX.Methanol in methylated spirits is converted into formic acid, which also inhibits the same oxidase system. High levels of ATP can allosterically inhibit cytochrome c oxidase, binding from within the mitochondrial matrix.
Extramitochondrial and subcellular localizations
Cytochrome c oxidase has 3 subunits which are encoded by mitochondrial DNA (cytochrome c oxidase subunit I, subunit II, and subunit III). Of these 3 subunits encoded by mitochondrial DNA, two have been identified in extramitochondrial locations. In pancreatic acinar tissue, these subunits were found in zymogen granules. Additionally, in the anterior pituitary, relatively high amounts of these subunits were found in growth hormone secretory granules. The extramitochondrial function of these cytochrome c oxidase subunits has not yet been characterized. Besides cytochrome c oxidase subunits, extramitochondrial localization has also been observed for large numbers of other mitochondrial proteins. This raises the possibility about existence of yet unidentified specific mechanisms for protein translocation from mitochondria to other cellular destinations.
Genetic defects and disorders
Defects involving genetic mutations altering cytochrome c oxidase (COX) functionality or structure can result in severe, often fatal metabolic disorders. Such disorders usually manifest in early childhood and affect predominantly tissues with high energy demands (brain, heart, muscle). Among the many classified mitochondrial diseases, those involving dysfunctional COX assembly are thought to be the most severe.The vast majority of COX disorders are linked to mutations in nuclear-encoded proteins referred to as assembly factors, or assembly proteins. These assembly factors contribute to COX structure and functionality, and are involved in several essential processes, including transcription and translation of mitochondrion-encoded subunits, processing of preproteins and membrane insertion, and cofactor biosynthesis and incorporation.Currently, mutations have been identified in seven COX assembly factors: SURF1, SCO1, SCO2, COX10, COX15, COX20, COA5 and LRPPRC. Mutations in these proteins can result in altered functionality of sub-complex assembly, copper transport, or translational regulation. Each gene mutation is associated with the etiology of a specific disease, with some having implications in multiple disorders. Disorders involving dysfunctional COX assembly via gene mutations include Leigh syndrome, cardiomyopathy, leukodystrophy, anemia, and sensorineural deafness.
Histochemistry
The increased reliance of neurons on oxidative phosphorylation for energy facilitates the use of COX histochemistry in mapping regional brain metabolism in animals, since it establishes a direct and positive correlation between enzyme activity and neuronal activity. This can be seen in the correlation between COX enzyme amount and activity, which indicates the regulation of COX at the level of gene expression. COX distribution is inconsistent across different regions of the animal brain, but its pattern of its distribution is consistent across animals. This pattern has been observed in the monkey, mouse, and calf brain. One isozyme of COX has been consistently detected in histochemical analysis of the brain. Such brain mapping has been accomplished in spontaneous mutant mice with cerebellar disease such as reeler and a transgenic model of Alzheimers disease. This technique has also been used to map learning activity in the animal brain.
Additional images
See also
Cytochrome c oxidase subunit I
Cytochrome c oxidase subunit II
Cytochrome c oxidase subunit III
Heme a
References
External links
The Cytochrome Oxidase home page at Rice University
Interactive Molecular model of cytochrome c oxidase (Requires MDL Chime)
UMich Orientation of Proteins in Membranes families/superfamily-4
Cytochrome-c+Oxidase at the US National Library of Medicine Medical Subject Headings (MeSH) |
Erythropoietic porphyria | Erythropoietic porphyria is a type of porphyria associated with erythropoietic cells. In erythropoietic porphyrias, the enzyme deficiency occurs in the red blood cells.
Types
There are three types:
Presentation
X-linked dominant erythropoietic protoporphyria is a relatively mild version of porphyria with the predominant symptom being extreme photosensitivity causing severe itching and burning sensation of the skin due to the buildup of protoporphyrin IX. One possible treatment was discovered when treating an individual with supplemental iron for a gastric ulcer. Levels of free protoporphyrin decreased significantly as there was iron available for the FECH to produce heme. Levels of zinc-protoporphyrin, however did not decrease.
Cause
X-linked sideroblastic anemia or "X-linked dominant erythropoietic protoporphyria", associated with ALAS2 (aminolevulinic acid synthase), has also been described. X-linked dominant erythropoietic protoporphyria (XDEPP) is caused by a gain of function mutation in the ALAS2 (5-aminolevulinate synthase) gene; that gene encodes the very first enzyme in the heme biosynthetic pathway. The mutation is caused by a frameshift mutation caused by one of two deletions in the ALAS2 exon 11, either c. 1706-1709 delAGTG or c. 1699-1700 delAT. This alters the 19th and 20th residues of the C-terminal domain thereby altering the secondary structure of the enzyme. The delAT mutation only occurred in one family studied whereas the delAGTG mutation occurred in several genetically distinct families. The delAGTG causes a loss of an α-helix which is replaced by a β-sheet.
Previously known mutations in the ALAS2 resulted in a loss-of-function mutation causing X-linked sideroblastic anemia. Erythropoietic protoporphyria (EPP) has similar symptoms as X-linked dominant erythropoietic protoporphyria but the mutation occurs as a loss-of-function in the FECH (ferrochelatase) enzyme; the very last enzyme in the pathway. All individuals studied presented symptoms without mutations in the FECH enzyme. The patterns of inheritance led the researchers to conclude the mutation must come from an enzyme on the X-chromosome with ALAS2 being the most likely candidate.
X-linked dominant erythropoietic protoporphyria is distinct from EPP in that there is no overload of Fe2+ ions. Additionally, unlike the other condition the arises out of a mutation of the ALAS2 gene, there is no anaemia. XDEPP is characterized by a buildup of protoporphyrin IX caused by in increased level of function in the ALAS2 enzyme. Because there is a buildup of protoporphyrin IX with no malfunction of the FECH enzyme, all the available Fe2+ is used in the production of heme, causing the FECH enzyme to use Zn2+ in its place, causing a buildup of zinc-protoporphyrin IX.
Diagnosis
See also
Hepatic porphyria
References
== External links == |
Self-abuse | Self-abuse may refer to:
Self-harm, the intentional, direct injuring of ones own body without suicidal intentions
Self-destructive behaviour, patterns of behaviour to inflict metaphorical or literal harm on oneself
Self-inflicted wound, harming oneself without psychological problems to take advantage of being injured
See also
Algolagnia, deriving sexual pleasure and stimulation from physical pain
Abuse § Self-abuse
Violence § Self-directed violence |
Chromium deficiency | Chromium deficiency is described as the consequence of an insufficient dietary intake of the mineral chromium. Chromium was first proposed as an essential element for normal glucose metabolism in 1959, and was widely accepted as being such by the 1990s. Cases of deficiency were described in people who received all of their nutrition intravenously for long periods of time.The essentiality of chromium has been challenged. Whereas the authorities in the European Union do not recognize chromium as an essential nutrient, those in the United States do, and identify an adequate intake for adults as between 25 and 45 μg/day, depending on age and sex. Dietary supplements containing chromium are widely available in the United States, with claims for benefits for fasting plasma glucose, hemoglobin A1C and weight loss. Reviews report the changes as modest, and without scientific consensus that the changes have a clinically relevant impact.
Signs and symptoms
The claimed symptoms of chromium deficiency caused by long-term total parenteral nutrition are severely impaired glucose tolerance, weight loss, peripheral neuropathy and confusion.
Diagnosis
According to the Dietary Reference Intake review, neither plasma nor urine concentrations can serve as useful clinical indicators of chromium status. Before chromium became a standard ingredient in total parenteral nutrition (TPN), people getting TPN as their sole source of nutrition developed symptoms that were reversed within two-week after chromium was added.
Dietary recommendations
The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for chromium in 2001. For chromium there was not sufficient information to set EARs and RDAs, so needs are described as estimates for Adequate Intakes (AIs). The current AIs for chromium for women ages 14 and up is 25 μg/day up to age 50 and 20 μg/day for older. AI for pregnancy is 30 μg/day. AI for lactation is 45 μg/day. For men ages 14 and up 35 μg/day up to age 50 and 30 μg/day for older. For infants to children ages 1–13 years the AI increases with age from 0.2 to 25 μg/day. As for safety, the IOM sets Tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. In the case of chromium there is not yet enough information and hence no UL. Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs).Japan designate chromium as an essential nutrient, identifying 10 μg/day as an Adequate Intake for adults.The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL defined the same as in United States. The EFSA does not consider chromium to be an essential nutrient, and so has not set PRIs, AIs or ULs. Chromium is the only mineral for which the United States and the European Union disagree on essentiality.For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For chromium labeling purposes 100% of the Daily Value was 120 μg, but as of 27 May 2016 it was revised to 35 μg to bring it into agreement with the RDA. Compliance with the updated labeling regulations was required by 1 January 2020, for manufacturers with $10 million or more in annual food sales, and by 1 January 2021 for manufacturers with less than $10 million in annual food sales. During the first six months following the 1 January 2020 compliance date, the FDA plans to work cooperatively with manufacturers to meet the new Nutrition Facts label requirements and will not focus on enforcement actions regarding these requirements during that time. A table of the old and new adult Daily Values is provided at Reference Daily Intake.
Sources
Approximately 2% of ingested chromium(III) is absorbed, with the remainder being excreted in the feces. Amino acids, vitamin C and niacin may enhance the uptake of chromium from the intestinal tract. After absorption, this metal accumulates in the liver, bone, and spleen. Trivalent chromium is found in a wide range of foods, including whole-grain products, processed meats, high-bran breakfast cereals, coffee, nuts, green beans, broccoli, spices, and some brands of wine and beer. Most fruits and vegetables and dairy products contain only low amounts.
Diabetes
Given the evidence for chromium deficiency causing problems with glucose management in the context of intravenous nutrition products formulated without chromium, research interest turned to whether chromium supplementation for people who have type 2 diabetes but are not chromium deficient could benefit. Looking at the results from four meta-analyses, one reported a statistically significant decrease in fasting plasma glucose levels (FPG) and a non-significant trend in lower hemoglobin A1C (HbA1C). A second reported the same, a third reported significant decreases for both measures, while a fourth reported no benefit for either. A review published in 2016 listed 53 randomized clinical trials that were included in one or more of six meta-analyses. It concluded that whereas there may be modest decreases in FPG and/or HbA1C that achieve statistical significance in some of these meta-analyses, few of the trials achieved decreases large enough to be expected to be relevant to clinical outcome. The authors also mentioned that trial design was for chromium as an addition to standard glycemic control medications, and so did not evaluate chromium as a first treatment for type 2 diabetes, or for prevention of progression from pre-diabetes to diabetes. The conclusion was that "...there is still little reason to recommend chromium dietary supplements to achieve clinically meaningful improvements in glycemic control." The American Diabetes Association publishes a standards of care review every year. The 2018 review makes no mention of chromium supplementation as a possible treatment.
Supplementation
Chromium supplementation in general is subject to a certain amount of controversy as it is by no means clear that chromium is an essential element in human biology. Nevertheless, chromium is an ingredient in total parenteral nutrition, along with other trace minerals. It is also in nutritional products for preterm infants. Many chromium-containing products, including chromium chloride, chromium citrate, chromium(III) picolinate, chromium(III) polynicotinate are sold as non-prescription dietary supplements.
Government-approved health claims
In 2005, the U.S. Food and Drug Administration approved a Qualified Health Claim for chromium picolinate with a requirement for very specific label wording: "One small study suggests that chromium picolinate may reduce the risk of insulin resistance, and therefore possibly may reduce the risk of type 2 diabetes. FDA concludes, however, that the existence of such a relationship between chromium picolinate and either insulin resistance or type 2 diabetes is highly uncertain." In 2010, chromium(III) picolinate was approved by Health Canada to be used in dietary supplements. Approved labeling statements included: "...provides support for healthy glucose metabolism." The European Food Safety Authority (EFSA) approved claims in 2010 that chromium contributed to normal macronutrient metabolism and maintenance of normal blood glucose concentration.
See also
Chromium toxicity
References
Further reading
A "possible resolution of controversies in chromium biology" is suggested by Wolfgang Maret in chapter 9, pp 246–248 of Essential Metals in Medicine: Therapeutic Use and Toxicity of Metal Ions in the Clinic. edited by Astrid Sigel, Eva Freisinger, Roland K. O. Sigel and Peggy L. Carver; de Gruyter GmbH (publisher), 2019 Berlin.
"Dietary Supplement Fact Sheet: Chromium". Office of Dietary Supplements, National Institutes of Health. Retrieved 24 February 2013.
Chromium in glucose metabolism
== External links == |
Paroxysmal cold hemoglobinuria | Paroxysmal cold hemoglobinuria (PCH) is an autoimmune hemolytic anemia featured by complement-mediated intravascular hemolysis after cold exposure. It can present as an acute non-recurrent postinfectious event in children, or chronic relapsing episodes in adults with hematological malignancies or tertiary syphilis. Described by Julius Donath (1870–1950) and Karl Landsteiner (1868–1943) in 1904, PCH is one of the first clinical entities recognized as an autoimmune disorder.
Signs and symptoms
Pediatric patients usually present with acute onset of hemolytic anemia with fatigue, exercise intolerance, pallor, jaundice, and hemoglobinuria, preceded by exposure to cold temperature and preceding viral-like illness. This may be complicated by acute renal failure due to nephrotoxic free hemoglobin and tubular obstruction. Although the disease may be fulminant during onset, the acute form generally follows a transient, self-limiting course.Chronic relapsing PCH manifests as episodic hemoglobinuria and anemic symptoms, usually milder than the acute form. While the classical syphilitic PCH becomes infrequent, paraneoplastic cause with underlying hematological malignancies especially in the elderly should be considered. Hepatosplenomegaly and adenomegaly are not pertinent to PCH, unless associated with underlying lymphoproliferative disorders. This form remains refractory if the underlying condition is not treated.
Cause
Infectious agents are implicated in the acute form of PCH. Viral agents include measles, mumps, Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, influenza virus, and adenovirus. Non-viral agents include Mycoplasma pneumoniae and Haemophilus influenzae. Chronic relapsing PCH is classically associated with syphilis, as well as hematological malignancies including non-Hodgkin lymphoma and myeloproliferative neoplasms.
Pathophysiology
The exact pathogenesis is not fully elucidated. The hallmark feature is the formation of polyclonal IgG autoantibody against the P antigen, which is a polysaccharide surface antigen on red cells in most humans. As a weak, biphasic antibody, it absorbs to the P antigen in the cold temperature as in the periphery in the primary phase, and fixes complement on recirculation to the core temperature in the secondary phase, resulting in intravascular hemolysis.
Diagnosis
The purposes of laboratory investigations are to:
Confirm the presence of intravascular hemolysis in terms of metabolic products of red cells and hematopoietic response.
Establish the diagnosis of autoimmune hemolytic anemia and differentiate from other AIHA.
Identify other supporting features as in hematopathological findings.For intravascular hemolysis, the laboratory parameters include increased serum free hemoglobin, lactate dehydrogenase, unconjugated bilirubin, and reduced haptoglobin. Urine tests may show elevated hemoglobinuria and hemosiderinuria in chronic cases. Reticulocytosis may not be apparent in the acute phase or when there is viral-induced myelosuppression.Once the clinical suspicion of autoimmune hemolytic anemia is made, direct antiglobulin test (DAT) or direct Coombs test is the first line of investigation to confirm the presence of warm autoantibodies. Testing with polyspecific and IgG-specific antiglobulin agents is usually negative, and that with C3-specific agent may be positive. On excluding warm autoimmune hemolytic anemia (WAIHA), the cold agglutinin titer should be examined for cold agglutinin disease (CAD). The diagnosis of PCH is suspected when both WAIHA and CAD are excluded. The complement level is usually low.
Donath-Landsteiner test is the confirmatory test for PCH. It involves the cooling of the patients serum to 4°C to allow the absorption of anti-P autoantibodies to the red cells, followed by warming to 37°C to activate complement fixation and hemolysis. Indirect DL test with addition of ABO-compatible P antigen-positive blood can be performed in case the direct DL test is negative, since the complement in the original serum may be consumed and result in false negative.The hematopathological findings can reflect both the presence of intravascular hemolysis and the underlying immunological process. The complete blood count usually shows normocytic anemia. Reticulocytosis may be subtle in the acute phase. Peripheral blood smear may show corresponding polychromasia. Neutrophil erythrophagocytosis is suggestive of PCH, while the absence of red cell agglutination as in CAD or microspherocytosis in WAIHA should also be noted.
Classification
AIHA can be classified as warm autoimmune hemolytic anemia or cold autoimmune hemolytic anemia, which includes cold agglutinin disease and paroxysmal cold hemoglobinuria. These classifications are based on the characteristics of the autoantibodies involved in the pathogenesis of the disease. Each has a different underlying cause, management, and prognosis, making classification important when treating a patient with AIHA.
Autoimmune hemolytic anemiaWarm-antibody typePrimary
Secondary (lymphoproliferative disorders, autoimmune disorders): 259 Cold-antibody type (anemia)Primary cold agglutinin disease
Secondary cold agglutinin syndromeAssociated with malignant disease
Acute, transient, infection-associated (acute cold antibody mediated AIHA complicating Mycoplasma pneumoniae or viral infections)
Chronic (lymphoproliferative disorders): 259 Paroxysmal cold hemoglobinuria: 259 Idiopathic
SecondaryAcute, transient (Infections other than syphilis): 259
Chronic (syphilis): 259 Mixed cold- and warm-antibody typeIdiopathic
Secondary (lymphoproliferative disorders, autoimmune disorders)Drug-induced immune hemolytic anemia: 259 Autoimmune type
Drug absorption type
Neoantigen type
Management
Acute PCH is usually transient and self-limiting. Supportive treatment includes rest, normothermia and transfusion when indicated. Intensive care for the development of acute kidney injury should be offered. Plasmapheresis is proposed to be an adjunctive measure to facilitate recovery. Steroids and other immunosuppressants are sometimes administered and the beneficial effect is uncertain. Immunotherapy is considered in refractory to corticosteroids and immunosuppression. Monoclonal antibodies e.g. rituximab (anti-CD20) and eculizumab (anti-C5) have been used but the therapeutic benefits are controversial. Antibiotic therapy should be given if syphilitic cause is confirmed, while investigations and management for hematological malignancies should be pursued in adult patients with unexplained PCH.
Epidemiology
Estimated incidence of PCH is 0.4 per 100000 population, and the prevalence ranges from 1.6% to 40% in patients with autoimmune hemolytic anemia. The prevalence depends on the sensitivity of the immunologic methods applied. The age of onset is often <5 years in the pediatric population, with male predominance ranging from 2.5:1 to 5:1 in male-to-female ratio.The majority of PCH were accounted by congenital or tertiary syphilis in the early 1900s. Since the application of antibiotic therapy and prenatal screening, syphilitic PCH has become a rare entity. It is now increasingly recognized in pediatric patients with preceding viral-like illness.
See also
Cold agglutinin disease
Cold sensitive antibody
Hemolytic anemia
List of hematologic conditions
References
== External links == |
Demodicosis | Demodicosis , also called Demodex folliculitis in humans and demodectic mange () or red mange in animals, is caused by a sensitivity to and overpopulation of Demodex spp. as the hosts immune system is unable to keep the mites under control.
Demodex is a genus of mite in the family Demodecidae. The mites are specific to their hosts, and each mammal species is host to one or two unique species of Demodex mites. Therefore, demodicosis cannot be transferred across species and has no zoonotic potential.
Signs and symptoms
Humans
Demodicosis in humans is usually caused by Demodex folliculorum and may have a rosacea-like appearance. Common symptoms include hair loss, itching, and inflammation. An association with pityriasis folliculorum has also been described.Demodicosis is most often seen in folliculitis (inflammation of the hair follicles of the skin). Depending on the location, it may result in small pustules (pimples) at the base of a hair shaft on inflamed, congested skin. Demodicosis may also cause itching, swelling, and erythema of the eyelid margins. Scales at the base of the eyelashes may develop. Typically, patients complain of eyestrain.
Dogs
Minor cases of demodectic mange usually do not cause much itching but might cause pustules, redness, scaling, leathery skin, hair loss, skin that is warm to the touch, or any combination of these. It most commonly appears first on the face, around the eyes, or at the corners of the mouth, and on the forelimbs and paws. It may be misdiagnosed as a "hot spot" or other skin ailment.
In the more severe form, hair loss can occur in patches all over the body and might be accompanied by crusting, pain, enlarged lymph nodes, and deep skin infections.
Typically, animals become infected through nursing from their mother. The transmission of these mites from mother to pup is normal (which is why the mites are normal inhabitants of the dogs skin), but some individuals are sensitive to the mites due to a cellular immune deficiency, underlying disease, stress, or malnutrition, which can lead to the development of clinical demodectic mange.
Some breeds appear to have an increased risk of mild cases as young dogs, including the Afghan Hound, American Staffordshire Terrier, Boston Terrier, Boxer, Chihuahua, Chow Chow, Shar-Pei, Collie, Dalmatian, Doberman Pinscher, Bulldog, French Bulldog, English Bull Terrier, Miniature Bull Terrier, German Shepherd, Great Dane, Old English Sheepdog, American Pit Bull Terrier, West Highland White Terrier, Rat Terrier, Yorkshire Terrier, Dachshund, and Pug.
Cats
There are two types of demodectic mange in cats. Demodex cati causes follicular mange, similar to that seen in dogs, though it is much less common. Demodex gatoi is a more superficial form of mange, causes an itchy skin condition, and is contagious amongst cats.
Other
Demodectic mange also occurs in other domestic and wild animals, including captive pandas.
Diagnosis
For demodectic mange, properly performed deep skin scrapings generally allow the veterinarian to identify the microscopic mites. Acetate tape impression with squeezing has recently found to be a more sensitive method to identify mites. It was originally thought that because the mite is a normal inhabitant of the dogs skin, the presence of the mites does not conclusively mean the dog has demodicosis. Recent research, however, found that the demodex mite is rarely found on clinically normal dogs, meaning that the presence of any number of mites in a sample is very likely to be significant. In breeds such as the West Highland White Terrier, relatively minor skin irritation which would otherwise be considered allergy should be carefully scraped because of the predilection of these dogs to demodectic mange. Skin scrapings may be used to follow the progress of treatment in demodectic mange.
Alternatively, plasma levels of zinc and copper have been seen to be decreased in dogs with demodicosis. This may be due to inflammation involved in the immune response of demodicosis which can lead to oxidative stress, resulting in dogs with demodicosis to exhibit higher levels of antioxidant productivity. The catalases involved in the antioxidant pathway require the trace minerals zinc and copper. Dogs with demodicosis show a decrease in plasma copper and zinc levels due to the increased demand for antioxidant activity. Therefore, this may be considered as a potential marker for demodicosis.
Treatment
Dogs
Localized demodectic mange is considered a common puppyhood ailment, with roughly 90% of cases resolving on their own with no treatment. Minor, localized cases should be left to resolve on their own to prevent masking of the more severe generalized form. If treatment is deemed necessary, Goodwinol, a rotenone-based insecticide ointment, is often prescribed, but it can be irritating to the skin. Demodectic mange with secondary infection is treated with antibiotics and medicated shampoos.
For more severe generalized cases, Amitraz is a parasiticidal dip that is licensed for use in many countries (the only FDA approved treatment in the USA) for treating canine demodicosis. It is applied weekly or biweekly for several weeks, until no mites can be detected by skin scrapings. Demodectic mange in dogs can also be managed with avermectins, although there are few countries which license these drugs, which are given by mouth daily, for this use. Ivermectin is used most frequently; collie-like herding breeds often do not tolerate this drug due to a defect in the blood–brain barrier, though not all of them have this defect. Other avermectin drugs that can be used include doramectin and milbemycin.
Recent results suggest that the isoxazolines afoxolaner and fluralaner, given orally, are effective in treating dogs with generalized demodicosis.
Because of the possibility of the immune deficiency being an inherited trait, many veterinarians believe that all puppies with generalized demodex should be spayed or neutered and not reproduce. Females with generalized demodex should be spayed because the stress of the estrus cycle will often bring on a fresh wave of clinical signs.
Cats
Cats with Demodex gatoi must be treated with weekly or bi-weekly sulfurated lime rinses. Demodex cati are treated similarly to canine demodicosis. With veterinary guidance, localized demodectic mange can also be treated with a topical keratolytic and antibacterial agent, followed by a lime sulfur dip or a local application of Rotenone. Ivermectin may also be used. Generalized demodectic mange in cats is more difficult to treat. There are shampoos available that can help to clear dead skin, kill mites and treat bacterial infections. Treatment is in most cases prolonged with multiple applications.
References
== External links == |
Hypertrichosis cubiti | Hypertrichosis cubiti (also known as "hairy elbow syndrome") is a cutaneous condition characterized by multiple terminal hairs on both elbows in children.
Causes
One known cause of hypertrichosis cubiti is Wiedemann-Steiner syndrome.
Diagnosis
See also
Hook nail
List of cutaneous conditions
== References == |
Parasitic twin | A parasitic twin, also known as an asymmetrical or unequal conjoined twin, is the result of the processes that also produce vanishing twins and conjoined twins, and may represent a continuum between the two. Parasitic twins occur when a twin embryo begins developing in utero, but the pair does not fully separate, and one embryo maintains dominant development at the expense of its twin. Unlike conjoined twins, one ceases development during gestation and is vestigial to a mostly fully formed, otherwise healthy individual twin. The undeveloped twin is defined as parasitic, rather than conjoined, because it is incompletely formed or wholly dependent on the body functions of the complete fetus. The independent twin is called the autosite.
Variants
Conjoined parasitic twins joined at the head are described as craniopagus or cephalopagus, and occipitalis if joined in the occipital region or parietalis if joined in the parietal region.
Craniopagus parasiticus is a general term for a parasitic head attached to the head of a more fully developed fetus or infant.
Fetus in fetu sometimes is interpreted as a special case of parasitic twin, but may be a distinct entity.
The twin reversed arterial perfusion, or T.R.A.P. sequence, results in an acardiac twin, a parasitic twin that fails to develop a head, arms and a heart. The parasitic twin, little more than a torso with or without legs, receives its blood supply from the host twin by means of an umbilical cord-like structure, much like a fetus in fetu, except the acardiac twin is outside the autosites body. The blood received by the parasitic twin has already been used by the normal fetus, and as such is already de-oxygenated, leaving little developmental nutrients for the acardiac twin. Because it is pumping blood for both itself and its acardiac twin, this causes extreme stress on the normal fetus heart. Many T.R.A.P. pregnancies result in heart failure for the healthy twin. This twinning condition usually occurs very early in pregnancy. A rare variant of the acardiac fetus is the acardius acormus where the head is well developed but the heart and the rest of the body are rudimentary. While it is thought that the classical T.R.A.P./Acardius sequence is due to a retrograde flow from the umbilical arteries of the pump twin to the iliac arteries of the acardiac twin resulting in preferential caudal perfusion, acardius acormus is thought to be a result of an early embryopathy.
Images of parasitic twins
Human
Animals
See also
Dipygus
Frank Lentini
Lakshmi Tatma
Lazarus and Joannes Baptista Colloredo
Rudy Santos
Vestigial twin
References
Further reading
Lebel, Robert Roger; Carlos Mock; Jeannette Israel; William Senica (June 1994). "Twin reversed arterial perfusion syndrome, acephalic presenting at full term". TheFetus.net. Retrieved 18 February 2013. |
Léri–Weill dyschondrosteosis | Léri–Weill dyschondrosteosis or LWD is a rare pseudoautosomal dominant genetic disorder which results in dwarfism with short forearms and legs (mesomelic dwarfism) and a bayonet-like deformity of the forearms (Madelungs deformity).
Causes
It is caused by mutations in the short-stature homeobox gene found in the pseudoautosomal region PAR1 of the X and Y chromosomes, at band Xp22.33 or Yp11.32.SHOX gene deletions have been identified as the major cause of Leri–Weill syndrome.Leri–Weill dyschondrosteosis is characterized by mesomelic short stature, with bowing of the radius more so than the ulna in the forearms and bowing of the tibia while sparing the fibula.
Diagnosis
Diagnosis is made following genetic blood testing.
Treatment
History
LWD was first described in 1929 by André Léri and Jean A. Weill.
References
== External links == |
Hydrometra | Hydrometra is a genus of water measurers in the family Hydrometridae. There are more than 120 described species in Hydrometra.
See also
List of Hydrometra species
References
Further reading
== External links == |
Astasia-abasia | Astasia-abasia refers to the inability to either stand or walk in a normal manner. Astasia refers to the inability to stand upright unassisted. Abasia refers to lack of motor coordination in walking. The term abasia literally means that the base of gait (the lateral distance between the two feet) is inconstant or unmeasurable. When seen in conversion disorder, the gait is bizarre and is not suggestive of a specific organic lesion: often the patient sways wildly and nearly falls, recovering at the last moment.
An acquired total inability to stand and walk can be seen in organic neurological diseases, including stroke, Parkinsons disease, damage to the cerebellum, Guillain–Barré syndrome, normal pressure hydrocephalus and many others. In normal pressure hydrocephalus, for example, when the condition remains untreated, the patients gait becomes shortened, with frequent shuffling and falls; eventually standing, sitting, and even rolling over in bed become impossible. This advanced state is referred to as "hydrocephalic astasia-abasia".
Phobias
Astasia and/or abasia are associated with the corresponding fears of walking and/or standing, variously called stasophobia, basophobia, stasiphobia, basiphobia, stasobasophobia, stasibasiphobia, etc., sometimes turning into pathological forms, i.e., phobias.
See also
Blocqs disease, an illness named after Paul Oscar Blocq
References
== External links == |
Postoperative nausea and vomiting | Postoperative nausea and vomiting (PONV) is the phenomenon of nausea, vomiting, or retching experienced by a patient in the postanesthesia care unit (PACU) or within 24 hours following a surgical procedure. PONV affects about 10% of the population undergoing general anaesthesia each year. PONV can be unpleasant and lead to a delay in mobilization and food, fluid, and medication intake following surgery.
Cause
Emetogenic drugs commonly used in anaesthesia include nitrous oxide, physostigmine, and opioids. The intravenous anaesthetic propofol is currently the least emetogenic general anaesthetic. These medications are thought to stimulate the chemoreceptor trigger zone. This area is on the floor of the fourth ventricle and is effectively outside of the blood-brain barrier, which makes it incredibly sensitive to toxin and pharmacological stimulation. Several neurotransmitters are known, such as histamine, dopamine, serotonin, acetylcholine, and the more recently discovered neurokinin-1 (substance P).
Risk factors
A 2008 study compared 121 Japanese patients who experienced PONV after being given the general anesthetic propofol to 790 people who were free of postoperative nausea after receiving it. Those with a G at both copies of rs1800497 were 1.6 times more likely to experience PONV within six hours of surgery compared to those with the AG or AA genotypes, but they were not significantly more likely to experience PONV more than six hours after surgery.PONV results from patient, surgical, and anesthetic factors.Surgical factors that confer increased risk for PONV include procedures of increased length and gynecological, abdominal, laparoscopic and ENT procedures, and strabismus procedures in children.
Anesthetic risk factors include the use of volatile anesthetics, nitrous oxide (N2O), opioids, and longer duration of anesthesia.
Patient factors that confer increased risk for PONV include female gender, obesity, age less than 16 years, past history of motion sickness or chemotherapy-induced nausea, high levels of preoperative anxiety, and patients with history of PONV.
Smokers and the elderly often have a decreased risk for PONV.
A risk-stratification method created by Apfel et al has been developed to determine a patients risk for PONV. The presence of 0, 1, 2, 3, or 4 of any of the following risk factors corresponds to a PONV respective risk of 10, 20, 40, 60, and 80%.- Female gender
- Non-smoking
- History of PONV or motion sickness
- Expectant use of postoperative opioid medications
Prevention
Treatment options to prevent PONV include medications such as antiemetics (for example, ondansetron or dexamethasone) or other drugs including tropisetron, dolasetron, cyclizine, and granisetron. Droperidol may cause QT prolongation and is not frequently used. Other approaches to reduce PONV include decision on the types of anaesthetic used during surgery and intravenous (IV) dextrose solutions. Increasing the IV fluids during surgery by giving additional fluid while the person is under general anaesthesia may reduce the risk of nausea/vomiting after surgery. For minor surgical procedures, more research is needed to determine the risks and benefits of this approach.
Management
Because currently no single antiemetic available is especially effective on its own, experts recommend a multimodal approach. Anesthetic strategies to prevent vomiting include using regional anesthesia whenever possible and avoiding medications that cause vomiting. Medications to treat and prevent PONV are limited by both cost and the adverse effects. People with risk factors likely warrant preventive medication, whereas a "wait and see" strategy is appropriate for those without risk factors.
Preoperative fasting
Fasting guidelines often restrict the intake of any oral fluid 2-6 hours preoperatively, but in a large retrospective analysis in Torbay Hospital, unrestricted clear oral fluids until transfer to theatre could significantly reduce the incidence of postoperative nausea and vomiting without an increased risk in the adverse outcomes for which such conservative guidance exists.
Medications
A multimodal approach to treating a patient with PONV can be efficacious. Numerous patient factors and medication adverse effects must be taken into consideration when selecting a treatment regimen.
Serotonin (5-HT3) receptor antagonists can be administered as a single dose at the end of surgery. Adverse effects include prolongation of the QT interval on electrocardiogram (EKG). Medications include ondansetron, granisetron, and dolasetron.
Anticholinergics can be used as a long-acting patch placed behind the patients ear. Adverse effects include dry mouth and blurry vision. Care must be taken when handling the patch, as transfer of medication to the eye can induce pupillary dilation. Avoid use in elderly patients. Medications include scopolamine.
Glucocorticoids have direct antiemetic effects and can reduce need for postoperative opioids. Adverse effects include a transient increase in serum glucose level, and poor wound healing (controversial). Medications include dexamethasone.
Butyrophenones are typically administered as a single injection at the end of surgery. Adverse effects include prolongation of the QT interval on EKG. Medications include droperidol and haloperidol.
Phenothiazines are particularly effective in treating opioid-induced PONV. Adverse effects are dose-dependent and include sedation and extrapyramidal symptoms. Medications include promethazine and prochlorperazine.
Neurokinin 1 (NK1) receptor antagonists prevent an emetic signal from being transmitted. Medications include aprepitant and rolapitant.
Histamine receptor antagonists can be administered by multiple routes, including orally, intramuscularly, or rectally. Adverse effects include dry mouth, sedation, and urinary retention. Medications include dimenhydrinate and diphenhydramine.
Propofol, an anesthetic medication, confers its own antiemetic properties.The 2020 Cochrane Anaesthesia Review Group review of Drugs for preventing postoperative nausea and vomiting in adults
after general anaesthesia: a network meta-analysis (Review) demonstrated that combination therapy is more effective than single anti-emetic, and that dexamethasone and ondansetron (a commonly used combination) are two of the most effective anti-emetics for PONV. The review adds robust evidence of efficacy for drugs in newer classes, such as aprepitant or fosapreitant, or newer agents in familiar classes, such as ramosetron. The review does not cover the cost effectiveness of the agents included and, despite increased efficacy for newer novel agents, this may preclude their immediate utilisation in anaesthetic practice.
Alternative medicine
In conjunction with antiemetic medications, at least one study has found that application to the pericardium meridian 6 acupressure point produced a positive effect in relieving PONV. Another study found no statistically significant difference. The two general types of alternative pressure therapy are sham acupressure and the use of the P6 point. A 2015 study found no significant difference between the use of either therapy in the treatment or prevention of PONV. In a review of 59 studies, both therapies significantly affected the nausea aspect, but had no significant effect on vomiting.
Cannabinoids have also been used for treatment of PONV, but its safety and efficacy are controversial.
Epidemiology
Typically, the incidence of nausea or vomiting after general anesthesia ranges between 25 and 30%. Nausea and vomiting can be extremely distressing for patients, and so is one of their major concerns. Vomiting has been associated with major complications, such as pulmonary aspiration of gastric content, and might endanger surgical outcomes after certain procedures, for example after maxillofacial surgery with wired jaws. Nausea and vomiting can delay discharge, and about 1% of patients scheduled for day surgery require unanticipated overnight admission because of uncontrolled PONV.
References
Further reading
Blackburn, J., Spencer, R. (2015). Postoperative nausea and vomiting.
Pleuvry, B. (2015). Physiology and pharmacology of nausea and vomiting.
== External links == |
Cebocephaly | Cebocephaly (from Greek kebos, "monkey" + kephale, "head") is a developmental anomaly that is part of a group of defects called holoprosencephaly. Cebocephaly involves the presence of two separate eyes set close together and a small, flat nose with a single nostril (no nasal septum). It may be diagnosed before or after birth. It has a very poor prognosis, with most affected infants dying soon after birth. It is very rare, having been estimated to affect around 1 in 40,000 deliveries.
Signs and symptoms
Cebocephaly causes:
two separate eyes set close together
a small, flat nose with a single nostril
ear abnormalities
mouth abnormalities (such as microstomia)The presence of a nasal septum precludes a diagnosis of cebocephaly. Cebocephaly may cause malformations of the sphenoid and ethmoid bones behind the orbit.
Cause
Cebocephaly can be caused by many factors, particularly genetic variations. These include 18p-, 14q deletion, 13q deletion, and some vertically transmitted infections. It is part of a group of defects called holoprosencephaly.
Diagnosis
Before birth, cebocephaly may sometimes be diagnosed using ultrasound. After birth, cebocephaly is diagnosed based on the characteristic symptoms. A CT scan may be used to confirm the diagnosis.
Prognosis
Most infants born with cebocephaly die soon after birth.
Epidemiology
Cebocephaly is very uncommon. Some estimates of its prevalence include 1 in 40,000 neonatal deliveries.
History
The word "cebocephaly" is derived from Greek kebos (monkey), and kephale (head).
See also
Cephalic disorder
== References == |
Galloway Mowat syndrome | Galloway Mowat syndrome is a very rare autosomal recessive genetic disorder, consisting of a variety of features including hiatal hernia, microcephaly and nephrotic syndrome.
Cause
The exact genetic defect in Galloway Mowat syndrome is yet to be discovered. However, mutations in podocyte proteins, such as nephrin, alpha-actinin 4, and podocin, are associated with proteinuria and nephrotic syndrome. There is reduced expression of synaptopodin, GLEPP1, and nephrin in Galloway-Mowat syndrome, but these are likely secondary to the proteinuria, likely not the proteins mutated in Galloway-Mowat syndrome.The biochemical lesion appears to be in the Kinase, Endopeptidase and Other Proteins of small Size (KEOPS)/Endopeptidase-like and Kinase associated to transcribed Chromatin (EKC) (KEOPS/EKC) complex. Sequencing of genes in 37 cases of this condition revealed mutations in the OSGEP, TP53RK, TPRKB and LAGE3 genes all of which encode subunits in the KEOPS complex. Members of this complex are found in bacteria, archaea and eukaryotes and are highly conserved. The function of this complex is still under investigation.The biochemical lesion in this condition appears to be in the N6-threonyl-carbamoylation of adenosine 37 of ANN-type tRNA pathway. This pathway uses two sequentially acting enzymes - YRDC and OSGEP. Mutations in these genes leads to this syndrome.
Genetics
Galloway Mowat syndrome is usually an autosomal recessive disorder, which means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. Multiple genes (10 genes as of October 2020) are causal for the clinical symptoms of Galloway Mowat syndrome. There is one gene, LAGE3, associated with X-linked inheritance of Galloway Mowat syndrome.
Diagnosis
Treatment
References
External links
Microcephaly, hiatal hernia and nephrotic syndrome at NIHs Office of Rare Diseases |
Ametropic amblyopia | Ametropic amblyopia is a medical condition in which the retina cannot focus on the image of a distant object, a condition often described as reduced visual acuity. This is due to large uncorrected refractive errors in the patients optic system of the eyes. Astigmatism is one of the most frequent causes of ametropic amblyopia.
References
Further reading
Moseley, Merrick J., et al. "Effectiveness of occlusion therapy in ametropic amblyopia: a pilot study." British Journal of Ophthalmology 81.11 (1997): 956–961.
Cavazos, H.; et al. (1993). "Ametropic Amblyopia". Strabismus. Informa Plc. 1 (2): 63–67. doi:10.3109/09273979309087719. PMID 21314500.
Abraham, S. V. "Bilateral ametropic amblyopia." J Pediatr Ophthalmol Strabismus 1 (1964): 57–61.
Werner, D. B., and W. E. Scott. "Amblyopia case reports--bilateral hypermetropic ametropic amblyopia." Journal of pediatric ophthalmology and strabismus 22.5 (1984): 203–205.
Moseley, Merrick J; et al. (1997). "Effectiveness of occlusion therapy in ametropic amblyopia: a pilot study". British Journal of Ophthalmology. BMJ Publishing Group Ltd. 81 (11): 956–961. doi:10.1136/bjo.81.11.956. PMC 1722055. PMID 9505818. |
Bronchitis | Bronchitis is inflammation of the bronchi (large and medium-sized airways) in the lungs that causes coughing. Bronchitis usually begins as an infection in your nose, ears, throat, or sinuses. The infection then makes its way down to the bronchi. Symptoms include coughing up sputum, wheezing, shortness of breath, and chest pain. Bronchitis can be acute or chronic.Acute bronchitis usually has a cough that lasts around three weeks, and is also known as a chest cold. In more than 90% of cases the cause is a viral infection. These viruses may be spread through the air when people cough or by direct contact. A small number of cases are caused by a bacterial infection such as Mycoplasma pneumoniae or Bordetella pertussis. Risk factors include exposure to tobacco smoke, dust, and other air pollution. Treatment of acute bronchitis typically involves rest, paracetamol (acetaminophen), and nonsteroidal anti-inflammatory drugs (NSAIDs) to help with the fever.Chronic bronchitis is defined as a productive cough – one that produces sputum – that lasts for three months or more per year for at least two years. Many people with chronic bronchitis also have chronic obstructive pulmonary disease (COPD). Tobacco smoking is the most common cause, with a number of other factors such as air pollution and genetics playing a smaller role. Treatments include quitting smoking, vaccinations, rehabilitation, and often inhaled bronchodilators and steroids. Some people may benefit from long-term oxygen therapy.Acute bronchitis is one of the more common diseases. About 5% of adults and 6% of children have at least one episode a year. Acute bronchitis is the most common type of bronchitis. By contrast in the United States, in 2018, 9.3 million people were diagnosed with the less common chronic bronchitis.
Acute bronchitis
Acute bronchitis, also known as a chest cold, is short term inflammation of the bronchi of the lungs. The most common symptom is a cough, that may or may not produce sputum. Other symptoms may include coughing up mucus, wheezing, shortness of breath, fever, and chest discomfort. Fever when present is mild. The infection may last from a few to ten days. The cough may persist for several weeks afterwards, with the total duration of symptoms usually around three weeks. Symptoms may last for up to six weeks.
Cause
In more than 90% of cases, the cause is a viral infection. These viruses may spread through the air when people cough or by direct contact. Risk factors include exposure to tobacco smoke, dust, and other air pollutants. A small number of cases are due to bacteria such as Mycoplasma pneumoniae or Bordetella pertussis.
Diagnosis
Diagnosis is typically based on a persons signs and symptoms. The color of the sputum does not indicate if the infection is viral or bacterial. Determining the underlying organism is usually not required. Other causes of similar symptoms include asthma, pneumonia, bronchiolitis, bronchiectasis, and COPD. A chest X-ray may be useful to detect pneumonia.Another common sign of bronchitis is a cough which lasts ten days to three weeks. If the cough lasts for longer than a month, it may become chronic bronchitis. In addition, a fever may be present. Acute bronchitis is normally caused by a viral infection. Typically, these infections are rhinovirus, parainfluenza, or influenza. No specific testing is normally needed in order to diagnose acute bronchitis.
Treatment
One form of prevention is to avoid smoking and other lung irritants. Frequent hand washing may also be protective. Treatment for acute bronchitis usually involves rest, paracetamol (acetaminophen), and NSAIDs to help with the fever. Cough medicine has little support for its use, and is not recommended in children under the age of six. There is tentative evidence that salbutamol may be useful in treating wheezing; however, it may result in nervousness and tremors. Antibiotics should generally not be used. An exception is when acute bronchitis is due to pertussis. Tentative evidence supports honey and pelargonium to help with symptoms. Getting plenty of rest and drinking enough fluids are often recommended as well. Chinese medicinal herbs are of unclear effect.
Epidemiology
Acute bronchitis is one of the most common diseases. About 5% of adults are affected, and about 6% of children have at least one episode a year. It occurs more often in the winter. More than 10 million people in the US visit a doctor each year for this condition, with about 70% receiving antibiotics which are mostly not needed. There are efforts to decrease the use of antibiotics in acute bronchitis. Acute bronchitis is the most common type of bronchitis.
Chronic bronchitis
Chronic bronchitis is a lower respiratory tract disease, defined by a productive cough that lasts for three months or more per year for at least two years. The cough is sometimes referred to as a smokers cough since it often results from smoking. When chronic bronchitis occurs together with decreased airflow it is known as chronic obstructive pulmonary disease (COPD). Many people with chronic bronchitis have COPD however, most people with COPD do not also have chronic bronchitis. Estimates of the number of people with COPD who have chronic bronchitis are 7 to 40%. Estimates of the number of people who smoke and have chronic bronchitis who also have COPD is 60%.The term "chronic bronchitis" was used in previous definitions of COPD but is no longer included in the definition. The term is still used clinically. While both chronic bronchitis and emphysema are often associated with COPD, neither is needed to make the diagnosis. A Chinese consensus commented on symptomatic types of COPD that include chronic bronchitis with frequent exacerbations.Chronic bronchitis is marked by mucus hypersecretion and mucins. The excess mucus is produced by an increased number of goblet cells, and enlarged submucosal glands in response to long-term irritation. The mucous glands in the submucosa secrete more than the goblet cells. Mucins thicken mucus, and their concentration has been found to be high in cases of chronic bronchitis, and also to correlate with the severity of the disease. Excess mucus can narrow the airways, thereby limiting airflow and accelerating the decline in lung function, and result in COPD. Excess mucus shows itself as a chronic productive cough and its severity and volume of sputum can fluctuate in periods of acute exacerbations. In COPD, those with the chronic bronchitic phenotype with associated chronic excess mucus, experience a worse quality of life than those without.The increased secretions are initially cleared by coughing. The cough is often worse soon after awakening, and the sputum produced may have a yellow or green color and may be streaked with specks of blood. In the early stages, a cough can maintain mucus clearance. However, with continued excessive secretion mucus clearance is impaired, and when the airways become obstructed a cough becomes ineffective. Effective mucociliary clearance depends on airway hydration, ciliary beating, and the rates of mucin secretion. Each of these factors is impaired in chronic bronchitis. Chronic bronchitis can lead to a higher number of exacerbations and a faster decline in lung function. The ICD-11 lists chronic bronchitis with emphysema (emphysematous bronchitis) as a "certain specified COPD".
Cause
Most cases of chronic bronchitis are caused by tobacco smoking. Chronic bronchitis in young adults who smoke is associated with a greater chance of developing COPD. There is an association between smoking cannabis and chronic bronchitis. In addition, chronic inhalation of air pollution, or irritating fumes or dust from hazardous exposures in occupations such as coal mining, grain handling, textile manufacturing, livestock farming, and metal moulding may also be a risk factor for the development of chronic bronchitis. Bronchitis caused in this way is often referred to as industrial bronchitis, or occupational bronchitis. Rarely genetic factors also play a role.Air quality can also affect the respiratory system with higher levels of nitrogen dioxide and sulfur dioxide contributing to bronchial symptoms. Sulfur dioxide can cause inflammation which can aggravate chronic bronchitis and make infections more likely.Air pollution in the workplace is the cause of several non-communicable diseases (NCDs) including chronic bronchitis.
Treatment
Decline in lung function in chronic bronchitis may be slowed by stopping smoking. Chronic bronchitis may be treated with a number of medications and occasionally oxygen therapy. Pulmonary rehabilitation may also be used.A distinction has been made between exacerbations (sudden worsenings) of chronic bronchitis, and otherwise stable chronic bronchitis. Stable chronic bronchitis can be defined as the normal definition of chronic bronchitis, plus the absence of an acute exacerbation in the previous four weeks. A Cochrane review found that mucolytics in chronic bronchitis may slightly decrease the chance of developing an exacerbation. The mucolytic guaifenesin is a safe and effective treatment for stable chronic bronchitis. This has an advantage in that it is available as an extended use tablet which lasts for twelve hours. Erdosteine is a mucolytic recommended by NICE. GOLD also supports the use of some mucolytics that are advised against when inhaled corticosteroids are being used, and singles out erdosteine as having good effects regardless of corticosteroid use. Erdosteine also has antioxidant properties. Erdosteine has been shown to significantly reduce the risk of exacerbations, shorten their duration, and hospital stays. In those with the chronic bronchitic phenotype of COPD, the phosphodiesterase-4 inhibitor roflumilast may decrease significant exacerbations.
Epidemiology
Chronic bronchitis affects about 3.4% to 22% of the general population. Individuals over 45 years of age, smokers, those that live or work in areas with high air pollution, and anybody with asthma all have a higher risk of developing chronic bronchitis. This wide range is due to the different definitions of chronic bronchitis that can be diagnosed based on signs and symptoms or the clinical diagnosis of the disorder. Chronic bronchitis tends to affect men more often than women. While the primary risk factor for chronic bronchitis is smoking, there is still a 4%-22% chance that non smokers can get chronic bronchitis. This might suggest other risk factors such as the inhalation of fuels, dusts, fumes and genetic factor. In the United States, in 2016, 8.6 million people were diagnosed with chronic bronchitis, and there were 518 reported deaths. Per 100,000 of population the death rate of chronic bronchitis was 0.2.
History
The condition of bronchitis has been recognised for many centuries, in several different cultures including the Ancient Greek, Chinese, and Indian, with the presence of excess phlegm and cough noted in recognition of the same condition. Early treatments of chronic bronchitis included garlic, cinnamon and ipecac, among others. Modern treatments were developed during the second half of the 20th century.In Britain in 1808, a physician Charles Badham was the first person to describe the condition and name the acute form as acute bronchitis. This was written of in a book entitled Inflammatory conditions of the bronchia. In this book Badham distinguished three forms of bronchitis including acute and chronic. A second edition of this book was renamed An Essay on Bronchitis and published in 1814. Bradham used the term catarrh to refer to the cardinal symptoms of chronic cough and mucus hypersecretion of chronic bronchitis, and described chronic bronchitis as a disabling disorder.In 1901 an article was published on the treatment of chronic bronchitis in the elderly. The symptoms described have remained unchanged. The cause was thought to be brought on by dampness, cold weather, and foggy conditions, and treatments were aimed towards various cough mixtures, respiratory stimulants, and tonics. It was noted that something other than the weather was thought to be at play. Exacerbations of the condition were also described at this time. Another physician Harry Campbell was referred to who had written in the British Medical Journal a week before. Campbell had suggested that the cause of chronic bronchitis was due to toxic substances, and recommended pure air, simple food, and exercise to remove them from the body.A joint research programme was undertaken in Chicago and London from 1951 to 1953 in which the clinical features of one thousand cases of chronic bronchitis were detailed. The findings were published in the Lancet in 1953. It was stated that since its introduction by Badham, chronic bronchitis had become an increasingly popular diagnosis. The study had looked at various associations such as the weather, conditions at home, and at work, age of onset, childhood illnesses, smoking habits, and breathlessness. It was concluded that chronic bronchitis invariably led to emphysema, particularly when the bronchitis had persisted for a long time.In 1957 it was noted that at the time there were many investigations being carried out into chronic bronchitis and emphysema in general, and among industrial workers exposed to dust. Excerpts were published dating from 1864 in which Charles Parsons had noted the occurring consequence of the development of emphysema from bronchitis. This was seen to be not always applicable. His findings were in association with his studies on chronic bronchitis among pottery workers.A CIBA (now Novartis) meeting in 1959, and a meeting of the American Thoracic Society in 1962, defined chronic bronchitis as a component of COPD, in the terms that have not changed.
Eosinophilic bronchitis
Eosinophilic bronchitis is a chronic dry cough, defined by the presence of an increased number of a type of white blood cell known as eosinophils. It has a normal finding on X-ray and has no airflow limitation.
Protracted bacterial bronchitis
Protracted bacterial bronchitis in children, is defined as a chronic productive cough with a positive bronchoalveolar lavage that resolves with antibiotics. Protracted bacterial bronchitis is usually caused by Streptococcus pneumoniae, non-typable Haemophilus influenzae, or Moraxella catarrhalis. Protracted bacterial bronchitis (lasting more than 4 weeks) in children may be helped by antibiotics.
Plastic bronchitis
Plastic bronchitis is a rarely found condition in which thickened secretions plug the bronchi. The plugs are rubbery or plastic-feeling (thus the name). The light-colored plugs take the branching shape of the bronchi that they fill, and are known as bronchial casts. When these casts are coughed up, they are firmer in texture from typical phlegm or the short, softer mucus plugs seen in some people with asthma. However, some people with asthma have larger, firmer, and more complex plugs. These differ from the casts seen in people whose plastic bronchitis is associated with congenital heart disease or lymphatic vessel abnormalities mainly because eosinophils and Charcot–Leyden crystals are present in the asthma-associated casts but not in the others.Casts obstruct the airflow, and can result in the overinflation of the opposite lung. Plastic bronchitis usually occurs in children. Some cases may result from abnormalities in the lymphatic vessels. Advanced cases may show imaging similarities to bronchiectasis.
Aspergillus bronchitis
Aspergillus bronchitis is one of the Aspergillosis spectrum of diseases, in which the bronchi are specifically subject to a fungal infection. This differs from the other pulmonary aspergillosis conditions, in that it need not affect just the immunocompromised.
References
External links
NIH entry on Bronchitis
MedlinePlus entries on Acute bronchitis and Chronic bronchitis
Mayo Clinic factsheet on bronchitis |
Trichobacteriosis axillaris | Trichobacteriosis axillaris is a superficial bacterial colonization of the hair shafts in sweat gland–bearing areas, such as the armpits and the groin. It is a trivial disease of worldwide occurrence that is believed to be caused by the genus Corynebacteria.The condition has been called extensively trichomycosis axillaris in the literature, but because it is a bacterial infection and not a fungal infection, it should be called trichobacteriosis.
Presentation
It is characterized by the presence of concretions along the hair shafts, clinically observed as yellow, and rarely as red or black nodules. These concretions derive from bacterial colonization along the hair shaft containing dried apocrine sweat with a cementing substance generated by the bacteria.
Cause
It is caused by several species of Corynebacterium.Obesity, hyperhidrosis, poor local hygiene, and warm, moist environments are common predisposing factors.
Diagnosis
The infection is diagnosed by close examination of the hair shafts where brown to yellow material called concretions are seen. There is usually an associated rancid odour. A microscopic examination can confirm the diagnosis, but this is rarely needed.Some patients with excessive sweating present the so-called corynebacterial triad, that is, the simultaneous presence of trichobacteriosis axillaris, erythrasma, and pitted keratolysis.
Treatment
No specific therapeutic studies on trichobacteriosis are available.Many authors consider that the most effective treatment consist in shaving of the affected area for a period of 2–3 weeks. The use of a concomitant treatment, such as sulfur soaps or benzoyl peroxide is also recommended. Rubbing whilst washing may help to disrupt the biofilm, hence increasing the accessibility of antiseptics to the bacteria.Patients who shave the affected area only once will generally experience a recurrence of the infection, since, the bacteria begin to develop the concretions once again as the hair grows back.Corynebacterium infections are related to excessive sweating; for this reason, deodorants containing an aluminum chloride solution may be used for treatment and prevention.Maintaining good local hygiene is recommended.
See also
List of cutaneous conditions
References
== External links == |
Shock (circulatory) | Shock is the state of insufficient blood flow to the tissues of the body as a result of problems with the circulatory system. Initial symptoms of shock may include weakness, fast heart rate, fast breathing, sweating, anxiety, and increased thirst. This may be followed by confusion, unconsciousness, or cardiac arrest, as complications worsen.Shock is divided into four main types based on the underlying cause: low volume, cardiogenic, obstructive, and distributive shock. Low volume shock, also known as hypovolemic shock, may be from bleeding, diarrhea, or vomiting. Cardiogenic shock may be due to a heart attack or cardiac contusion. Obstructive shock may be due to cardiac tamponade or a tension pneumothorax. Distributive shock may be due to sepsis, anaphylaxis, injury to the upper spinal cord, or certain overdoses.The diagnosis is generally based on a combination of symptoms, physical examination, and laboratory tests. A decreased pulse pressure (systolic blood pressure minus diastolic blood pressure) or a fast heart rate raises concerns. The heart rate divided by systolic blood pressure, known as the shock index (SI), of greater than 0.8 supports the diagnosis more than low blood pressure or a fast heart rate in isolation.Treatment of shock is based on the likely underlying cause. An open airway and sufficient breathing should be established. Any ongoing bleeding should be stopped, which may require surgery or embolization. Intravenous fluid, such as Ringers lactate or packed red blood cells, is often given. Efforts to maintain a normal body temperature are also important. Vasopressors may be useful in certain cases. Shock is both common and has a high risk of death. In the United States about 1.2 million people present to the emergency room each year with shock and their risk of death is between 20 and 50%.
Signs and symptoms
The presentation of shock is variable, with some people having only minimal symptoms such as confusion and weakness. While the general signs for all types of shock are low blood pressure, decreased urine output, and confusion, these may not always be present. While a fast heart rate is common, those on β-blockers, those who are athletic, and in 30% of cases of those with shock due to intra abdominal bleeding, heart rate may be normal or slow. Specific subtypes of shock may have additional symptoms.
Dry mucous membrane, reduced skin turgor, prolonged capillary refill time, weak peripheral pulses, and cold extremities can be early signs of shock.
Low volume
Hypovolemic shock is the most common type of shock and is caused by insufficient circulating volume. The most common cause of hypovolemic shock is hemorrhage (internal or external); however, vomiting and diarrhea are more common causes in children. Other causes include burns, as well as excess urine loss due to diabetic ketoacidosis and diabetes insipidus.Signs and symptoms of hypovolemic shock include:
A rapid, weak, thready pulse due to decreased blood flow combined with tachycardia
Cool skin due to vasoconstriction and stimulation of vasoconstriction
Rapid and shallow breathing due to sympathetic nervous system stimulation and acidosis
Hypothermia due to decreased perfusion and evaporation of sweat
Thirst and dry mouth, due to fluid depletion
Cold and mottled skin (livedo reticularis), especially extremities, due to insufficient perfusion of the skinThe severity of hemorrhagic shock can be graded on a 1–4 scale on the physical signs. The shock index (heart rate divided by systolic blood pressure) is a stronger predictor of the impact of blood loss than heart rate and blood pressure alone. This relationship has not been well established in pregnancy-related bleeding.
Cardiogenic
Cardiogenic shock is caused by the failure of the heart to pump effectively. This can be due to damage to the heart muscle, most often from a large myocardial infarction. Other causes of cardiogenic shock include dysrhythmias, cardiomyopathy/myocarditis, congestive heart failure (CHF), myocardial contusion, or valvular heart disease problems.Symptoms of cardiogenic shock include:
Distended jugular veins due to increased jugular venous pressure
Weak or absent pulse
Abnormal heart rhythms, often a fast heart rate
Pulsus paradoxus in case of tamponade
Reduced blood pressure
Shortness of breath, due to pulmonary congestion
Obstructive
Obstructive shock is a form of shock associated with physical obstruction of the great vessels of the systemic or pulmonary circulation. Several conditions can result in this form of shock.
Cardiac tamponade in which fluid in the pericardium prevents inflow of blood into the heart (venous return). Constrictive pericarditis, in which the pericardium shrinks and hardens, is similar in presentation.
Tension pneumothorax Through increased intrathoracic pressure, bloodflow to the heart is prevented (venous return).
Pulmonary embolism is the result of a thromboembolic incident in the blood vessels of the lungs and hinders the return of blood to the heart.
Aortic stenosis hinders circulation by obstructing the ventricular outflow tract
Hypertrophic sub-aortic stenosis is overly thick ventricular muscle that dynamically occludes the ventricular outflow tract.
Abdominal compartment syndrome defined as an increase in intra-abdominal pressure to > 20 mmHg with organ dysfunction. Increased intraabdominal pressure can be due to sepsis and severe abdominal trauma. This increased pressure reduces blood flow back to the heart, thereby reducing blood flow to the body and resulting in signs and symptoms of shock.Many of the signs of obstructive shock are similar to cardiogenic shock, however treatments differ. Symptoms of obstructive shock include:
Abnormal heart rhythms, often a fast heart rate.
Reduced blood pressure.
Cool, clammy, mottled skin, often due to low blood pressure and vasoconstriction.
Decreased urine output.
Distributive
Distributive shock is low blood pressure due to a dilation of blood vessels within the body. This can be caused by systemic infection (septic shock), a severe allergic reaction (anaphylaxis), or spinal cord injury (neurogenic shock).
Septic shock is the most common cause of distributive shock. It is caused by an overwhelming systemic infection resulting in vasodilation leading to hypotension. Septic shock can be caused by Gram negative bacteria such as (among others) Escherichia coli, Proteus species, Klebsiella pneumoniae (which have an endotoxin on their surface that produces adverse biochemical, immunological and occasionally neurological effects which are harmful to the body), other Gram-positive cocci, such as pneumococci and streptococci, and certain fungi as well as Gram-positive bacterial toxins. Septic shock also includes some elements of cardiogenic shock. In 1992, the ACCP/SCCM Consensus Conference Committee defined septic shock: " ... sepsis-induced hypotension (systolic blood pressure < 90 mmHg or a reduction of 40 mmHg from baseline) despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to: lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are receiving inotropic or vasopressor agents may have a normalized blood pressure at the time that perfusion abnormalities are identified. The pathophysiology behind septic shock is as follows: 1) Systemic leukocyte adhesion to endothelial cells 2) Reduced contractility of the heart 3) Activation of the coagulation pathways, resulting in disseminated intravascular coagulation 4). Increased levels of neutrophilsThe main manifestations of septic shock are due to the massive release of histamine which causes intense dilation of the blood vessels. People with septic shock will also likely be positive for SIRS criteria. The most generally accepted treatment for these patients is early recognition of symptoms, and early administration of broad spectrum and organism specific antibiotics.
Signs of septic shock include:
Abnormal heart rhythms, often a fast heart rate
Reduced blood pressure
Decreased urine output
Altered mental status
Anaphylactic shock is caused by a severe anaphylactic reaction to an allergen, antigen, drug, or foreign protein causing the release of histamine which causes widespread vasodilation, leading to hypotension and increased capillary permeability. Signs typically occur after exposure to an allergen and may include:
Skin changes, such as hives, itching, flushing, and swelling.
Wheezing and shortness of breath.
Abdominal pain, diarrhea, and vomiting.
Lightheadedness, confusion, headaches, loss of consciousness.
High spinal injuries may cause neurogenic shock, which is commonly classified as a subset of distributive shock. The classic symptoms include a slow heart rate due to loss of cardiac sympathetic tone and warm skin due to dilation of the peripheral blood vessels. (This term can be confused with spinal shock which is a recoverable loss of function of the spinal cord after injury and does not refer to the hemodynamic instability.)
Endocrine
Although not officially classified as a subcategory of shock, many endocrinology disturbances in their severe form can result in shock.
Hypothyroidism (can be considered a form of cardiogenic shock) in people who are critically ill patients, reduces cardiac output and can lead to hypotension and respiratory insufficiency.
Thyrotoxicosis (cardiogenic shock) may induce a reversible cardiomyopathy.
Acute adrenal insufficiency (distributive shock) is frequently the result of discontinuing corticosteroid treatment without tapering the dosage. However, surgery and intercurrent disease in patients on corticosteroid therapy without adjusting the dosage to accommodate for increased requirements may also result in this condition.
Relative adrenal insufficiency (distributive shock) in critically ill patients where present hormone levels are insufficient to meet the higher demands.
Cause
Shock is a common end point of many medical conditions. Shock triggered by a serious allergic reaction is known as anaphylactic shock, shock triggered by severe dehydration or blood loss is known as hypovolemic shock, shock caused by sepsis is known as septic shock, etc. Shock itself is a life-threatening condition as a result of compromised body circulation. It can be divided into four main types based on the underlying cause: hypovolemic, distributive, cardiogenic, and obstructive. A few additional classifications are occasionally used, such as endocrinologic shock.
Pathophysiology
There are four stages of shock. Shock is a complex and continuous condition, and there is no sudden transition from one stage to the next. At a cellular level, shock is the process of oxygen demand becoming greater than oxygen supply.One of the key dangers of shock is that it progresses by a positive feedback loop. Poor blood supply leads to cellular damage, which results in an inflammatory response to increase blood flow to the affected area. Normally, this causes the blood supply level to match with tissue demand for nutrients. However, if there is enough increased demand in some areas, it can deprive other areas of sufficient supply, which then start demanding more. This then leads to an ever escalating cascade.
As such, shock is a runaway condition of homeostatic failure, where the usual corrective mechanisms relating to oxygenation of the body no longer function in a stable way. When it occurs, immediate treatment is critical in order to return an individuals metabolism into a stable, self-correcting trajectory. Otherwise the condition can become increasingly difficult to correct, surprisingly fast, and then progress to a fatal outcome. In the particular case of anaphylactic shock, progression to death might take just a few minutes.
Initial
During the Initial stage (Stage 1), the state of hypoperfusion causes hypoxia. Due to the lack of oxygen, the cells perform lactic acid fermentation. Since oxygen, the terminal electron acceptor in the electron transport chain, is not abundant, this slows down entry of pyruvate into the Krebs cycle, resulting in its accumulation. The accumulating pyruvate is converted to lactate (lactic acid) by lactate dehydrogenase. The accumulating lactate causes lactic acidosis.
Compensatory
The Compensatory stage (Stage 2) is characterised by the body employing physiological mechanisms, including neural, hormonal, and bio-chemical mechanisms, in an attempt to reverse the condition. As a result of the acidosis, the person will begin to hyperventilate in order to rid the body of carbon dioxide (CO2). CO2 indirectly acts to acidify the blood, so the body attempts to return to acid–base homeostasis by removing that acidifying agent. The baroreceptors in the arteries detect the hypotension resulting from large amounts of blood being redirected to distant tissues, and cause the release of epinephrine and norepinephrine. Norepinephrine causes predominately vasoconstriction with a mild increase in heart rate, whereas epinephrine predominately causes an increase in heart rate with a small effect on the vascular tone; the combined effect results in an increase in blood pressure. The renin–angiotensin axis is activated, and arginine vasopressin (anti-diuretic hormone) is released to conserve fluid by reducing its excretion via the renal system. These hormones cause the vasoconstriction of the kidneys, gastrointestinal tract, and other organs to divert blood to the heart, lungs and brain. The lack of blood to the renal system causes the characteristic low urine production. However the effects of the renin–angiotensin axis take time and are of little importance to the immediate homeostatic mediation of shock.
Progressive/decompensated
The Progressive stage (stage 3) results if the underlying cause of the shock is not successfully treated. During this stage, compensatory mechanisms begin to fail. Due to the decreased perfusion of the cells in the body, sodium ions build up within the intracellular space while potassium ions leak out. Due to lack of oxygen, cellular respiration diminishes and anaerobic metabolism predominates. As anaerobic metabolism continues, the arteriolar smooth muscle and precapillary sphincters relax such that blood remains in the capillaries. Due to this, the hydrostatic pressure will increase and, combined with histamine release, will lead to leakage of fluid and protein into the surrounding tissues. As this fluid is lost, the blood concentration and viscosity increase, causing sludging of the micro-circulation. The prolonged vasoconstriction will also cause the vital organs to be compromised due to reduced perfusion. If the bowel becomes sufficiently ischemic, bacteria may enter the blood stream, resulting in the increased complication of endotoxic shock.
Refractory
At Refractory stage (stage 4), the vital organs have failed and the shock can no longer be reversed. Brain damage and cell death are occurring, and death will occur imminently. One of the primary reasons that shock is irreversible at this point is that much of the cellular ATP (the basic energy source for cells) has been degraded into adenosine in the absence of oxygen as an electron receptor in the mitochondrial matrix. Adenosine easily perfuses out of cellular membranes into extracellular fluid, furthering capillary vasodilation, and then is transformed into uric acid. Because cells can only produce adenosine at a rate of about 2% of the cells total need per hour, even restoring oxygen is futile at this point because there is no adenosine to phosphorylate into ATP.
Diagnosis
The diagnosis of shock is commonly based on a combination of symptoms, physical examination, and laboratory tests. Many signs and symptoms are not sensitive or specific for shock, thus many clinical decision-making tools have been developed to identify shock at an early stage. A high degree of suspicion is necessary for the proper diagnosis of shock.
The first change seen in shock is increased cardiac output followed by a decrease in mixed venous oxygen saturation (SmvO2) as measured in the pulmonary artery via a pulmonary artery catheter. Central venous oxygen saturation (ScvO2) as measured via a central line correlates well with SmvO2 and are easier to acquire. If shock progresses anaerobic metabolism will begin to occur with an increased blood lactic acid as the result. While many laboratory tests are typically performed, there is no test that either conclusively makes or excludes the diagnosis. A chest X-ray or emergency department ultrasound may be useful to determine volume status.
Management
The best evidence exists for the treatment of septic shock in adults. However, the pathophysiology of shock in children appears to be similar so treatment methodologies have been extrapolated to children. Management may include securing the airway via intubation if necessary to decrease the work of breathing and for guarding against respiratory arrest. Oxygen supplementation, intravenous fluids, passive leg raising (not Trendelenburg position) should be started and blood transfusions added if blood loss is severe. In select cases, compression devices like non-pneumatic anti-shock garments (or the deprecated military anti-shock trousers) can be used to prevent further blood loss and concentrate fluid in the bodys head and core. It is important to keep the person warm to avoid hypothermia as well as adequately manage pain and anxiety as these can increase oxygen consumption. Negative impact by shock is reversible if its recognized and treated early in time.
Fluids
Aggressive intravenous fluids are recommended in most types of shock (e.g. 1–2 liter normal saline bolus over 10 minutes or 20 mL/kg in a child) which is usually instituted as the person is being further evaluated. Colloids and crystalloids appear to be equally effective with respect to outcomes., Balanced crystalloids and normal saline also appear to be equally effective in critically ill patients. If the person remains in shock after initial resuscitation, packed red blood cells should be administered to keep the hemoglobin greater than 100 g/L.For those with hemorrhagic shock, the current evidence supports limiting the use of fluids for penetrating thorax and abdominal injuries allowing mild hypotension to persist (known as permissive hypotension). Targets include a mean arterial pressure of 60 mmHg, a systolic blood pressure of 70–90 mmHg, or until the patient has adequate mentation and peripheral pulses. Hypertonic fluid may also be an option in this group.
Medications
Vasopressors may be used if blood pressure does not improve with fluids. Common vasopressors used in shock include: norepinephrine, phenylephrine, dopamine, and dobutamine.
There is no evidence of substantial benefit of one vasopressor over another; however, using dopamine leads to an increased risk of arrhythmia when compared with norepinephrine. Vasopressors have not been found to improve outcomes when used for hemorrhagic shock from trauma but may be of use in neurogenic shock. Activated protein C (Xigris), while once aggressively promoted for the management of septic shock, has been found not to improve survival and is associated with a number of complications. Activated protein C was withdrawn from the market in 2011, and clinical trials were discontinued. The use of sodium bicarbonate is controversial as it has not been shown to improve outcomes. If used at all it should only be considered if the blood pH is less than 7.0.People with anaphylactic shock are commonly treated with epinephrine. Antihistamines, such as Benadryl (diphenhydramine) or ranitidine are also commonly administered. Albuterol, normal saline, and steroids are also commonly given.
Mechanical support
Intra-aortic balloon pump (IABP) – a device inserted into the aorta that mechanically raises the blood pressure. Use of Intra-aortic balloon pumps is not recommended in cardiogenic shock.
Ventricular assist device (VAD) – A mechanical pump that helps pump blood throughout the body. Commonly used in short term cases of refractory primary cardiogenic shock.
Artificial heart (TAH)
Extracorporeal membrane oxygenation (ECMO) – an external device that completely replaces the work of the heart.
Treatment goals
The goal of treatment is to achieve a urine output of greater than 0.5 mL/kg/h, a central venous pressure of 8–12 mmHg and a mean arterial pressure of 65–95 mmHg. In trauma the goal is to stop the bleeding which in many cases requires surgical interventions. A good urine output indicates that the kidneys are getting enough blood flow.
Epidemiology
Septic shock (a form of distributive shock), is the most common form of shock. Shock from blood loss occurs in about 1–2% of trauma cases. Overall, up to one-third of people admitted to the intensive care unit (ICU) are in circulatory shock. Of these, cardiogenic shock accounts for approximately 20%, hypovolemic about 20%, and septic shock about 60% of cases.
Prognosis
The prognosis of shock depends on the underlying cause and the nature and extent of concurrent problems. Low volume, anaphylactic, and neurogenic shock are readily treatable and respond well to medical therapy. Septic shock, especially septic shock where treatment is delayed or the antimicrobial drugs are ineffective, however has a mortality rate between 30% and 80%; cardiogenic shock has a mortality rate of up to 70% to 90%, though quick treatment with vasopressors and inotropic drugs, cardiac surgery, and the use of assistive devices can lower the mortality.
History
There is no evidence of the word shock being used in its modern-day form prior to 1743. However, there is evidence that Hippocrates used the word exemia to signify a state of being "drained of blood". Shock or "choc" was first described in a trauma victim in the English translation of Henri-François LeDrans 1740 text, Traité ou Reflexions Tirees de la Pratique sur les Playes darmes à feu (A treatise, or reflections, drawn from practice on gun-shot wounds.) In this text he describes "choc" as a reaction to the sudden impact of a missile. However, the first English writer to use the word shock in its modern-day connotation was James Latta, in 1795.
Prior to World War I, there were several competing hypotheses behind the pathophysiology of shock. Of the various theories, the most well regarded was a theory penned by George W. Crile who suggested in his 1899 monograph, "An Experimental Research into Surgical Shock", that shock was quintessentially defined as a state of circulatory collapse (vasodilation) due to excessive nervous stimulation. Other competing theories around the turn of the century included one penned by Malcom in 1907, in which the assertion was that prolonged vasoconstriction led to the pathophysiological signs and symptoms of shock. In the following World War I, research concerning shock resulted in experiments by Walter B. Cannon of Harvard and William M. Bayliss of London in 1919 that showed that an increase in permeability of the capillaries in response to trauma or toxins was responsible for many clinical manifestations of shock. In 1972 Hinshaw and Cox suggested the classification system for shock which is still used today.
References
== External links == |
Facial symmetry | Facial symmetry is one specific measure of bodily symmetry. Along with traits such as averageness and youthfulness it influences judgments of aesthetic traits of physical attractiveness and beauty. For instance, in mate selection, people have been shown to have a preference for symmetry.Facial bilateral symmetry is typically defined as fluctuating asymmetry of the face comparing random differences in facial features of the two sides of the face. The human face also has systematic, directional asymmetry: on average, the face (mouth, nose and eyes) sits systematically to the left with respect to the axis through the ears, the so-called aurofacial asymmetry.
Directional asymmetry
Directional asymmetry is a systematic asymmetry of some parts of the face across the population. A theory of directional asymmetries in the human body is the axial twist hypothesis. As predicted by this theory, the eyes, nose and mouth are, on average, located slightly to the left of the axis through the ears. This aurofacial asymmetry is very small in young adults (0.5 degree), but much larger in small children (4 degrees).
Fluctuating asymmetry
Fluctuating asymmetry is the non-systematic variation of individual facial landmarks with respect to the facial midline, i.e., the line perpendicular to the line through the eyes, which crosses the tip of the nose and the chin.
A wide variety of methods have been used to examine the claim that facial symmetry plays a role in judgments of beauty. Blending of multiple faces to create a composite and face-half mirroring have been among the techniques used.
Conclusions derived from face mirroring, however, have been called into question, because it has been shown that mirroring face-halves creates artificial features. For example, if the nose of an individual is slightly bent to the right side, then mirroring the right side of the face will lead to an over-sized nose, while mirroring the left side will lead to an unnaturally small nose.
Attractiveness
Facial symmetry has been found to increase ratings of attractiveness in human faces. More symmetrical faces are perceived as more attractive in both males and females, although facial symmetry plays a larger role in judgments of attractiveness concerning female faces.While studies employing the composite faces produced results that indicate that more symmetrical faces are perceived as more attractive, studies applying the face-half mirroring technique have indicated that humans prefer slight asymmetry. Also, studies have shown that nearly symmetrical faces are considered highly attractive as compared to asymmetrical ones. The symmetry of the nose seems to be more important than that of the lips.
Dynamic asymmetries
Highly conspicuous directional asymmetries can be temporary ones. For example, during speech, most people (76%) tend to express greater amplitude of movement on the right side of their mouth. This is most likely caused by the uneven strengths of contralateral neural connections between the left hemisphere of the brain (linguistic localization) and the right side of the face.
Facial averageness vs. symmetry
Experiments suggest that symmetry and averageness make independent contributions to attractiveness.
Aging
Facial symmetry is also a valid marker of cognitive aging. Progressive changes occurring throughout life in the soft tissues of the face will cause more prominent facial asymmetry in older faces. Therefore, symmetrical transformation of older faces generally increases their attractiveness while symmetrical transformation in young adults and children will decrease their attractiveness.
Personality and Big Five personality traits
Research indicates that facial symmetry is correlated with the big-five model of personality. The five factors are:
Openness to experience (inventive/curious vs. consistent/cautious)
Conscientiousness (efficient/organized vs. easy-going/careless)
Extraversion (outgoing/energetic vs. solitary/reserved)
Agreeableness (friendly/compassionate vs. challenging/detached)
Neuroticism (sensitive/nervous vs. secure/confident)A consistent finding is that facial symmetry is positively correlated with extraversion, indicating that individuals with more symmetric faces are also more extroverted. More symmetrical faces are also judged to be lower on neuroticism but higher on conscientiousness and agreeableness (asymmetrical faces were rated as less agreeable than normal ones, but the more symmetrical were again rated as somewhat less agreeable than the normal). More symmetrical faces are also more likely to have more desirable social attributes assigned to them, such as sociable, intelligent or lively.However, the relationship of facial symmetry and the big-five personality model remains somewhat unclear with regard to neuroticism, openness, agreeableness and conscientiousness. Openness and agreeableness appear to be significantly negatively related to facial symmetry, while neuroticism and conscientiousness do not seem to be linked to facial symmetry. With respect to trustworthiness it has been found that the facial muscles become imbalanced when lying.
Evolution and sexual selection
Sexual selection is a theoretical construct within evolution theory. According to sexual selection, mate choice can have profound influence on the preferred features. Sexual selection can only influence features that potential mates can perceive, such as smell, audition (e.g. song) and vision. Such features might be reliable indicators of hidden fitness parameters such as a good immune system or developmental stability.
It has been argued that more symmetric faces are preferred because symmetry might be a reliable sign of such hidden fitness parameters. However it is possible that high facial symmetry in an individual is not due to their superior genetics but due to a lack of exposure to stressors during development.It has been found that more symmetrical faces are rated as healthier than less symmetrical faces. Indeed, facial symmetry was found to be positively associated with the perceived healthiness of the facial skin. Also, facial asymmetry was found to be correlated with physiological, psychological and emotional distress.Some evidence suggests that face preferences in adults might be correlated to infections in childhood.
See also
Beauty
Symmetry in nature
Patterns in nature
Physical attractiveness
References
External links
FaceResearch – Online studies on facial symmetry by researchers affiliated with University of Aberdeen (Scotland) School of Psychology, and University of St. Andrews (Scotland).
"A facial symmetry plugin for the GIMP"—Try experimenting with facial symmetry, using open source software.
"Psychological Image Collection at Stirling (PICS) Free Database of pictures of faces
"FaceBase An interdisciplinary research consortium for facial symmetry
"Tübinger Face Database An open research database of 200 merged 3-D faces
"A facial symmetry app for iPhone Experiment with facial symmetry, using a free iPhone app. |
Upper airway resistance syndrome | Upper airway resistance syndrome is a sleep disorder characterized by the narrowing of the airway that can cause disruptions to sleep. The symptoms include unrefreshing sleep, fatigue, sleepiness, chronic insomnia, and difficulty concentrating. UARS can be diagnosed by polysomnograms capable of detecting Respiratory Effort-related Arousals. It can be treated with lifestyle changes, orthodontics, surgery, or CPAP therapy. UARS is considered a variant of sleep apnea, although some scientists and doctors believe it to be a distinct disorder.
History
Upper airway resistance syndrome was first recognized at Stanford University in the late 1980s and the article that described it by name along with its relationship to OSA was published in 1992 by Dr. Christian Guilleminault et al.
Signs and symptoms
Symptoms of UARS are similar to those of obstructive sleep apnea, but not inherently overlapping. Fatigue, insomnia, daytime sleepiness, unrefreshing sleep, anxiety, and frequent awakenings during sleep are the most common symptoms. Oxygen desaturation is minimal or absent in UARS, with most having a minimum oxygen saturation >92%.Many patients experience chronic insomnia that creates both a difficulty falling asleep and staying asleep. As a result, patients typically experience frequent sleep disruptions. Most patients with UARS snore, but not all.Some patients experience hypotension, which may cause lightheadedness, and patients with UARS are also more likely to experience headaches and irritable bowel syndrome.Predisposing factors include a high and narrow hard palate, an abnormally small intermolar distance, an abnormal overjet greater than or equal to 3 millimeters, and a thin soft palatal mucosa with a short uvula. In 88% of the subjects, there is a history of early extraction or absence of wisdom teeth. There is an increased prevalence of UARS in east Asians.
Pathophysiology
Upper airway resistance syndrome is caused when the upper airway narrows without closing. Consequently, airflow is either reduced or compensated for through an increase in inspiratory efforts. This increased activity in inspiratory muscles leads to the arousals during sleep which patients may or may not be aware of.A typical UARS patient is not obese and possesses small jaws, which can result in a smaller amount of space in the nasal airway and behind the base of the tongue. Patients may have other anatomical abnormalities that can cause UARS such as deviated septum, inferior turbinate hypertrophy, a narrow hard palate that reduces nasal volume, enlarged tonsils, or nasal valve collapse. UARS affects equal numbers of males and females.Why some patients with airway obstruction present with UARS and not OSA is thought to be caused by alterations in nerves located in the palatal mucosa. UARS patients have largely intact and responsive nerves, while OSA patients show clear impairment and nerve damage. Functioning nerves in the palatal mucosa allow UARS patients to more effectively detect and respond to flow limitations before apneas and hypopneas can occur. Patients with intact nerves are able to dilate the genioglossus muscle, a key compensatory mechanism utilized in the presence of airway obstruction. What damages the nerves is not definitively known, but it is hypothesized to be caused by the long term effects of gastroesophageal reflux and/or snoring.
Diagnosis
UARS is diagnosed using the Respiratory Disturbance Index (RDI). A patient is considered to have UARS when they have an Apnea-Hypopnea Index (AHI) less than 5, but an RDI greater than or equal to 5. Unlike the Apnea-Hypopnea Index, the Respiratory Disturbance Index includes Respiratory Effort-related Arousals (RDI = AHI + RERA Index). In 2005, the definition of Sleep Apnea was changed to include patients with UARS by using RDI to determine sleep apnea severity.
The diagnosis of UARS is based on findings on a polysomnogram. On polysomnograms, a UARS patient will have very few apneas and hypopneas, but many Respiratory effort-related Arousals. RERAs are periods of increased respiratory effort lasting for more than ten seconds and ending in arousal. Whether or not an event is classified as a RERA or Hypopnea depends on the definition of Hypopnea used by the sleep technician. The American Academy of Sleep Medicine currently recognizes two definitions. The scoring of Respiratory Effort-related Arousals is currently designated as "optional" by the AASM. Thus, many patients who receive sleep studies may receive a negative result, even if they have UARS.Based on symptoms, patients are commonly misdiagnosed with idiopathic insomnia, idiopathic hypersomnia, chronic fatigue syndrome, fibromyalgia, or a psychiatric disorder such as ADHD or depression. Studies have found that children with UARS are frequently misdiagnosed with ADHD. One study found UARS or OSA present in up to 56% of children with ADHD. Studies show that symptoms of ADHD caused by UARS significantly improve or remit with treatment in surgically treated children.
Management
Behavioral modification
Behavioral modifications include getting at least 7–8 hours of sleep and various lifestyle changes, such as positional therapy. Sleeping on ones side rather than in a supine position or using positional pillows can provide relief, but these modifications may not be sufficient to treat more severe cases. Avoiding sedatives including alcohol and narcotics can help prevent the relaxation of airway muscles, and thereby reduce the chance of their collapse. Avoiding sedatives may also help to reduce snoring.
Medications
Nasal steroids may be prescribed in order to ease nasal allergies and other obstructive nasal conditions that could cause UARS.
Positive airway pressure therapy
If left untreated, UARS can develop into obstructive sleep apnea. Treatments for OSA such as positive airway pressure therapy can be effective at stopping the progression of UARS.Positive airway pressure therapy is similar to that in obstructive sleep apnea and works by stenting the airway open with pressure, thus reducing the airway resistance. Use of a CPAP can help ease the symptoms of UARS. Therapeutic trials have shown that using a CPAP with pressure between four and eight centimeters of water can help to reduce the number of arousals and improve sleepiness. CPAPs are the most promising treatment for UARS, but effectiveness is reduced by low patient compliance.
Oral appliances
Oral appliances to protrude the tongue and lower jaw forward have been used to reduce sleep apnea and snoring, and hold potential for treating UARS, but this approach remains controversial. Oral appliances may be a suitable alternative for patients who cannot tolerate CPAP.
Surgery
For nasal obstruction, options can be septoplasty, turbinate reductions, or surgical palate expansion.Orthognathic surgeries that expands the airway, such as Maxillomandibular advancement (MMA) or Surgically Assisted Rapid Palatal Expansion (SARPE) are the most effective surgeries for sleep disordered breathing. MMA is often completely curative.Though less common methods of treatment, various surgical options including uvulopalatopharyngoplasty (UPPP), hyoid suspension, and linguloplasty exist. These procedures increase the dimensions of the upper airway and reduce the collapsibility of the airway. One should also be screened for the presence of a hiatal hernia, which may result in abnormal pressure differentials in the esophagus, and in turn, constricted airways during sleep. Palatal tissue reduction via radiofrequency ablation has also been successful in treating UARS.
Maxillary Expansion
Orthodontic treatment to expand the volume of the nasal airway, such as nonsurgical Rapid Palatal expansion is common in children. Due to the ossification of the median palatine suture, traditional tooth-born expanders cannot achieve maxillary expansion in adults as the mechanical forces instead tip the teeth and dental alveoli. Mini-implant assisted rapid palatal expansion (MARPE) has been recently developed as a minimally invasive option for the transverse expansion of the maxilla in adults. This method increases the volume of the nasal cavity and nasopharynx, leading to increased airflow and reduced respiratory arousals during sleep.
See also
Airway resistance
Sleep apnea
== References == |
Intermediate uveitis | Intermediate uveitis is a form of uveitis localized to the vitreous and peripheral retina. Primary sites of inflammation include the vitreous of which other such entities as pars planitis, posterior cyclitis, and hyalitis are encompassed. Intermediate uveitis may either be an isolated eye disease or associated with the development of a systemic disease such as multiple sclerosis or sarcoidosis. As such, intermediate uveitis may be the first expression of a systemic condition. Infectious causes of intermediate uveitis include Epstein–Barr virus infection, Lyme disease, HTLV-1 virus infection, cat scratch disease, and hepatitis C.
Permanent loss of vision is most commonly seen in patients with chronic cystoid macular edema (CME). Every effort must be made to eradicate CME when present. Other less common causes of visual loss include retinal detachment, glaucoma, band keratopathy, cataract, vitreous hemorrhage, epiretinal membrane and choroidal neovascularization.
Signs and symptoms
Clinical signs include redness of the eye, pain, blurring of vision, photophobia and floaters.
However, some individuals, particularly children, can present with few to no symptoms.
Associated conditions
Associations of the disease with such entities as multiple sclerosis, sarcoidosis, or inflammatory bowel disease suggest an autoimmune component in at least a subset of patients. The clustering of familial cases has led to the investigation of human leukocyte antigen (HLA) associations. The inciting event appears to be peripheral retinal perivasculitis and vascular occlusion leading to ocular inflammation, vitritis and snowbank formation. The etiology of the antigenic stimulus is not clear and may be either vitreal or perivascular in nature. It is evident that genetics plays some role in the pathophysiology of intermediate uveitis, but the importance remains unclear.
Pathophysiology
Pars planitis is considered a subset of intermediate uveitis and is characterized by the presence of white exudates (snowbanks) over the pars plana or by aggregates of inflammatory cells in the vitreous (snowballs) in the absence of an infectious or a systemic disease. Some physicians believe that patients with pars planitis have worse vitritis, more severe macular edema, and a guarded prognosis compared to other patients with intermediate uveitis.
Treatment
Peri-ocular injection of corticosteroids (injection of corticosteroids very close but not into the eye). In resistant cases oral administration of corticosteroids, immunosuppressive drugs, and laser or cryotherapy of the involved area may be indicated.
Steroid implants have been explored as a treatment option for individuals with non-infectious uveitis. Research comparing fluocinolone acetonide intravitreal implants to standard-of-care treatments (prednisolone with immunosuppressive agents) found that while the steroid implant treatment possibly prevents the recurrence of uveitis, there may be adverse safety outcomes, such as the increased risk for needing cataract surgery and surgery to lower intraocular pressure.
Epidemiology
Although intermediate uveitis can develop at any age, it primarily afflicts children and young adults. There is a bimodal distribution with one peak in the second decade and another peak in the third or fourth decade.
In the United States the proportion of patients with intermediate uveitis is estimated to be 4-8% of uveitis cases in referral centers. The National Institutes of Health reports a higher percentage (15%), which may indicate improved awareness or the nature of the uveitis referral clinic. In the pediatric population, intermediate uveitis can account for up to 25% of uveitis cases.
== References == |
Neonatal meningitis | Neonatal meningitis is a serious medical condition in infants that is rapidly fatal if untreated. Meningitis is an inflammation of the meninges, the protective membranes of the central nervous system, is more common in the neonatal period (infants less than 44 days old) than any other time in life, and is an important cause of morbidity and mortality globally. Mortality is roughly half in developing countries and ranges from 8%-12.5% in developed countries.Symptoms seen with neonatal meningitis are often unspecific and may point to several conditions, such as sepsis (whole body inflammation). These can include fever, irritability, and dyspnea. The only method to determine if meningitis is the cause of these symptoms is lumbar puncture (an examination of the cerebrospinal fluid).The most common cause of neonatal meningitis is bacterial infection of blood, known as bacteremia. Organisms responsible are different; most commonly group B streptococci (i.e. Streptococcus agalactiae), Escherichia coli, and Listeria monocytogenes. Although there is a low mortality rate in developed countries, there is a 50% prevalence rate of neurodevelopmental disabilities after meningitis caused by E. coli and Streptococcus agalactiae, and a 79% prevalence after meningitis caused by Gram-negative rods other than E. coli. Delayed treatment of neonatal meningitis may cause cerebral palsy, blindness, deafness, seizure disorders, and learning deficiencies.
Signs and symptoms
The following is a list of common signs and symptoms of neonatal meningitis.
Fever
poor appetite
anterior fontanelle bulging
seizures
jitteriness
dyspnea
irritability
anorexia
vomiting
diarrhea
abdominal distention (increase in abdominal size)
neck rigidity
cyanosis
jaundice
sunset eyes (downward gaze of the eyes)
abnormal body temperature (hypo-or hyperthermia)
change of activity (lethargy or irritability)These symptoms are unspecific and may point to many different conditions.
Complications
Neuroimaging (X-ray imaging of the brain) is recommended to detect the complications of meningitis. Complications should be suspected when the clinical course is characterized by shock, respiratory failure, focal neurological deficits, a positive cerebrospinal fluid culture after 48 to 72 hours of appropriate antibiotic therapy, or infection with certain organisms, such as Citrobacter koseri and Cronobacter sakazakii for example. Ultrasounds are useful for early imaging to determine ventricular size and hemorrhaging. CT scans later in the therapy should be used to dictate prolonged treatment.If intracranial abscesses (collection of pus in the brain) are found, treatment consisting of a combination of surgical drainage of the abscess and antimicrobial therapy for 4 to 6 weeks is recommended. More imaging should be completed after the end of antibiotic treatment because abscesses have been found after weeks from start of treatment.Relapses have also occurred after appropriate treatment when infected by Gram-negative enteric bacilli.
Hearing Loss
Meningitis is one of the leading causes of acquired deafness. Nearly 8% of those with Meningitis will have a permanent sensorineural hearing loss. The longer meningitis is left untreated, the greater the risk of seizures and permanent neurological damage such as hearing loss, memory difficulty, learning disabilities, brain damage, gait problems, kidney failure, shock, and even death. Hearing loss in those with Meningitis can occur when the body is fighting off the infection and the cells reach the inner ear where the hair cells and nerve fibers become damaged. Hearing loss can also occur after Meningitis is resolved due to an increased risk for ossification of the cochlea. Ossification of the cochlea can make it difficult to place a Cochlear Implant for hearing losses that are treated unsuccessfully with hearing aids. Bacterial Meningitis is likely to lead to hearing loss. It is important to have a hearing test as soon as possible. It would be best to complete a hearing test before leaving the hospital or within four weeks of improvement of symptoms. Fluctuating hearing loss has been observed in a large number of patients, so it is best to have routine hearing tests to monitor the hearing loss. Viral Meningitis is less likely to cause hearing loss and it is recommended to perform a hearing test if the patient is experiencing any hearing difficulties. All hearing losses are different so there is no predictive loss for Meningitis. Children are assessed through behavioral testing (if old enough), Otoacoustic Emissions (OAEs), and Auditory Brainstem Response (ABR).Impact in Children for Communication
If hearing loss is left undetected and/or untreated, this can lead to later acquisition of language and delayed reading skills. Since untreated Meningitis can cause brain damage and learning disabilities, children with a history of Meningitis may be developmentally delayed when compared to their typically developing peers.
Laboratory features
Laboratory features that are characteristic of neonatal bacterial meningitis include:
Isolation of a bacterial pathogen from the cerebrospinal fluid by culture and/or visualization by Gram stain
Increased cerebrospinal fluid white blood cell count (typically >1000 white blood cells/μL, but may be lower, especially with Gram-positive bacteria), usually with a predominance of neutrophils
Elevated cerebrospinal fluid protein concentration (>150 mg/dL in preterm (premature birth) and >100 mg/dL in term infants)
Decreased cerebrospinal fluid glucose concentration (<20 mg/dL [1.1 mmol/L] in preterm (premature birth) and <30 mg/dL [1.7 mmol/L] in term (on time) infants)
Causes
Neonatal meningitis is caused by group B streptococci Streptococcus agalactiae (39%-48% of cases), Escherichia coli (30%-35%), other Gram-negative rods (8%-12%), Streptococcus pneumoniae (about 6%), and Listeria monocytogenes (5%-7%). Meningitis is typically caused from either a bacterial or viral infection, however, it can be caused by fungal, parasitic, or amebic infections as well. Even more rare, Meningitis can be caused by some cancers, Lupus, specific drugs, head injuries, and brain surgeries. Most neonatal meningitis results from bacteremia (bacterial infection of the blood) with hematogenous spread to the central nervous system (CNS).
Early-onset
In early-onset neonatal meningitis, acquisition of the bacteria is from the mother either before the baby is born or during birth. The most common bacteria found in early-onset are Streptococcus agalactiae, Escherichia coli, and Listeria monocytogenes. In developing countries, Gram-negative enteric (gut) bacteria are responsible for the majority of early onset meningitis.
Late-onset
Late-onset meningitis may be caused by other Gram-negative bacteria and staphylococcal species. In developing countries, Streptococcus pneumoniae accounts for most cases of late onset.
Herpes Simplex Virus
Herpes simplex virus is a rare cause of meningitis, occurring only 0.165 in 10,000 live births in the UK and 0.2-5 in 10,000 live births in the US Both HSV-1 and HSV-2 can cause neonatal meningitis, however, HSV-2 accounts for 70% of the cases.Herpes simplex virus is transmitted to neonates mainly during delivery (when infected maternal secretions come into contact with the baby and accounting for 85% of cases), but also occur in utero (while the fetus is still in the womb, 5% of cases) or even post-delivery, receiving the infection from the community (10% of cases). The most important factors impacting the transmission of the virus is the stage of the mothers infection (symptomatic or non-symptomatic) and the damage of any maternal membranes during birth (the longer the tissue is damaged, the higher the chance of neonatal infection).
Pathogenesis
Generally, the progression of neonatal meningitis starts with bacteria colonizing the gastrointestinal tract. The bacteria then invades through the intestinal mucosa layer into the blood, causing bacteremia followed by invasion of the cerebrospinal fluid. The neonates less efficient immune system (especially the alternative complement system) lessens their defense against invading bacteria. Colonization of the mother plays an important role in transmission to the neonate, causing early-onset meningitis.
Group B Streptococcus
Neonatal Streptococcus agalactiae infection is acquired in utero or during passage through the vagina. Evidence suggests that vaginal colonization by Streptococcus agalactiae during pregnancy increases the risk of vertical transmission and early-onset disease in neonates.
Neonatal meningitis-causing E. coli
Some strains of E. coli have a capsule, called K1, which protects the bacteria from the innate immune system and allows it to penetrate the central nervous system. The capsule contains sialic acid, which is found widely in humans and so does not set off the defenses of the body. Sialic acid also plays a role in the bacterias ability to invade through the blood-brain barrier. The capsule can be variably O-acetylated.
Diagnosis
Bacterial Infection
A lumbar puncture (spinal tap) is necessary to diagnose meningitis. Cerebrospinal fluid culture is the most important study for the diagnosis of neonatal bacterial meningitis because clinical signs are non-specific and unreliable. Blood cultures may be negative in 15-55% of cases, making them unreliable as well. However, a cerebrospinal fluid to blood glucose ratio below two-thirds has a strong relationship to bacterial meningitis. A spinal tap should be done in all neonates with suspected meningitis, with suspected or proven sepsis (whole body inflammation) and should be considered in all neonates in whom sepsis is a possibility. The role of the spinal tap in neonates who are healthy appearing but have maternal risk factors for sepsis is more controversial; its diagnostic yield in these patients may be low.Early-onset is deemed when infection is within one week of birth. Late-onset is deemed after the first week.
Viral Infection
Babies born from mothers with symptoms of Herpes simplex virus should be tested for viral infection. Liver tests, complete blood count, cerebrospinal fluid analysis, and a chest X-ray should all be completed to diagnose meningitis. Samples should be taken from skin, conjunctiva (eye), mouth and throat, rectum, urine, and the cerebrospinal fluid for viral culture and polymerase chain reaction.
Prevention
Bacterial
Prevention of neonatal meningitis is primarily intrapartum (during labor) antibiotic prophylaxis (prevention) of pregnant mothers to decrease chance of early-onset meningitis by Streptococcus agalactiae. For late-onset meningitis, prevention is passed onto the caretakers to stop the spread of infectious microorganisms. Proper hygiene habits are first and foremost, while stopping improper antibiotic use; such as over-prescriptions, use of broad spectrum antibiotics, and extended dosing times will aid prevention of late-onset neonatal meningitis. A possible prevention may be vaccination of mothers against Streptococcus agalactiae and E. coli, however, this is still under development.
Viral
The only form of prevention from viral infection of the neonate is a Caesarean section form of delivery if the mother is showing symptoms of infection.
Treatment
Treatment for meningitis is antibiotics. The particular drugs used are based on culture results that identify the infecting bacteria, but a mix of ampicillin, gentamicin, and cefotaxime is used for early-onset meningitis before their identification. A regimen of antistaphylococcal antibiotic, such as nafcillin or vancomycin, plus cefotaxime or ceftazidime with or without an aminoglycoside is recommended for late-onset neonatal meningitis. The aim for these treatments is to sterilize the cerebrospinal fluid of all pathogens. A repeat spinal tap 24 to 48 hours after treatment has been started should be done to confirm sterilization.Limited evidence suggests that adjuvant corticosteroids may reduce the short-term risk of hearing loss in newborn infants with meningitis, but it is uncertain whether corticosteroids help to reduce the risk of death or longer-term hearing loss.
Group B Streptococci
For meningitis suspected to be caused by Streptococcus agalactiae, the following treatment is recommended by the American Academy of Pediatrics: doses of penicillin up to 450 000 U/kg daily (270 mg/kg/day) divided 8 hourly if <7 days of age and divided 6 hourly if >7 days of age. For penicillin [the recommended dose is up to 300 mg/kg/daily divided 8 hourly if <7 days of age or 4–6 hourly if >7 days of age. After confirmation of Streptococcus agalactiae by culture, penicillin alone should be used for the rest of the course of treatment, including the 14-day post-sterilization therapy.
Gram-negative Enterics
For suspected Gram-negative enteric (including E. coli) meningitis a combination of cefotaxime and aminoglycoside, usually gentamicin, is recommended. This treatment should last for 14 days after sterilization and then only cefotaxime for another 7 days creating a minimum of 21 days of therapy after sterilization.
Listeria monocytogenes
Meningitis caused by Listeria monocytogenes should be treated with a combination of ampicillin and gentamicin because it is synergistic in vitro and provides more rapid bacterial clearance in animal models of infection.
Streptococcus pneumoniae
Streptococcus pneumoniae can be treated with either penicillin or ampicillin.
Herpes Simplex Virus
In cases of meningitis caused by Herpes simplex virus, antiviral therapy with (acyclovir or vidarabine) must be started immediately for a favorable outcome. Acyclovir is a better antiviral because it shows a similar effect on the infection as vidarabine and is safer to use in neonates. The recommended dosage is 20 mg/kg every six hours for 21 days.
Epidemiology
In industrialized countries, the incidence of bacterial meningitis is approximately 3 in 10,000 live births. The incidence of Herpes simplex virus meningitis is estimated to be 0.2-5.0 cases per 10,000 live births. Neonatal meningitis is much more common in developing countries. Neonatal meningitis ranges from 4.8 per 10,000 live births in Hong Kong to 24 per 10,000 live births in Kuwait. In Africa and South Asia, figures ranging from 8.0 to 61 per 10,000 live births are found. It is expected that these numbers are lower than reality due to the difficulty of diagnosing and the healthcare available to underdeveloped countries in Asia and Africa.
== References == |
Presbycusis | Presbycusis (also spelled presbyacusis, from Greek πρέσβυς presbys "old" + ἄκουσις akousis "hearing"), or age-related hearing loss, is the cumulative effect of aging on hearing. It is a progressive and irreversible bilateral symmetrical age-related sensorineural hearing loss resulting from degeneration of the cochlea or associated structures of the inner ear or auditory nerves. The hearing loss is most marked at higher frequencies. Hearing loss that accumulates with age but is caused by factors other than normal aging (nosocusis and sociocusis) is not presbycusis, although differentiating the individual effects of distinct causes of hearing loss can be difficult.
The cause of presbycusis is a combination of genetics, cumulative environmental exposures and pathophysiological changes related to aging. At present there are no preventive measures known; treatment is by hearing aid or surgical implant.
Presbycusis is the most common cause of hearing loss, affecting one out of three persons by age 65, and one out of two by age 75. Presbycusis is the second most common illness next to arthritis in aged people.
Many vertebrates such as fish, birds and amphibians do not experience presbycusis in old age as they are able to regenerate their cochlear sensory cells, whereas mammals including humans have genetically lost this regenerative ability.
Presentation
Primary symptoms:
sounds or speech becoming dull, muffled or attenuated
need for increased volume on television, radio, music and other audio sources
difficulty using the telephone
loss of directionality of sound
difficulty understanding speech, especially women and children
difficulty in speech discrimination against background noise (cocktail party effect)Secondary symptoms:
hyperacusis, heightened sensitivity to certain volumes and frequencies of sound, resulting from "recruitment"
tinnitus, ringing, buzzing, hissing or other sounds in the ear when no external sound is presentUsually occurs after age 50, but deterioration in hearing has been found to start very early, from about the age of 18 years. The ISO standard 7029 shows expected threshold changes due purely to age for carefully screened populations (i.e. excluding those with ear disease, noise exposure etc.), based on a meta-analysis of published data. Age affects high frequencies more than low, and men more than women. One early consequence is that even young adults may lose the ability to hear very high frequency tones above 15 or 16 kHz. Despite this, age-related hearing loss may only become noticeable later in life. The effects of age can be exacerbated by exposure to environmental noise, whether at work or in leisure time (shooting, music, etc.). This is noise-induced hearing loss (NIHL) and is distinct from presbycusis. A second exacerbating factor is exposure to ototoxic drugs and chemicals.
Over time, the detection of high-pitched sounds becomes more difficult, and speech perception is affected, particularly of sibilants and fricatives. Patients typically express a decreased ability to understand speech. Once the loss has progressed to the 2–4 kHz range, there is increased difficulty understanding consonants. Both ears tend to be affected. The impact of presbycusis on communication depends on both the severity of the condition and the communication partner.Older adults with presbycusis often exhibit associated symptoms of social isolation, depression, anxiety, frailty and cognitive decline.
The risk of having cognitive impairment increased 7 percent for every 10 dB of hearing loss at baseline. No effect of hearing aids was seen in the Lin Baltimore study.
Causes
The aging process has three distinct components: physiologic degeneration, extrinsic damage (nosocusis), and intrinsic damage (sociocusis). These factors are superimposed on a genetic substrate, and may be overshadowed by general age-related susceptibility to diseases and disorders.
Hearing loss is only weakly correlated with age. In preindustrial and non-industrial societies, persons retain their hearing into old age. In the Framingham cohort study, only 10% of the variability of hearing with age could be explained by age-related physiologic deterioration. Within family groups, heredity factors were dominant; across family groups, other, presumably sociocusis and nosocusis factors were dominant.
Heredity: factors like early aging of the cochlea and susceptibility of the cochlea for drug insults are genetically determined.
Oxidative stress
General inflammatory conditions
Sociocusis
Sociocusis is the condition of those who have hearing loss attributed to continuous noise exposures, unrelated to their job or occupation. This exposure to these stimuli is frequent, and are often considered common "background noises" that affect the hearing abilities of individuals. Examples of sociocusis-related stimuli are the continuous noises from traffic, home appliances, music, television, and radio. The accumulated exposure to these noises over many years can lead to a condition similar to pure presbycusis.
Nosocusis
Nosocusis factors are those that can cause hearing loss, which are not noise-based and separate from pure presbycusis. They may include:
Ototoxic drugs: Ingestion of ototoxic drugs like aspirin may hasten the process of presbycusis.
vascular degeneration
Atherosclerosis: May diminish vascularity of the cochlea, thereby reducing its oxygen supply.
Dietary habits: Increased intake of saturated fat may accelerate atherosclerotic changes in old age.
Smoking: Is postulated to accentuate atherosclerotic changes in blood vessels aggravating presbycusis.
Diabetes: May cause vasculitis and endothelial proliferation in the blood vessels of the cochlea, thereby reducing its blood supply.
Hypertension: causes potent vascular changes, like reduction in blood supply to the cochlea, thereby aggravating presbycusis.However, a recent study found that diabetes, atherosclerosis and hypertension had no correlation to presbycusis, suggesting that these are nosocusis (acquired hearing loss) factors, not intrinsic factors.
Pathophysiology
Examples of microscopic changes seen in this condition are hair cell degeneration of the cochlea and giant stereociliary degeneration.
There are four pathological phenotypes of presbycusis:
Sensory: characterised by degeneration of the organ of Corti, the sensory organ for hearing. Located within the scala media, it contains hair cells with stereocilia, which extend to the tectorial membrane. The organs outer hair cells play a significant role in the amplification of sound and is extremely sensitive to external and internal factors. If the outer hair cells are damaged, they do not regenerate. This results in a loss of sensitivity of hearing, as well as an abnormal perceived loudness in the aspect of the tonotopic spectrum that the damaged cells serve.
Neural: characterised by degeneration of cells of the spiral ganglion.
Strial/metabolic: characterised by atrophy of stria vascularis in all turns of cochlea. Located in the lateral wall of the cochlea, the stria vascularis contains sodium-potassium-ATPase pumps that are responsible for producing the endolymph resting potential. As individuals age, a loss of capillaries leads to the endolymphatic potential becoming harder to maintain, which brings a decrease in cochlear potential.
Cochlear conductive: due to stiffening of the basilar membrane thus affecting its movement. This type of pathology has not been verified as contributing to presbycusis.In addition there are two other types:
Mixed
IndeterminateThe shape of the audiogram categorizes abrupt high-frequency loss (sensory phenotype) or flat loss (strial phenotype).
The mainstay of SNHL is strial, with only about 5% of cases being sensory. This type of presbycusis is manifested by a low-frequency hearing loss, with unimpaired speech recognition.
Classically, audiograms in neural presbycusis show a moderate downward slope into higher frequencies with a gradual worsening over time. A severe loss in speech discrimination is often described, out of proportion to the threshold loss, making amplification difficult due to poor comprehension.
The audiogram associated with sensory presbycusis is thought to show a sharply sloping high-frequency loss extending beyond the speech frequency range, and clinical evaluation reveals a slow, symmetric, and bilateral progression of hearing loss.
Diagnosis
Hearing loss is classified as mild, moderate, severe or profound. Pure-tone audiometry for air conduction thresholds at 250, 500, 1000, 2000, 4000, 6000 and 8000 Hz is traditionally used to classify the degree of hearing loss in each ear. Normal hearing thresholds are considered to be 25 dB sensitivity, though it has been proposed that this threshold is too high, and that 15 dB (about half as loud) is more typical. Mild hearing loss is thresholds of 25–45 dB; moderate hearing loss is thresholds of 45–65 dB; severe hearing loss is thresholds of 65–85 dB; and profound hearing loss thresholds are greater than 85 dB.
Tinnitus occurring in only one ear should prompt the clinician to initiate further evaluation for other etiologies. In addition, the presence of a pulse-synchronous rushing sound may require additional imaging to exclude vascular disorders.
Otoscopy
An examination of the external ear canal and tympanic membrane performed by a medical doctor, otolaryngologist, or audiologist using an otoscope, a visual instrument inserted into the ear. This also allows some inspection of the middle ear through the translucent tympanic membrane.
Tympanometry
A test administered by a medical doctor, otolaryngologist or audiologist of the tympanic membrane and middle ear function using a tympanometer, an air-pressure/sound wave instrument inserted into the ear canal. The result is a tympanogram showing ear canal volume, middle ear pressure and eardrum compliance. Normal middle ear function (Type A tympanogram) with a hearing loss may suggest presbycusis. Type B and Type C tympanograms indicate an abnormality inside the ear and therefore may have an additional effect on the hearing.
Laboratory studies
This may include a blood or other sera test for inflammatory markers such as those for autoinflammatory diseases.
Audiometry
A hearing test administered by a medical doctor, otolaryngologist (ENT) or audiologist including pure tone audiometry and speech recognition may be used to determine the extent and nature of hearing loss, and distinguish presbycusis from other kinds of hearing loss. Otoacoustic emissions and evoked response testing may be used to test for audio neuropathy. The diagnosis of a sensorineural pattern hearing loss is made through audiometry, which shows a significant hearing loss without the "air-bone gap" that is characteristic of conductive hearing disturbances. In other words, air conduction is equal to bone conduction. Persons with cochlear deficits fail otoacoustic emissions testing, while persons with 8th cranial nerve (vestibulocochlear nerve) deficits fail auditory brainstem response testing.
Presbycusis audiogram
Magnetic resonance imaging (MRI)
As part of differential diagnosis, an MRI scan may be done to check for vascular anomalies, tumors, and structural problems like enlarged mastoids. MRI and other types of scan cannot directly detect or measure age-related hearing loss.
Treatment
At present, presbycusis, being primarily sensorineural in nature, cannot be prevented, ameliorated or cured. Treatment options fall into three categories: pharmacological, surgical and management.
There are no approved or recommended pharmaceutical treatments for presbycusis.
Cochlear implant
In cases of severe or profound hearing loss, a surgical cochlear implant is possible. This is an electronic device that replaces the cochlea of the inner ear. Electrodes are typically inserted through the round window of the cochlea, into the fluid-filled scala tympani. They stimulate the peripheral axons of the primary auditory neurons, which then send information to the brain via the auditory nerve. The cochlea is tonotopically mapped in a spiral fashion, with lower frequencies localizing at the apex of the cochlea, and high frequencies at the base of the cochlea, near the oval and round windows. With age, comes a loss in distinction of frequencies, especially higher ones. The electrodes of the implant are designed to stimulate the array of nerve fibers that previously responded to different frequencies accurately. Due to spatial constraints, the cochlear implant may not be inserted all the way into the cochlear apex. It provides a different kind of sound spectrum than natural hearing, but may enable the recipient to recognize speech and environmental sounds.
Middle ear implants
These are surgically implanted hearing aids inserted onto the middle ear. These aids work by directly vibrating the ossicles, and are cosmetically favorable due to their hidden nature.
Management
Hearing aids help improve hearing of many elderly. Hearing aids can now be tuned to specific frequency ranges of hearing loss.
Aural rehabilitation for the affected person and their communication partners may reduce the impact on communication. Techniques such as squarely facing the affected person, enunciating, ensuring adequate light, minimizing noise in the environment, and using contextual cues are used to improve comprehension.
Research
Pharmaceuticals
Pharmacological treatment options are limited, and remain clinically unproven. Among these are the water-soluble coenzyme Q10 formulation, the prescription drug Tanakan, and combination antioxidant therapy.
In a study performed in 2010, it was found that the water-soluble formulation of coenzyme Q10 (CoQ10) caused a significant improvement in liminar tonal audiometry of the air and bone thresholds at 1000 Hz, 2000 Hz, 4000 Hz, and 8000 Hz.
Antioxidant therapy – age-related hearing loss was reduced in animal models with a combination agent comprising six antioxidant agents that target four sites within the oxidative pathway: L-cysteine-glutathione mixed disulfide, ribose-cysteine, NW-nitro-L-arginine methyl ester, vitamin B12, folate, and ascorbic acid. It is thought that these supplements attenuate the decline of cochlear structure due to prolonged oxidative stress. However, more recent studies have had conflicting results. In 2012, a study was done with CBA/J female mice. They were placed on an antioxidant-rich diet for 24 months consisting of vitamins A, C, E, L-carnitine, and α-lipoic acid. While this increased the inner ears antioxidant capacity, the actual hearing loss was unaffected. Therefore, in this study, antioxidants were shown not to improve presbycusis mechanisms.
The effects of the pharmaceutical drug Tanakan were observed when treating tympanophonia in elderly women. Tanakan was found to decrease the intensity of tympanitis and improve speech and hearing in aged patients, giving rise to the idea of recommending treatment with it to elderly patients with presbycusis or normal tonal hearing.
AM-111, an otoprotective peptide, was shown in a chinchilla study to rescue and protect against hearing loss following impulse noise trauma. AM-111 acts as a cell-permeable inhibitor of JNK-mediated apoptosis. IP injections or local injections into membrane of the round window were given, and permanent threshold shifts (PTS) were measured three weeks after impulse noise exposure. AM-111 animals had significantly lower PTS, implicating AM-111 as a possible protective agent against JNK-mediated cochlear cell death and against permanent hearing deficits after noise trauma.
The anti-inflammatory, anti-oxidant substance Ebselen was observed to reduce hearing loss in a study done in 2007. It has been previously shown that noise trauma correlates with decreases in glutathione peroxidase (GPx) activity, which has been linked to loss of the outer hair cells. GPx1, an isoform of GPx, is predominantly expressed in stria vascularis, cochlea, spiral ligament, organ of Corti, and spiral ganglion cells. The stria vascularis displayed significant decreases in GPx1 immunoreactivity and increased swelling following noise exposure in rats. There was also significant outer hair cell loss in the cochlea within five hours of noise exposure. Administration of Ebselen before and after the noise stimulus reduced stria vascularis swelling as well as cochlear outer hair cell loss. This implicates Ebselen as a supplement for GPx1 in the outer hair cell degradation mechanism of hearing loss. This treatment is currently in active clinical trials.
A γ-secretase inhibitor of Notch signaling was shown to induce new hair cells and partially recover hearing loss. Auditory hair cell loss is permanent damage due to the inability of these cells to regenerate. Therefore, deafness due to this pathology is viewed as irreversible. Hair cell development is mediated by Notch signaling, which exerts lateral inhibition onto hair cells. Notch signaling in supporting hair cells leads to prevention of differentiation in surrounding hair cells. After identifying a potent γ-secretase inhibitor selective for stimulating differentiation in inner ear stem cells, it was administered in acoustically injured mice. The animals who received the injury and treatment displayed an increased hair cell number and stimulated hearing recovery. This suggests that γ-secretase inhibition of Notch signaling can be a potential pharmacological therapy in approaching what was previously viewed as permeant deafness.
Stem cell therapy
A fetal thymus graft, or rejuvenation of the recipient immunity by inoculation of young CD4+ T cells, also prevents presbycusis as well as up-regulation of the interleukin 1 receptor type II gene (IL1R2) in CD4+ T cells and degeneration of the spiral ganglion in Samp1 mice, a murine model of human senescence. This technology remains years or even decades away from human application.
Popular culture
Abilities of young people to hear high frequency tones inaudible to those over 25 or so has led to the development of technologies to disperse groups of young people around shops (The Mosquito), and development of a cell phone ringtone, Teen Buzz, for students to use in school, that older people cannot hear. In September 2006 this technique was used to make a dance track called Buzzin. The track had two melodies, one that everyone could hear and one that only younger people could hear.
Animals
Many vertebrates such as fish, birds and amphibians do not experience presbycusis in old age as they are able to regenerate their cochlear sensory cells, whereas mammals including humans have genetically lost this ability. A number of laboratories worldwide are conducting comparative studies of birds and mammals that aim to find the differences in regenerative capacity, with a view to developing new treatments for human hearing problems.
See also
Presbyopia – age-related degeneration of the eyes
References
== External links == |
Autoimmune hypophysitis | Autoimmune hypophysitis is defined as inflammation of the pituitary gland due to autoimmunity.
Signs and symptoms
Autoimmune hypophysitis can lead to deficiencies in one or more pituitary hormones, causing central diabetes insipidus if the posterior pituitary gland is affected as well as central adrenal insufficiency and central hypothyroidism if the anterior pituitary gland is affected. The symptoms depend on what part of the pituitary is affected. Lymphocytic adenohypophysitis (LAH) occurs when the anterior pituitary cells are affected by autoimmune inflammation resulting in either no symptoms, adrenal insufficiency (if the ACTH producing cells are affected), hypothyroidism (if the TSH producing cells are damaged), or hypogonadism (if the LH and/or FSH producing cells are involved). In some cases, the presence of inflammation within the pituitary gland leads to interruption of dopamine flow from the hypothalamus into the pituitary causing high levels of the hormone prolactin and, often as a consequence, milk production from the breasts (in older girls and women). Lymphocytic Infundibuloneurohypophysitis (LINH) occurs when the posterior pituitary is affected resulting in diabetes insipidus. Both LAH and LINH may also lead to symptoms of an intracranial mass such as headache or disturbance of vision, i.e. bitemporal hemianopia. The pituitary produces multiple hormones relating to various metabolic functions. Sufficiently low production of certain pituitary hormones can be fatal resulting in the failure of the thyroid or adrenal glands.
Common symptoms include nausea, vomiting, fatigue, loss of libido, amenorrhea, and dizziness. It is estimated that, typically, it takes from 12 to 40 years for autoimmune destruction to present symptoms. However, there have been cases of isolated attacks as a result of drug reactions (i.e., use of blocking antibody ipilimumab) or idiopathic events that have presented symptoms which may disappear after relatively short term treatment (i.e., 1 year on corticoids or other immune suppressants). However, more rapid development of the disorder is the rule when it occurs during, or shortly after, pregnancy (even after miscarriage or abortion). Indeed, autoimmune hypophysitis occurs more commonly during and shortly after pregnancy than at any other time.
Antibodies
80% of patients with pituitary antibodies also have antibodies to thyroid gland or its hormones. Likewise, 20% of autoimmune thyroid patients also have pituitary antibodies. It follows that a subset of thyroid patients may have a disease related to autoimmune hypophysitis. Recent research has focused on a defect at the CTLA-4 gene which, coupled with other factors, may result in autoimmunity primarily focusing on certain endocrine glands including the pituitary and thyroid.
Cause
Diagnosis
Lymphocytic hypophysitis continues to be a diagnosis of exclusion, and histopathology with tissue biopsy is needed for a definitive diagnosis.[3] However, clinical, laboratory data, and imaging can all help with the diagnosis.[8] First and foremost, patients present with symptoms of hypopituitarism and must undergo pituitary hormone function evaluation. Biopsy is the only means of accurate diagnosis as no autoantigen has been discovered. Biopsy of the pituitary gland is not easily performed with safety as it sits under the brain, however, a test does exist to detect antibodies to the pituitary without biopsy: autoantibodies to M(r) 49,000 pituitary cytosolic protein may represent markers for an immunological process affecting the pituitary gland. Tests for normal pituitary gland hormone production tend to be expensive and in some cases difficult to administer. In addition, certain hormone levels vary largely throughout the day and in response to metabolic factors, making abnormal levels difficult to calibrate—further hampering diagnosis. Assessment for other autoimmune and inflammatory diseases should also be performed by obtaining complete blood count, complete metabolic panel, c-reactive protein, erythrocyte sedimentation rate, antinuclear antibody, and lupus antibodies at the very least. Gadolinium-enhanced MRI of the pituitary is the imagining of choice as well, and it is important to distinguish lymphocytic hypophysitis from a pituitary adenoma.
Treatment
Inflammation resolves usually after several months of glucocorticoid treatment For those that show no improvement with corticosteroids or have relapsed after treatment with corticosteroids, immunosuppressive medications such as methotrexate, azathioprine, and cyclosporine can be used as well. There have also been some cases where dopamine agonists such as cabergoline/bromocriptine have also been successfully used in those with hyperprolactinemia due to pituitary inflammation. Surgery is only an option for those suffering from visual problems/ophthalmoplegia, have a mass like an effect from compression of nearby structures, or for those that require histology for diagnosis.
Epidemiology
A large scale study on cadavers done in Sweden, performed biopsies on hundreds of pituitary glands. The study indicated that perhaps as much as 5% of the population experiences some amount of autoimmune pituitary destruction. It is further hypothesized that perhaps half that many show, or may experience, clinical manifestations. The prevalence of all the types of hypophysitis is low, with an incidence of approximately 1 in 9 million. However, it is thought that this may be an underestimate, especially due to the recent use of immune checkpoint inhibitors for cancer treatments, which have endocrine side effects affecting the pituitary gland. Although cases have been reported in children and the elderly, the mean age of diagnosis for men is 44.7 years, and the mean age of diagnosis for women is 34 years.
History
Autoimmune attack of the pituitary gland resulting in reduced hormone production was first discovered as a result of an autopsy in 1962. The autopsy described destruction of the pituitary and thyroid consistent with autoimmune attack and included atrophy of the adrenal glands. As magnetic resonance imaging became more available diagnosis increased dramatically. At this time it is believed that the disease is far more prevalent than is diagnosed. Nevertheless, autoimmune hypophysitis is frequently referred to as a rare disease and the most recent estimates as to its prevalence give it a value of around 5 per million.
See also
Hypophysitis
Hypopituitarism
Pituitary disease
References
== External links == |
Autoimmune pancreatitis | Autoimmune Pancreatitis (AIP) is an increasingly recognized type of chronic pancreatitis that can be difficult to distinguish from pancreatic carcinoma but which responds to treatment with corticosteroids, particularly prednisone. Although autoimmune pancreatitis is quite rare, it constitutes an important clinical problem for both patients and their clinicians: the disease commonly presents itself as a tumorous mass which is diagnostically indistinguishable from pancreatic cancer, a disease that is much more common in addition to being very dangerous. Hence, some patients undergo pancreatic surgery, which is associated to substantial mortality and morbidity, out of the fear by patients and clinicians to undertreat a malignancy. However, surgery is not a good treatment for this condition as AIP responds well to immunosuppressive treatment. There are two categories of AIP: Type 1 and Type 2, each with distinct clinical profiles.
Type 1 AIP is now regarded as a manifestation of IgG4-related disease, and those affected have tended to be older and to have a high relapse rate. Type 1 is associated with pancreatitis, Sjogren syndrome, Primary sclerosing cholangitis and Inflammatory bowel disease. Patients with Type 2 AIP do not experience relapse, tend to be younger and not associated with systemic disease. AIP occurring in association with an autoimmune disorder has been referred to as "secondary" or "syndromic" AIP. AIP does not affect long-term survival.
Signs and symptoms
Autoimmune pancreatitis may cause a variety of symptoms and signs, which include pancreatic and biliary (bile duct) manifestations, as well as systemic effects of the disease. Two-thirds of patients present with either painless jaundice due to bile duct obstruction or a "mass" in the head of the pancreas, mimicking carcinoma. As such, a thorough evaluation to rule out cancer is important in cases of suspected AIP.Type 1 AIP typically presents in a 60–70-year-old male with painless jaundice. In some cases, imaging reveals a mass in the pancreas or diffuse pancreatic enlargement. Narrowing in the pancreatic duct called strictures may occur. Rarely, Type 1 AIP presents with acute pancreatitis. Type 1 AIP presents with manifestations of autoimmune disease (IgG4 related) in at least half of cases. The most common form of systemic involvement is cholangitis, which occurs in up to 80 percent of cases of Type 1 AIP. Additional manifestations include inflammation in the salivary glands (chronic sclerosing sialadenitis), in the lungs resulting in scarring (pulmonary fibrosis) and nodules, scarring within the chest cavity (mediastinal fibrosis) or in the anatomic space behind the abdomen (retroperitoneal fibrosis) and inflammation in the kidneys (tubulointerstitial nephritis).AIP is characterized by the following features:
Scleral Icterus (yellow eyes), jaundice (yellow skin) which is usually painless, usually without acute attacks of pancreatitis.
Relatively mild symptoms, such as minimal weight loss or nausea.
Increased serum levels of gamma globulins, immunoglobulin G (IgG) or IgG4.
The presence of serum autoantibodies such as anti-nuclear antibody (ANA), anti-lactoferrin antibody, anti-carbonic anhydrase II antibody, and rheumatoid factor (RF).
Contrast-enhanced CT demonstrates a diffusely enlarged (sausage-shaped) pancreas.
Diffuse irregular narrowing of the main pancreatic duct, and stenosis of the intrapancreatic bile duct on endoscopic retrograde cholangiopancreatography (ERCP).
Rare pancreatic calcification or cyst formation.
Marked responsiveness to treatment with corticosteroids.
Histopathology
Histopathologic examination of the pancreas reveals a characteristic lymphoplasmacytic infiltrate of CD4- or CD8-positive lymphocytes and IgG4-positive plasma cells, and exhibits interstitial fibrosis and acinar cell atrophy in later stages. At the initial stages, typically, there is a cuff of lymphoplasma cells surrounding the ducts but also more diffuse infiltration in the lobular parenchyma. However, localization and the degree of duct wall infiltration are variable. Whereas histopathologic examination remains the primary method for differentiation of AIP from acute and chronic pancreatitis, lymphoma, and cancer. By Fine Needle Aspiration (FNA) the diagnosis can be made if adequate tissue is obtained. In such cases, lymphoplasmacytic infiltration of the lobules are the key finding. Rarely, granulomatous reaction could be observed. It has been proposed that a cytologic smear primarily composed of acini rich in chronic inflammatory cells (lymphocytes, plasma cells), with rare ductal epithelial cells lacking atypia, favors the diagnosis of AIP. The sensitivity and the specificity of these criteria for differentiating AIP from neoplasia are unknown. In cases of systemic manifestation of AIP, the pathologic features are similar in other organs.Although the exact mechanism explaining the clinical manifestations of autoimmune pancreatitis remain for an important part obscure, most professionals would agree that the development of IgG4 antibodies, recognizing an epitiope on the membrane of pancreatic ancinar cells is an important factor in the pathophysiology of the disease. These antibodies are postulated to provoke an immune response against these ancinar cells resulting in pancreatic inflammation and destruction. Knowing the auto-antigens involved would allow early diagnosis of the disease, its differentiation from a diagnosis of pancreatic cancer, and potentially even prevention, but unfortunately these remain obscure. An earlier publication suggested that the human ubiquitin-protein ligase E3 component n-recognin 2 (UBR2) was an important antigen but follow up studies suggested this finding is likely to be an artifact. Hence improved diagnosis, understanding and treatment of autoimmune pancreatitis awaits the identification of the auto-antigens involved.
Diagnosis
Criteria
Most recently the fourteenth Congress of the International Association of Pancreatology developed the International Consensus Diagnostic Criteria (ICDC) for AIP. The ICDC emphasizes five cardinal features of AIP which includes the imaging appearance of pancreatic parenchyma and the pancreatic duct, serum IgG4 level, other organ involvement with IgG4-related disease, pancreatic histology and response to steroid therapy.In 2002, the Japanese Pancreas Society proposed the following diagnostic criteria for autoimmune pancreatitis:
I. Pancreatic imaging studies show diffuse narrowing of the main pancreatic duct with irregular wall (more than 1/3 of length of the entire pancreas).
II. Laboratory data demonstrate abnormally elevated levels of serum gamma globulin and/or IgG, or the presence of autoantibodies.
III. Histopathologic examination of the pancreas shows fibrotic changes with lymphocyte and plasma cell infiltrate.For diagnosis, criterion I (pancreatic imaging) must be present with criterion II (laboratory data) and/or III (histopathologic findings).Mayo Clinic has come up with five diagnostic criteria called HISORt criteria which stands for histology, imaging, serology, other organ involvement, and response to steroid therapy.
Radiologic features
Computed tomography (CT) findings in AIP include a diffusely enlarged hypodense pancreas or a focal mass that may be mistaken for a pancreatic malignancy. A low-density, capsule-like rim on CT (possibly corresponding to an inflammatory process involving peripancreatic tissues) is thought to be an additional characteristic feature (thus the mnemonic: sausage-shaped). Magnetic resonance imaging (MRI) reveals a diffusely decreased signal intensity and delayed enhancement on dynamic scanning. The characteristic ERCP finding is segmental or diffuse irregular narrowing of the main pancreatic duct, usually accompanied by an extrinsic-appearing stricture of the distal bile duct. Changes in the extrapancreatic bile duct similar to those of primary sclerosing cholangitis (PSC) have been reported.The role of endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration (EUS-FNA) in the diagnosis of AIP is not well described, and EUS findings have been described in only a small number of patients. In one study, EUS revealed a diffusely swollen and hypoechoic pancreas in 8 of the 14 (57%) patients, and a solitary, focal, irregular mass was observed in 6 (46%) patients. Whereas EUS-FNA is sensitive and specific for the diagnosis of pancreatic malignancy, its role in the diagnosis of AIP remains unclear.
Treatment
AIP often completely resolves with steroid treatment. The failure to differentiate AIP from malignancy may lead to unnecessary pancreatic resection, and the characteristic lymphoplasmacytic infiltrate of AIP has been found in up to 23% of patients undergoing pancreatic resection for suspected malignancy who are ultimately found to have benign disease. In this subset of patients, a trial of steroid therapy may have prevented a Whipple procedure or complete pancreatectomy for a benign disease which responds well to medical therapy. "This benign disease resembles pancreatic carcinoma both clinically and radiographically. The diagnosis of autoimmune pancreatitis is challenging to make. However, accurate and timely diagnosis may preempt the misdiagnosis of cancer and decrease the number of unnecessary pancreatic resections." Autoimmune pancreatitis responds dramatically to corticosteroid treatment.If relapse occurs after corticosteroid treatment or corticosteroid treatment is not tolerated, immunomodulators may be used. Immunomodulators such as azathioprine, and 6-mercaptopurine have been shown to extend remission of autoimmune pancreatitis after corticosteroid treatment. If corticosteroid and immunomodulator treatments are not sufficient, rituximab may also be used. Rituximab has been shown to induce and maintain remission.
Prognosis
AIP does not affect long-term survival.
Epidemiology
AIP is relatively uncommon, with an overall global prevalence less than 1 per 100,000. Type 1 AIP is more common in East Asia, whereas type 2 is relatively more common in the US and Europe. The prevalence of AIP may be increasing in Japan. Type 1 AIP occurs three times more often in men than women.
Controversies in nomenclature
As the number of published cases of AIP has increased, efforts have been focused on defining AIP as a distinct clinical and pathologic entity and toward developing some generally agreed upon diagnostic criteria and nomenclature. Terms frequently encountered are autoimmune or autoimmune-related pancreatitis, lymphoplasmacytic sclerosing pancreatitis, idiopathic tumefactive chronic pancreatitis, idiopathic pancreatitis with focal irregular narrowing of the main pancreatic duct, and non-alcoholic duct destructive chronic pancreatitis. There are also a large number of case reports employing descriptive terminology such as pancreatitis associated with Sjögrens syndrome, primary sclerosing cholangitis, or inflammatory bowel disease. Some of the earliest cases were reported as pancreatic pseudotumor or pseudolymphoma.
References
== External links == |
Cyclopes | In Greek mythology and later Roman mythology, the Cyclopes ( sy-KLOH-peez; Greek: Κύκλωπες, Kýklōpes, "Circle-eyes" or "Round-eyes"; singular Cyclops SY-klops; Κύκλωψ, Kýklōps) are giant one-eyed creatures. Three groups of Cyclopes can be distinguished. In Hesiods Theogony, the Cyclopes are the three brothers Brontes, Steropes, and Arges, who made for Zeus his weapon the thunderbolt. In Homers Odyssey, they are an uncivilized group of shepherds, the brethren of Polyphemus encountered by Odysseus. Cyclopes were also famous as the builders of the Cyclopean walls of Mycenae and Tiryns.
In Cyclops, the fifth-century BC play by Euripides, a chorus of satyrs offers comic relief based on the encounter of Odysseus and Polyphemus. The third-century BC poet Callimachus makes the Hesiodic Cyclopes the assistants of smith-god Hephaestus; as does Virgil in the Latin epic Aeneid, where he seems to equate the Hesiodic and Homeric Cyclopes.
From at least the fifth century BC, Cyclopes have been associated with the island of Sicily and the volcanic Aeolian Islands.
Kinds
Three groups of Cyclopes can be distinguished: the Hesiodic, the Homeric and the wall-builders. In Hesiods Theogony, the Cyclopes are the three brothers: Brontes, Steropes, and Arges, sons of Uranus and Gaia, who made for Zeus his characteristic weapon, the thunderbolt. In Homers Odyssey, the Cyclopes are an uncivilized group of shepherds, one of whom, Polyphemus, the son of Poseidon, is encountered by Odysseus. Cyclopes were also said to have been the builders of the Cyclopean walls of Mycenae and Tiryns. A scholiast, quoting the fifth-century BC historian Hellanicus, tells us that, in addition to the Hesiodic Cyclopes (whom the scholiast describes as "the gods themselves"), and the Homeric Cyclopes, there was a third group of Cyclopes: the builders of the walls of Mycenae.
Hesiodic Cyclopes
Hesiod, in the Theogony (c. 700 BC), described three Cyclopes: Brontes, Steropes, and Arges, who were the sons of Uranus (Sky) and Gaia (Earth), and the brothers of the Titans and Hundred-Handers, and who had a single eye set in the middle of their foreheads. They made for Zeus his all-powerful thunderbolt, and in so doing, the Cyclopes played a key role in the Greek succession myth, which told how the Titan Cronus overthrew his father Uranus, and how in turn Zeus overthrew Cronus and his fellow Titans, and how Zeus was eventually established as the final and permanent ruler of the cosmos. The names that Hesiod gives them: Arges (Bright), Brontes (Thunder), and Steropes (Lightning), reflect their fundamental role as thunderbolt makers. As early as the late seventh-century BC, the Cyclopes could be used by the Spartan poet Tyrtaeus to epitomize extraordinary size and strength.According to the accounts of Hesiod and mythographer Apollodorus, the Cyclopes had been imprisoned by their father Uranus. Zeus later freed the Cyclopes, and they repaid him by giving him the thunderbolt. The Cyclopes provided for Hesiod, and other theogony-writers, a convenient source of heavenly weaponry, since the smith-god Hephaestus—who would eventually take over that role—had not yet been born. According to Apollodorus, the Cyclopes also provided Poseidon with his trident and Hades with his cap of invisibility, and the gods used these weapons to defeat the Titans.
Although the primordial Cyclopes of the Theogony were presumably immortal (as were their brothers the Titans), the sixth-century BC Hesiodic Catalogue of Women, has them being killed by Apollo. Later sources tell us why: Apollos son Asclepius had been killed by Zeus thunderbolt, and Apollo killed the Cyclopes, the makers of the thunderbolt, in revenge. According to a scholiast on Euripides Alcestis, the fifth-century BC mythographer Pherecydes supplied the same motive, but said that Apollo, rather than killing the Cyclopes, killed their sons (one of whom he named Aortes) instead. No other source mentions any offspring of the Cyclopes. A Pindar fragment suggests that Zeus himself killed the Cyclopes to prevent them from making thunderbolts for anyone else.The Cyclopes prowess as craftsmen is stressed by Hesiod who says "strength and force and contrivances were in their works." Being such skilled craftsmen of great size and strength, later poets, beginning with the third-century BC poet Callimachus, imagine these Cyclopes, the primordial makers of Zeus thunderbolt, becoming the assistants of the smith-god Hephaestus, at his forge in Sicily, underneath Mount Etna, or perhaps the nearby Aeolian Islands. In his Hymn to Artemis, Callimachus has the Cyclopes on the Aeolian island of Lipari, working "at the anvils of Hephaestus", make the bows and arrows used by Apollo and Artemis. The first-century BC Latin poet Virgil, in his epic Aeneid, has the Cyclopes: "Brontes and Steropes and bare-limbed Pyracmon" toil under the direction of Vulcan (Hephaestus), in caves underneath Mount Etna and the Aeolian islands. Virgil describes the Cyclopes, in Vulcans smithy forging iron, making a thunderbolt, a chariot for Mars, and Pallass Aegis, with Vulcan interrupting their work to command the Cyclopes to fashion arms for Aeneas. The later Latin poet Ovid also has the Hesiodic Cyclopes Brontes and Steropes (along with a third Cyclops named Acmonides), work at forges in Sicilian caves.According to a Hellenistic astral myth, the Cyclopes were the builders of the first altar. The myth was a catasterism, which explained how the constellation the Altar (Ara) came to be in the heavens. According to the myth, the Cyclopes built an altar upon which Zeus and the other gods swore alliance before their war with the Titans. After their victory, "the gods placed the altar in the sky in commemoration", and thus began the practice, according to the myth, of men swearing oaths upon altars "as a guarantee of their good faith".According to the second-century geographer Pausanias, there was a sanctuary called the "altar of the Cyclopes" on the Isthmus of Corinth at a place sacred to Poseidon, where sacrifices were offered to the Cyclopes. There is no evidence for any other cult associated with the Cyclopes. According to a version of the story in the Iliad scholia (found nowhere else), when Zeus swallowed Metis, she was pregnant with Athena by the Cyclops Brontes.Although described by Hesiod as "having very violent hearts" (ὑπέρβιον ἦτορ ἔχοντας), and while their extraordinary size and strength would have made them capable of great violence, there is no indication of the Hesiodic Cyclopes having behaved in any other way than as dutiful servants of the gods.Walter Burkert suggests that groups or societies of lesser gods, like the Hesiodic Cyclopes, "mirror real cult associations (thiasoi)... It may be surmised that smith guilds lie behind Cabeiri, Idaian Dactyloi, Telchines, and Cyclopes."
Homeric Cyclopes
In an episode of Homers Odyssey (c. 700 BC), the hero Odysseus encounters the Cyclops Polyphemus, the son of Poseidon, a one-eyed man-eating giant who lives with his fellow Cyclopes in a distant land. The relationship between these Cyclopes and Hesiods Cyclopes is unclear. Homer described a very different group of Cyclopes, than the skilled and subservient craftsman of Hesiod. Homers Cyclopes live in the "world of men" rather than among the gods, as they presumably do in the Theogony. The Homeric Cyclopes are presented as uncivilized shepherds, who live in caves, savages with no regard for Zeus. They have no knowledge of agriculture, ships or craft. They live apart and lack any laws.The fifth-century BC playwright Euripides also told the story of Odysseus encounter with Polyphemus in his satyr play Cyclops. Euripides Cyclopes, like Homers, are uncultured cave-dwelling shepherds. They have no agriculture, no wine, and live on milk, cheese and the meat of sheep. They live solitary lives, and have no government. They are inhospitable to strangers, slaughtering and eating all who come to their land. While Homer does not say if the other Cyclopes are like Polyphemus in their appearance and parentage, Euripides makes it explicit, calling the Cyclopes "Poseidons one-eyed sons". And while Homer is vague as to their location, Euripides locates the land of the Cyclopes on the island of Sicily near Mount Etna.Like Euripides, Virgil has the Cyclopes of Polyphemus live on Sicily near Etna. For Virgil apparently, these Homeric Cyclopes are members of the same race of Cyclopes as Hesiods Brontes and Steropes, who live nearby.
Cyclopean wall-builders
Cyclopes were also said to have been the builders of the so-called Cyclopean walls of Mycenae, Tiryns, and Argos. Although they can be seen as being distinct, the Cyclopean wall-builders share several features with the Hesiodic Cyclopes: both groups are craftsmen of supernatural skill, possessing enormous strength, who lived in primordial times. These builder Cyclopes were apparently used to explain the construction of the stupendous walls at Mycenae and Tiryns, composed of massive stones that seemed too large and heavy to have been moved by ordinary men.These master builders were famous in antiquity from at least the fifth century BC onwards. The poet Pindar has Heracles driving the cattle of Geryon through the "Cyclopean portal" of the Tirynian king Eurystheus. The mythographer Pherecydes says that Perseus brought the Cyclopes with him from Seriphos to Argos, presumably to build the walls of Mycenae. Proetus, the mythical king of ancient Argos, was said to have brought a group of seven Cyclopes from Lycia to build the walls of Tiryns.The late fifth and early fourth-century BC comic poet Nicophon wrote a play called either Cheirogastores or Encheirogastores (Hands-to-Mouth), which is thought to have been about these Cyclopean wall-builders. Ancient lexicographers explained the title as meaning "those who feed themselves by manual labour", and, according to Eustathius of Thessalonica, the word was used to describe the Cyclopean wall-builders, while "hands-to-mouth" was one of the three kinds of Cyclopes distinguished by scholia to Aelius Aristides. Similarly, possibly deriving from Nicophons comedy, the first-century Greek geographer Strabo says these Cyclopes were called "Bellyhands" (gasterocheiras) because they earned their food by working with their hands.The first-century natural philosopher Pliny the Elder, in his Natural History, reported a tradition, attributed to Aristotle, that the Cyclopes were the inventors of masonry towers. In the same work Pliny also mentions the Cyclopes, as being among those credited with being the first to work with iron, as well as bronze. In addition to walls, other monuments were attributed to the Cyclopes. For example, Pausanias says that at Argos there was "a head of Medusa made of stone, which is said to be another of the works of the Cyclopes".
Principal sources
Hesiod
According to the Theogony of Hesiod, Uranus (Sky) mated with Gaia (Earth) and produced eighteen children. First came the twelve Titans, next came the three one-eyed Cyclopes:
Then [Gaia] bore the Cyclopes, who have very violent hearts, Brontes (Thunder) and Steropes (Lightning) and strong-spirited Arges (Bright), those who gave thunder to Zeus and fashioned the thunderbolt. These were like the gods in other regards, but only one eye was set in the middle of their foreheads; and they were called Cyclopes (Circle-eyed) by name, since a single circle-shaped eye was set in their foreheads. Strength and force and contrivances were in their works.
Following the Cyclopes, Gaia next gave birth to three more monstrous brothers, the Hecatoncheires, or Hundred-Handed Giants. Uranus hated his monstrous children, and as soon as each was born, he imprisoned them underground, somewhere deep inside Gaia. Eventually Uranus son, the Titan Cronus, castrated Uranus, becoming the new ruler of the cosmos, but he did not release his brothers, the Cyclopes and the Hecatoncheires, from their imprisonment in Tartarus.For this failing, Gaia foretold that Cronus would eventually be overthrown by one of his children, as he had overthrown his own father. To prevent this, as each of his children were born, Cronus swallowed them whole; as gods they were not killed, but imprisoned within his belly. His wife, Rhea, sought her mothers advice to avoid losing all of her children in this way, and Gaia advised her to give Cronus a stone wrapped in swaddling clothes. In this way, Zeus was spared the fate of his elder siblings, and was hidden away by his mother. When he was grown, Zeus forced his father to vomit up his siblings, who rebelled against the Titans. Zeus released the Cyclopes and Hecatoncheires, who became his allies. While the Hundred-Handed Giants fought alongside Zeus and his siblings, the Cyclopes gave Zeus his great weapon, the thunderbolt, with the aid of which he was eventually able to overthrow the Titans, establishing himself as the ruler of the cosmos.
Homer
In Book 9 of the Odyssey, Odysseus describes to his hosts the Phaeacians his encounter with the Cyclops Polyphemus. Having just left the land of the Lotus-eaters, Odysseus says "Thence we sailed on, grieved at heart, and we came to the land of the Cyclopes".
Homer had already (Book 6) described the Cyclopes as "men overweening in pride who plundered [their neighbors the Phaeacians] continually", driving the Phaeacians from their home. In Book 9, Homer gives a more detailed description of the Cyclopes as:
an overweening and lawless folk, who, trusting in the immortal gods, plant nothing with their hands nor plough; but all these things spring up for them without sowing or ploughing, wheat, and barley, and vines, which bear the rich clusters of wine, and the rain of Zeus gives them increase. Neither assemblies for council have they, nor appointed laws, but they dwell on the peaks of lofty mountains in hollow caves, and each one is lawgiver to his children and his wives, and they reck nothing one of another.
According to Homer, the Cyclopes have no ships, nor ship-wrights, nor other craftsman, and know nothing of agriculture. They have no regard for Zeus or the other gods, for the Cyclopes hold themselves to be "better far than they".Homer says that "godlike" Polyphemus, the son of Poseidon and the nymph Thoosa, the daughter of Phorcys, is the "greatest among all the Cyclopes". Homer describes Polyphemus as a shepherd who:
mingled not with others, but lived apart, with his heart set on lawlessness. For he was fashioned a wondrous monster, and was not like a man that lives by bread, but like a wooded peak of lofty mountains, which stands out to view alone, apart from the rest,... [and as] a savage man that knew naught of justice or of law.
Although Homer does not say explicitly that Polyphemus is one-eyed, for the account of his blinding to make sense he must be. If Homer meant for the other Cyclopes to be assumed (as they usually are) to be like Polyphemus, then they too will be one-eyed sons of Poseidon; however Homer says nothing explicit about either the parentage or appearance of the other Cyclopes.
Euripides
The Hesiodic Cyclopes: makers of Zeus thunderbolts, the Homeric Cyclopes: brothers of Polyphemus, and the Cyclopean wall-builders, all figure in the plays of the fifth-century BC playwright Euripides. In his play Alcestis, where we are told that the Cyclopes who forged Zeus thunderbolts, were killed by Apollo. The prologue of that play has Apollo explain:
House of Admetus! In you I brought myself to taste the bread of menial servitude, god though I am. Zeus was the cause: he killed my son Asclepius, striking him in the chest with the lightning bolt, and in anger at this I slew the Cyclopes who forged Zeus’s fire. As my punishment for this Zeus compelled me to be a serf in the house of a mortal.
Euripides satyr play Cyclops tells the story of Odysseus encounter with the Cyclops Polyphemus, famously told in Homers Odyssey. It takes place on the island of Sicily near the volcano Mount Etna where, according to the play, "Poseidon’s one-eyed sons, the man-slaying Cyclopes, dwell in their remote caves." Euripides describes the land where Polyphemus brothers live, as having no "walls and city battlements", and a place where "no men dwell". The Cyclopes have no rulers and no government, "they are solitaries: no one is anyone’s subject." They grow no crops, living only "on milk and cheese and the flesh of sheep." They have no wine, "hence the land they dwell in knows no dancing". They show no respect for the important Greek value of Xenia ("guest friendship). When Odysseus asks if they are pious and hospitable toward strangers (φιλόξενοι δὲ χὤσιοι περὶ ξένους), he is told: "most delicious, they maintain, is the flesh of strangers... everyone who has come here has been slaughtered."Several of Euripides plays also make reference to the Cyclopean wall-builders. Euripides calls their walls "heaven-high" (οὐράνια), describes "the Cyclopean foundations" of Mycenae as "fitted snug with red plumbline and mason’s hammer", and calls Mycenae "O hearth built by the Cyclopes". He calls Argos "the city built by the Cyclopes", refers to "the temples the Cyclopes built" and describes the "fortress of Perseus" as "the work of Cyclopean hands".
Callimachus
For the third-century BC poet Callimachus, the Hesiodic Cyclopes Brontes, Steropes and Arges, become assistants at the forge of the smith-god Hephaestus. Callimachus has the Cyclopes make Artemis bow, arrows and quiver, just as they had (apparently) made those of Apollo. Callimachus locates the Cyclopes on the island of Lipari, the largest of the Aeolian Islands in the Tyrrhenian Sea off the northern coast of Sicily, where Artemis finds them "at the anvils of Hephaestus" making a horse-trough for Poseidon:
And the nymphs were affrighted when they saw the terrible monsters like unto the crags of Ossa: all had single eyes beneath their brows, like a shield of fourfold hide for size, glaring terribly from under; and when they heard the din of the anvil echoing loudly, and the great blast of the bellows and the heavy groaning of the Cyclopes themselves. For Aetna cried aloud, and Trinacia cried, the seat of the Sicanians, cried too their neighbour Italy, and Cyrnos therewithal uttered a mighty noise, when they lifted their hammers above their shoulders and smote with rhythmic swing the bronze glowing from the furnace or iron, labouring greatly. Wherefore the daughters of Oceanus could not untroubled look upon them face to face nor endure the din in their ears. No shame to them! on those not even the daughters of the Blessed look without shuddering, though long past childhood’s years. But when any of the maidens doth disobedience to her mother, the mother calls the Cyclopes to her child—Arges or Steropes; and from within the house comes Hermes, stained with burnt ashes. And straightway he plays bogey to the child and she runs into her mother’s lap, with her hands upon her eyes. But thou, Maiden, even earlier, while yet but three years old, when Leto came bearing thee in her arms at the bidding of Hephaestus that he might give thee handsel and Brontes set thee on his stout knees—thou didst pluck the shaggy hair of his great breast and tear it out by force. And even unto this day the mid part of his breast remains hairless, even as when mange settles on a man’s temples and eats away the hair.
And Artemis asks:
Cyclopes, for me too fashion ye a Cydonian bow and arrows and a hollow casket for my shafts; for I also am a child of Leto, even as Apollo. And if I with my bow shall slay some wild creature or monstrous beast, that shall the Cyclopes eat.
Virgil
The first-century BC Roman poet Virgil seems to combine the Cyclopes of Hesiod with those of Homer, having them live alongside each other in the same part of Sicily. In his Latin epic Aeneid, Virgil has the hero Aeneas follow in the footsteps of Odysseus, the hero of Homers Odyssey. Approaching Sicily and Mount Etna, in Book 3 of the Aeneid, Aeneas manages to survive the dangerous Charybdis, and at sundown comes to the land of the Cyclopes, while "near at hand Aetna thunders". The Cyclopes are described as being "in shape and size like Polyphemus... a hundred other monstrous Cyclopes [who] dwell all along these curved shores and roam the high mountains." After narrowly escaping from Polyphemus, Aeneas tells how, responding to the Cyclops "mighty roar":
the race of the Cyclopes, roused from the woods and high mountains, rush to the harbour and throng the shores. We see them, standing impotent with glaring eye, the Aetnean brotherhood, their heads towering to the sky, a grim conclave: even as when on a mountaintop lofty oaks or cone-clad cypresses stand in mass, a high forest of Jove or grove of Diana.
Later, in Book 8 of the same poem, Virgil has the Hesiodic Cyclopes Brontes and Steropes, along with a third Cyclopes which he names Pyracmon, work in an extensive network of caverns stretching from Mount Etna to the Aeolian Islands. As the assistants of the smith-god Vulcan, they forge various items for the gods: thunderbolts for Jupiter, a chariot for Mars, and armor for Minerva:
In the vast cave the Cyclopes were forging iron—Brontes and Steropes and bare-limbed Pyracmon. They had a thunderbolt, which their hands had shaped, like the many that the Father hurls down from all over heaven upon earth, in part already polished, while part remained unfinished. Three shafts of twisted hail they had added to it, three of watery cloud, three of ruddy flame and the winged South Wind; now they were blending into the work terrifying flashes, noise, and fear, and wrath with pursuing flames. Elsewhere they were hurrying on for Mars a chariot and flying wheels, with which he stirs upmen and cities; and eagerly with golden scales of serpents were burnishing the awful aegis, armour of wrathful Pallas, the interwoven snakes, and on the breast of the goddess the Gorgon herself, with neck severed and eyes revolving.
Apollodorus
The mythographer Apollodorus, gives an account of the Hesiodic Cyclopes similar to that of Hesiods, but with some differences, and additional details. According to Apollodorus, the Cyclopes were born after the Hundred-Handers, but before the Titans (unlike Hesiod who makes the Titans the eldest and the Hundred-Handers the youngest).Uranus bound the Hundred-Handers and the Cyclopes, and cast them all into Tartarus, "a gloomy place in Hades as far distant from earth as earth is distant from the sky." But the Titans are, apparently, allowed to remain free (unlike in Hesiod). When the Titans overthrew Uranus, they freed the Hundred-Handers and Cyclopes (unlike in Hesiod, where they apparently remained imprisoned), and made Cronus their sovereign. But Cronus once again bound the six brothers, and reimprisoned them in Tartarus.As in Hesiods account, Rhea saved Zeus from being swallowed by Cronus, and Zeus was eventually able to free his siblings, and together they waged war against the Titans. According to Apollodorus, in the tenth year of that war, Zeus learned from Gaia, that he would be victorious if he had the Hundred-Handers and the Cyclopes as allies. So Zeus slew their warder Campe (a detail not found in Hesiod) and released them, and in addition to giving Zeus his thunderbolt (as in Hesiod), the Cyclopes also gave Poseidon his trident, and Hades a helmet (presumably the same cap of invisibility which Athena borrowed in the Iliad), and "with these weapons the gods overcame the Titans".Apollodorus also mentions a tomb of Geraestus, "the Cyclops" at Athens upon which, in the time of king Aegeus, the Athenians sacrificed the daughters of Hyacinth.
Nonnus
Dionysiaca, composed in the 4th or 5th century BC, is the longest surviving poem from antiquity – 20,426 lines. It is written by the poet Nonnus in the Homeric dialect, and its main subject is the life of Dionysus. It describes a war that occurred between Dionysus troops and those of the Indian king Deriades. In book 28 of the Dionysiaca the Cyclopes join with Dionysian troops, and they prove to be great warriors and crush most of the Indian kings troops.
Transformations of |
Cyclopes | Polyphemus
Depictions of the Cyclops Polyphemus have differed radically, depending on the literary genres in which he has appeared, and have given him an individual existence independent of the Homeric herdsman encountered by Odysseus. In the epic he was a man-eating monster dwelling in an unspecified land. Some centuries later, a dithyramb by Philoxenus of Cythera, followed by several episodes by the Greek pastoral poets, created of him a comedic and generally unsuccessful lover of the water nymph Galatea. In the course of these he woos his love to the accompaniment of either a cithara or the pan-pipes. Such episodes take place on the island of Sicily, and it was here that the Latin poet Ovid also set the tragic love story of Polyphemus and Galatea recounted in the Metamorphoses. Still later tradition made him the eventually successful husband of Galatea and the ancestor of the Celtic and Illyrian races.
Location
From at least the fifth-century BC onwards, Cyclopes have been associated with the island of Sicily, or the volcanic Aeolian islands just off Sicilys north coast. The fifth-century BC historian Thucydides says that the "earliest inhabitants" of Sicily were reputed to be the Cyclopes and Laestrygones (another group of man-eating giants encountered by Odysseus in Homers Odyssey). Thucydides also reports the local belief that Hephaestus (along with his Cyclopean assistants?) had his forge on the Aeolian island of Vulcano.Euripides locates Odysseus Cyclopes on the island of Sicily, near the volcano Mount Etna, and in the same play addresses Hephaestus as "lord of Aetna". The poet Callimachus locates the Cyclopes forge on the island of Lipari, the largest of the Aeolians. Virgil associates both the Hesiodic and the Homeric Cyclopes with Sicily. He has the thunderbolt makers: "Brontes and Steropes and bare-limbed Pyracmon", work in vast caverns extending underground from Mount Etna to the island of Vulcano, while the Cyclops brethren of Polyphemus live on Sicily where "near at hand Aetna thunders".As Thucydides notes, in the case of Hephaestus forge on Vulcano, locating the Cyclopes forge underneath active volcanoes provided an explanation for the fire and smoke often seen rising from them.
Etymology
For the ancient Greeks the name "Cyclopes" meant "Circle-eyes" or "Round-eyes", derived from the Greek kúklos ("circle") and ops ("eye"). This meaning can be seen as early as Hesiods Theogony (8th–7th century BC), which explains that the Cyclopes were called that "since a single circle-shaped eye was set in their foreheads". Adalbert Kuhn, expanding on Hesiods etymology, proposed a connection between the first element kúklos (which can also mean "wheel") and the "wheel of the sun", producing the meaning "wheel (of the sun)-eyes". Other etymologies have been proposed which derive the second element of the name from the Greek klops ("thief") producing the meanings "wheel-thief" or "cattle-thief". Although Walter Burkert has described Hesiods etymology as "not too attractive", Hesiods explanation still finds acceptance by modern scholars.
Possible origins
A possible origin for one-eyed Cyclopes was advanced by the palaeontologist Othenio Abel in 1914. Abel proposed that fossil skulls of Pleistocene dwarf elephants, commonly found in coastal caves of Italy and Greece, may have given rise to the Polyphemus story. Abel suggested that the large, central nasal cavity (for the trunk) in the skull might have been interpreted as a large single eye-socket.Cyclopia, a rare birth defect, can result in foetuses which have a single eye. Although the possibility has been raised of a link between this deformity and the myth of the one-eyed Cyclopes, in such cases, the eye is below the nose—rather than above as in ancient Greek depictions.As noted above, Walter Burkert sees the possibility of the Hesiodic Cyclopes having ancient smith guilds as their basis.
See also
Polyphemus § Possible origins, for stories of other cyclopian giants similar to the story of Polyphemus encounter with Odysseus
List of one-eyed creatures in mythology and fiction
Notes
References
Apollodorus, Apollodorus, The Library, with an English Translation by Sir James George Frazer, F.B.A., F.R.S. in 2 Volumes. Cambridge, Massachusetts, Harvard University Press; London, William Heinemann Ltd. 1921. Online version at the Perseus Digital Library.
Bakker, Egbert J., The Meaning of Meat and the Structure of the Odyssey, Cambridge University Press, 2013. ISBN 978-0-521-11120-1.
Bremmer, J.N. (1987). Odysseus versus the Cyclops, in Myth and Symbol. The Norwegian Institute.
Burkert, Walter (1982). Structure and History in Greek Mythology and Ritual. University of California Press. ISBN 978-0-520-04770-9.
Burkert, Walter (1991). Greek Religion. Wiley-Blackwell. ISBN 978-0-631-15624-6.
Caldwell, Richard, Hesiods Theogony, Focus Publishing/R. Pullins Company (1987). ISBN 978-0-941051-00-2.
Callimachus, Callimachus and Lycophron with an English translation by A. W. Mair ; Aratus, with an English translation by G. R. Mair, London: W. Heinemann, New York: G. P. Putnam 1921. Internet Archive.
Creese, David, "Erogenous Organs: The Metamorphosis of Polyphemus Syrinx in Ovid, Metamorphoses 13.784" in The Classical Quarterly, New Series, Vol. 59, No. 2 (Dec., 2009), pp. 562–577. JSTOR 20616706.
Diodorus Siculus, Library of History, Volume III: Books 4.59-8. Translated by C. H. Oldfather. Loeb Classical Library No. 340. Cambridge, Massachusetts: Harvard University Press, 1939. ISBN 978-0-674-99375-4. Online version at Harvard University Press. Online version by Bill Thayer
Dowden, Ken, Zeus, Routledge, 2006. ISBN 0-415-30502-0.
Euripides, Alcestis in Euripides: Cyclops, Alcestis, Medea, edited and translated by David Kovacs, Loeb Classical Library No. 12, Cambridge, Massachusetts, Harvard University Press, 2001. ISBN 978-0-674-99560-4. Online version at Harvard University Press.
Euripides, Cyclops in Euripides: Cyclops, Alcestis, Medea, edited and translated by David Kovacs, Loeb Classical Library No. 12, Cambridge, Massachusetts, Harvard University Press, 2001. ISBN 978-0-674-99560-4. Online version at Harvard University Press.
Eratosthenes, C. Julius Hyginus, Aratus, Constellation Myths: With Aratuss Phaenomena, translated by Robin Hard, Oxford University Press, 2015. ISBN 978-0-19-871698-3.
Fowler, R. L. (2000), Early Greek Mythography: Volume 1: Text and Introduction, Oxford University Press, 2000. ISBN 978-0198147404.
Fowler, R. L. (2013), Early Greek Mythography: Volume 2: Commentary, Oxford University Press, 2013. ISBN 978-0198147411.
Frame, Douglas, The Myth of Return in Early Greek Epic, Yale University Press, 1978. ISBN 978-0300019407. Internet Archive.
Gantz, Timothy, Early Greek Myth: A Guide to Literary and Artistic Sources, Johns Hopkins University Press, 1996, Two volumes: ISBN 978-0-8018-5360-9 (Vol. 1), ISBN 978-0-8018-5362-3 (Vol. 2).
Griffin, H. F., "Unrequited Love: Polyphemus and Galatea in Ovids Metamorphoses", in Greece & Rome, Vol. 30, No. 2 (Oct., 1983), pp. 190–197. JSTOR 642570.
Grimal, Pierre, The Dictionary of Classical Mythology, Wiley-Blackwell, 1996. ISBN 978-0-631-20102-1.
Hansen, William, Handbook of Classical Mythology, ABC-CLIO, 2004. ISBN 978-1576072264.
Hard, Robin, The Routledge Handbook of Greek Mythology: Based on H.J. Roses "Handbook of Greek Mythology", Psychology Press, 2004, ISBN 9780415186360. Google Books.
Heubeck, Alfred, J. B. Hainsworth, Stephanie West, A Commentary on Homers Odyssey: Volume I: Introduction and Books I–VIII, Oxford University Press, 1990. ISBN 0-19-814747-3.
Heubeck, Alfred, Arie Hoekstra, A Commentary on Homers Odyssey: Volume II: Books IX–XVI, Oxford University Press, 1990. ISBN 0-19-872144-7.
Hesiod, Theogony, in The Homeric Hymns and Homerica with an English Translation by Hugh G. Evelyn-White, Cambridge, Massachusetts., Harvard University Press; London, William Heinemann Ltd. 1914. Online version at the Perseus Digital Library.
Homer, The Odyssey with an English Translation by A.T. Murray, PH.D. in two volumes. Cambridge, Massachusetts., Harvard University Press; London, William Heinemann, Ltd. 1919. Online version at the Perseus Digital Library.
Hyginus, Gaius Julius, Fabulae in Apollodorus Library and Hyginus Fabulae: Two Handbooks of Greek Mythology, Translated, with Introductions by R. Scott Smith and Stephen M. Trzaskoma, Hackett Publishing Company, 2007. ISBN 978-0-87220-821-6.
Leroi, Armand Marie, Mutants: On Genetic Variety and the Human Body, Penguin, 2003. ISBN 0-670-03110-0.
Mayor, Adrienne (2011), The First Fossil Hunters: Dinosaurs, Mammoths, and Myth in Greek and Roman Times, Princeton University Press, 2011. ISBN 978-0-691-15013-0.
Mondi, Robert, "The Homeric Cyclopes: Folktale, Tradition, and Theme", Transactions of the American Philological Association (1974–2014), Vol. 113 (1983), pp. 17–38. JSTOR 28400.
Most, G.W. (2018a), Hesiod, Theogony, Works and Days, Testimonia, Edited and translated by Glenn W. Most, Loeb Classical Library No. 57, Cambridge, Massachusetts, Harvard University Press. ISBN 978-0-674-99720-2. Online version at Harvard University Press.
Most, G.W. (2018b), Hesiod: The Shield, Catalogue of Women, Other Fragments, Loeb Classical Library, No. 503, Cambridge, Massachusetts, Harvard University Press, 2007, 2018. ISBN 978-0-674-99721-9. Online version at Harvard University Press.
Nelson, Edward, "The One-Eyed Ones" in The Journal of American Folklore, Vol. 71, No. 280 (Apr. – Jun., 1958), pp. 159–61. JSTOR 537689
Nonnus, Dionysiaca; translated by Rouse, W H D, II Books XVI–XXXV. Loeb Classical Library No. 345, Cambridge, Massachusetts, Harvard University Press; London, William Heinemann Ltd. 1940. Internet Archive.
Ovid, Ovids Fasti: With an English translation by Sir James George Frazer, London: W. Heinemann LTD; Cambridge, Massachusetts, Harvard University Press, 1959. Internet Archive.
Ovid, Metamorphoses, Brookes More. Boston. Cornhill Publishing Co. 1922. Online version at the Perseus Digital Library.
Pausanias, Pausanias Description of Greece with an English Translation by W.H.S. Jones, Litt.D., and H.A. Ormerod, M.A., in 4 Volumes. Cambridge, Massachusetts, Harvard University Press; London, William Heinemann Ltd. 1918. Online version at the Perseus Digital Library.
Pliny the Elder, Natural History, Volume II: Books 3–7. Translated by H. Rackham. Loeb Classical Library No. 352. Cambridge, Massachusetts, Harvard University Press, 1942. ISBN 978-0-674-99388-4. Online version at Harvard University Press.
Roller, Duane W. Roller, A Historical and Topographical Guide to the Geography of Strabo, Cambridge University Press, 2018. ISBN 9781316853153.
Rose, H. J., s.v. Cyclopes, in The Oxford Classical Dictionary, Hammond, N.G.L. and Howard Hayes Scullard (editors), second edition, Oxford University Press, 1992. ISBN 0-19-869117-3.
Storey, Ian C., Fragments of Old Comedy, Volume II: Diopeithes to Pherecrates, edited and translated by Ian C. Storey, Loeb Classical Library No. 514, Cambridge, Massachusetts, Harvard University Press, year. Online version at Harvard University Press. ISBN 978-0-674-99663-2.
Strabo, Geography, translated by Horace Leonard Jones; Cambridge, Massachusetts: Harvard University Press; London: William Heinemann, Ltd. (1924). Online version at the Perseus Digital Library, Books 6–14
Theocritus in Theocritus, Moschus, Bion, edited and translated by Neil Hopkinson, Loeb Classical Library No. 28, Cambridge, Massachusetts, Harvard University Press, 2015. Online version at Harvard University Press. ISBN 978-0-674-99644-1.
Thucydides, The Peloponnesian War. London, J. M. Dent; New York, E. P. Dutton. 1910. Online version at the Perseus Digital Library.
Tripp, Edward, Crowells Handbook of Classical Mythology, Ty Crowell Co; First edition (1970). ISBN 069022608X.
Tyrtaeus in Tyrtaeus, Solon, Theognis, Mimnermus. Greek Elegiac Poetry: From the Seventh to the Fifth Centuries BC, edited and translated by Douglas E. Gerber, Loeb Classical Library No. 258, Cambridge, Massachusetts, Harvard University Press, Online version at Harvard University Press. ISBN 978-0-674-99582-6.
Virgil, Aeneid [books 1–6], in Eclogues, Georgics, Aeneid: Books 1–6, translated by H. Rushton Fairclough, revised by G. P. Goold, Loeb Classical Library No. 63, Cambridge, Massachusetts, Harvard University Press, 1999. Online version at Harvard University Press. ISBN 978-0-674-99583-3.
Virgil, Aeneid [books 7–12], in Aeneid: Books 7–12. Appendix Vergiliana, translated by H. Rushton Fairclough, revised by G. P. Goold, Loeb Classical Library No. 64, Cambridge, Massachusetts, Harvard University Press, 2000. Online version at Harvard University Press. ISBN 978-0-674-99586-4.
West, M. L. (1966), Hesiod: Theogony, Oxford University Press. ISBN 0-19-814169-6.
West, M. L. (1983), The Orphic Poems, Clarendon Press. ISBN 978-0-19-814854-8.
West, M. L. (1988), Hesiod: Theogony and Works and Days, Oxford University Press. ISBN 978-0-19-953831-7.
Yasumura, Noriko, Challenges to the Power of Zeus in Early Greek Poetry, A&C Black, 2013. ISBN 9781472519672.
External links
The dictionary definition of Κύκλωψ at Wiktionary
Media related to Cyclops at Wikimedia Commons
Cyclops - World History Encyclopedia
Harry Thurston Peck, Harpers Dictionary of Classical Antiquities (1898)
Perseus Encyclopedia: Cyclopes |
Colpocephaly | Colpocephaly is a cephalic disorder involving the disproportionate enlargement of the occipital horns of the lateral ventricles and is usually diagnosed early after birth due to seizures. It is a nonspecific finding and is associated with multiple neurological syndromes, including agenesis of the corpus callosum, Chiari malformation, lissencephaly, and microcephaly. Although the exact cause of colpocephaly is not known yet, it is commonly believed to occur as a result of neuronal migration disorders during early brain development, intrauterine disturbances, perinatal injuries, and other central nervous system disorders. Individuals with colpocephaly have various degrees of motor disabilities, visual defects, spasticity, and moderate to severe intellectual disability.
No specific treatment for colpocephaly exists, but patients may undergo certain treatments to improve their motor function or intellectual disability.
Symptoms
There are various symptoms of colpocephaly and patients can experience effects ranging from mild to severe. Some patients do not show most of the symptoms related to colpocephaly, such as psychomotor abnormalilities and agenesis of the corpus callosum. In some cases, signs appear later on in life and a significant number of children only develop minor disabilities.
The following list includes common symptoms of colpocephaly.
partial or complete agenesis of the corpus callosum
intellectual disability
motor abnormalities
visual defects such as, crossing of the eyes, missing visual fields, and optic nerve hypoplasia
spasticity
seizures
cerebral palsyIntracranial abnormalities include:
Microcephaly
Agenesis of the corpus callosum
Meningomyelocele
Lissencephaly
Periventricular leukomalacia (PVL)
Enlargement of the cisterna magna
Cerebellar hypoplasia
Causes
There is no known definitive single mechanism that causes colpocephaly. However, researchers believe there are many possible causes of colpocephaly. It is a common symptom of other neurological disorders in newborns, can be caused as a result of shunt treatment of hydrocephalus, developmental disorders in premature infants, due to intrauterine disturbances during pregnancy, genetic disorders, underdevelopment or lack of white matter in the cerebrum, and exposure of the mother and the developing fetus to medications, infections, radiation, or toxic substances. Also, it is usually more common in premature infants than in full-term infants, especially in babies born with hypoxia or lung immaturity.
Some of the central nervous system disorders which are associated with colpocephaly are as follows:
polymicrogyria
Periventricular leukomalacia (PVL)
intraventricular hemorrhage
Hydrocephalus
schizencephaly
microgyria
microcephaly
Pierre-Robin syndrome
NeurofibromatosisOften colpocephaly occurs as a result of hydrocephalus. Hydrocephalus is the accumulation of cerebrospinal fluid (CSF) in the ventricles or in the subarachnoid space over the brain. The increased pressure due to this condition dilates occipital horns causing colpocephaly.
The most generally accepted theory is that of neuronal migration disorders occurring during the second to fifth months of fetal life. Neuronal migration disorders are caused by abnormal migration, proliferation, and organization of neurons during early brain development. During the seventh week of gestation, neurons start proliferating in the germinal matrix which is located in the subependymal layer of the walls of the lateral ventricles. During the eighth week of gestation, the neurons then start migrating from the germinal zone to cortex along specialized radial glial fibers. Next, neurons organize themselves into layers and form synaptic contacts with other neurons present in the cortex. Under normal conditions, the neurons forming a germinal layer around ventricles migrate to the surface of the brain and form the cerebral cortex and basal ganglia. If this process is abnormal or disturbed it could result in the enlargement of the occipital horns of the lateral ventricles. Common prenatal disturbances that have been shown to disturb the neuronal migration process include the following:
continuation of oral contraceptives
exposure to alcohol
intrauterine malnutrition
intrauterine infections such as toxoplasmosis
maternal drug ingestion during early pregnancy such as corticosteroids, salbutamol, and theophyllineResearchers also believe that these factors can cause destruction of neural elements that have previously been normally formed.It is suggested that the underdevelopment or lack of white matter in the developing fetus could be a cause of colpocephaly. The partial or complete absence of white matter, also known as agenesis of the corpus callosum results in anatomic malformations that can lead to colpocephaly. This starts to occur around the middle of the second month to the fifth month of pregnancy. The lateral ventricles are formed as large cavities of the telencephalic vesicle. The size of the ventricles are decreased in normal development after the formation of the Foramen of Magendie, which decompresses the ventricular cavities. Myelination of the ventricular walls and association fibers of the corpus callosum and the calcarine fissure helps shape the occipital horns. In cases where this developmental process is interrupted, occipital horns are disproportionately enlarged.Colpocephaly has been associated with chromosomal abnormalities such as trisomy 8 mosaic and trisomy 9 mosaic. A few reports of genetically transmitted colpocephaly are also found in literature. Some of these are of two siblings, monozygotic twins, and non-identical twins. The authors suggest a genetic origin with an autosomal or X-linked recessive inheritance rather than resulting from early prenatal disturbances.
Diagnosis
Presentation
Colpocephaly is characterized by disproportionately large occipital horns of the lateral ventricles (also frontal and temporal ventricles in some cases). MRI and CT scans of patients demonstrate abnormally thick gray matter with thin poorly myelinated white matter. This happens as a result of partial or complete absence of the corpus callosum. Corpus callosum is the band of white matter connecting the two cerebral hemispheres. The corpus callosum plays an extremely important role in interhemispheric communication, thus lack of or absence of these neural fibers results in a number of disabilities.The lemon sign on CT scans of patients refers to the shape of the fetal skull when the frontal bones lose their normal convex contour and appear flattened or inwardly scalloped. This gives the skull a shape similar to that of a lemon. The sign is seen on transverse sonograms of the fetal cranium obtained at the level of the ventricles.
A special case is found in literature where lissencephaly, colpocephaly, and septal agenesis are all present together. The CT scans of the patient shows the ventricular system having a unique appearance of a crown of a king. This is referred to as the CROWN SIGN.
Prenatal
Diagnosing colpocephaly prenatally is difficult because in many cases signs start to appear after birth. Prenatal diagnosis is made by detecting enlargement of either or both occipital horns of the lateral ventricles. Usually prenatal ultrasounds dont show cephalic abnormalities and in cases that they do show abnormality is of low accuracy, making it difficult to diagnose colpocephaly. Often, abnormalities in prenatal ultrasounds can be misdiagnosed as hydrocephalus.
Postnatal
After birth, MR imaging can be done to look for cephalic abnormalities. This is the most commonly used method for diagnosing colpocephaly. Physicians look for abnormally large occipital horns of the lateral ventricles and diminished thickness of white matter. Spinal tapping is not a preferred method for diagnosis because newborn babies with colpocephaly or hydrocephaly have open fontanelles which makes it difficult to collect CSF. Also, colpocephaly is not associated with increased pressure.
Treatment
Colpocephaly is usually non-fatal. There has been relatively little research conducted to improve treatments for colpocephaly, and there is no known definitive treatment of colpocephaly yet. Specific treatment depends on associated symptoms and the degree of dysfunction. Anticonvulsant medications can be given to prevent seizure complications, and physical therapy is used to prevent contractures (shrinkage or shortening of muscles) in patients that have limited mobility. Patients can also undergo surgeries for stiff joints to improve motor function. The prognosis for individuals with colpocephaly depends on the severity of the associated conditions and the degree of abnormal brain development.A rare case of colpocephaly is described in literature which is associated with macrocephaly instead of microcephaly. Increased intracranial pressure was also found in the condition. Similar symptoms (absence of corpus callosum and increased head circumference) were noted as in the case of colpocephaly that is associated with microcephaly. A bi-ventricular peritoneal shunt was performed, which greatly improved the symptoms of the condition. Ventriculo-peritoneal shunts are used to drain the fluid into the peritoneal cavity.
History
These brain abnormalities were first described by Benda in 1940 as vesiculocephaly. In 1946, Yakovlev and Wadsworth coined the term colpocephaly from the Greek word kolpos (hollow) and kephalos (head). It was suggested that the enlargement of ventricles occurred as a result of white matter development arrest during early fetal life. They stated that "in the apparent dilatation of the occipital horns...it represented a failure of development of the cerebral wall with persistence of the embryonal vesicular character of the brain." Yakovlev meant for this term to apply to the result of disturbances during the development of the brain. He suggested the term hydrocephalus ex vauco to be used for enlargement of the occipital horns of the lateral ventricles as a result of damage to the brain after it is normally formed. However, today the term colpocephaly is used to describe both the situations.
Future Research
Stem cell therapy is considered a very promising treatment for patients with colpocephaly. Oligodendroglial cells can be used which will increase the production of myelin and alleviate symptoms of colpocephaly. Damage to the developing oligodendrocytes near the cerebral ventricles causes cerebral palsy as well as other demyelinating diseases such as multiple sclerosis and leukodystrophies. Demyelination reduces the speed of conduction in affected nerves resulting in disabilities in cognition, sensation, and motor. Therefore, by using oligodendrocyte stem cells the effects of cerebral palsy can be treated and other symptoms of colpocephaly can be alleviated.
== References == |
Sleep apnea | Sleep apnea, also spelled sleep apnoea, is a sleep disorder in which pauses in breathing or periods of shallow breathing during sleep occur more often than normal. Each pause can last for a few seconds to a few minutes and they happen many times a night. In the most common form, this follows loud snoring. There may be a choking or snorting sound as breathing resumes. Because the disorder disrupts normal sleep, those affected may experience sleepiness or feel tired during the day. In children, it may cause hyperactivity or problems in school.Sleep apnea may be either obstructive sleep apnea (OSA), in which breathing is interrupted by a blockage of air flow, central sleep apnea (CSA), in which regular unconscious breath simply stops, or a combination of the two. OSA is the most common form. OSA has four key contributors; these include a narrow, crowded, or collapsible upper airway, an ineffective pharyngeal dilator muscle function during sleep, airway narrowing during sleep and unstable control of breathing (high loop gain). It is often a chronic condition. Other risk factors include being overweight, a family history of the condition, allergies, and enlarged tonsils. Some people with sleep apnea are unaware they have the condition. In many cases it is first observed by a family member. Sleep apnea is often diagnosed with an overnight sleep study. For a diagnosis of sleep apnea, more than five episodes per hour must occur.In central sleep apnea (CSA), the basic neurological controls for breathing rate malfunction and fail to give the signal to inhale, causing the individual to miss one or more cycles of breathing. If the pause in breathing is long enough, the percentage of oxygen in the circulation will drop to a lower than normal level (hypoxaemia) and the concentration of carbon dioxide will build to a higher than normal level (hypercapnia). In turn, these conditions of hypoxia and hypercapnia will trigger additional effects on the body. Brain cells need constant oxygen to live, and if the level of blood oxygen goes low enough for long enough, brain damage and even death will occur.
A systemic disorder, sleep apnea is associated with a wide array of effects, including increased risk of car accidents, hypertension, cardiovascular disease, myocardial infarction, stroke, atrial fibrillation, insulin resistance, higher incidence of cancer, and neurodegeneration. The exact effects of the condition will depend on how severe the apnea is and on the individual characteristics of the person having the apnea.
Treatment may include lifestyle changes, mouthpieces, breathing devices, and surgery. Effective lifestyle changes may include avoiding alcohol, losing weight, stopping smoking, and sleeping on ones side. Breathing devices include the use of a CPAP machine. With proper use, CPAP improves outcomes. Evidence suggests that CPAP may improve sensitivity to insulin, blood pressure, and sleepiness. Long term compliance, however, is an issue with more than half of people not appropriately using the device. In 2017, only 15% of potential patients in developed countries used CPAP machines, while in developing countries well under 1% of potential patients used CPAP. Without treatment, sleep apnea may increase the risk of heart attack, stroke, diabetes, heart failure, irregular heartbeat, obesity, and motor vehicle collisions.Alzheimers disease and severe obstructive sleep apnea are connected because there is an increase in the protein beta-amyloid as well as white-matter damage. These are the main indicators of Alzheimers, which in this case comes from the lack of proper rest or poorer sleep efficiency resulting in neurodegeneration. Having sleep apnea in mid-life brings a higher likelihood of developing Alzheimers in older age, and if one has Alzheimers then one is also more likely to have sleep apnea. This is demonstrated by cases of sleep apnea even being misdiagnosed as dementia. With the use of treatment through CPAP, there is a reversible risk factor in terms of the amyloid proteins. This usually restores brain structure and diminishes cognitive impairment.OSA is a common sleep disorder. A large analysis in 2019 of the estimated prevalence of OSA found that OSA affects 936 million—1 billion people between the ages of 30-69 globally, or roughly every 1 in 10 people, and up to 30% of the elderly. Sleep apnea is somewhat more common in men than women, roughly a 2:1 ratio of men to women, and in general more people are likely to have it with older age and obesity.
Signs and symptoms
People with sleep apnea have problems with excessive daytime sleepiness (EDS) and impaired alertness. OSA may increase risk for driving accidents and work-related accidents. If OSA is not treated, people are at increased risk of other health problems, such as diabetes.
Due to the disruption in daytime cognitive state, behavioral effects may be present. These can include moodiness, belligerence, as well as a decrease in attentiveness and energy. These effects may become intractable, leading to depression.There is evidence that the risk of diabetes among those with moderate or severe sleep apnea is higher. Finally, because there are many factors that could lead to some of the effects previously listed, some people are not aware that they have sleep apnea and are either misdiagnosed or ignore the symptoms altogether.
Risk factors
Sleep apnea can affect people regardless of sex, race, or age. However, risk factors include:
being male
obesity
age over 40
large neck circumference (greater than 16–17 inches)
enlarged tonsils or tongue
narrow upper jaw
nasal congestion
allergies
receding chin
gastroesophageal reflux
a family history of sleep apnea
smokingAlcohol, sedatives and tranquilizers may also promote sleep apnea by relaxing throat muscles. People who smoke tobacco have sleep apnea at three times the rate of people who have never done so.Central sleep apnea is more often associated with any of the following risk factors:
being male
an age above 65
having heart disorders such as atrial fibrillation or atrial septal defects such as PFO
strokeHigh blood pressure is very common in people with sleep apnea.
Mechanism
When breathing is paused, carbon dioxide builds up in the bloodstream. Chemoreceptors in the bloodstream note the high carbon dioxide levels. The brain is signaled to awaken the person, which clears the airway and allows breathing to resume. Breathing normally will restore oxygen levels and the person will fall asleep again. This carbon dioxide build-up may be due to the decrease of output of the brainstem regulating the chest wall or pharyngeal muscles, which causes the pharynx to collapse. People with sleep apnea experience reduced or no slow-wave sleep and spend less time in REM sleep.
Complication
It is considered that OSA is a serious medical condition. Daytime fatigue and sleepiness, cardiovascular problems and eye problems are also be considered as a potential complications of OSA. OSA may also be a risk factor of COVID-19. It is found that people with OSA have a higher risk of developing severe complications of COVID-19.
Diagnosis
Despite this medical consensus, the variety of apneic events (e.g., hypopnea vs apnea, central vs obstructive), the variability of patients physiologies, and the inherent shortcomings and variability of equipment and methods, this field is subject to debate.
Within this context, the definition of an event depends on several factors (e.g., patients age) and account for this variability through a multi-criteria decision rule described in several, sometimes conflicting, guidelines.
Oximetry
Oximetry, which may be performed over one or several nights in a persons home, is a simpler, but less reliable alternative to a polysomnography. The test is recommended only when requested by a physician and should not be used to test those without symptoms. Home oximetry may be effective in guiding prescription for automatically self-adjusting continuous positive airway pressure.
Classification
There are three types of sleep apnea. OSA accounts for 84%, CSA for 0.9%, and 15% of cases are mixed.
Obstructive sleep apnea
Obstructive sleep apnea (OSA) is the most common category of sleep-disordered breathing. The muscle tone of the body ordinarily relaxes during sleep, and at the level of the throat, the human airway is composed of collapsible walls of soft tissue that can obstruct breathing. Mild occasional sleep apnea, such as many people experience during an upper respiratory infection, may not be significant, but chronic severe obstructive sleep apnea requires treatment to prevent low blood oxygen (hypoxemia), sleep deprivation, and other complications.
Individuals with low muscle-tone and soft tissue around the airway (e.g., because of obesity) and structural features that give rise to a narrowed airway are at high risk for obstructive sleep apnea. The elderly are more likely to have OSA than young people. Men are more likely to develop sleep apnea than women and children are, though it is not uncommon in the last two population groups.The risk of OSA rises with increasing body weight, active smoking and age. In addition, patients with diabetes or "borderline" diabetes have up to three times the risk of having OSA.
Common symptoms include loud snoring, restless sleep, and sleepiness during the daytime. Diagnostic tests include home oximetry or polysomnography in a sleep clinic.
Some treatments involve lifestyle changes, such as avoiding alcohol or muscle relaxants, losing weight, and quitting smoking. Many people benefit from sleeping at a 30-degree elevation of the upper body or higher, as if in a recliner. Doing so helps prevent the gravitational collapse of the airway. Lateral positions (sleeping on a side), as opposed to supine positions (sleeping on the back), are also recommended as a treatment for sleep apnea, largely because the gravitational component is smaller in the lateral position. Some people benefit from various kinds of oral appliances such as the Mandibular advancement splint to keep the airway open during sleep. Continuous positive airway pressure (CPAP) is the most effective treatment for severe obstructive sleep apnea, but oral appliances are considered a first-line approach equal to CPAP for mild to moderate sleep apnea, according to the AASM parameters of care. There are also surgical procedures to remove and tighten tissue and widen the airway.
Snoring is a common finding in people with this syndrome. Snoring is the turbulent sound of air moving through the back of the mouth, nose, and throat. Although not everyone who snores is experiencing difficulty breathing, snoring in combination with other risk factors has been found to be highly predictive of OSA. The loudness of the snoring is not indicative of the severity of obstruction, however. If the upper airways are tremendously obstructed, there may not be enough air movement to make much sound. Even the loudest snoring does not mean that an individual has sleep apnea syndrome. The sign that is most suggestive of sleep apneas occurs when snoring stops.
Up to 78% of genes associated with habitual snoring also increase the risk for OSA.Other indicators include (but are not limited to): hypersomnolence, obesity (BMI ≥ 30), large neck circumference—16 in (410 mm) in women, 17 in (430 mm) in men — enlarged tonsils and large tongue volume, micrognathia, morning headaches, irritability/mood-swings/depression, learning and/or memory difficulties, and sexual dysfunction.
The term "sleep-disordered breathing" is commonly used in the U.S. to describe the full range of breathing problems during sleep in which not enough air reaches the lungs (hypopnea and apnea). Sleep-disordered breathing is associated with an increased risk of cardiovascular disease, stroke, high blood pressure, arrhythmias, diabetes, and sleep deprived driving accidents. When high blood pressure is caused by OSA, it is distinctive in that, unlike most cases of high blood pressure (so-called essential hypertension), the readings do not drop significantly when the individual is sleeping. Stroke is associated with obstructive sleep apnea.Obstructive sleep apnea is associated with problems in daytime functioning, such as daytime sleepiness, motor vehicle crashes, psychological problems, decreased cognitive functioning, and reduced quality of life. Other associated problems include cerebrovascular diseases (hypertension, coronary artery disease, and stroke) and diabetes. These problems could be, at least in part, caused by risk factors of OSA.
Central sleep apnea
In pure central sleep apnea or Cheyne–Stokes respiration, the brains respiratory control centers are imbalanced during sleep. Blood levels of carbon dioxide, and the neurological feedback mechanism that monitors them, do not react quickly enough to maintain an even respiratory rate, with the entire system cycling between apnea and tachypnea, even during wakefulness. The sleeper stops breathing and then starts again. There is no effort made to breathe during the pause in breathing: there are no chest movements and no struggling. After the episode of apnea, breathing may be faster (tachypnea) for a period of time, a compensatory mechanism to blow off retained waste gases and absorb more oxygen.
While sleeping, a normal individual is "at rest" as far as cardiovascular workload is concerned. Breathing is regular in a healthy person during sleep, and oxygen levels and carbon dioxide levels in the bloodstream stay fairly constant. Any sudden drop in oxygen or excess of carbon dioxide (even if tiny) strongly stimulates the brains respiratory centers to breathe.
In any person, hypoxia and hypercapnia have certain common effects on the body. The heart rate will increase, unless there are such severe co-existing problems with the heart muscle itself or the autonomic nervous system that makes this compensatory increase impossible. The more translucent areas of the body will show a bluish or dusky cast from cyanosis, which is the change in hue that occurs owing to lack of oxygen in the blood ("turning blue"). Overdoses of drugs that are respiratory depressants (such as heroin, and other opiates) kill by damping the activity of the brains respiratory control centers. In central sleep apnea, the effects of sleep alone can remove the brains mandate for the body to breathe.
Normal Respiratory Drive: After exhalation, the blood level of oxygen decreases and that of carbon dioxide increases. Exchange of gases with a lungful of fresh air is necessary to replenish oxygen and rid the bloodstream of built-up carbon dioxide. Oxygen and carbon dioxide receptors in the blood stream (called chemoreceptors) send nerve impulses to the brain, which then signals reflex opening of the larynx (so that the opening between the vocal cords enlarges) and movements of the rib cage muscles and diaphragm. These muscles expand the thorax (chest cavity) so that a partial vacuum is made within the lungs and air rushes in to fill it.
Physiologic effects of central apnea: During central apneas, the central respiratory drive is absent, and the brain does not respond to changing blood levels of the respiratory gases. No breath is taken despite the normal signals to inhale. The immediate effects of central sleep apnea on the body depend on how long the failure to breathe endures. At worst, central sleep apnea may cause sudden death. Short of death, drops in blood oxygen may trigger seizures, even in the absence of epilepsy. In people with epilepsy, the hypoxia caused by apnea may trigger seizures that had previously been well controlled by medications. In other words, a seizure disorder may become unstable in the presence of sleep apnea. In adults with coronary artery disease, a severe drop in blood oxygen level can cause angina, arrhythmias, or heart attacks (myocardial infarction). Longstanding recurrent episodes of apnea, over months and years, may cause an increase in carbon dioxide levels that can change the pH of the blood enough to cause a respiratory acidosis.
Mixed apnea
Some people with sleep apnea have a combination of both types; its prevalence ranges from 0.56% to 18%. The condition is generally detected when obstructive sleep apnea is treated with CPAP and central sleep apnea emerges. The exact mechanism of the loss of central respiratory drive during sleep in OSA is unknown but is most likely related to incorrect settings of the CPAP treatment and other medical conditions the person has.
Management
The treatment of obstructive sleep apnea is different than that of central sleep apnea. Treatment often starts with behavioral therapy. Many people are told to avoid alcohol, sleeping pills, and other sedatives, which can relax throat muscles, contributing to the collapse of the airway at night.
Changing sleep position
More than half of people with obstructive sleep apnea have some degree of positional obstructive sleep apnea, meaning that it gets worse when they sleep on their backs. Sleeping on their sides is an effective and cost-effective treatment for positional obstructive sleep apnea.
Continuous positive airway pressure
For moderate to severe sleep apnea, the most common treatment is the use of a continuous positive airway pressure (CPAP) or automatic positive airway pressure (APAP) device. These splint the persons airway open during sleep by means of pressurized air. The person typically wears a plastic facial mask, which is connected by a flexible tube to a small bedside CPAP machine.Although CPAP therapy is effective in reducing apneas and less expensive than other treatments, some people find it uncomfortable. Some complain of feeling trapped, having chest discomfort, and skin or nose irritation. Other side effects may include dry mouth, dry nose, nosebleeds, sore lips and gums.Whether or not it decreases the risk of death or heart disease is controversial with some reviews finding benefit and others not. This variation across studies might be driven by low rates of compliance—analyses of those who use CPAP for at least four hours a night suggests a decrease in cardiovascular events.
Weight loss
Excess body weight is thought to be an important cause of sleep apnea. People who are overweight have more tissues in the back of their throat which can restrict the airway, especially when sleeping. In weight loss studies of overweight individuals, those who lose weight show reduced apnea frequencies and improved apnoea–hypopnoea index (AHI). Weight loss effective enough to relieve obesity hypoventilation syndrome (OHS) must be 25–30% of body weight. For some obese people, it can be difficult to achieve and maintain this result without bariatric surgery.
Rapid palatal expansion
In children, orthodontic treatment to expand the volume of the nasal airway, such as nonsurgical rapid palatal expansion is common. The procedure has been found to significantly decrease the AHI and lead to long-term resolution of clinical symptoms.Since the palatal suture is fused in adults, regular RPE using tooth-borne expanders cannot be performed. Mini-implant assisted rapid palatal expansion (MARPE) has been recently developed as a non-surgical option for the transverse expansion of the maxilla in adults. This method increases the volume of the nasal cavity and nasopharynx, leading to increased airflow and reduced respiratory arousals during sleep. Changes are permanent with minimal complications.
Palatal expansion is a unique treatment in that it is minimally invasive, has lasting changes and requires minimal patient compliance for treatment success.
Surgery
Several surgical procedures (sleep surgery) are used to treat sleep apnea, although they are normally a third line of treatment for those who reject or are not helped by CPAP treatment or dental appliances. Surgical treatment for obstructive sleep apnea needs to be individualized to address all anatomical areas of obstruction.
Nasal obstruction
Often, correction of the nasal passages needs to be performed in addition to correction of the oropharynx passage. Septoplasty and turbinate surgery may improve the nasal airway, but has been found to be ineffective at reducing respiratory arousals during sleep.
Pharyngeal obstruction
Tonsillectomy and uvulopalatopharyngoplasty (UPPP or UP3) are available to address pharyngeal obstruction.
The "Pillar" device is a treatment for snoring and obstructive sleep apnea; it is thin, narrow strips of polyester. Three strips are inserted into the roof of the mouth (the soft palate) using a modified syringe and local anesthetic, in order to stiffen the soft palate. This procedure addresses one of the most common causes of snoring and sleep apnea — vibration or collapse of the soft palate. It was approved by the FDA for snoring in 2002 and for obstructive sleep apnea in 2004. A 2013 meta-analysis found that "the Pillar implant has a moderate effect on snoring and mild-to-moderate obstructive sleep apnea" and that more studies with high level of evidence were needed to arrive at a definite conclusion; it also found that the polyester strips work their way out of the soft palate in about 10% of the people in whom they are implanted.
Hypopharyngeal or base of tongue obstruction
Base-of-tongue advancement by means of advancing the genial tubercle of the mandible, tongue suspension, or hyoid suspension (aka hyoid myotomy and suspension or hyoid advancement) may help with the lower pharynx.
Other surgery options may attempt to shrink or stiffen excess tissue in the mouth or throat, procedures done at either a doctors office or a hospital. Small shots or other treatments, sometimes in a series, are used for shrinkage, while the insertion of a small piece of stiff plastic is used in the case of surgery whose goal is to stiffen tissues.
Multi-level surgery
Maxillomandibular advancement (MMA) is considered the most effective surgery for people with sleep apnea, because it increases the posterior airway space (PAS). However, health professionals are often unsure as to who should be referred for surgery and when to do so: some factors in referral may include failed use of CPAP or device use; anatomy which favors rather than impedes surgery; or significant craniofacial abnormalities which hinder device use.
Potential complications
Several inpatient and outpatient procedures use sedation. Many drugs and agents used during surgery to relieve pain and to depress consciousness remain in the body at low amounts for hours or even days afterwards. In an individual with either central, obstructive or mixed sleep apnea, these low doses may be enough to cause life-threatening irregularities in breathing or collapses in a patients airways. Use of analgesics and sedatives in these patients postoperatively should therefore be minimized or avoided.
Surgery on the mouth and throat, as well as dental surgery and procedures, can result in postoperative swelling of the lining of the mouth and other areas that affect the airway. Even when the surgical procedure is designed to improve the airway, such as tonsillectomy and adenoidectomy or tongue reduction, swelling may negate some of the effects in the immediate postoperative period. Once the swelling resolves and the palate becomes tightened by postoperative scarring, however, the full benefit of the surgery may be noticed.
A person with sleep apnea undergoing any medical treatment must make sure their doctor and anesthetist are informed about the sleep apnea. Alternative and emergency procedures may be necessary to maintain the airway of sleep apnea patients.
Other
Neurostimulation
Diaphragm pacing, which involves the rhythmic application of electrical impulses to the diaphragm, has been used to treat central sleep apnea.In April 2014, the U.S. Food and Drug Administration granted pre-market approval for use of an upper airway stimulation system in people who cannot use a continuous positive airway pressure device. The Inspire Upper Airway Stimulation system senses respiration and applies mild electrical stimulation during inspiration, which pushes the tongue slightly forward to open the airway.
Medications
There is currently insufficient evidence to recommend any medication for OSA. This may result in part because people with sleep apnea have tended to be treated as a single group in clinical trials. Identifying specific physiological factors underlying sleep apnea makes it possible to test drugs specific to those causal factors: airway narrowing, impaired muscle activity, low arousal threshold for waking, and unstable breathing control.
Those who experience low waking thresholds may benefit from eszopiclone, a sedative typically used to treat insomnia. The antidepressant desipramine may stimulate upper airway muscles and lessen pharyngeal collapsibility in people who have limited muscle function in their airways.There is limited evidence for medication, but 2012 AASM guidelines suggested that acetazolamide "may be considered" for the treatment of central sleep apnea; zolpidem and triazolam may also be considered for the treatment of central sleep apnea, but "only if the patient does not have underlying risk factors for respiratory depression".
Low doses of oxygen are also used as a treatment for hypoxia but are discouraged due to side effects.
Oral appliances
An oral appliance, often referred to as a mandibular advancement splint, is a custom-made mouthpiece that shifts the lower jaw forward and opens the bite slightly, opening up the airway. These devices can be fabricated by a general dentist. Oral appliance therapy (OAT) is usually successful in patients with mild to moderate obstructive sleep apnea. While CPAP is more effective for sleep apnea than oral appliances, oral appliances do improve sleepiness and quality of life and are often better tolerated than CPAP.
Nasal EPAP
Nasal EPAP is a bandage-like device placed over the nostrils that uses a persons own breathing to create positive airway pressure to prevent obstructed breathing.
Oral pressure therapy
Oral pressure therapy uses a device that creates a vacuum in the mouth, pulling the soft palate tissue forward. It has been found useful in about 25 to 37% of people.
Prognosis
Death could occur from untreated OSA due to lack of oxygen to the body.There is increasing evidence that sleep apnea may lead to liver function impairment, particularly fatty liver diseases (see steatosis).It has been revealed that people with OSA show tissue loss in brain regions that help store memory, thus linking OSA with memory loss. Using magnetic resonance imaging (MRI), the scientists discovered that people with sleep apnea have mammillary bodies that are about 20% smaller, particularly on the left side. One of the key investigators hypothesized that repeated drops in oxygen lead to the brain injury.The immediate effects of central sleep apnea on the body depend on how long the failure to breathe endures. At worst, central sleep apnea may cause sudden death. Short of death, drops in blood oxygen may trigger seizures, even in the absence of epilepsy. In people with epilepsy, the hypoxia caused by apnea may trigger seizures that had previously been well controlled by medications. In other words, a seizure disorder may become unstable in the presence of sleep apnea. In adults with coronary artery disease, a severe drop in blood oxygen level can cause angina, arrhythmias, or heart attacks (myocardial infarction). Longstanding recurrent episodes of apnea, over months and years, may cause an increase in carbon dioxide levels that can change the pH of the blood enough to cause a respiratory acidosis.
Epidemiology
The Wisconsin Sleep Cohort Study estimated in 1993 that roughly one in every 15 Americans was affected by at least moderate sleep apnea. It also estimated that in middle-age as many as 9% of women and 24% of men were affected, undiagnosed and untreated.The costs of untreated sleep apnea reach further than just health issues. It is estimated that in the U.S., the average untreated sleep apnea patients annual health care costs $1,336 more than an individual without sleep apnea. This may cause $3.4 billion/year in additional medical costs. Whether medical cost savings occur with treatment of sleep apnea remains to be determined.
Frequency and population
Sleep disorders including sleep apnea have been become an important health issue in the United States. Twenty-two million Americans have been estimated to have sleep apnea, with 80% of moderate and severe OSA cases undiagnosed.OSA can occur at any age, but it happens more frequently in men who are over 40 and overweight.
History
A type of CSA was described in the German myth of Ondines curse where the person when asleep would forget to breathe. The clinical picture of this condition has long been recognized as a character trait, without an understanding of the disease process. The term "Pickwickian syndrome" that is sometimes used for the syndrome was coined by the famous early 20th-century physician William Osler, who must have been a reader of Charles Dickens. |
Sleep apnea | The description of Joe, "the fat boy" in Dickenss novel The Pickwick Papers, is an accurate clinical picture of an adult with obstructive sleep apnea syndrome.The early reports of obstructive sleep apnea in the medical literature described individuals who were very severely affected, often presenting with severe hypoxemia, hypercapnia and congestive heart failure.
Treatment
The management of obstructive sleep apnea was improved with the introduction of continuous positive airway pressure (CPAP), first described in 1981 by Colin Sullivan and associates in Sydney, Australia. The first models were bulky and noisy, but the design was rapidly improved and by the late 1980s, CPAP was widely adopted. The availability of an effective treatment stimulated an aggressive search for affected individuals and led to the establishment of hundreds of specialized clinics dedicated to the diagnosis and treatment of sleep disorders. Though many types of sleep problems are recognized, the vast majority of patients attending these centers have sleep-disordered breathing. Sleep apnea awareness day is April 18 in recognition of Colin Sullivan.
See also
References
== External links == |
Mareks disease | Mareks disease is a highly contagious viral neoplastic disease in chickens. It is named after József Marek, a Hungarian veterinarian who described it in 1907. Mareks disease is caused by an alphaherpesvirus known as "Mareks disease virus" (MDV) or Gallid alphaherpesvirus 2 (GaHV-2). The disease is characterized by the presence of T cell lymphoma as well as infiltration of nerves and organs by lymphocytes. Viruses related to MDV appear to be benign and can be used as vaccine strains to prevent Mareks disease. For example, the related herpesvirus found in turkeys (HVT), causes no apparent disease in the birds, and continues to be used as a vaccine strain for prevention of Mareks disease.
Birds infected with GaHV-2 can be carriers and shedders of the virus for life. Newborn chicks are protected by maternal antibodies for a few weeks. After infection, microscopic lesions are present after one to two weeks, and gross lesions are present after three to four weeks. The virus is spread in dander from feather follicles and transmitted by inhalation.
Syndromes
Six syndromes are known to occur after infection with Mareks disease. These syndromes may overlap.
Classical Mareks disease or neurolymphomatosis causes asymmetric paralysis of one or more limbs. With vagus nerve involvement, difficulty breathing or dilation of the crop may occur. Besides lesions in the peripheral nerves, there are frequently lymphomatous infiltration/tumours in the skin, skeletal muscle, visceral organs. Organs that are commonly affected include the ovary, spleen, liver, kidneys, lungs, heart, proventriculus and adrenals.
Acute Mareks disease is an epidemic in a previously uninfected or unvaccinated flock, causing depression, paralysis, and death in a large number of birds (up to 80%). The age of onset is much earlier than the classic form; birds are four to eight weeks old when affected. Infiltration into multiple organs/tissue is observed.
Ocular lymphomatosis causes lymphocyte infiltration of the iris (making the iris turn grey), unequal size of the pupils, and blindness.
Cutaneous Mareks disease causes round, firm lesions at the feather follicles.
Atherosclerosis is induced in experimentally infected chickens.
Immunosuppression is impairment of the T-lymphocytes resulting from Mareks disease, preventing a competent immunological response against pathogenic challenge, with the affected birds become more susceptible to disease conditions such as coccidiosis and Escherichia coli infection. Furthermore, without stimulation by cell-mediated immunity, the humoral immunity conferred by the B-cell lines from the Bursa of Fabricius also shuts down, thus resulting in birds that are totally immunocompromised.
Diagnosis
Diagnosis of lymphoid tumors in poultry is complicated due to multiple etiological agents capable of causing very similar tumors. It is not uncommon that more than one avian tumor virus can be present in a chicken, thus one must consider both the diagnosis of the disease/tumors (pathological diagnosis) and of the virus (etiological diagnosis). A step-wise process has been proposed for diagnosis of Mareks disease, which includes:
History, epidemiology, clinical observations and gross necropsy;
Characteristics of the tumor cell, and;
Virological characteristicsThe demonstration of peripheral nerve enlargement along with suggestive clinical signs in a bird that is around three to four months old (with or without visceral tumors) is highly suggestive of Mareks disease. Histological examination of nerves reveals infiltration of pleomorphic neoplastic and inflammatory lymphocytes. Peripheral neuropathy should also be considered as a principal rule-out in young chickens with paralysis and nerve enlargement without visceral tumors, especially in nerves with interneuronal edema and infiltration of plasma cells.The presence of nodules on the internal organs may also suggest Mareks disease, but further testing is required for confirmation. This is done through histological demonstration of lymphomatous infiltration into the affected tissue. A range of leukocytes can be involved, including lymphocytic cell lines such as large lymphocyte, lymphoblast, primitive reticular cells, and occasional plasma cells, as well as macrophage and plasma cells. The T cells are involved in the malignancy, showing neoplastic changes with evidence of mitosis. The lymphomatous infiltrates need to be differentiated from other conditions that affect poultry including lymphoid leukosis and reticuloendotheliosis, as well as an inflammatory event associated with hyperplastic changes of the affected tissue.
Key clinical signs as well as gross and microscopic features that are most useful for differentiating Mareks disease from lymphoid leukosis and reticuloendotheliosis include:
Age: Mareks disease can affect birds at any age, including <16 weeks of age;
Clinical signs: Frequent wing and leg paralysis;
Incidence: >5% in unvaccinated flocks;
Potential nerve enlargement;
Interfollicular tumors in the bursa of Fabricius;
CNS involvement;
Lymphoid proliferation in skin and feather follicles;
Pleomorphic lymphoid cells in nerves and tumors; and
T-cell lymphomas.In addition to gross pathology and histology, other advanced procedures used for a definitive diagnosis of Mareks disease include immunohistochemistry to identify cell type and virus-specific antigens, standard and quantitative PCR for identification of the virus, virus isolation to confirm infections, and serology to confirm/exclude infections.
The World Organisation for Animal Health (OIE) reference laboratory for Mareks disease is Avian Viral Oncogenesis group (led by Professor Venugopal Nair OBE) at The Pirbright Institute, UK.PCR blood testing can also detect Mareks disease, and proper testing can differentiate between a vaccinated bird with antibodies and a true positive for Mareks disease.
Mareks disease is not treatable, however, supportive care can help.
It is recommended that all flocks positive for Mareks disease remain closed, with no bird being introduced or leaving the flock. Strict biosecurity and proper cleaning is essential, using products like Activated Oxine or Virkon S and reducing dander buildup in the environment. Proper diet, regular deworming and vitamin supplements can also help keep infected flocks healthier. Reducing stress is also a key component, as stress will often bring about illness in birds infected with Mareks disease.
Prevention
Vaccination is the only known method to prevent the development of tumors when chickens are infected with the virus. However, administration of the vaccine does not prevent an infected bird from shedding the virus, though it does reduce the amount of virus shed in the dander, hence reducing horizontal spread of the disease. Mareks disease does not spread vertically.
Before the development of the vaccine for Mareks disease, Mareks disease caused substantial revenue loss in the poultry industries of the United States and the United Kingdom. The vaccine can be administered to one-day-old chicks through subcutaneous inoculation or by in ovo vaccination when the eggs are transferred from the incubator to the hatcher. In ovo vaccination is the preferred method, as it does not require handling of the chicks and can be done rapidly by automated methods. Immunity develops within two weeks.Because vaccination does not prevent infection with the virus, Mareks is still transmissible from vaccinated flocks to other birds, including the wild bird population. The first Mareks disease vaccine was introduced in 1970. The disease would cause mild paralysis, with the only identifiable lesions being in neural tissue. Mortality of chickens infected with Mareks disease was quite low. Current strains of Marek virus, decades after the first vaccine was introduced, cause lymphoma formation throughout the chickens body and mortality rates have reached 100% in unvaccinated chickens. The Mareks disease vaccine is a "leaky vaccine", which means that only the symptoms of the disease are prevented. Infection of the host and the transmission of the virus are not inhibited by the vaccine. This contrasts with most other vaccines, where infection of the host is prevented.
Under normal conditions, highly virulent strains of the virus are not selected for by evolution. This is because such a severe strain would kill the host before the virus would have an opportunity to transmit to other potential hosts and replicate. Thus, less virulent strains are selected. These strains are virulent enough to induce symptoms but not enough to kill the host, allowing further transmission. However, the leaky vaccine changes this evolutionary pressure and permits the evolution of highly virulent strains. The vaccines inability to prevent infection and transmission allows the spread of highly virulent strains among vaccinated chickens. The fitness of the more virulent strains is increased by the vaccine.
The evolution of Mareks disease due to vaccination has had a profound effect on the poultry industry. All chickens across the globe are now vaccinated against Mareks disease (birds hatched in private flocks for laying or exhibition are rarely vaccinated). Highly virulent strains have been selected to the point that any chicken that is unvaccinated will die if infected. Other leaky vaccines are commonly used in agriculture. One vaccine in particular is the vaccine for avian influenza. Leaky vaccine use for avian influenza can select for virulent strains.
References
External links
Mareks Disease Information at poultrykeeper.com
Vaccines could affect how the coronavirus evolves – but that’s no reason to skip your shot at The Conservation |
Endodermal sinus tumor | Endodermal sinus tumor (EST) is a member of the germ cell tumor group of cancers. It is the most common testicular tumor in children under three, and is also known as infantile embryonal carcinoma. This age group has a very good prognosis. In contrast to the pure form typical of infants, adult endodermal sinus tumors are often found in combination with other kinds of germ cell tumor, particularly teratoma and embryonal carcinoma. While pure teratoma is usually benign, endodermal sinus tumor is malignant.
Cause
Causes for this cancer are poorly understood.
Diagnosis
The histology of EST is variable, but usually includes malignant endodermal cells. These cells secrete alpha-fetoprotein (AFP), which can be detected in tumor tissue, serum, cerebrospinal fluid, urine and, in the rare case of fetal EST, in amniotic fluid. When there is incongruence between biopsy and AFP test results for EST, the result indicating presence of EST dictates treatment. This is because EST often occurs as small "malignant foci" within a larger tumor, usually teratoma, and biopsy is a sampling method; biopsy of the tumor may reveal only teratoma, whereas elevated AFP reveals that EST is also present. GATA-4, a transcription factor, also may be useful in the diagnosis of EST.Diagnosis of EST in pregnant women and in infants is complicated by the extremely high levels of AFP in those two groups. Tumor surveillance by monitoring AFP requires accurate correction for gestational age in pregnant women, and age in infants. In pregnant women, this can be achieved simply by testing maternal serum AFP rather than tumor marker AFP. In infants, the tumor marker test is used, but must be interpreted using a reference table or graph of normal AFP in infants.
Pathology
EST can have a multitude of morphologic patterns including: reticular, endodermal sinus-like, microcystic, papillary, solid, glandular, alveolar, polyvesicular vitelline, enteric and hepatoid.Schiller–Duval bodies on histology are pathognomonic and seen in the context of the endodermal sinus-like pattern. Rarely, it can be found in the vagina.
Treatment
Most treatments involve some combination of surgery and chemotherapy. Treatment with cisplatin, etoposide, and bleomycin has been described. Before modern chemotherapy, this type of neoplasm was highly lethal, but the prognosis has significantly improved since then. When endodermal sinus tumors are treated promptly with surgery and chemotherapy, fatal outcomes are exceedingly rare.
See also
Germ cell tumor
Testicular cancer
References
== External links == |
1p36 deletion syndrome | 1p36 deletion syndrome is a congenital genetic disorder characterized by moderate to severe intellectual disability, delayed growth, hypotonia, seizures, limited speech ability, malformations, hearing and vision impairment, and distinct facial features. The symptoms may vary, depending on the exact location of the chromosomal deletion.The condition is caused by a genetic deletion (loss of a segment of DNA) on the outermost band on the short arm (p) of chromosome 1. It is one of the most common deletion syndromes. It is estimated that the syndrome occurs in one in every 5,000 to 10,000 births.
Signs and symptoms
There are a number of signs and symptoms characteristic of monosomy 1p36, but no one individual will display all of the possible features. In general, children will exhibit failure to thrive and global delays.
Developmental and behavioral
Most young children with 1p36 deletion syndrome have delayed development of speech and motor skills. Speech is severely affected, with many children learning only a few words or having no speech at all. Behavioral problems are also common, and include temper outbursts, banging or throwing objects, striking people, screaming episodes, and self-injurious behavior (wrist biting, head striking/banging). A significant proportion of affected people are on the autism spectrum, and many exhibit stereotypy.
Neurologic
Most people with 1p36 deletion syndrome have some structural abnormality of the brain, and approximately half have epilepsy or other seizures. Almost all children exhibit some degree of hypotonia. Common structural brain abnormalities include agenesis of the corpus callosum, cerebral cortical atrophy, gait abnormalities, and ventriculomegaly. Dysphagia, esophageal reflux, and other feeding difficulties are also common.
Vision
The most common visual abnormalities associated with 1p36 deletion syndrome include farsightedness (hypermetropia), myopia (nearsightedness), and strabismus (cross-eyes). Less common but still recognized are blepharophimosis, cataracts, ocular albinism, optic atrophy, optic disk pallor, and optic nerve coloboma.
Distinct facial features
The facial features of 1p36 deletion syndrome have been considered to be characteristic, although few patients have been diagnosed solely on the basis of facial appearance. These features may include microcephaly (small head), which may be combined with brachycephaly (short head); small, deep-set eyes; straight eyebrows; epicanthal folds; a broad, flat nose and nasal bridge; underdevelopment of the midface (midface hypoplasia); a long philtrum; pointed chin; and abnormally shaped, rotated, low-set ears. Infants may have a large anterior fontanelle, or the anterior fontanelle may close late.
Other congenital defects
Skeletal
Short feet, brachydactyly (short fingers), and camptodactyly (permanent flexion of a finger), fifth finger clinodactyly (abnormal curvature) and other skeletal anomalies are sometimes found in conjunction with 1p36 deletion.
Heart
These patients may have congenital heart defects ranging from cardiac septal defects to valvular anomalies and tetralogy of Fallot. In particular, some of the patients may have LV noncompaction a form of dilated cardiomyopathy. This form of LV noncompaction cardiomyopathy is thought to be related to the deletion of the gene CASZ1, this gene in mice leads to ventricular noncompaction.
Genitourinary and kidneys
Genetics
1p36 deletion syndrome is caused by the deletion of the most distal light band of the short arm of chromosome 1.
The breakpoints for 1p36 deletion syndrome have been variable and are most commonly found from 1p36.13 to 1p36.33. 40 percent of all breakpoints occur 3 to 5 million base pairs from the telomere. The size of the deletion ranges from approximately 1.5 million base pairs to greater than 10 million.Most deletions in chromosome 1p36 are de novo mutations. 20% of patients with 1p36 deletion syndrome inherit the disease from one parent who carries a balanced or symmetrical translocation.
Diagnosis
1p36 deletion syndrome is usually suspected based on the signs and symptoms and confirmed by fluorescence in situ hybridization (FISH). Chromosomal microarray or karyotype analysis may also be used to diagnose 1p36 deletion.
Treatment
There is no cure for 1p36 deletion syndrome, and treatment is focused on relieving symptoms of the disease. Of particular importance are appropriate medication for endocrine and neurologic manifestations, such as anti-seizure medications. Feeding difficulties can be managed with specialized assistive devices or with a gastrostomy (feeding) tube.
Epidemiology
1p36 deletion syndrome is the most common terminal deletion syndrome in humans. It occurs in between 1 in 5000 and 1 in 10000 live births. And only 100 cases have been reported since 1981.
== References == |
Mycetoma | Mycetoma is a chronic infection in the skin caused by either bacteria (actinomycetoma) or fungi (eumycetoma), typically resulting in a triad of painless firm skin lumps, the formation of weeping sinuses, and a discharge that contains grains. 80% occur in feet.Most eumycetoma is caused by M. mycetomatis, whereas most actinomycetoma is caused by N. brasiliensis, S. somaliensis, A. madurae and Actinomadura pelletieri. People who develop mycetoma likely have a weakened immune system. It can take between 3 months to 50 years from time of infection to first seeking healthcare advice.Diagnosis requires ultrasound and fine needle aspiration.While most cases of mycetoma occur in Sudan, Venezuela, Mexico, and India, its true prevalence and incidence are not well-known. It appears most frequently in people living in rural areas, particularly in farmers and shepherds, who are often men between 20 and 40 years earning the primary incomes for their families. It has been reported since 1840. Noteworthy, the diagnosis of Mycetoma in non-endemic or low endemic areas as Europe and North Africa is challenging. Physicians in these areas are usually unfamiliar with the disease-specific manifestations and need to exercise extra vigilance regarding those patients who are at high risk of contracting Mycetoma infections. Recent evidence suggests that Egypt which borders Sub-Saharan Africa, is a low-endemic country. Additionally, recent evidence suggests that Pakistan which borders India, is a moderate-endemic country. Unlike bacterial acute hematogenous osteomyelitis and septic arthritis, misdiagnosed or delayed diagnosis of Mycetoma osteomyelitis can result in amputation or radical resection. The disease is listed by the World Health Organization (WHO) as a neglected tropical disease.
Risk
Frequent exposure to penetrating wounds by thorns or splinters is a risk factor. This risk can be reduced by disinfecting wounds and wearing shoes.
Pathogenesis
Mycetoma is caused by common saprotrophs found in the soil and on thorny shrubs in semi-desert climates. Some common causative agents are:
Madurella mycetomatis (fungus)
Nocardia brasiliensis (bacteria)
Actinomadure madura (bacteria)
Streptomyces somaliensis (bacteria)
Actinomadura pelletieri (bacteria)Infection is caused as a result of localized skin trauma, such as stepping on a needle or wood splinter, or through a pre-existing wound.The first visible symptom of mycetoma is a typically painless swelling beneath the skin; over several years, this will grow to a nodule (lump). Affected people will experience massive swelling and hardening of the area, in addition to skin rupture and the formation of sinus tracts that discharge pus and grains filled with organisms. In many instances, the underlying bone is affected. Some people with mycetoma will not experience pain or discomfort, while others will report itching and/or pain.
Diagnosis
There are currently no rapid diagnostic tools for mycetoma. Mycetoma is diagnosed through microscopic examination of the grains in the nodule and by analysis of cultures. Since the bacterial form and the fungal form of mycetoma infection of the foot share similar clinical and radiological features, diagnosis can be a challenge. Magnetic resonance imaging is a very valuable diagnostic tool. However, its results should be closely correlated with the clinical, laboratory and pathological findings.
Treatment
While treatment will vary depending on the cause of the condition, it may include antibiotics or antifungal medication. Actinomycetoma, the bacterial form, can be cured with antibiotics. Eumycetoma, the fungal form, is treated with antifungals. Surgery in the form of bone resection may be necessary in late presenting cases or to enhance the effects of medical treatment. In the more extensive cases amputation is another surgical treatment option. For both forms, extended treatment is necessary.
Epidemiology
Mycetoma is endemic in some regions of the tropics and subtropics. India, Sub-Saharan Africa as Sudan, and Mexico are most affected. Pakistan is probably a moderate-endemic country. Sporadic cases have been reported across some North African countries. Egypt is probably a low-endemic country.
Other animals
In cats, mycetoma can be treated with complete surgical removal. Antifungal drugs are rarely effective.
References
External links
DermNet NZ: an online resource about skin diseases from the New Zealand Dermatological Society Incorporated.
Orphanet: a reference portal from Europe that provides information on rare diseases and orphan drugs.
ClinicalTrials.gov: a list of clinical trials related to mycetoma. |
Evans syndrome | Evans syndrome is an autoimmune disease in which an individuals immune system attacks their own red blood cells and platelets, the syndrome can include immune neutropenia. These immune cytopenias may occur simultaneously or sequentially.Its overall phenotype resembles a combination of autoimmune hemolytic anemia and immune thrombocytopenic purpura.
Autoimmune hemolytic anemia is a condition in which the red blood cells that normally carry oxygen are destroyed by an autoimmune process. Immune thrombocytopenic purpura is a condition in which platelets are destroyed by an autoimmune process. Platelets are a component of blood that contribute to the formation of blood clots in the body to prevent bleeding.
The syndrome was first described in 1951 by R. S. Evans and colleagues.
Signs and symptoms
The symptoms of Evans syndrome vary between patients depending on which blood cells are affected. If red blood cells are attacked, symptoms may include weakness and fatigue, paleness or jaundice, shortness of breath, lightheadedness, and/or a fast heartbeat. If platelets are attacked, symptoms may include increased bruising, prolonged nosebleeds, increased bleeding from minor cuts, and/or Petechiae. In the less common instance that white blood cells are attacked, symptoms may include increased proneness to infection, fevers, and/or mouth sores.It has been variously reported that between 7.8% and 23% of patients who have autoimmune hemolytic anemia, will also have thrombocytopenia and thus Evans syndrome. The two cytopenias may occur together or sequentially.
Causes
Although Evans syndrome seems to be a disorder of immune regulation, the exact pathophysiology is unknown, but a gradual loss of self-tolerance is postulated. Autoantibodies targeted at different antigenic determinants on red cells and platelets are assumed to cause isolated episodes of hemolytic anemia and thrombocytopenia, respectively.
Diagnosis
Diagnosis of Evans syndrome is separated into primary and secondary presentation. There is no single test to confirm a diagnosis of either form of Evans syndrome. It is instead a diagnosis made after a thorough clinical history, documentation of common symptoms, clinical evaluation, and exclusion of all other possible conditions.The diagnosis of primary Evans syndrome is made upon blood tests to confirm not only hemolytic anemia and immune thrombocytopenic purpura, but also a positive direct antiglobulin test (DAT) and an absence of any known underlying cause. Additional tests used to eliminate the possibility of other conditions include a computed tomography (CT) scan and a biopsy of bone marrow.A diagnosis of secondary Evans syndrome is indicative of occurrence after another autoimmune disease is already present. In 27% to 50% of cases there is an associated malignancy or a predisposing autoimmune disease. Pre-existing autoimmune diseases can include autoimmune lymphoproliferative syndrome (ALPS), combined variable immunodeficiency (CVID), systemic autoimmune disease, or another disorder of immune dysregulation.Other antibodies may occur directed against neutrophils and lymphocytes, and "immunopancytopenia" has been suggested as an alternative term for this syndrome.
Treatment
Initial treatment is with glucocorticoid corticosteroids or intravenous immunoglobulin, a treatment that is also used in ITP cases. In children, it can remain well controlled with a long term immunosuppressant therapy that will occasionally lead to a spontaneous complete resolution of the condition. Although the majority of cases initially respond well to treatment, relapses are not uncommon and immunosuppressive drugs (e.g. ciclosporin, mycophenolate mofetil, vincristine and danazol) are subsequently used, or combinations of these.The off-label use of rituximab (trade name Rituxan) has produced some good results in acute and refractory cases, although further relapse may occur within a year. Splenectomy is effective in some cases, but relapses are not uncommon.The only prospect for a permanent cure is the high-risk option of an allogeneic hematopoietic stem cell transplantation (SCT).
Prognosis
In a nationwide study of Evans syndrome the median survival was 7.2 years (primary Evans syndrome: 10.9 years; secondary Evans syndrome: 1.7 years). Secondary Evans syndrome was associated with higher mortality rate than primary Evans syndrome, with a 5-year survival of 38%. Among patients with Evans syndrome, the prevailing causes of death were bleeding, infections, and hematological cancer.It has been observed that there is a risk of developing other autoimmune problems and hypogammaglobulinemia, in one cohort 58% of children with Evans syndrome had CD4-/CD8- T cells which is a strong predictor for having autoimmune lymphoproliferative syndrome.
Epidemiology
Evans syndrome is considered a very rare autoimmune disease. Only one study has estimated incidence and prevalence adults. In Denmark in 2016 the annual incidence was 1.8 per 1,000,000 person years, and the prevalence was 21.3 per 1,000,000 living persons. In pre-pubertal children the incidence has been estimated to be between 0.7 and 1.2 per 1,000,000 person-years.
See also
Hematology
References
== External links == |
Body-focused repetitive behavior | Body-focused repetitive behavior (BFRB) is an umbrella name for impulse control behaviors involving compulsively damaging ones physical appearance or causing physical injury.Body-focused repetitive behavior disorders (BFRBDs) in ICD-11 is in development.BFRB disorders are currently estimated to be under the obsessive-compulsive spectrum. They are also associated with ADHD and anxiety.
Causes
The cause of BFRBs is unknown.Emotional variables may have a differential impact on the expression of BFRBs.Research has suggested that the urge to repetitive self-injury is similar to a body-focused repetitive behavior but others have argued that for some the condition is more akin to a substance abuse disorder.Researchers are investigating a possible genetic component.
Onset
BFRBs most often begin in late childhood or in the early teens.
Diagnosis
Types
The main BFRB disorders are:
Skin
Dermatillomania (excoriation disorder), skin picking
Dermatophagia, skin nibbling
Mouth
Morsicatio buccarum, cheek biting
Morsicatio labiorum, inner lip biting
Morsicatio linguarum, tongue biting
Hands
Onychophagia, nail biting
Onychotillomania, nail picking
Nose
Rhinotillexomania, compulsive nose picking
Hair
Trichophagia, hair nibbling
Trichotemnomania, hair cutting
Trichotillomania, hair pulling
Eyes
Mucus fishing syndrome - compulsion to remove or "fish" strands of mucus from the eye
Treatment
Psychotherapy
Treatment can include behavior modification therapy, medication, and family therapy. The evidence base criteria for BFRBs is strict and methodical. Individual behavioral therapy has been shown as a "probably effective" evidence-based therapy to help with thumb sucking, and possibly nail biting. Cognitive behavioral therapy was cited as experimental evidence based therapy to treat trichotillomania and nail biting; a systematic review found best evidence for habit reversal training and decoupling. Another form of treatment that focuses on mindfulness, stimuli and rewards has proven effective in some people. However, no treatment was deemed well-established to treat any form of BFRBs.
Pharmacotherapy
Excoriation disorder, and trichotillomania have been treated with inositol and N-acetylcysteine.
Prevalence
BFRBs are among the most poorly understood, misdiagnosed, and undertreated groups of disorders. BFRBs may affect at least 1 out of 20 people. These collections of symptoms have been known for a number of years, but only recently have appeared in widespread medical literature. Trichotillomania alone is believed to affect 10 million people in the United States.
See also
Stereotypic movement disorder
Rhythmic Movement Disorder
Body dysmorphic disorder
Habit reversal training
Decoupling treatment
References
== External links == |
Monomelic amyotrophy | Monomelic amyotrophy (MMA) is a rare motor neuron disease first described in 1959 in Japan. Its symptoms usually appear about two years after adolescent growth spurt and is significantly more common in males, with an average age of onset between 15 and 25 years. MMA is reported most frequently in Asia but has a global distribution. It is typically marked by insidious onset of muscle atrophy of an upper limb, which plateaus after two to five years from which it neither improves nor worsens. There is no pain or sensory loss associated with MMA. MMA is not believed to be hereditary.Both the names for the disorder and its possible causes have been evolving since first reported in 1959. It is most commonly believed the condition occurs by asymmetrical compression of the cervical spinal column by the cervical dural sac, especially when the neck is flexed. However, the disease is uncommon and diagnosis is confused by several atypical reports.
Symptoms
In terms of the signs and symptoms that are consistent for an individual who has monomelic amyotrophy are the following (although this does not reflect a complete list):
Initially most people notice weakness in one hand; they may feel contracture of middle and ring finger and notice a thinning of the subdigital palm of the affected fingers. Progress of the condition varies, and weakness in the arm ranges from minimal to significant. Fasciculations are uncommon (>20%); increased weakness under cold conditions is commonly reported (cold paresis).
Cause
The disability originates with impaired functioning of the anterior horn cells of the lower cervical cord (lower neck), but the cause of the decline is not fully understood and is still considered unknown. Researchers, including Hirayama, believe that "forward displacement of the cervical dural sac and compressive flattening of the lower cervical cord during neck flexion" is the contributing factor. Studies consistently note a loss of normal neck curvature (the cervical lordosis) and compression of the cervical chord by the dural sac in forward flexion.
"There is a debate about whether this condition represents a focal form of primary LMN degeneration (ie, a focal form of spinal muscular atrophy) or a local consequence of chronic compression from a dural expansion in the cervical spine."A familial link has been found in a minor percentage of cases, including parent-child and sibling-sibling. Because of the unusual distribution of the disease, some researchers speculate that there could be an ethnic link.
Diagnosis
The condition presents almost exclusively in 15- to 25-year-old adults experiencing weakness in hand and arm. A patient history and a neurological exam narrows down the possible diagnosis; this preliminary exam typically includes strength and reflex tests. Cold paresis (increased weakness in cold weather) is reported by most patients (> 80%). Fasciculations are reported as uncommon (< 20%) to common; larger tremors are more consistently cited. Males are far more likely to be diagnosed with the condition.The disease is rare and several cited cases deviate from the expected norm, making diagnosis more difficult. Proposed diagnostic criteria:
Distal predominant muscle weakness and atrophy in forearm and hand
Involvement of the unilateral upper extremity almost always all the time
Onset between the ages of 10 to early 20s
Insidious onset with gradual progression for the first several years, followed by stabilization
No lower extremity involvement
No sensory disturbance and tendon reflex abnormalities
Exclusion of other diseases (e.g., motor neuron disease, multifocal motor neuropathy, brachial plexopathy, spinal cord tumors, syringomyelia, cervical vertebral abnormalities, anterior interosseous, or deep ulnar neuropathy)
A neurological exam can suggest different motor neuron diseases (such as MMA), but to more confidently distinguish MMA from the diseases it mimics, advanced diagnostic tools are called for. These include exam tools such as magnetic resonance imaging (MRI), and electromyography (EMG) and nerve conduction velocity (NCV) tests. An MRI examination of the neck would typically reveal—for a positive MMA diagnosis—some constriction of the cervical cord and an abnormal forward extension of the neck, ("loss of cervical lordosis"); pressure by the dura on the nerve cord apparently causes the flattening / narrowing. An EMG test reveals loss of the nerve supply, or denervation, in the affected limb without a conduction block (a nerve blockage restricted to a small segment of the nerve).In early stages of the disease MMA may be confused for amyotrophic lateral sclerosis (ALS), cervical spondylotic amyotrophy (CSA), and other challenging neurological diseases, as well as conditions that are minor but that call for very different treatments, such as advanced carpal tunnel syndrome (CTS). Symptoms somewhat differ. Pain and tingling in the hand is typically present in CTS and absent from MMA; loss of function presents differently; with careful electrophysiological study and neurological exams the two are distinguished. In early stages, ALS, SCA, and MMA, presentation may be similar. Both CSA and ALS ultimately have more extensive symptoms. MMA is more prevalent in young people while ALS and CSA are more common in older populations. With ALS, hand symptoms usually more commonly both proximal and distal vs in MMA mostly distal only, and with ALS fasciculations (twitching) are often present in upper extremities, but rarely in MMA. MMA is usually eliminated from consideration if disability expresses itself in more than one extremity or in lower extremities (legs), but symptomatic absence may not rule out ALS for three to five years after initial onset. Electrophysiological texts and reflex tests tend to yield different results, but interpretation is at times subjective.
Treatment
At present there is no cure for MMA. The impact on the affected individual ranges from minimal to significant depending on the extent of the weakness. Physical and occupational therapies include muscle strengthening exercises and training in hand coordination. Early use of a cervical collar is increasingly encouraged as therapeutic for arresting further compression of the cervical spinal cord. Spinal surgery on patients with more advanced symptoms has met with reported success, but is still regarded as experimental.
Prognosis
The symptoms of MMA usually progress slowly for two to five years and then remain stable for many years. The weakness can progress to the opposite limb, although whether this progression is typical or rare is under discussion. Cases of patient improvement and deterioration have both been described, but are atypical. Initially MMA can be confused for slowly progressing case of other neurological diseases such as amyotrophic lateral sclerosis (ALS); initial symptoms can be similar, but their causes are apparently different, and their outcomes markedly so. Diagnostic tools have improved since first described, and a few therapies are being introduced. But sometimes several years of observation are needed before a definitive diagnosis can be made.Use of a cervical collar may afford relief, and some researchers advocate its therapeutic use. There is also a slowly progressive variant of MMA known as OSullivan-McLeod syndrome, which only affects the small muscles of the hand and forearm and has a slowly progressive course.
Epidemiology
MMA is described most frequently in Asia, with studies of a few hundred individuals emerging from Japan, China and India; it is much less commonly seen in North America and Europe. The disease (disorder) was first described by Keizo Hirayama in 1959 as "juvenile muscular atrophy of unilateral upper extremity". In 1984 Mandavilli Gourie-Devi (et al.) introduced the term "monomelic amyotrophy". The disease primarily (but not exclusively) affects young (15- to 25-year-old) males. As of 2014 there had been less than 1500 described cases, starting with the patients in Hirayamas 1959 study. The condition is disproportionately high in Asia but no conclusive reason has been found for this. To date the largest studies recorded are Japan (333 cases), India (279 cases), and China (179 cases).
Etymology
Both the names for the disorder and its possible causes have been evolving since first reported. Because this condition has been found almost exclusively in healthy young adults and stabilizes after a few years, a span of 23 years elapsed between the time Hirayama first described the condition, and the first death (from cancer), and autopsy. Over the several decades since first reported, a majority of researchers now describe this as a biomechanical condition linked to adolescent growth spurt. However, this is not yet a universal conclusion and there are anomalous reports that suggest an incomplete understanding of the condition.
See also
Lower motor neuron lesion
Notes
References
External links
monomelic_amyotrophy at NINDS |
Milk fever | Milk fever, postparturient hypocalcemia, or parturient paresis is a disease, primarily in dairy cattle but also seen in beef cattle and non-bovine domesticated animals, characterized by reduced blood calcium levels (hypocalcemia). It occurs following parturition, at onset of lactation, when demand for calcium for colostrum and milk production exceeds the bodys ability to mobilize calcium. "Fever" is a misnomer, as body temperature during the disease is generally not elevated. Milk fever is more commonly seen in older animals (which have reduced ability to mobilize calcium from bone) and in certain breeds (such as Channel Island breeds).
Clinical signs
The clinical signs of milk fever can be divided into three distinct stages:
Stage 1
Cows are mobile but show signs of hypersensitivity and excitability such as restlessness, tremors, ear twitching, head bobbing, and mild ataxia. If not treated, symptoms usually progress to stage 2.
Stage 2
Cows can no longer stand and present in sternal recumbency. Tachycardia, weakened heart contraction and peripheral pulses. Cows appear dull, have dry muzzles, cold extremities and a lower than normal body temperature. Smooth muscle paralysis can cause bloat, and the inability to urinate or defecate. Cows often tuck their heads into their flanks.
Stage 3
Lateral recumbency, muscle flaccidity, unresponsiveness to stimuli, and loss of consciousness progressing to coma. Heart rate can approach 120 bpm, with peripheral pulses becoming undetectable. If untreated, progression will continue to death.
Cause
During the dry period (late gestation, non-lactating), dairy cattle have relatively low calcium requirements, with a need to replace approximately 30 g of calcium per day due to utilization for fetal growth and fecal and urinary losses. At parturition, the requirement for calcium is greatly increased due to initiation of lactation, when mammary drainage of calcium may exceed 50g per day. Due to this large increase in demand for calcium, most cows will experience some degree of hypocalcemia for a short period following parturition as the metabolism adjusts to the increased demand. When the mammary drain of plasma calcium causes hypocalcemia severe enough to compromise neuromuscular function, the cow is considered to have clinical milk fever.
Mechanism
In normal calcium regulation, a decrease in plasma calcium levels causes the parathyroid glands to secrete parathyroid hormone (PTH), which regulates the activation of Vitamin D3 in the kidney. These two compounds act to increase blood calcium levels by increasing absorption of dietary calcium from the intestine, increasing renal tubular reabsorption of calcium in the kidney, and increasing resorption of calcium from bones.It has been found that tissue is less responsive to parathyroid hormone prepartum, compared to postpartum. It is believed that hypocalcemia causing milk fever is due to a lower level of responsiveness of the cows tissues to circulating parathyroid hormone.The resultant decreased plasma calcium causes hyperexcitability of the nervous system and weakened muscle contractions, which result in both tetany and paresis.
Prevention
Diet
Proper dietary management will prevent most cases of milk fever. This generally involves close attention to mineral and fiber levels in the diet prior to calving, as well as improving cow comfort to eliminate other problems that may interfere with appetite (and so trigger hypocalcemia). General advice is to restrict calcium intake before calving, as this leads to the parathyroid gland stimulating the release of calcium from bones.
Calcium Salts
A synthetic analogue of 25-hydroxycholecalciferol can be given by injection in the days leading up to calving, although the timing of this prophylaxis makes it difficult to use.Oral administration of a dose of a calcium salt in a gel has been advised by some veterinarians. An orally administered bolus containing a much higher concentration of calcium than the injectable solutions can also be given so long as the cow is standing or sitting up. If the cow is lying flat out then immediate intravenous therapy is required to avoid death.
Treatment
Treatment generally involves calcium injection by intravenous, intramuscular or subcutaneous routes. Before calcium injection was employed, treatment comprised inflation of the udder using a pneumatic pump. Inflation of the udder worked because the increased pressure created in the udder pushed the calcium in the udder back into the bloodstream of the cow.Intravenous calcium, though indicated in many cases, is potentially fatal through "heart blockade", or transient high calcium levels stopping the heart, so should be administered with care. Cows are to be fed jaggery along with the lime water mixture. In unclear cases of downer cows, intravenous calcium injection can lead to diagnosis. The typical reaction will be a generalized tremor of the skeletal muscles, and sometimes cardiac arrhythmia. Defecation, urination and eructation are frequent during the treatment, due to pharmacological effect of calcium on the smooth muscles.
Prognosis
The prognosis is generally good, even in advanced cases. However, some cows can relapse the following day, and even a third time the day after. Without treatment, between 60% and 80% of cows usually die, although death rates as high as 90% have been recorded.
History
It is thought that milk fever has existed for a very long time in dairy cattle. The first reports in veterinary literature can be traced to around 1793.
Early Theories
Early treatments involved venesection, but this proved ineffective.
Potassium Iodide
In the late 1800s, Jurgens Schmidt proposed the use of an infused solution of potassium iodide for treatment. A follow-up study of this treatment by Danish veterinarians showed that 90% of cows recovered after use of the treatment, compared with only 20-40% survival without. A study in Iowa showed that 76.5% of cows recovered after use of the treatment. However, the premise of the Schmidt treatment was misleading, as later veterinarians used water alone to the same success rate.
Udder Inflation
In 1901, Anderson and Evers trialled a treatment of udder inflation with air, which reduced mortality rates to just 1%. although with the added complication of mastitis. Although this was an effective treatment (and is still used as a backup today), it was not understood at the time why it worked, and remains the source of some debate. Some scientists believed that udder inflation could cause stimulation that then prevents calcium loss. Other scientists suggested that udder inflation prevented milk secretion, reducing calcium loss overall. This may prevent calcium being taken from the blood plasma.
Later Theories
The true cause of milk fever was first suggested by Prof John Russell Greig and Henry Dryerre in March 1925, at the Moredun Research Institute in Scotland. This idea was later confirmed experimentally by Little and Wright in May 1925. By 1933, Pulles began treatments with magnesium chloride and calcium chloride, which is the basis for modern pharmaceutical treatments.
References
External links
Prevention of Milk Fever, University of Kentucky
Parturient Paresis in Cows (Milk fever, Hypocalcemia), The Merck Veterinary Manual |
Facioscapulohumeral muscular dystrophy | Facioscapulohumeral muscular dystrophy (FSHD) is a type of muscular dystrophy, a group of heritable diseases that cause degeneration of muscle and progressive weakness. Per the name, FSHD tends to sequentially weaken the muscles of the face, those that position the scapula, and those overlying the humerus bone of the upper arm. These areas can be spared, and muscles of other areas usually are affected, especially those of the chest, spine, abdomen, and shin. Almost any skeletal muscle can be affected in severe disease. Abnormally positioned, or winged, scapulas are common, as is the inability to lift the foot, known as foot drop. The two sides of the body are often affected unequally. Weakness typically manifests at ages 15 – 30 years. FSHD can also cause hearing loss and blood vessel abnormalities in the back of the eye.
FSHD is caused by a genetic mutation leading to deregulation of the DUX4 gene. Normally, DUX4 is expressed (i.e., turned on) in cells of the ovary and in very early human development, becoming repressed (i.e., turned off) by the time an embryo is several days old. In FSHD, DUX4 is inadequately repressed, allowing sporadic expression throughout life. Deletion of DNA in the region surrounding DUX4 is the causative mutation in 95% of cases, termed "D4Z4 contraction" and defining FSHD type 1 (FSHD1). FSHD caused by other mutations is FSHD type 2 (FSHD2). For disease to develop, also required is a 4qA allele, which is a common variation in the DNA next to DUX4. The chances of a D4Z4 contraction with a 4qA allele being passed on to a child is 50% (autosomal dominant); in 30% of cases, the mutation arose spontaneously. Mutations of FSHD cause inadequate DUX4 repression by unpacking the DNA around DUX4, making it accessible to be copied into messenger RNA (mRNA). The 4qA allele stabilizes this DUX4 mRNA, allowing it to be used for production of DUX4 protein. DUX4 protein is a modulator of hundreds of other genes, many of which are involved in muscle function. How this genetic modulation causes muscle damage remains unclear.Signs, symptoms, family history, and diagnostic tests can suggest FSHD; genetic testing can provide definitive diagnosis. No intervention has proven effective for slowing progression of weakness. Screening allows for early detection and intervention for various disease complications. Symptoms can be addressed with physical therapy, bracing, and reconstructive surgery such as surgical fixation of the scapula to the thorax. FSHD affects up to 1 in 8,333 people, putting it in the three most common muscular dystrophies with myotonic dystrophy and Duchenne muscular dystrophy. Prognosis is variable. Many are not significantly limited in daily activity, whereas a wheel chair or scooter is required in 20% of cases. Life expectancy is not affected, although death can rarely be attributed to respiratory insufficiency due to FSHD.FSHD was first distinguished as a disease in the 1870s and 1880s when French physicians Louis Théophile Joseph Landouzy and Joseph Jules Dejerine followed a family affected by it, thus the initial name Landouzy–Dejerine muscular dystrophy. Their work is predated by descriptions of probable individual FSHD cases. The significance of D4Z4 contraction on chromosome 4 was established in the 1990s. The DUX4 gene was discovered in 1999, found to be expressed and toxic in 2007, and in 2010 the genetic mechanism causing its expression was elucidated. In 2012, the gene most frequently mutated in FSHD2 was identified. In 2019, the first drug designed to counteract DUX4 expression entered clinical trials.
Signs and symptoms
Classically, weakness develops in the face, then the shoulder girdle, then the upper arm. These muscles can be spared and other muscles usually are affected. The order of muscle involvement can cause the appearance of weakness "descending" from the face to the legs. Distribution and degree of muscle weakness is extremely variable, even between identical twins. Musculoskeletal pain is very common, most often described in the neck, shoulders, lower back, and the back of the knee. Fatigue is also common. Muscle weakness usually becomes noticeable on one side of the body before the other, a hallmark of the disease. The right shoulder and arm muscles are more often affected than the left upper extremity muscles, independent of handedness.: 139 Otherwise, neither side of the body has been found to be at more risk. Classically, symptoms appear in those 15 – 30 years of age, although infantile onset, adult onset, and absence of symptoms despite having the causal genetics also occur. FSHD1 with a very large D4Z4 deletion (EcoRI 10-11 kb) is more strongly associated with infantile onset and severe weakness. On average, FSHD2 presents 10 year later than FSHD1. Otherwise, FSHD1 and FSHD2 are indistinguishable on the basis of weakness. Disease progression is slow, and long static phases, in which no progression is apparent, is not uncommon. Less commonly, individual muscles rapidly deteriorate over several months.
Face
Weakness of the muscles of the face is the most distinguishing sign of FSHD. It is typically the earliest sign, although it is rarely the initial complaint. At least mild facial weakness can be found in 90% or more with FSHD. One of the most common deficits is inability to close the eyelids, which can result in sleeping with the eyelids open and dry eyes. The implicated muscle is the orbicularis oculi muscle. Another common deficit is inability to purse the lips, causing inability to pucker, whistle, or blow up a balloon. The implicated muscle is the orbicularis oris muscle. A third common deficit is inability raise the corners of the mouth, causing a "horizontal smile," which looks more like a grin. Responsible is the zygomaticus major muscle.Weakness of various facial muscles contributes to difficulty pronouncing the letters M, B, and P. Facial expressions can appear diminished, arrogant, grumpy, or fatigued. Muscles used for chewing and moving the eyes are not affected. Difficulty swallowing is not typical, although can occur in advanced cases. FSHD is generally progressive, but it is not established whether facial weakness is progressive or stable throughout life.
Shoulder, chest, and arm
After the facial weakness, weakness usually develops in the muscles of the chest and those that span from scapula to thorax. Symptoms involving the shoulder, such as difficulty working with the arms overhead, are the initial complaint in 80% of cases. Predominantly, the serratus anterior and middle and lower trapezii muscles are affected; the upper trapezius is often spared. Trapezius weakness causes the scapulas to become downwardly rotated and protracted, resulting in winged scapulas, horizontal clavicles, and sloping shoulders; arm abduction is impaired. Serratus anterior weaknesss impairs arm flexion, and worsening of winging can be demonstrated when pushing against a wall. Muscles spanning from the scapula to the arm are generally spared, which include deltoid and the rotator cuff muscles. The deltoid can be affected later on, especially the upper portion.Severe muscle wasting can make bones and spared shoulder muscles very visible, a characteristic example being the "poly-hill" sign elicited by arm elevation. The first "hill" or bump is the upper corner of scapula appearing to "herniate" up and over the rib cage. The second hill is the AC joint, seen between a wasted upper trapezius and wasted upper deltoid. The third hill is the lower deltoid, distinguishable between the wasted upper deltoid and wasted humeral muscles. Shoulder weakness and pain can in turn lead to shoulder instability, such as recurrent dislocation, subluxation, or downward translation of the humeral head.Also affected is the chest, particularly the parts of the pectoralis major muscle that connect to the sternum and ribs. The part that connects to the clavicle is less often affected. This muscle wasting pattern can contribute to a prominent horizontal anterior axillary fold. Beyond this point the disease does not progress further in 30% of familial cases. After upper torso weakness, weakness can "descend" to the upper arms (biceps muscle and, particularly, the triceps muscle). The forearms are usually spared, resulting in an appearance some compare to the fictional character Popeye, although when the forearms are affected in advanced disease, the wrist extensors are more often affected.
Lower body and trunk
After the upper body, weakness can next appear in either the pelvis, or it "skips" the pelvis and involves the tibialis anterior (shin muscle), causing foot drop. One author considers the pelvic and thigh muscles to be the last group affected. Pelvic muscle weakness can manifest as pelvic tilt, causing the hips to be held in slight flexion. Pelvic weakness can also cause a Trendelenburgs sign. Weakness of the back of the thigh (hamstrings) is more common than weakness of the front of the thigh (quadriceps).Weakness can also occur in the abdominal muscles and paraspinal muscles, which can manifest as a protuberant abdomen and lumbar hyperlordosis. Abdominal weakness can cause inability to do a sit-up or the inability to turn from one side to the other while lying on ones back. Of the rectus abdominis muscle, the lower portion is preferentially affected, manifesting as a positive Beevors sign. In advanced cases, neck extensor weakness can cause the head to lean towards the chest, termed head drop.
Non-muscular
The most common non-musculoskeletal manifestation of FSHD is abnormalities in the small arteries (arterioles) in the retina. Tortuosity of the arterioles is seen in approximately 50% of those with FSHD. Less common arteriole abnormalities include telangiectasias and microaneurysms. These abnormalities of arterioles usually do not affect vision or health, although a severe form of it mimics Coats disease, a condition found in about 1% of FSHD cases and more frequently associated with large 4q35 deletions. High-frequency hearing loss can occur in those with large 4q35 deletions, but otherwise is no more common compared to the general population. Large 4q35 deletion can lead to various other rare manifestations.Scoliosis can occur, thought to result from weakness of abdominal, hip extensor, and spinal muscles. Conversely, scoliosis can be viewed as a compensatory mechanism to weakness. Breathing can be affected, associated with kyphoscoliosis and wheelchair use; it is seen in one-third of wheelchair-using patients. However, ventilator support (nocturnal or diurnal) is needed in only 1% of cases. Although there are reports of increased risk of cardiac arrhythmias, general consensus is that the heart is not affected.
Genetics
The genetics of FSHD is complex. FSHD and the myotonic dystrophies have unique genetic mechanisms that differ substantially from the rest of genetic myopathies. The DUX4 gene is the focal point of FSHD genetics. Normally, DUX4 is expressed during embryogenesis and later repressed in all tissues except the testes. In FSHD, there is failure of DUX4 repression and continued production of DUX4 protein, which is toxic to muscles. The mechanism of failed DUX4 repression is hypomethylation of DUX4 and its surrounding DNA on the tip of chromosome 4 (4q35), allowing transcription of DUX4 into messenger RNA (mRNA). Several mutations can result in disease, upon which FSHD is sub-classified into FSHD type 1 (FSHD1) and FSHD type 2 (FSHD2). Disease can only result when a mutation is present in combination with select, commonly found variations of 4q35, termed haplotype polymorphisms. There are at least 17 4q35 haplotype polymorphisms, roughly dividable into the groups 4qA and 4qB. A 4qA haplotype polymorphism, often referred to as a 4qA allele, is necessary for disease, as it contains a polyadenylation sequence that allows DUX4 mRNA to resist degradation long enough to be translated into DUX4 protein.
DUX4 and the D4Z4 repeat array
DUX4 resides within the D4Z4 macrosatellite repeat array, a series of tandemly repeated DNA segments in the subtelomeric region (4q35) of chromosome 4. Each D4Z4 repeat is 3.3 kilobase pairs (kb) long and is the site of epigenetic regulation, containing both heterochromatin and euchromatin structures. In FSHD, the heterochromatin structure is lost, becoming euchromatin.The subtelomeric region of chromosome 10q contains a tandem repeat structure highly homologous (99% identical) to 4q35, containing "D4Z4-like" repeats with protein-coding regions identical to DUX4 (D10Z10 repeats and DUX4L10, respectively). Because 10q usually lacks a polyadenylation sequence, it is usually not implicated in disease. However, chromosomal rearrangements can occur between 4q and 10q repeat arrays, and involvement in disease is possible if a 4q D4Z4 repeat and polyadenylation signal are transferred onto 10q, or if rearrangement causes FSHD1.
DUX4 consists of three exons. Exons 1 and 2 are in each repeat. Exon 3 is in the pLAM region telomeric to the last partial repeat. Multiple RNA transcripts are produced from the D4Z4 repeat array, both sense and antisense. Some transcripts might be degraded in areas to produce si-like small RNAs. Some transcripts that originate centromeric to the D4Z4 repeat array at the non-deleted element (NDE), termed D4Z4 regulatory element transcripts (DBE-T), could play a role in DUX4 derepression. One proposed mechanism is that DBE-T leads to the recruitment of the trithorax-group protein Ash1L, an increase in H3K36me2-methylation, and ultimately de-repression of 4q35 genes.
FSHD1
FSHD involving deletion of D4Z4 repeats (termed D4Z4 contraction) on 4q is classified as FSHD1, which accounts for 95% of FSHD cases. Typically, chromosome 4 includes between 11 and 150 D4Z4 repeats. In FSHD1, there are 1–10 D4Z4 repeats. The number of repeats is roughly inversely related to disease severity. Namely, those with 8 - 10 repeats tend to have the mildest presentations, sometimes with no symptoms; those with 4 - 7 repeats have moderate disease that is highly variable; and those with 1 - 3 repeats are more likely to have severe, atypical, and early-onset disease. Deletion of the entire D4Z4 repeat array does not result in FSHD because then there are no complete copies of DUX4 to be expressed, although other birth defects result. One contracted D4Z4 repeat array with an adjoining 4qA allele is sufficient to cause disease, so inheritance is autosomal dominant. De novo (new) mutations are implicated in 10 - 30% of cases, 50% of which exhibit somatic mosaicism.It has been proposed that FSHD1 undergoes anticipation, a trend primarily associated with trinucleotide repeat disorders in which disease manifestation worsens with each subsequent generation. As of 2019, more detailed studies are needed to definitively show whether or not anticipation plays a role. If anticipation does occur in FSHD, the mechanism is different than that of trinucleotide repeat disorders, since D4Z4 repeats are much larger than trinucleotide repeats, an underabundance of repeats (rather than overabundance) causes disease, and the repeat array size in FSHD is stable across generations.
FSHD2
FSHD without D4Z4 contraction is classified as FSHD2, which constitutes 5% of FSHD cases. Various mutations cause FSHD2, all resulting in D4Z4 hypomethylation, at which the genetic mechanism converges with FSHD1. Approximately 80% of FSHD2 cases are due to deactivating mutations in the gene SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18. SMCHD1 is responsible for DNA methylation, and its deactivation results in hypomethylation of the D4Z4 repeat array. Another cause of FSHD2 is mutation in DNMT3B (DNA methyltransferase 3B), which also plays a role in DNA methylation. As of 2020, early evidence indicates that a third cause of FSHD2 is mutation in both copies of the LRIF1 gene, which encodes the protein ligand-dependent nuclear receptor-interacting factor 1 (LRIF1). LRIF1 is known to interact with the SMCHD1 protein. As of 2019, there are presumably additional mutations at other unidentified genetic locations that can cause FSHD2.Mutation of a single allele of SMCHD1 or DNMT3B can cause disease. Mutation of both copies LRIF1 has been tentatively shown to cause disease in a single person as of 2020. As in FSHD1, a 4qA allele must be present for disease to result. However, unlike the D4Z4 array, the genes implicated in FSHD2 are not in proximity with the 4qA allele, and so they are inherited independently from the 4qA allele, resulting in a digenic inheritance pattern. For example, one parent without FSHD can pass on an SMCHD1 mutation, and the other parent, also without FSHD, can pass on a 4qA allele, bearing a child with FSHD2.
Two ends of a disease spectrum
Initially, FSHD1 and FSHD2 were described as two separate genetic causes of the same disease. However, they can also be viewed not as distinct causes, but rather as risk factors. Not rarely do both contribute to disease in the same individual.In those with FSHD2, although they have do not have a 4qA allele with D4Z4 repeat number less than 11, they still often have one less than 17 (relatively short compared to the general population), suggesting that a large number of D4Z4 repeats can prevent the effects of an SMCHD1 mutation. Further studies need to be done to determine the upper limit of D4Z4 repeats in which FSHD2 can occur.In those with a 4qA allele and 10 or fewer repeats, an additional SMCHD1 mutation has shown to worsen disease, classifying them as both FSHD1 and FSHD2. In these FSHD1/FSHD2 individuals, the methylation pattern of the D4Z4 repeat array resembles that seen in FSHD2. This combined FSHD1/FSHD2 presentation is most common in those with 9 - 10 repeats, and is seldom found in those with 8 or less repeats. The relative abundance of SMCHD1 mutations in the 9 - 10 repeat group is likely because a sizable portion of the general population has 9 - 10 repeats with no disease, yet with the additive effect of an SMCHD1 mutation, symptoms develop and a diagnosis is made. In those with 8 or fewer repeats, symptoms are more likely than in those with 9 - 10 repeats, leading to diagnosis regardless of an additional SMCHD1 mutation.The apparent frequency of FSHD1/FSHD2 cases in the 9 - 10 repeat range, combined with the FSHD2-like methylation pattern, suggest the 9 - 10 repeat size to be an overlap zone between FSHD1 and FSDH2.
Pathophysiology
Molecular
As of 2020, there seems to be a consensus that aberrant expression of DUX4 in muscle is the cause of FSHD. DUX4 is expressed in extremely small amounts, detectable in 1 out of every 1000 immature muscle cells (myoblast), which appears to increase after myoblast maturation, in part because the cells fuse as they mature, and a single nucleus expressing DUX4 can provide DUX4 protein to neighboring nuclei from fused cells.It remains an area of active research how DUX4 protein causes muscle damage. DUX4 protein is a transcription factor that regulates many other genes. Some of these genes are involved in apoptosis, such as p53, p21, MYC, and β-catenin, and indeed it seems that DUX4 protein makes muscle cells more prone to apoptosis. Other DUX4 protein-regulated genes are involved in oxidative stress, and indeed it seems that DUX4 expression lowers muscle cell tolerance of oxidative stress. Variation in the ability of individual muscles to handle oxidative stress could partially explain the muscle involvement patterns of FSHD. DUX4 protein downregulates many genes involved in muscle development, including MyoD, myogenin, desmin, and PAX7, and indeed DUX4 expression has shown to reduce muscle cell proliferation, differentiation, and fusion. DUX4 protein regulates a few genes that are involved in RNA quality control, and indeed DUX4 expression has been shown to cause accumulation of RNA with subsequent apoptosis. Estrogen seems to play a role in modifying DUX4 protein effects on muscle differentiation, which could explain why females are lesser affected than males.
The cellular hypoxia response has been reported in a single study to be the main driver of DUX4 protein-induced muscle cell death. The hypoxia-inducible factors (HIFs) are upregulated by DUX4 protein, possibly causing pathologic signaling leading to cell death.Another study found that DUX4 expression in muscle cells led to the recruitment and alteration of fibrous/fat progenitor cells, which helps explain why muscles become replaced by fat and fibrous tissue.A single study implicated RIPK3 in DUX4-mediated cell death.
Muscle histology
Unlike other muscular dystrophies, early muscle biopsies show only mild degrees of fibrosis, muscle fiber hypertrophy, and displacement of nuclei from myofiber peripheries (central nucleation). More often found is inflammation. There can be endomysial inflammation, primarily composed of CD8+ T-cells, although these cells do not seem to directly cause muscle fiber death. Endomysial blood vessels can be surrounded by inflammation, which is relatively unique to FSHD, and this inflammation contains CD4+ T-cells. Inflammation is succeeded by deposition of fat (fatty infiltration), then fibrosis. Individual muscle fibers can appear whorled, moth-eaten, and, especially, lobulated.
Muscle involvement pattern
Why certain muscles are preferentially affected in FSHD remains unknown. There are multiple trends of involvement seen in FSHD, possibly hinting at underlying pathophysiology. Individual muscles can weaken while adjacent muscles remain healthy. The right shoulder and arm muscles are more often affected than the left upper extremity muscles, a pattern also seen in Poland syndrome and hereditary neuralgic amyotrophy; this could reflect a genetic, developmental/anatomic, or functional-related mechanism. The deltoid is often spared, which is not seen in any other condition that affects the muscles around the scapula.Medical imaging (CT and MRI) have shown muscle involvement not readily apparent otherwise
A single MRI study shows the teres major muscle to be commonly affected.
The semimembranosus muscle, part of the hamstrings, is commonly affected, deemed by one author to be "the most frequently and severely affected muscle."
Of the quadriceps muscles, the rectus femoris is preferentially affected
Of the gastrocnemius, the medial section is preferentially affected;
The iliopsoas, a hip flexor muscle, is very often spared.
Retinopathy
Tortuosity of the retinal arterioles, and less often microaneurysms and telangiectasia, are commonly found in FSHD. Abnormalities of the capillaries and venules are not observed. One theory for why the arterioles are selectively affected is that they contain smooth muscle. The degree of D4Z4 contraction correlates to the severity of tortuosity of arterioles. It has been hypothesized that retinopathy is due to DUX4-protein-induced modulation of the CXCR4–SDF1 axis, which has a role in endothelial tip cell morphology and vascular branching.
Diagnosis
FSHD can be presumptively diagnosed in many cases based on signs, symptoms, and/or non-genetic medical tests. Genetic testing can provide definitive diagnosis. In the absence of an established family history of FSHD, diagnosis can be difficult due to the variability in how FSHD manifests.
Genetic testing
Genetic testing is the gold standard for FSHD diagnosis, as it is the most sensitive and specific test available. Commonly, FSHD1 is tested for first. A shortened D4Z4 array length (EcoRI length of 10 kb to 38 kb) with an adjacent 4qA allele supports FSHD1. If FSHD1 is not present, commonly FSHD2 is tested for next by assessing methylation at 4q35. Low methylation (less than 20%) in the context of a 4qA allele is sufficient for diagnosis. The specific mutation, usually one of various SMCHD1 mutations, can be identified with next-generation sequencing (NGS).
Assessing D4Z4 length
Measuring D4Z4 length is technically challenging due to the D4Z4 repeat array consisting of long, repetitive elements. For example, NGS is not useful for assessing D4Z4 length, because it breaks DNA into fragments before reading them, and it is unclear from which D4Z4 repeat each sequenced fragment came. In 2020, optical mapping became available for measuring D4Z4 array length, which is more precise and less labor-intensive than southern blot.Molecular combing is also available for assessing D4Z4 array length. These methods, which physical measure the size of the D4Z4 repeat array, require specially prepared high quality and high molecular weight genomic DNA (gDNA) from serum, increasing cost and reducing accessibility to testing.
Restriction fragment length polymorphism (RFLP) analysis was the first genetic test developed and is still used as of 2020, although it is being phased out by newer methods. It involves dicing the DNA with restriction enzymes and sorting the resulting restriction fragments by size using southern blot. The restriction enzymes EcoRI and BlnI are commonly used. EcoRI isolates the 4q and 10q repeat arrays, and BlnI dices the 10q sequence into small pieces, allowing 4q to be distinguished. The EcoRI restriction fragment is composed of three parts: 1) 5.7 kb proximal part, 2) the central, variable size D4Z4 repeat array, and 3) the distal part, usually 1.25 kb. The proximal portion has a sequence of DNA stainable by the probe p13E-11, which is commonly used to visualize the EcoRI fragment during southern blot. The name "p13E-11" reflects that it is a subclone of a DNA sequence designated as cosmid 13E during the human genome project. Considering that each D4Z4 repeat is 3.3 kb, and the EcoRI fragment contains 6.9 kb of DNA |
Facioscapulohumeral muscular dystrophy | that is not part of the D4Z4 repeat array, the number of D4Z4 units can be calculated.
D4Z4 repeats = (EcoRI length - 6.9) / 3.3Sometimes 4q or 10q will have a combination of D4Z4 and D4Z4-like repeats due to DNA exchange between 4q and 10q, which can yield erroneous results, requiring more detailed workup. Sometimes D4Z4 repeat array deletions can include the p13E-11 binding site, warranting use of alternate probes.
Assessing methylation status
Methylation status of 4q35 is traditionally assessed after FSHD1 testing is negative. Methylation sensitive restriction enzyme (MSRE) digestion showing hypomethylation has long been considered diagnostic of FSHD2. Other methylation assays have been proposed or used in research settings, including methylated DNA immunoprecipitation and bisulfite sequencing, but are not routinely used in clinical practice. Bisulfite sequencing, if validated, would be valuable due to it being able to use lower quality DNA sources, such as those found in saliva.
Auxiliary testing
Other tests can support the diagnosis of FSHD, although they are all less sensitive and less specific than genetic testing. Nonetheless, they can rule out similar-appearing conditions.
Creatine kinase (CK) blood level is often ordered when muscle damage is suspected. CK is an enzyme found in muscle, leaking into the blood when muscles become damaged. In FSHD, CK level is normal to mildly elevated, never exceeding five times the upper limit of normal.
Electromyogram (EMG) measures the electrical activity in the muscle. EMG can show nonspecific signs of muscle damage or irritability.
Nerve conduction velocity (NCV) measures the how fast signals travel along a nerve. The nerve signals are measured with surface electrodes (similar to those used for an electrocardiogram) or needle electrodes.
Muscle biopsy is the surgical removal and examination of a small piece of muscle, usually from the arm or leg. Microscopy and a variety of biochemical tests are used for examination. Findings in FSHD are nonspecific, such as presence of white blood cells or variation in muscle fiber size. This test is rarely indicated.
Muscle MRI is sensitive for detecting muscle damage, even in mild cases. Because of the particular muscle involvement patterns of FSHD, MRI can help differentiate FSHD from other muscle diseases, directing genetic testing.
Differential diagnosis
Included in the differential diagnosis of FSHD are limb-girdle muscular dystrophy (especially calpainopathy), scapuloperoneal myopathy, mitochondrial myopathy, Pompe disease, and polymyositis. Calpainopathy and scapuloperoneal myopathy, like FSHD, present with scapular winging. Features that suggest FSHD are facial weakness, asymmetric weakness, and lack of benefit from immunosuppression medications. Features the suggest an alternative diagnosis are contractures, respiratory insufficiency, weakness of muscles controlling eye movement, and weakness of the tongue or throat.
Management
No intervention has proven to significantly slow progression of weakness or improve strength.
Screening and monitoring of complications
The American Academy of Neurology (AAN) recommends several medical tests to detect complications of FSHD. A dilated eye exam to look for retinal abnormalities is recommended in those newly diagnosed with FSHD; for those with large D4Z4 deletions, an evaluation by a retinal specialist is recommended yearly. A hearing test is recommended for individuals with early-onset FSHD prior to starting school, or for any other FSHD-affected individual with symptoms of hearing loss. Pulmonary function testing (PFT) is recommended in those newly diagnosed to establish baseline pulmonary function, and recurrently for those with pulmonary insufficiency symptoms or risks. Routine screening for heart conditions, such as through an electrocardiogram (EKG) or echocardiogram (echo), is considered unnecessary in those without symptoms of heart disease.
Physical and occupational therapy
Aerobic exercise has been shown to reduce chronic fatigue and decelerate fatty infiltration of muscle in FSHD. The ANN recommends that people with FSHD engage in low-intensity aerobic exercise to promote energy levels, muscle health, and bone health. Moderate-intensity strength training appears to do no harm, although it has not been shown to be beneficial. Physical therapy can address specific symptoms; there is no standardized protocol for FSHD. Anecdotal reports suggest that appropriately applied kinesiology tape can reduce pain. Occupational therapy can be used for training in activities of daily living (ADLs) and to help adapt to new assistive devices. Cognitive behavioral therapy (CBT) has been shown to reduce chronic fatigue in FSHD, and it also decelerates fatty infiltration of muscle when directed towards increasing daily activity.Braces are often used to address muscle weakness. Scapular bracing can improve scapular positioning, which improves shoulder function, although it is often deemed as ineffective or impractical. Ankle-foot orthoses can improve walking, balance, and quality of life.
Pharmacologic management
No pharmaceuticals have definitively proven effective for altering the disease course. Although a few pharmaceuticals have shown improved muscle mass in limited respects, they did not improve quality of life, and the AAN recommends against their use for FSHD.
Reconstructive surgery
Scapular winging is amenable to surgical correction, namely operative scapular fixation. Scapular fixation is restriction and stabilization of the position of the scapula, putting it in closer apposition to the rib cage and reducing winging. Absolute restriction of scapular motion by fixation of the scapula to the ribs is most commonly reported. This procedure often involves inducing bony fusion, called arthrodesis, between the scapula and ribs. Names for this include scapulothoracic fusion, scapular fusion, and scapulodesis. This procedure increases arm active range of motion, improves arm function, decreases pain, and improves cosmetic appearance. Active range of motion of the arm increases most in the setting of severe scapular winging with an unaffected deltoid muscle; however, passive range of motion decreases. In other words, the patient gains the ability to slowly raise their arms to 90+ degrees, but they lose the ability to "throw" their arm up to a full 180 degrees. The AAN states that scapular fixation can be offered cautiously to select patients after balancing these benefits against the adverse consequences of surgery and prolonged immobilization.Another form of operative scapular fixation is scapulopexy. "Scapulo-" refers to the scapula bone, and "-pexy" is derived from the Greek root "to bind." Some versions of scapulopexy accomplish essentially the same result as scapulothoracic fusion, but instead of inducing bony fusion, the scapula is secured to the ribs with only wire, tendon grafts, or other material. Some versions of scapulopexy do not completely restrict scapular motion, examples including tethering the scapula to the ribs, vertebrae, or other scapula. Scapulopexy is considered to be more conservative than scapulothoracic fusion, with reduced recovery time and less effect on breathing. However, they also seem more susceptible to long-term failure. Another form of scapular fixation, although not commonly done in FSHD, is tendon transfer, which involves surgically rearranging the attachments of muscles to bone. Examples include pectoralis major transfer and the Eden-Lange procedure.
Various other surgical reconstructions have been described. Upper eyelid gold implants have been used for those unable to close their eyes. Drooping lower lip has been addressed with plastic surgery. Select cases of foot drop can be surgically corrected with tendon transfer, in which the tibialis posterior muscle is repurposed as a tibialis anterior muscle, a version of this being called the Bridle procedure. Severe scoliosis caused by FSHD can be corrected with spinal fusion; however, since scoliosis is a compensatory change in response to muscle weakness, correction of spinal alignment can result in further impaired muscle function.
Scapular winging management
Prognosis
Genetics partially predicts prognosis. Those with large D4Z4 repeat deletions (with a remaining D4Z4 repeat array size of 10-20 kbp, or 1-4 repeats) are more likely to have severe and early disease, as well as non-muscular symptoms. Those who have the genetic mutations of both FSHD1 and FSHD2 are more likely to have severe disease. It has also been observed that disease manifestation is milder when a prominent family history is present, as opposed to a new mutation. In some large families, 30% of those with the mutation do not show symptoms, and 30% of those with symptoms do not progress beyond facial and shoulder weakness. Women are less likely to be symptomatic, and if symptomatic have less severe manifestations.Remaining variations in disease course are attributed to unknown environmental factors. A single study found that disease course is not worsened by tobacco smoking or alcohol consumption, common risk factors for other diseases.
Pregnancy
Pregnancy outcomes are overall good in mothers with FSHD; there is no difference in rate of preterm labor, rate of miscarriage, and infant outcomes. However, weakness can increase the need for assisted delivery.A single review found that weakness worsens, without recovery, in 12% of mothers with FSHD during pregnancy, although this might be due to weight gain or deconditioning.
Epidemiology
The prevalence of FSHD ranges from 1 in 8,333 to 1 in 15,000. The Netherlands reports a prevalence of 1 in 8,333, after accounting for the undiagnosed. The prevalence in the United States is commonly quoted as 1 in 15,000.After genetic testing became possible in 1992, average prevalence was found to be around 1 in 20,000, a large increase compared to before 1992. However, 1 in 20,000 is likely an underestimation, since many with FSHD have mild symptoms and are never diagnosed, or they are siblings of affected individuals and never seek definitive diagnosis.Race and ethnicity have not been shown to affect FSHD incidence or severity.Although the inheritance of FSHD shows no predilection for biological sex, the disease manifests less often in women, and even when it manifests in women, they on average are less severely affected than affected males. Estrogen has been suspected to be a protective factor that accounts for this discrepancy. One study found that estrogen reduced DUX4 activity. However, another study found no association between disease severity and lifetime estrogen exposure in females. The same study found that disease progression was not different through periods of hormonal changes, such as menarche, pregnancy, and menopause.
History
The first description of a person with FSHD in medical literature appears in an autopsy report by Jean Cruveilhier in 1852. In 1868, Duchenne published his seminal work on Duchenne muscular dystrophy, and as part of its differential was a description of FSHD. First in 1874, then with a more commonly cited publication in 1884, and again with pictures in 1885, the French physicians Louis Landouzy and Joseph Dejerine published details of the disease, recognizing it as a distinct clinical entity, and thus FSHD is sometimes referred to as Landouzy Dejerine disease. In their paper of 1886, Landouzy and Dejerine drew attention to the familial nature of the disorder and mentioned that four generations were affected in the kindred that they had investigated. Formal definition of FSHDs clinical features did not occur until 1952 when a large Utah family with FSHD was studied. Beginning about 1980 an increasing interest in FSHD led to increased understanding of the great variability in the disease and a growing understanding of the genetic and pathophysiological complexities. By the late 1990s, researchers were finally beginning to understand the regions of chromosome 4 associated with FSHD.Since the publication of the unifying theory in 2010, researchers continued to refine their understanding of DUX4. With increasing confidence in this work, researchers proposed the first a consensus view in 2014 of the pathophysiology of the disease and potential approaches to therapeutic intervention based on that model.Alternate and historical names for FSHD include the following:
facioscapulohumeral disease
faciohumeroscapular
Landouzy-Dejerine disease (or syndrome or type of muscular dystrophy)
Erb-Landouzy-Dejerine syndrome
Chronology of important FSHD-related genetic research
Past pharmaceutical development
Early drug trials, before the pathogenesis involving DUX4 was discovered, were untargeted and largely unsuccessful. Compounds were trialed with goals of increasing muscle mass, decreasing inflammation, or addressing provisional theories of disease mechanism. The following drugs failed to show efficacy:
Prednisone, a steroid, based on its antiinflammatory properties and therapeutic effect in Duchenne muscular dystrophy.
Oral albuterol, a β2 agonist, on the basis of its anabolic properties. Although it improved muscle mass and certain measures of strength in those with FSHD, it did not improve global strength or function. Interestingly, β2 agonists were later shown to reduce DUX4 expression.
Diltiazem, a calcium channel blocker, on the bases of anecdotal reports of benefit and the theory that calcium dysregulation played a part in muscle cell death.
MYO-029 (Stamulumab), an antibody that inhibits myostatin, was developed to promote muscle growth. Myostatin is a protein that inhibits the growth of muscle tissue.
ACE-083, a TGF-β inhibitor, was developed to promote muscle growth.
Society and culture
Media
In the Amazon Video series The Man in the High Castle, Obergruppenführer John Smiths son, Thomas, is diagnosed with Landouzy-Dejerine syndrome.
In the biography Stuart: A Life Backwards, the protagonist was affected by muscular dystrophy, presumably FSHD.
Patient and research organizations
The FSHD Society (named "FSH Society" until 2019) was founded in 1991 on the East Coast by two individuals with FSHD, Daniel Perez and Stephen Jacobsen. The FSHD Society claims to have advocated for the standardization of the disease name facioscapulohumeral muscular dystrophy and its abbreviation FSHD. The FSHD Society claims to have raised funding for seed grants for FSHD research and co-wrote the MD-CARE Act of 2001, which provided federal funding for all muscular dystrophies. The FSHD Society has grown into the worlds largest grassroots organization advocating for patient education and scientific and medical research for FSHD. One notable spokesperson for FSHD Society has been Max Adler, an actor on the TV series Glee.
Friends of FSH Research is a research-oriented nonprofit organization founded in 2004 by Terry and Rick Colella from Kirkland, Washington after their son was diagnosed with FSHD.
The FSHD Global Research Foundation was founded in 2007 by Bill Moss in Australia, a former Macquarie Bank executive affected by FSHD. It is currently directed by Mosss daughter. It was named Australian charity of the year for 2017. It is the largest funder of FSHD medical research outside of the United States as of 2018.
FSHD EUROPE was founded in 2010. Spanning multiple countries in Europe, it has launched the European Trial Network.
Notable cases
Chip Wilson is a Canadian billionaire and founder of Lululemon. He has pledged 100 million Candian dollars to research through the venture Solve FSHD.
Chris Carrino is the radio voice of the Brooklyn Nets. He founded the Chris Carrino Foundation for FSHD, oriented towards research funding.
Morgan Hoffman is an American professional golfer. He started the Morgan Hoffman Foundation, oriented towards research funding.
Research directions
Pharmaceutical development
After achieving consensus on FSHD pathophysiology in 2014, researchers proposed four approaches for therapeutic intervention:
enhance the epigenetic repression of the D4Z4
target the DUX4 mRNA, including altering splicing or polyadenylation;
block the activity of the DUX4 protein
inhibit the DUX4-induced process, or processes, that leads to pathology.Small molecule drugs
Most drugs used in medicine are "small molecule drugs," as opposed to biologic medical products that include proteins, vaccines, and nucleic acids. Small molecule drugs can typically be taken by ingestion, rather than injection.
Losmapimod, a selective inhibitor of p38α/β mitogen-activated protein kinases, was identified by Fulcrum Therapeutics as a potent suppressor of DUX4 in vitro. Results of a phase IIb clinical trial, revealed in June 2021, showed statistically significant slowing of muscle function deterioration. Further trials are pending.
Casein kinase 1 (CK1) inhibition has been identified by Facio Therapies, a Dutch pharmaceutical company, to repress DUX4 expression and is in preclinical development. Facio Therapies claims that CK1 inhibition leaves myotube fusion intact, unlike BET inhibitors, p38 MAPK inhibitors, and β2 agonists.Gene therapy
Gene therapy is the administration of nucleotides to treat disease. Multiple types of gene therapy are in the preclinical stage of development for the treatment of FSHD.
Antisense therapy utilizes antisense oligonucleotides that bind to DUX4 messenger RNA, inducing its degradation and preventing DUX4 protein production. Phosphorodiamidate morpholinos, an oligonucleotide modified to increase its stability, have been shown to selectively reduce DUX4 and its effects; however, these antisense nucleotides have poor ability to penetrate muscle.
MicroRNAs (miRNAs) directed against DUX4, delivered by viral vectors, have shown to reduce DUX4, protect against muscle pathology, and prevent loss of grip strength in mouse FSHD models. Arrowhead pharmaceuticals is developing an RNA interference therapeutic against DUX4, named ARO-DUX4, and intends to file for regulatory clearance in third quarter of 2021 to begin clinical trials.
Genome editing, the permanent alteration of genetic code, is being researched. One study tried to use CRISPER-Cas9 to knockout the polyadenylation signal in lab dish models, but was unable to show therapeutic results.Potential drug targets
Inhibition of the hyaluronic acid (HA) pathway is a potential therapy. One study found that many DUX4-induced molecular pathologies are mediated by HA signaling, and inhibition of HA biosynthesis with 4-methylumbelliferone prevented these molecular pathologies.
P300 inhibition has shown to inhibit the deleterious effects of DUX4
BET inhibitors have been shown to reduce DUX4 expression.
Antioxidants could potentially reduce the effects of FSHD. One study found that vitamin C, vitamin E, zinc gluconate, and selenomethionine supplementation increased endurance and strength of the quadriceps, but had no significant benefit on walking performance. Further study is warranted.
Outcome measures
Ways of measuring the disease are important for studying disease progression and assessing the efficacy of drugs in clinical trials.
Quality of life can be measured with questionnaires, such as the FSHD Health Index.
How the disease affects daily activities can measured with questionnaires, such as the FSHD‐Rasch‐built overall disability scale (FSHD-RODS) or FSHD composite outcome measure (FSHD-COM).
Electrical impedance myography is being studied as a way to measure muscle damage.
Muscle MRI is useful for assessment of all the muscles in the body. Muscles can be scored based on the degree of fat infiltration.
References
External links
World FSHD Alliance: FSHD patient advocacy organizations across the world
list of clinical trials for FSHD, Clinicaltrials.gov.
fsh at NIH/UW GeneTests |
Pyruvate carboxylase deficiency | Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid to accumulate in the blood. High levels of these substances can damage the bodys organs and tissues, particularly in the nervous system. Pyruvate carboxylase deficiency is a rare condition, with an estimated incidence of 1 in 250,000 births worldwide. Type A of the disease appears to be much more common in some Algonkian Indian tribes in eastern Canada, while the type B disease is more present in European populations.
Signs and symptoms
Pyruvate carboxylase deficiency causes lactic acidosis and hyperammonaemia. Lactic acidosis may then lead to liver failure, hepatomegaly, reduced ketone body synthesis, and demyelination of neurons.
Genetics
Pyruvate carboxylase deficiency is caused by mutations in the PC gene. The PC gene provides instructions for making an enzyme called pyruvate carboxylase.
This condition is inherited in an autosomal recessive pattern, which means two copies of the gene must be inherited for the disorder to be present. The parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene, but do not show signs and symptoms of the disorder.
Mechanism
Pyruvate carboxylase is active in mitochondria in cells. It is involved in the generation of glucose through gluconeogenesis. By generating oxaloacetate, it catalyses an important anaplerotic reaction that maintains the citric acid cycle to generate energy by aerobic respiration. Pyruvate carboxylase also plays a role in the formation of the myelin sheath that surrounds certain nerve cells, and the production of neurotransmitters for communication between neurons.
Mutations in the PC gene reduce the amount of pyruvate carboxylase in cells or disrupt the enzymes activity. The missing or altered enzyme cannot carry out its essential role in generating glucose, which impairs the bodys ability to make energy in mitochondria. Additionally, a loss of pyruvate carboxylase allows potentially toxic compounds, such as lactic acid and ammonia, to build up and damage organs and tissues. Loss of pyruvate carboxylase function in the nervous system, particularly the role of the enzyme in myelin formation and neurotransmitter production, may contribute to the neurological features of pyruvate carboxylase deficiency.
Diagnosis
Classification
There are at least three types of pyruvate carboxylase deficiency, which are distinguished by the severity of their signs and symptoms.
Type A
Type A, which has been identified mostly in people from North America, has moderately severe symptoms that begin in infancy. Characteristic features include developmental delay and a buildup of lactic acid in the blood (lactic acidosis). Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, and difficulty breathing. In some cases, episodes of lactic acidosis are triggered by an illness or periods without food. Children with pyruvate carboxylase deficiency type A typically survive only into early childhood.
Type B
Pyruvate carboxylase deficiency type B has life-threatening signs and symptoms that become apparent shortly after birth. This form of the condition has been reported mostly in Europe, particularly France. Affected infants have severe lactic acidosis, a build-up of ammonia in the blood (hyperammonemia), and liver failure. They experience neurological problems including weak muscle tone (hypotonia), abnormal movements, seizures, and coma. Infants with this form of the condition usually survive for less than 3 months after birth.
Type C
This type is characterised by its late onset and is associated with isolated mild intellectual delay.
Treatment
Pyruvate carboxylase deficiency treatment typically consists of providing the body with alternate sources of energy (anaplerotic therapy). This may include a diet rich in proteins and carbohydrates but not lipids.
Acutely, triheptanoin may be administered as a source of acetyl-CoA.
Epidemiology
Pyruvate carboxylase deficiency is very rare, and is estimated to affect around 1 in 250,000 people.
References
External links
GeneReview/NCBI/NIH/UW entry on Pyruvate Carboxylase Deficiency
Pyruvate carboxylase deficiency at NLM Genetics Home Reference This article incorporates text from this source, which is in the public domain. |
Auditory neuropathy spectrum disorder | Auditory neuropathy spectrum disorder (ANSD) is a specific form of hearing loss defined by the presence of normal or near-normal otoacoustic emissions (OAEs) but the absence of normal middle ear reflexes and severely abnormal or completely absent auditory brainstem response (ABRs).
Individuals presenting with this recently recognised hearing loss appear to display sporadic windows of hearing and not. Very few (1 in 14) will go on to develop normal speech and language but with poor speech perception in background noise and in others, no speech perception and therefore language development is possible.
The condition was originally termed auditory neuropathy (AN) and in 2001 as Auditory Neuropathy / Auditory Dys-synchrony (AN/AD) (to include those cases where no true neuropathy was apparent). In 2008 at a meeting convened at Lake Como in Italy (Guidelines Development
Conference on the Identification and Management
of Infants with Auditory Neuropathy, International
Newborn Hearing Screening Conference, Como, Italy,
June 19–21, 2008), a group of leading authorities on the condition reached a consensus and renamed it as auditory neuropathy spectrum disorder.
See also
Audiologist
Auditory brainstem response
Auditory neuropathy
Auditory processing disorder
Cochlear implant
Hearing aids
Otoacoustic emissions
Sensorineural hearing impairment
References
External links
Alices Story - A Blog Dedicated to a Beautiful Little Girl Who Has Ears That Need New Batteries |
Achondrogenesis | Achondrogenesis is a number of disorders that are the most severe form of congenital chondrodysplasia (malformation of bones and cartilage). These conditions are characterized by a small body, short limbs, and other skeletal abnormalities. As a result of their serious health problems, infants with achondrogenesis are usually born prematurely, are stillborn, or die shortly after birth from respiratory failure. Some infants, however, have lived for a while with intensive medical support.
Researchers have described at least three forms of achondrogenesis, designated as Achondrogenesis type 1A, achondrogenesis type 1B and achondrogenesis type 2. These types are distinguished by their signs and symptoms, inheritance pattern, and genetic cause. Other types of achondrogenesis may exist, but they have not been characterized or their cause is unknown.
Achondrogenesis type 1A is caused by a defect in the microtubules of the Golgi apparatus. In mice, a nonsense mutation in the thyroid hormone receptor interactor 11 gene (Trip11), which encodes the Golgi microtubule-associated protein 210 (GMAP-210), resulted in defects similar to the human disease. When their DNA was sequenced, human patients with achondrogenesis type 1A also had loss-of-function mutations in GMAP-210. GMAP-210 moves proteins from the endoplasmic reticulum to the Golgi apparatus. Because of the defect, GMAP-210 is not able to move the proteins, and they remain in the endoplasmic reticulum, which swells up. The loss of Golgi apparatus function affects some cells, such as those responsible for forming bone and cartilage, more than others.Achondrogenesis type 1B is caused by a similar mutation in SLC26A2, which encodes a sulfate transporter.
Achondrogenesis, type 2 is one of several skeletal disorders caused by mutations in the COL2A1 gene. Achondrogenesis, type 2 and hypochondrogenesis (a similar skeletal disorder) together affect 1 in 40,000 to 60,000 births.
References
This article incorporates public domain text from The U.S. National Library of Medicine
== External links == |
Lupus vasculitis | Lupus vasculitis is a complication of systemic lupus erythematosus in which the autoimmune response causes the deposition of immune complexes, such as rheumatoid factor, within the blood vessels. It may manifest in as high as 56% of lupus patients throughout their life, in contrast to antiphospholipid syndrome which has a prevalence of 15%. Vasculitis more often affects younger men.
== References == |
Lichen spinulosus | Lichen spinulosus is a rare skin disorder characterized by follicular keratotic papules that are grouped into large patches. It is a variant of keratosis pilaris named for its resemblance to a patch of lichen.
See also
Hook nail
List of cutaneous conditions
Notes
References
Friedman S (1990). "Lichen spinulosus. Clinicopathologic review of thirty-five cases". J Am Acad Dermatol. 22 (2 Pt 1): 261–4. doi:10.1016/0190-9622(90)70035-G. PMID 2179296.
External links
Derm Net NZ
Emedicine
Thehinhso |
Ring chromosome 20 syndrome | Ring chromosome 20, ring-shaped chromosome 20 or r(20) syndrome is a rare human chromosome abnormality where the two arms of chromosome 20 fuse to form a ring chromosome. The syndrome is associated with epileptic seizures, behaviour disorders and intellectual disability.When not all cells contain a ring chromosome 20, the individual has ring 20 chromosomal mosaicism. Ring Chromosome 20 syndrome is thought to be an underdiagnosed condition. Since chromosomal analysis or karyotype testing is not a routine investigation for patients with epilepsy, the diagnosis of ring chromosome 20 syndrome is typically delayed or unrecognized.
Presentation
Recurrent seizures are the most recognizable feature of this syndrome and are most often the first sign of this syndrome. These syndromes are often ongoing and poorly responsive to anti-seizure medications. Most patients develop seizures the first few years of life, but the age of onset ranges from ages 1 to 17. Different types of seizure have been reported in this syndrome. The most common seizure type appears to be brief focal onset epileptic seizures with impairment of consciousness and awareness, known as complex partial seizures. Other features you may see in these complex partial seizures include staring, oral automatisms, unspecified automatic behavior, involuntary motor movements and/or head turning.
Furthermore, many patients have subtle nighttime behavioral changes, such as stretching, rubbing, and turning resembling a nighttime awakening. However, electroencephalography (EEG) studies during these events show abnormal electrical seizure activity, indicating that nocturnal behavioral events are actually subtle nocturnal seizures or non-convulsive status epilepticus. Many of these patients experience their seizures only during sleep. They can have seemingly bizarre features as they originate from the frontal lobe of the brain. Often, individuals with ring chromosome 20 syndrome are initially found to have complex partial seizures of frontal lobe origin, though imaging studies do not show a corresponding structural brain abnormality. In certain patients, these seizures may secondarily generalized.
Individuals from the ages of 0–17 years should be considered for ring 20 chromosome analysis if they have: predominantly complex partial seizures, medically refractory cryptogenic epilepsy, Lennox-Gastaut-like features with no cause identified, frequent subtle nocturnal seizures, an EEG showing prolonged high voltage frontally dominant slowing intermixed with spikes or sharp waves, an EEG showing overlapping features of continuous slow spike and wave discharges in sleep (CSWS) and electrical status epilepticus in sleep (ESES), and/or subsequent cognitive impairment/learning difficulties/mild retardation.These patients will typically have a normal childhood development until onset of epilepsy and lack evidence of dysmorphism or other congenital malformations.
Genetics
Rather than the typical linear pattern of a chromosome, deletion of the endings of a chromosome can lead to ring formation. A chromosome has two arms, one long and one short. Deletion of the short arm of chromosome 20 does not appear to result in epilepsy; however, terminal deletion of the long arm is associated with epilepsy. Therefore, some gene loss from the terminal segment could be responsible for the manifestation of epilepsy in ring chromosome 20 syndrome. The most common breakpoint in patients is in the q13.33 region of chromosome 20.
As chromosomes occur in pairs, the affected individual usually has one normal chromosome and the other replaced by a ring chromosome. However, this is not usually the case for every cell in the patient. In most individuals with ring chromosome 20 syndrome, a certain percentage have two normal chromosome 20s and the remainder have one normal and one ring 20 chromosome. This mixture is called mosaicism. A higher degree (percentage) of mosaicism appears to be associated with earlier age of seizure onset and presence of malformations. Yet, the degree of mosaicism does not determine response to drug treatment. Since the range in age of onset of seizures and IQ for a given mosaic ratio is relatively wide, prediction of phenotype based on the mosaicism ratio is somewhat limited.
Occasionally, there is a variation, where the ring chromosome 20 syndrome is characterized by an extra ring chromosome in addition to the two normal ones and hence gives rise to a partial trisomy or supernumerary ring 20. This supernumerary ring 20 can cause multiple anomalies but no epilepsy, and this resulting syndrome should be differentiated from ring chromosome 20 syndrome. This confusion has persisted even in the literature.
The genes in the q13.33 region of chromosome 20 have yet to be fully delineated. However, this telomeric region includes two genes that are related to other distinct epilepsy syndromes, autosomal dominant nocturnal frontal lobe epilepsy and benign familial neonatal convulsions. The genes identified in these two syndromes are the nicotinic acetylcholine receptor alpha-4 subunit and potassium voltage-gated channel subfamily KQT member 2 respectively. Mutations in these genes lead to the clinical manifestations found in these disorders. It is theorized that deletions in these regions from the ringed chromosome may lead to epilepsy in affected patient. A similar association between a ring chromosome and an autosomal-dominant disease has been reported for ring 17 chromosome and Miller-Dieker syndrome.
The recurrence risk for ring chromosome 20 syndrome is very low. The ring formation is typically not identified in parents, and occurs de novo during pre-natal development.
Diagnosis
The ring 20 abnormality may be limited to as few as 5% of cells, so a screen for chromosomal mosaicism is critical. Newer array technology will not detect the ring chromosome and the standard metaphase chromosome analysis has been recommended. A karyotype analysis examining at least 50 cells should be requested to properly detect mosaicism.
Treatment
Successful management of seizures plays a key role in improving quality of life. Antiepileptic medications are the main therapies for seizures; however, it appears that seizures in this syndrome do not respond well to drugs. In the cases reported in literature, numerous new and old antiepileptic drugs have been tried, but no one drug appears to be more efficacious than others. Therefore, no recommendations can be made regarding the selection of the most appropriate antiepileptic drug. As not all cases of ring chromosome 20 syndrome are the same, different individuals may respond to treatment in different ways.Alternates to antiepileptic drug treatment include the ketogenic diet and vagus nerve stimulation but not epilepsy surgery.
Ketogenic Diet
The ketogenic diet is a high fat, low carbohydrate diet reserved for intractable childhood epilepsies. There are no published reports on the use of the ketogenic diet in patients with ring chromosome 20 syndrome. However, its efficacy and safety are well established in other difficult to control epilepsy syndromes.
Epilepsy Surgery
Epilepsy surgery investigations are performed to identify a discrete seizure focus. Extensive investigations in ring chromosome 20 syndrome patients fails to identify a discrete seizure focus and published data supports that that epilepsy in ring chromosome 20 syndrome is not amenable to resective surgery. The Cost ranges between £50,000 - £200,000.
VNS Therapy
The vagal nerve stimulator is a battery-powered device similar to a pacemaker that is implanted under the skin. It delivers a mild electrical stimulation to the brain via the vagus nerve and has proven to be effective for the treatment of complex partial seizures. There are only a few published reports on the success of this therapy in ring chromosome 20 epilepsy syndrome, making it unclear if this is the optimal therapy.
Prognosis
Limited data is available for the long-term prognosis of ring chromosome 20 syndrome since only over 60 patients with this syndrome have been reported in published literature. Optimal control of seizures appears to be the determining factor, but early diagnosis and a comprehensive management plan with multidisciplinary support is also thought be to be important.
Research
Two international research studies are currently underway. The International Genetic Study done with the Spinner Laboratory at The Childrens Hospital of Philadelphia studies the ring 20 chromosome at the molecular level. The Clinical Research Study collects clinical information from parents to create a database of about the full spectrum of patients with ring chromosome 20 syndrome.
References
Further reading
Schinzel A, Niedrist D (2001). "Chromosome imbalances associated with epilepsy". Am. J. Med. Genet. 106 (2): 119–24. doi:10.1002/ajmg.1576. PMID 11579431.
External links
Ring Chromosome 20 Syndrome Map |
Situs inversus | Situs inversus (also called situs transversus or oppositus) is a congenital condition in which the major visceral organs are reversed or mirrored from their normal positions. The normal arrangement of internal organs is known as situs solitus. Although cardiac problems are more common, many people with situs inversus have no medical symptoms or complications resulting from the condition, and until the advent of modern medicine, it was usually undiagnosed.
Situs inversus is found in about 0.01% of the population, or about 1 person in 10,000. In the most common situation, situs inversus totalis, it involves complete transposition (right to left reversal) of all of the viscera. The heart is not in its usual position in the left chest, but is on the right, a condition known as dextrocardia (literally, "right-hearted"). Because the relationship between the organs is not changed, most people with situs inversus have no associated medical symptoms or complications.An uncommon form of situs inversus is isolated levocardia, in which the position of the heart is not mirrored alongside the other organs. Isolated levocardia carries a risk of heart defects, and so patients with the condition may require surgery to correct them.
In rarer cases such as situs ambiguus or heterotaxy, situs cannot be determined. In these patients, the liver may be midline, the spleen absent or multiple, and the bowel malrotated. Often, structures are duplicated or absent altogether. This is more likely to cause medical problems than situs inversus totalis.
Signs and symptoms
In the absence of congenital heart defects, individuals with situs inversus are homeostatically normal, and can live standard healthy lives, without any complications related to their medical condition. There is a 5–10% prevalence of congenital heart disease in individuals with situs inversus totalis, most commonly transposition of the great vessels. The incidence of congenital heart disease is 95% in situs inversus with levocardia.Many people with situs inversus totalis are unaware of their unusual anatomy until they seek medical attention for an unrelated condition, such as a rib fracture or a bout of appendicitis. The condition may also be discovered during the administration of certain medicines or during tests such as a barium meal or enema. The reversal of the organs may then lead to some confusion, as many signs and symptoms will be on the atypical side. For example, if an individual with situs inversus develops appendicitis, they will present to the physician with lower left abdominal pain, since that is where their appendix lies. Thus, in the event of a medical problem, the knowledge that the individual has situs inversus can expedite diagnosis. People with this rare condition should inform their doctors before an examination, so the doctor can redirect their search for heart sounds and other signs. Wearing a medical identification tag can help inform health care providers in the event the person is unable to communicate.Situs inversus also complicates organ transplantation operations as donor organs will more likely come from situs solitus (normal) donors. As hearts and livers are chiral, geometric problems arise placing an organ into a cavity shaped in the mirror image. For example, a person with situs inversus who requires a heart transplant needs all their great vessels reattached to the donor heart. However, the orientation of these vessels in a person with situs inversus is reversed, necessitating steps so that the blood vessels join properly.
Cause
Situs inversus is generally an autosomal recessive genetic condition, although it can be X-linked or found in identical "mirror image" twins.About 25% of individuals with situs inversus have an underlying condition known as primary ciliary dyskinesia (PCD). PCD is a dysfunction of the cilia that occurs during early embryonic development. Normally functioning cilia determine the position of the internal organs during early development, and so embryos with PCD have a 50% chance of developing situs inversus. If they do, they are said to have Kartagener syndrome, characterized by the triad of situs inversus, chronic sinusitis, and bronchiectasis. Cilia are also responsible for clearing mucus from the lung, and the dysfunction causes increased susceptibility to lung infections. Kartagener syndrome can also manifest with male infertility as functional cilia are required for proper sperm flagella function.
Effect on anatomy
The condition affects all major structures within the thorax and abdomen. Generally, the organs are simply transposed through the sagittal plane. The heart is located on the right side of the thorax, the stomach and spleen on the right side of the abdomen and the liver and gall bladder on the left side. The hearts normal right atrium occurs on the left, and the left atrium is on the right. The lung anatomy is reversed and the left lung has three lobes while the right lung has two lobes. The intestines and other internal structures are also reversed from the normal, and the blood vessels, nerves, and lymphatics are also transposed.
If the heart is swapped to the right side of the thorax, it is known as "situs inversus with dextrocardia" or "situs inversus totalis". If the heart remains on the normal left side of the thorax, a much rarer condition (1 in 2,000,000 of the general population), it is known as "situs inversus with levocardia" or "situs inversus incompletus".
Situs inversus of the optic disc may occur unilaterally or bilaterally, associated with reduced binocularity and stereoacuity resembling monofixation syndrome. It is characterized by emergence of the retinal vessels in an anomalous direction (from the nasal rather than the temporal aspect) with dysversion (tilt) of the optic disc.Situs inversus does not appear to significantly affect rates of handedness. Based on a 2004 study documenting situs inversus in individuals with primary ciliary dyskinesia, the proportion of right-handedness among those with situs inversus did not differ significantly from that of those with situs solitus.
Diagnosis
Diagnosis of situs inversus can be made using imaging techniques such as x-ray, ultrasound, CT scan, and magnetic resonance imaging (MRI).Any potential treatment for situs inversus would involve a complete and highly invasive surgical rearrangement of the internal viscera of the patient. Such a procedure is unnecessary, given that situs inversus rarely causes any additional symptoms. No treatment, medical or surgical, is prescribed for situs inversus patients, with medical professionals instead treating any other symptoms the patient may have with awareness of the unique anatomy of the patient.
Epidemiology
Situs inversus is very rare, affecting 0.01% of the population. This is equivalent to 1 in 10,000 people.
History
Dextrocardia (the heart being located on the right side of the thorax) was seen and drawn by Leonardo da Vinci, and then recognised by Marco Aurelio Severino in 1643. Situs inversus was first described more than a century later by Matthew Baillie.
Etymology
The term situs inversus is a short form of the Latin phrase situs inversus viscerum, meaning "inverted position of the internal organs".
Notable cases
Notable individuals with documented cases of situs inversus include:
Enrique Iglesias, a Spanish singer, songwriter, actor and record producer.
Catherine OHara, Canadian-American actress, writer and comedian.
Randy Foye, an American basketball player in the NBA. He has suffered no discernible complications, and the condition is not expected to affect his career as a professional athlete, as all his organs are in reverse.
Ginggaew Lorsoongnern, a Thai convict executed by firing squad. Her condition was discovered after she was shot in the left side of her chest and survived. After waking up in the morgue she was taken back and executed.
Tim Miller, director of the Ashtanga Yoga Center in Carlsbad, California.
Rose Marie Bentley, a Molalla, Oregon woman who unknowingly had the rare variant situs inversus with levocardia, and lived to 99 years without any complications. She donated her body to Oregon Health & Science University, where her condition was discovered during an anatomy class after students noticed the unusual arrangement of her hearts blood vessels, prompting further investigation of the cadaver.
See also
Ectopia cordis
Asplenia
Polysplenia
Chirality (mathematics)
Johann Friedrich Meckel, the Elder
Notes
References
Further reading
External links
00698 at CHORUSChest X-ray & CT scan Radiology Teaching File |
Odontogenic keratocyst | An odontogenic keratocyst is a rare and benign but locally aggressive developmental cyst. It most often affects the posterior mandible and most commonly presents in the third decade of life. Odontogenic keratocysts make up around 19% of jaw cysts.In the WHO/IARC classification of head and neck pathology, this clinical entity had been known for years as the odontogenic keratocyst; it was reclassified as keratocystic odontogenic tumour (KCOT) from 2005 to 2017. In 2017 it reverted to the earlier name, as the new WHO/IARC classification reclassified OKC back into the cystic category. Under The WHO/IARC classification, Odontogenic Keratocyst underwent the reclassification as it is no longer considered a neoplasm due to a lack of quality evidence regarding this hypothesis, especially with respect to clonality. Within the Head and Neck pathology community there is still controversy surrounding the reclassification, with some pathologists still considering Odontogenic Keratocyst as a neoplasm in line with the previous classification.
Signs and symptoms
Odontogenic keratocysts can occur at any age, however they are more common in the third to sixth decades. The male to female ratio is approximately 2:1. The majority are found in the mandible, with half occurring at the angle of the mandible.
Early odontogenic keratocysts usually do not display symptoms. Typically, clinical signs and symptoms present with bony expansion, or infection. However, bony expansion is uncommon as odontogenic keratocysts grow due to increased epithelial turnover rather than osmotic pressure. When symptoms are present they usually take the form of pain, swelling and discharge due to secondary infection. Odontogenic keratocysts are usually noted as incidental radiographic findings. Radiographically they can be seen as unilocular or multilocular radiolucencies. They can be mistaken for other cysts such as residual cysts or a dentigerous cyst if they occur over an unerupted tooth.
Pathogenesis
Odontogenic keratocysts originate from the odontogenic epithelium (dental lamina) in the alveolus left from tooth development stages. They are mainly thought to arise from rests of Serres.
Genetics
Sporadic (non-syndromic) and syndromic OKCs are associated with mutations in the gene PTCH found on chromosome 9q, which is part of the Hedgehog signaling pathway. PTCH is a tumour suppressor gene. Loss of PTCH activity leads to a brake in the cell cycle. A third of OKCs show mutations in PTCH, resulting in the cyst epithelium undergoing highly proliferative activity. This leads to growth of the cyst wall and when removed favours recurrence if following incomplete removal of the epithelium.
Nevoid basal-cell carcinoma syndrome
Multiple odontogenic keratocysts are a feature, and major diagnostic criteria, of nevoid basal cell carcinoma syndrome (NBCCS, also known as Gorlin-Goltz Syndrome). Almost all individuals with NBCCS have odontogenic keratocysts which require numerous treatments. Consideration of the syndrome needs to be taken into account if found in children or if multiple OKCs are present; diagnosis of multiple OKCs in a child necessitates referral for genetic evaluation. Histologically, the cysts are indistinguishable to non-syndromic cysts and over 80% will have PTCH mutations.
Diagnosis
Diagnosis is usually radiological. However, definitive diagnosis is through biopsy. Aspirational biopsy of odontogenic keratocysts contains a greasy fluid which is pale in colour and contains keratotic squames. Protein content of cyst fluid below 4g% is diagnostic of odontogenic keratocysts. Smaller and unilocular lesions resembling other types of cysts may require a biopsy to confirm the diagnosis. On a CT scan, the radiodensity of a keratocystic odontogenic tumour is about 30 Hounsfield units, which is about the same as ameloblastomas. However, ameloblastomas show more bone expansion and seldom show high density areas.Radiographs of odontogenic keratocysts show well-defined radiolucent areas with rounded or scalloped margins which are well demarcated. These areas can be multilocular or unilocular. The growth pattern of the lesion is very characteristic from which a diagnosis can be made as there is growth and spread both forward and backward along the medullary cavity with little expansion. No resorption of teeth or inferior dental canal and minimal displacement of teeth is seen. Due to lack of expansion of the odontogenic keratocyst, the lesion can be very large when radiographically discovered.
Differential diagnosis
Radiologically
Odontogenic myxoma
Ameloblastoma
Central giant-cell granuloma
Adenomatoid odontogenic tumor
Dentigerous cyst (follicular cyst)Histologically
Orthokeratocyst
Radicular cyst (particularly if the OKC is very inflamed)
Ameloblastoma
Histology
Odontogenic keratocysts have a diagnostic histological appearance. Under the microscope, OKCs vaguely resemble keratinized squamous epithelium; however, they lack rete ridges and often have an artifactual separation from their basement membrane.The fibrous wall of the cyst is usually thin and uninflamed. The epithelial lining is thin with even thickness and parakeratinised with columnar cells in the basal layer which have focal reverse polarisation (nuclei are on the opposite pole of the cell). The basal cells are an indication of the odontogenic origin as they resemble pre-ameloblasts. The epithelium can separate from the wall, resulting in islands of epithelium. These can go on to form satellite or daughter cysts, leading to an overall multilocular cyst. Presence of daughter cysts is particularly seen in those with NBCCS. Inflamed cysts show hyperplastic epithelium which is no longer characteristic of OKCs and can have resemblance to radicular cysts instead. Due to areas of focal inflammation, a larger biopsy is required for correct diagnosis of odontogenic keratocysts.
Treatment
As the condition is quite rare, opinions among experts about how to treat OKCs differ. A 2015 Cochrane review found that there is currently no high quality evidence to suggest the effectiveness of specific treatments for the treatment of odontogenic keratocysts. Treatment depends on extent of multilocularity and cyst. Small multilocular and unilocular cysts can be treated more conservatively through enucleation and curretage. Treatment options for KTOC may vary according to its size, extent, site, and adjacent structures.
Treatment options:
Surgical enucleation: surgical removal of the entire epithelial lining of the cyst.
Marsupialisation followed by enucleation: this method is carried out by surgeons for larger cysts.
Curettage involving simple excision and scraping-out of cavity.
Carnoys solution fixative (ethanol, chloroform and acetic acid) which is usually used in conjunction with excision and curretage. Cavity wall can be treated with the fixative either before enucleation to kill the lining of the wall or added after curretage to bony walls, killing any residual epithelial cells to a depth of 1-2mm. Used with care near mandibular canal and the neurovascular bundle within.
Marsupialization which involves the surgical opening of the cyst cavity and a creation of a marsupial-like pouch. This allows the cavity to be in contact with the outside of the cyst for an extended period of time. Marsupialisation results in slow shrinkage of the cyst allowing later enucleation. However, resolution can take up to 20 months and patients are required to clean the open cavity and irrigate it.
Peripheral ostectomy after curettage and/or enucleation. Extensive cysts may require a bone graft after bone resection and reconstruction of the area.
Simple excision
Enucleation and cryotherapy. Decompression followed by enucleation has been shown to be most successful with lowest recurrence rates.
Topical application of 5FU after enucleation
Ostectomy or En – bloc resection: in addition to the above treatments, these may be required due to the issue of recurrence. Ostectomy is removal of peripheral bone. En – block resection is removal of the cyst with the surrounding tissue. Extensive cysts may require a bone graft after bone resection and reconstruction of the area.
Follow-up
Annual radiographic review has been recommended. Long-term clinical follow-up is also recommended due to recurrences occurring many years after treatment.
Recurrence and neoplastic nature
Malignant transformation to squamous cell carcinoma may occur, but is unusual.Recurrence is likely when treated by simple enucleation. Contributing causes include thin and fragile epithelium leading to incomplete removal, cyst extensions extending into cancellous bone, satellite cysts found in the wall, experience of the surgeon, formation of further new cysts from other remnants of the dental epithelium. With current treatment techniques the recurrence rate is around 2-3% but can be as high as 50%. Recurrence can occur as early as 5 years and as late as 40 years after removal. Recurrence is usually seen within 5 years of treatment. Early findings of recurrence can be easily treated with minor surgery and curretage. Any fragment of the cyst that is left behind has the potential to survive and grow. Therefore, the success of enucleation depends on how well the cyst is removed. Larger cysts have a higher rate of recurrence after enucleation as they are more difficult to remove.
Pronto genie keratocysts are well known to recur in the posterior mandible. A substantial amount of odontogenic keratocysts also recur in the tooth-bearing area of the jaws, requiring attention from clinicians.The neoplastic nature of odontogenic keratocysts has been debated. Due to high recurrence rate, late detection when the cyst has grown very large and causation by tumour suppressor gene inactivation, some have classified OKCs as benign neoplasms. The best evidence to suggest that this type of cyst is not a neoplasm is that it responds very well to marsupialisation.
See also
Cysts of the jaws
References
== External links == |
Rud syndrome | Rud syndrome is a poorly characterized disorder, probably of X-linked recessive inheritance, named after Einar Rud who described 2 patients with the case in 1927 and 1929. It was argued that all reported cases of Rud syndrome are genetically heterogeneous and significantly differ from the original case reports of Rud and that the designation Rud syndrome should be eliminated and that the patients with such diagnosis should be reassigned to other syndromes, such as Refsum disease and Sjögren-Larsson syndrome. Some consider Rud syndrome and Sjögren-Larsson syndrome the same entity and that Rud syndrome does not exist.
Presentation
While inclusion criteria for Rud syndrome have varied considerably, the major manifestations include congenital ichthyosis, hypogonadism, small stature, mental retardation, and epilepsy.: 502 : 564 Ocular findings were inconsistently reported and included strabismus, blepharoptosis, blepharospasm, glaucoma, cataract, nystagmus, and retinitis pigmentosa. Other systemic includes metabolic, bony, neurologic, and muscular abnormalities.
Diagnosis
Treatment
Eponym
In 1929, the Danish physician Einar Rud described a 22-year-old Danish male had ichthyosis, hypogonadism, short stature, epilepsy, anemia, and polyneuritis. In 1929, he described a 29-year-old female with ichthyosis, hypogonadism, partial gigantism, and diabetes mellitus.
References
== External links == |
Juvenile idiopathic arthritis | Juvenile idiopathic arthritis (JIA) is the most common, chronic rheumatic disease of childhood, affecting approximately one per 1,000 children. Juvenile, in this context, refers to disease onset before 16 years of age, while idiopathic refers to a condition with no defined cause, and arthritis is inflammation within the joint.JIA is an autoimmune, noninfective, inflammatory joint disease, the cause of which remains poorly understood. It is characterised by chronic joint inflammation. JIA is a subset of childhood arthritis, but unlike other, more transient forms of childhood arthritis, JIA persists for at least six weeks, and in some children is a lifelong condition. It differs significantly from forms of arthritis commonly seen in adults (osteoarthritis, rheumatoid arthritis), in terms of cause, disease associations, and prognosis.
The prognosis for children with JIA has improved dramatically over recent decades, particularly with the introduction of biological therapies and a shift towards more aggressive treatment strategies. JIA treatment aims for normal physical and psychosocial functioning, which is an achievable goal for some children with this condition.
Signs and symptoms
Arthritis means inflammation within the joint, and is usually recognised by swelling, pain, stiffness and restricted joint movement. Symptoms of JIA vary from individual to individual. This is mainly because JIA is an umbrella term for several subtypes of JIA, which differ according to the number of affected joints, severity of disease and presence or absence of inflammation in other parts of the body.The key clinical feature in JIA is persistent swelling of the affected joints. Any joint can be affected, but large joints such as the knee and ankle are most commonly involved. Involvement of small joints of the hands and feet is more likely when many joints are affected (polyarthritis). Swollen joints may also feel warmer to touch. Swelling may be difficult to detect clinically, especially for joints such as those of the spine, sacroiliac joints, shoulder, hip, and jaw; imaging techniques such as ultrasound or MRI can be very useful to identify the inflammation.Joint pain is an important symptom, although some children experience minimal or no pain with their arthritis. In these children, the first sign of arthritis may be limping, especially in the morning. Young children are often very good at changing how they move when they have joint pain: they learn to move so that it does not hurt. For example, a child will not push up using an inflamed wrist when climbing, instead putting their weight through the forearm. Morning stiffness that improves later in the day is a common feature (this implies inflammatory-type joint pain versus mechanical-type joint pain).Swelling and pain usually result in limited movement of the affected joints, for example a knee held bent causing a limp, or being unable to make a full fist. Limited movement may reduce a childs ability to fully participate in activities and undertake usual tasks such as those used for self-care. In some JIA subtypes, more non-specific symptoms of being unwell may be present, such as lethargy, fatigue and poor appetite. Children with systemic JIA usually present with fever and a classic rash and may become quite ill. Late effects of arthritis can include joint contractures (stiff, bent joints with loss of movement) due to joint damage; limb length discrepancies and muscle wasting. Children with JIA vary in the degree to which they are affected by particular symptoms.
Extra-articular
Eye disease: JIA is associated with inflammation in the front of the eye (specifically iridocyclitis, a form of chronic anterior uveitis), which affects about one in six children with JIA. Eye involvement occurs most commonly in girls, those with only a few joints involved (oligoarthritis), and those with a positive anti-nuclear antibody (ANA). It usually follows the onset of arthritis or may be detected at the same time as arthritis; occasionally it may occur before joint involvement. The factors linking eye and joint disease are not clearly understood, and the two do not necessarily follow the same course. This complication is usually asymptomatic (without symptoms) and can occur when the joints are not active. It can be detected by an experienced optometrist or ophthalmologist using a slit lamp to look for inflammatory cells in the fluid inside the eye. Most children with JIA will require referral for regular slit lamp screening examinations. Poorly controlled chronic anterior uveitis may result in permanent eye damage, including blindness.Systemic JIA: children with the Systemic JIA subtype often experience extra-articular manifestations including fever, rash, enlarged lymph nodes, enlarged liver or spleen, serositis and anaemia.
Complications
JIA is a chronic disorder, which if neglected, can lead to serious complications. However, with regular follow-up and modern treatments, complications have reduced and outcomes improved. If inflammation is not treated, it can damage the joint, the cartilage and the bone. With the advent of modern therapies, these complications of JIA have become much less common.Children with JIA may have a reduced overall rate of growth, especially if the disease involves many joints or other body systems. This may be due to a combination of the disease itself, as well as its treatments, particularly corticosteroid use. Paradoxically, limbs where a large joint (such as the knee) is inflamed may have increased growth in the short term, leading to limb-length discrepancy (i.e. one arm or leg is slightly longer than the other). This is due to increased blood supply to the bony growth plates surrounding the inflamed joints. Bone density and bone strength may be reduced through a combination of inflammation, corticosteroid use and reduced physical activity levels. Other musculoskeletal complications may include joint contractures, muscle weakness or muscle wasting.Uveitis, if left untreated, can result in scarring, glaucoma, cataracts, and even blindness. Regular monitoring allows for early detection and treatment. Steroid eye drops are usually the first line treatment for anterior uveitis. However, other treatments – many of which also treat arthritis (e.g. methotrexate, biologics) – may be required to keep the inflammation under control, and to minimise steroid use over the longer term. Long term steroid use can cause contribute to the development of cataracts.Macrophage activation syndrome (MAS) is a severe, potentially life-threatening complication that can occur in patients with the systemic subtype of JIA. MAS involves uncontrolled activation of the immune system, sometimes referred to as a cytokine storm, which can present with a sepsis-like picture of fever, rash, enlarged liver and spleen, enlarged lymph nodes and cardiorespiratory compromise. It is recognised by a series of characteristic changes in laboratory parameters, including a high ferritin and a paradoxically low erythrocyte sedimentation rate.
Causes
The cause of JIA remains unknown. However, the disorder is autoimmune — meaning that the bodys own immune system starts to attack and destroy cells and tissues (particularly in the joints) for no apparent reason. The immune system is thought to be provoked by changes in the environment, in combination with mutations in many associated genes and/or other causes of differential expression of genes. Experimental studies have shown that certain mutated viruses may be able to trigger JIA. The disease appears to be more common in girls, and is most common in Caucasians.The cause of JIA, as the word "idiopathic" suggests, is unknown and an area of active research. Current understanding of JIA suggests that it arises in a genetically susceptible individual due to environmental factors.
Diagnosis
The diagnosis of JIA can be difficult, in part because joint pain in children is so common and may be from many causes other than JIA. The characteristic feature of arthritis is joint swelling which is sometimes – but not always – associated with pain. The presence of joint stiffness is another typical feature, particularly when present in the morning and improving with activity.No single test can confirm a diagnosis of JIA: a combination of presenting signs and symptoms, blood tests, and if necessary medical imaging, is used to make the diagnosis. The blood tests may measure levels of inflammatory markers, as well as the presence of specific immune markers which may include anti-nuclear antibody, HLA-B27, rheumatoid factor and anti–citrullinated protein antibody. These serological markers may be negative in children with JIA, and are often present in healthy children; as such they should not be interpreted in isolation but in the context of the clinical presentation. Many children with JIA have normal blood work. X-rays may be required to ensure that the joint pain and swelling is not from a fracture, cancer, infection, or congenital abnormality. In some cases, fluid from the joint can be aspirated and analysed to assist in making a diagnosis. This test can assist by ruling out other causes of arthritis such as infection.
Classification
The current classification system by the International League of Associations for Rheumatology (ILAR) recognizes seven distinct subtypes of JIA, based on their presentation within the first six months:
Each subtype has a specific pattern of features as outlined in the table and descriptions below. (The seventh category, not included in the table, is Undifferentiated and includes any patient with JIA who does not meet criteria for other subtypes, or who meets criteria for two or more subtypes).
Oligoarticular arthritis
Oligoarticular (or pauciarticular) JIA is the most common JIA subtype, and occurs when there are up to four joints involved during the first six months of disease. Two subtypes of oligoarticular arthritis exist: persistent oligoarthritis, where no more than four joints are affected throughout the whole disease course; and extended oligoarthritis, where more than four joints are affected after the first six months of disease. Patients in this subtype are often young, typically aged two to three years and with a female preponderance. The most commonly involved joint is the knee, but other affected joints may include the ankles, wrists, elbows and others. The anti-nuclear antigen (ANA) is positive in up to 80% of patients with oligoarthritis and is associated with a higher risk of associated eye disease (uveitis), particularly in younger patients. The prefixes oligo- and pauci- mean few.
Differential diagnosis
There are several other disorders and diseases that present with symptoms like JIA. These causes include, but are not limited to, infectious (for example septic arthritis or osteomyelitis) and post-infectious conditions (reactive arthritis, acute rheumatic fever, and in some geographic areas Lyme disease); hematologic and neoplastic diseases such as leukemia or bony tumors; and other connective tissue diseases (such as systemic lupus erythematosus). For the systemic-onset form of JIA, the differential diagnosis also includes Kawasaki disease and periodic fever syndromes. Some genetic skeletal dysplasias as forms of mucopolysaccharidosis especially type1 Scheie syndrome, progressive pseudorheumatoid dysplasia and multicentric osteolysis, nodulosis, and arthropathy syndrome may also mimic JIA, as they may present with joint swelling, joint restriction, stiffness, and pain. The clinical and radiologic overlap between genetic skeletal dysplasias and JIA can be great that molecular analysis may be need to confirm the diagnosis. Rarely, metabolic diseases, such as Farber disease may also mimic JIA. Patients with Farber disease typically have subcutaneous nodules and a hoarse or weak voice due to growth of nodules on the larynx.
Treatment
The major emphasis of the treatment of JIA is helping the child or young person regain normal levels of physical and social functioning by controlling inflammation and extra-articular symptoms. Clinical remission should be the primary target for all patients and treatment should be adjusted until this is achieved. Prompt recognition and management is important as early initiation of therapy increases the likelihood of a response to first-line treatments and of achieving drug-free remission later in life. While overarching consensus treatment guidelines exist, all treatments should be specifically tailored to the individuals needs in discussion with the child or young person and their family.Optimal management of JIA requires a multidisciplinary team working to address the needs of an individual patient. Optimising physical and social functioning is accomplished via a two-pronged approach: non-pharmacological strategies such as physical therapies, pain management strategies, and social supports; and the swift use of medication to control inflammation and extra-articular symptoms. Early diagnosis and treatment are imperative in helping reduce joint damage and other symptoms, which will help reduce levels of permanent damage leading to long term disability.
Non-pharmacological treatments
The optimal approach to treating a child with JIA typically involves a team of medical professionals, which may include (but is not limited to) paediatric rheumatologists, paediatric rheumatology nurses, general paediatricians, general practitioners, adult rheumatologists, physical therapists (PTs), occupational therapists (OTs), podiatrists, psychologists, social workers, pharmacists, ophthalmologists and orthopaedic surgeons. The multi-disciplinary team (MDT) work in conjunction with the child and their parents, the local health service and medical team, the childs school and teachers, community leaders and sports coaches to best support the child and their family.Together, the team help children to participate as fully and independently as possible in their daily activities by maximising quality of life, maximising function and minimising disruption to the life of the child or young person.
The multidisciplinary team work together to provide the child and their family with support and education about JIA, strategies to promote age-appropriate self-sufficiency and help the child to adapt and adjust to any challenges they face. There are many ways to make daily tasks easier or more manageable. One of the key ways the multidisciplinary team helps children with JIA is to involve them, and their families, in the decision-making process regarding their treatment and rehabilitation.
In young children with JIA, symptoms may result in either delay or regression in developmental milestones such as walking, running or climbing. Upper limb function may also be affected. Members of the multidisciplinary team can perform developmental assessments to identify deficits and guide treatments. The information gathered can be shared with schools and child care facilities.
One of the key ways occupational or physical therapists help young children with JIA is by developing a home therapy program based around play. Exercises are prescribed by both physical therapists and occupational therapists to increase the range a child can move a joint, to strengthen the muscles around a joint, to decrease pain and stiffness and to prevent further limitations in their joint movements. OTs and PTs can provide children with age-appropriate games and activities to allow the children to practice their exercises while playing and socializing with friends. Examples are crafts, swimming, and sports.Children with JIA may experience challenges with low mood, social interaction, reduced self-confidence and negative self-image. Psychologists, OTs, nurses, social workers and other team members can work with the child and their family to develop strategies to help with these issues. Many JIA support organisations run camps and activities for children with JIA and their families.
Surgery is only used to treat the most severe cases of JIA and is now rarely required.
Physical therapy and exercise
Maintaining physical activity is important in all children, but especially for children with JIA. The physical therapist has a role in guiding physical rehabilitation (muscle stretching and strengthening, enhancing joint range of movement, improving balance, etc.); optimising physical functioning; goal-setting; and improving a childs confidence in their own body. They usually work with the child and family to develop a home exercise program which changes over time as the child makes progress.
Arthritis in childhood can be associated with muscle weakness and wasting around the affected joints. It can also lead to low bone density, which may predispose to osteoporosis and fractures in adulthood. Getting regular exercise is an important part of the management of JIA to promote bone and muscle health.There is variation in the exact exercise prescription which best promotes musculoskeletal health whilst reducing fatigue, pain and swelling. Consensus is that children with JIA should be following national public health standards of physical activity and participating in moderate fitness, flexibility, and strengthening exercises, compatible with their abilities and disease restrictions.It is important that – across the week – the exercise is a combination of moderate to vigorous cardiovascular activity (e.g. walking to school, scooting, bike-riding, playing tag, dancing, doing physical education, sports such as basketball or football) and strengthening exercises. Bone strengthening activities build up muscles; by having the muscles push and pull against the bone, the bones themselves get stronger. This can include things like playing on climbing equipment, swinging on monkey-bars, using weights, carrying groceries, skipping or running.
A Cochrane meta-analysis looking at existing RCTs showed in all studies that exercise does not have a detrimental effect on JIA. In fact, there is evidence to show that both low and high-intensity exercise programs result in improved physical function and reduced pain in children with JIA. Guidelines indicate that children with JIA should be encouraged to be physically active and can safely participate in sports without disease exacerbation. Those with actively inflamed joints should limit activities within pain limits, then gradually return to full activity following a disease flare.It may be necessary to use aids like splints or casts to correct biomechanics, but prolonged splinting and casting are now rarely indicated for children with JIA. Following joint injections, children are often advised to take it easy, often undertaking one to two days of low activity, although advice around this varies. When a joint (usually a knee) loses range of motion due to prolonged inflammation and pain, a series of plaster casts may be used to gradually extend shortened muscles and restore range. These serial casts are usually applied over days to weeks. Active strengthening and lengthening is used in conjunction with serial casting for optimal results.
Some children may benefit from foot orthotics to support and correct body position and function. Orthotics maintain biomechanical alignment and may reduce discomfort in the legs and back when children participate in physical activities such as sports.
Self-management
Pain is the most common and often the most distressing symptom of JIA (although some children with JIA do have joint inflammation without any pain at all). Pain can occur even when children are receiving effective doses of therapies which are managing their underlying disease.
Pain has been found to negatively impact all aspects of quality of life and is associated with a reduction in physical, social and emotional functioning. Children who have higher levels of pain tend to have reduced levels of socialization, school attendance and participation in activities. Increased pain is also correlated with poor sleep and higher fatigue in children with JIA.
The causation of pain in JIA is multifactorial. There are disease-related factors, which relate to the inflammatory process, and anatomical or biomechanical changes that are associated with joint swelling and joint disease. There are psychological factors around dealing with stress, coping with a chronic illness and managing anxiety or depression which can influence the perception of pain and the degree of functional impairment. There are also social factors, which relate to family and peer relationships, parental distress and social and financial supports.
Given the waxing and waning nature of JIA, childrens physical abilities, pain and mood can change during periods of flare or remission. Coping with chronic illness during childhood and adolescence is associated with significant stress that can put children at risk for emotional or behavioural distress and can interfere with compliance and adherence to treatment regimes. Managing JIA can be a challenge and it is important to have a toolbox of skills, supports and strategies to draw upon to manage the ups and downs of having a chronic illness.
There are many things that can help children with JIA to grow up to have full and active lives. Having good sleep habits and routines gives a child the best chance of having a refreshing nights sleep and preventing daytime fatigue. This in turn affects concentration, energy levels, memory and mood. Most children need between eight and twelve hours of sleep to feel refreshed, depending on age. Simple strategies like maintaining regular bedtimes, limiting screen time to two hours before bed, having a sleep ritual, avoiding napping during the day, avoiding sugary and caffeinated drinks, having a healthy well-balanced diet, regular exercise and using relaxation techniques can assist in having good nights sleep.
Relaxation techniques can also help to reduce stress, physical tension and be a useful pain management technique. There are a variety of mindfulness strategies which include things like deep breathing, guided-imagery or progressive muscle relaxation. All techniques need to be practiced over time, and it may be necessary to try different combinations to find the method that works best for each individual. These techniques are readily available online, in books, recordings, apps or by seeing a trained professional such as a psychologist.
Education and employment
Most children with JIA will be able to consistently attend school, without too many disruptions, even during a disease flare. However, they may require extra help or adaptations in order to do so. Maximising school attendance involves collaboration between the family, the school and the health care team. Prolonged or repeated school absences can have academic, social and emotional implications; except in rare circumstances they are rarely necessary (other than absences for medical or therapy appointments).
These adaptations may include requiring extra time to get between classes or during examinations, using specialised pens or switching to typing rather than handwriting, or minimising the load of heavy books or equipment to be carried in a childs school bag. The exact requirements will vary from child-to-child and will depend on the joints affected. In many instances, the childs treating team will be able to provide specific advice and information for teachers and coaches to smooth the transition back to school. This may take the form of an individualized plan outlining any extra measures that need to be taken at school, what to do in the case of unexpected events or medication administration during school hours. Importantly, JIA can be disruptive not just to the academic aspects of school. It is equally important to optimise school attendance so that the child can maintain friendships and keep up with opportunities to socialize with peers.
As adolescents progress through high school, they may need to factor their current medical status and functional abilities into decisions around their future education and employment plans. Most children with JIA will not be restricted in their study goals or professional aspirations. Students with JIA can usually apply for special arrangements during assessment periods, such as additional time to allow for rest/stretch periods and use of adaptive equipment in some situations. These applications often need to be supported by the treating medical team. The treating team can assist adolescents in finding ways to tell their employers about their condition in a positive way. OTs and social workers can also help teenagers understand their rights as an employee with a chronic illness. It is important that adolescents with JIA understand how to take care of themselves and manage their disease when working full-time or attending higher education. The team will also support those patients who still require medical input through the transition process from paediatric to adult services.
eHealth and mobile Health (mHealth) interventions
A new emerging area of support for disease management is through digital technology using eHealth and mobile health (mHealth) interventions. These interventions have to potential to support the development of self-management skills, or assist the healthcare team to monitor symptoms. For JIA, current studies have focused on the health issues pain, health related quality of life, physical activity and disease management. Children and adolescents have used these interventions through a range of devices including computers, laptops, personal digital assistants, multimedia-players, and wearable accelerometers synchronised to smart phone. This allows access to these interventions from home. Early usability studies have been gaining positive feedback by children and adolescents. They are familiar with this type of technology and report liking these interventions. However further research is still needed to understand their full potential in supporting children and adolescents living with complex needs.
Prognosis
At the time of receiving a JIA diagnosis, children and their families often have many questions regarding prognosis. Recent therapeutic advances in the management of JIA have made inactive disease and clinical remission achievable goals for the majority of children with access to modern treatments. Clinical remission can be defined as the absence of signs and symptoms of inflammatory disease activity, including extra-articular manifestations of the disease. Differentiating subtypes of JIA helps to target treatment and leads to more positive outcomes, however subtype is not the only predictor of JIA outcome. Poor prognostic factors include arthritis of the hip, cervical spine, ankles or wrists; prolonged elevation of inflammatory markers; and radiographic evidence of joint damage including erosions or joint space narrowing. Patients with RF-positive polyarthritis often have worse outcomes associated with more aggressive disease. Despite this, the probability of this subgroup achieving inactive disease at least once within five years was shown to be 90% in a large Canadian study. Research is currently being undertaken into clinical prediction models to allow earlier identification of children who are likely to have a worse prognosis. Compliance with therapy, especially medication, has a positive correlation with disease outcome.
Research into specific JIA biomarkers is currently underway, with the goal of forming more personalized treatment plans, reducing medication side effects and improving remission rates. Current areas of investigation include clinical, protein, genetic and radiological markers, amongst others.Children with JIA demonstrate similar levels of depression and anxiety to children with other chronic diseases; however, causality has not been established. The unpredictable and undulating course of JIA disease activity and the need for ongoing procedural interventions may contribute.
It has been previously suggested that children with JIA are at an increased risk of malignancies when being treated with anti-TNF therapy. More recent data has not confirmed this association: it is thought that the disease itself is linked with a slightly higher background risk of malignancy. Ongoing data analysis on large patient populations continues in this area.
Epidemiology
Juvenile Idiopathic Arthritis is the most common, chronic rheumatic disease of childhood. In high-income countries, yearly incidence has been estimated at 2–20 cases per 100,000 population; prevalence in these areas is estimated at 16–150 cases per 100,000 population. However, there is also a suggestion that these numbers underestimate disease prevalence: one community-based survey of school children in Western Australia reported a prevalence of 400 per 100,000. Overall prevalence is often summarised as one per thousand children.Incidence and prevalence data vary across different population and ethnic groups, with lower overall prevalence in Afro-Caribbean and Asian populations. There are also ethnic differences in the frequency of JIA subtypes: for example, oligoarthritis is the most common subtype in European populations, whilst polyarticular disease predominates in many other countries including Costa Rica, India, New Zealand, and South Africa.There are differences in age of onset, gender and disease outcomes based on JIA subtype: these are outlined in the table above.
Terminology
The terminology used to describe JIA is evolving, and each term has some limitations.
Previous terminology included Juvenile Rheumatoid Arthritis and Juvenile Chronic Arthritis. These terms were replaced in 1997 with the release of the revised ILAR (International League of Associations for Rheumatology) classification criteria.There is currently an international movement underway to further revise the classification criteria for JIA, although this is in a preliminary phase.MeSH uses "juvenile arthritis" as the primary entry, and uses "idiopathic", "chronic" and "rheumatoid" in alternate entries.
Society
Some famous people with this condition are:
Antoni Gaudi, architect
Clark Middleton, actor
Claire Cottrill, singer-songwriter
Rosemary Sutcliff, author
References
External links
Arthritis Australia, Juvenile Idiopathic Arthritis
JIA@NRAS (UK)
JIA - NIH Medline Plus. |
Pinealoma | A pinealoma is a tumor of the pineal gland, a part of the brain that produces melatonin. If a pinealoma destroys the cells of the pineal gland in a child, it can cause precocious puberty.
Signs and symptoms
The pineal gland produces the hormone melatonin which plays a role in regulating circadian rhythms. A pinealoma may disrupt production of this hormone, and insomnia may result.Frequently, paralysis of upward gaze along with several ocular findings such as convergence retraction nystagmus and eyelid retraction also known as Colliers sign and Light Near Dissociation (pupil accommodates but doesnt react to light) are known collectively as Parinauds syndrome or Dorsal Mid-brain syndrome, are the only physical symptoms seen. This is caused by the compression of the vertical gaze center in the midbrain tectum at the level of the superior colliculus and cranial nerve III. Work-up usually includes Neuro-imaging as seen on the right.A pinealoma may cause interruption of hypothalamic inhibiting pathways, sometimes leading to beta-hCG secretion and consequent Leydigs cell stimulation (endocrine syndrome).Other symptoms may include hydrocephalus, gait disturbances, and precocious puberty.
Cause
Pinealomas can be due to proliferation of primary pineocytes (pineocytomas, pineoblastomas), astrocytes (astrocytoma), or germ cells (germinoma). Germinomas are the most common tumor in the pineal gland.
Diagnosis
Treatment
Prognosis
Of the different types of pinealomas, the type with the most favorable prognosis is the pineocytoma.
References
External links
00322 at CHORUS |
Vaginal disease | A vaginal disease is a pathological condition that affects part or all of the vagina.
Types
Sexually transmitted infections
Sexually transmitted disease that affect the vagina include:
Herpes genitalis. The herpes simplex virus (HSV) can infect the vulva, vagina, and cervix, and this may result in small, painful, recurring blisters and ulcers. It is also common for there to be an absence of any noticeable symptoms.
Gonorrhea
Chlamydia
Trichomoniasis
Human papillomavirus (HPV), which may cause genital warts.Because of STIs, health authorities and other health outlets recommend safe sex practices when engaging in sexual activity.
Other infectious diseases
Candidal vulvovaginitis
Bacterial vaginosis (BV) associated with the Gardnerella, formerly called "nonspecific vaginitis"
Vaginismus
Vaginismus, which is not the same thing as vaginitis (an inflammation of the vagina), is an involuntary tightening of the vagina due to a conditioned reflex of the muscles in the area during vaginal penetration. It can affect any form of vaginal penetration, including sexual intercourse, insertion of tampons and menstrual cups, and the penetration involved in gynecological examinations. Various psychological and physical treatments are possible to help alleviate it.
Obstruction
A vaginal obstruction is often caused by an imperforate hymen or, less commonly, a transverse vaginal septum. A sign of vaginal obstruction is hydrocolpos, that is, accumulation of watery fluid within the vagina. It may extend to become hydrometrocolpos, that is, accumulation of watery fluid within the vagina as well as within the uterus.
Hypoplasia
Vaginal hypoplasia is the underdevelopment or incomplete development of the vagina. Vaginal hypoplasia can vary in severity from being smaller than normal to being completely absent. The absence of a vagina is a result of vaginal agenesis. Diagnostically, it may look similar to a vaginal obstruction. It is frequently associated with Mayer-Rokitansky-Küstner-Hauser (MRKH) syndrome, in which the most common result is an absent uterus in conjunction with a deformed or missing vagina, despite the presence of normal ovaries and normal external genitalia. It is also associated with cervical agenesis, in which the uterus is present but the uterine cervix is absent.
Lumps
The presence of unusual lumps in the wall or base of the vagina is always abnormal. The most common of these is Bartholins cyst. The cyst, which can feel like a pea, is formed by a blockage in glands which normally supply the opening of the vagina. This condition is easily treated with minor surgery or silver nitrate. Other less common causes of small lumps or vesicles are herpes simplex. They are usually multiple and very painful with a clear fluid leaving a crust. They may be associated with generalized swelling and are very tender. Lumps associated with cancer of the vaginal wall are very rare and the average age of onset is seventy years. The most common form is squamous cell carcinoma, then cancer of the glands or adenocarcinoma and finally, and even more rarely, vaginal melanoma.
Persistent genital arousal disorder
Persistent genital arousal disorder (PGAD), which results in a spontaneous, persistent, and uncontrollable genital arousal, with or without orgasm, unrelated to any feelings of sexual desire. Because PGAD is relatively rare and, as its own concept apart from clitoral priapism (a rare, potentially painful medical condition in which, for an unusually extended period of time, the erect clitoris does not return to its relaxed state), has only been researched since 2001, there is little research into what may cure or remedy the disorder. In some recorded cases, PGAD was caused by, or caused, a pelvic arterial-venous malformation with arterial branches to the clitoris; surgical treatment was effective in these cases.
Other
Vulvodynia
Vaginal prolapse may result in the case of weakened pelvic muscles, which is a common result of childbirth; in the case of this prolapse, the rectum, uterus, or bladder pushes on the vagina, and severe cases result in the vagina protruding out of the body. Kegel exercises have been used to strengthen the pelvic floor, and may help prevent or remedy vaginal prolapse.
Cervical cancer (may be prevented by Pap smear screening and HPV vaccines)
Vaginal cancer is very rare, but its symptoms include abnormal vaginal bleeding or vaginal discharge.
Air embolism is a potentially fatal condition where an air bubble travels throughout the bloodstream and can obstruct a vessel. It can result if air is blown into a pregnant womans vagina during cunnilingus; this is because pregnant women have an increased vascularity of the vagina and uterus, and an air embolism can force air into the uterine veins.
Symptoms
Discharge
Most vaginal discharges occur due to normal bodily functions, such as menstruation or sexual arousal (vaginal lubrication). Abnormal discharges, however, can indicate disease. Normal vaginal discharges include blood or menses (from the uterus), the most common, and clear fluid either as a result of sexual arousal or secretions from the cervix. Other non-infective causes include dermatitis. Non-sexually transmitted discharges occur from bacterial vaginosis, aerobic vaginitis and thrush or candidiasis. The final group of discharges include the sexually transmitted diseases gonorrhea, chlamydia, and trichomoniasis. The discharge from thrush is slightly pungent and white, that from trichomoniasis more foul and greenish, and that from foreign bodies resembling the discharge of gonorrhea, greyish or yellow and purulent (pus-like).
Sores
All sores involve a breakdown in the walls of the fine membrane of the vaginal wall. The most common of these are abrasions and small ulcers caused by trauma. While these can be inflicted during rape most are actually caused by excessive rubbing from clothing or improper insertion of a sanitary tampon. The typical ulcer or sore caused by syphilis is painless with raised edges. These are often undetected because they occur mostly inside the vagina. The sores of herpes which occur with vesicles are extremely tender and may cause such swelling that passing urine is difficult. In the developing world, a group of parasitic diseases also cause vaginal ulceration, such as leishmaniasis, but these are rarely encountered in the west. All of the aforementioned local vulvovaginal diseases are easily treated. Often, only shame prevents patients from presenting for treatment.
Inflammation
Vaginitis an inflammation of the vagina, such as caused by infection, hormone disturbance and irritation/allergy.
See also
List of bacterial vaginosis microbiota
== References == |
Stickler syndrome | Stickler syndrome (hereditary progressive arthro-ophthalmodystrophy) is a group of rare genetic disorders affecting connective tissue, specifically collagen. Stickler syndrome is a subtype of collagenopathy, types II and XI. Stickler syndrome is characterized by distinctive facial abnormalities, ocular problems, hearing loss, and joint and skeletal problems. It was first studied and characterized by Gunnar B. Stickler in 1965.
Signs and symptoms
Individuals with Stickler syndrome experience a range of signs and symptoms. Some people have no signs and symptoms; others have some or all of the features described below. In addition, each feature of this syndrome may vary from subtle to severe.A characteristic feature of Stickler syndrome is a somewhat flattened facial appearance. This is caused by underdeveloped bones in the middle of the face, including the cheekbones and the bridge of the nose. A particular group of physical features, called the Pierre Robin sequence, is common in children with Stickler syndrome. Robin sequence includes a U-shaped or sometimes V-shaped cleft palate (an opening in the roof of the mouth) with a tongue that is too large for the space formed by the small lower jaw. Children with a cleft palate are also prone to ear infections and occasionally swallowing difficulties.Many people with Stickler syndrome are very nearsighted (described as having high myopia) because of the shape of the eye. People with eye involvement are prone to increased pressure within the eye (ocular hypertension) which could lead to glaucoma and tearing or detachment of the light-sensitive retina of the eye (retinal detachment). Cataract may also present as an ocular complication associated with Sticklers Syndrome. The jelly-like substance within the eye (the vitreous humour) has a distinctive appearance in the types of Stickler syndrome associated with the COL2A1 and COL11A1 genes. As a result, regular appointments to a specialist ophthalmologist are advised. The type of Stickler syndrome associated with the COL11A2 gene does not affect the eye.People with this syndrome have problems that affect things other than the eyes and ears. Arthritis, abnormality to ends of long bones, vertebrae abnormality, curvature of the spine, scoliosis, joint pain, and double jointedness are all problems that can occur in the bones and joints. Physical characteristics of people with Stickler can include flat cheeks, flat nasal bridge, small upper jaw, pronounced upper lip groove, small lower jaw, and palate abnormalities, these tend to lessen with age and normal growth and palate abnormalities can be treated with routine surgery. Another characteristic of this syndrome is a mild spondyloepiphyseal dysplasia which can cause reduced height.Another sign of Stickler syndrome is mild to severe hearing loss that, for some people, may be progressive (see hearing loss with craniofacial syndromes). The joints of affected children and young adults may be very flexible (hypermobile). Arthritis often appears at an early age and worsens as a person gets older. Learning difficulties not due to a deficit in intelligence can also occur because of hearing and sight impairments if the school is not informed and the student is not assisted within the learning environment.Stickler syndrome is thought to be associated with an increased incidence of mitral valve prolapse of the heart, although no definitive research supports this.
Causes
The syndrome is thought to arise from a mutation of several collagen genes during fetal development. It is a sex independent autosomal dominant trait meaning a person with the syndrome has a 50% chance of passing it on to each child. There are three variants of Stickler syndrome identified, each associated with a collagen biosynthesis gene. A metabolic defect concerning the hyaluronic acid and the collagen of the 2-d type is assumed to be the cause of this syndrome.
Genetics
Mutations in the COL11A1, COL11A2 and COL2A1 genes cause Stickler syndrome. These genes are involved in the production of type II and type XI collagen. Collagens are complex molecules that provide structure and strength to connective tissue (the tissue that supports the bodys joints and organs). Mutations in any of these genes disrupt the production, processing, or assembly of type II or type XI collagen. Defective collagen molecules or reduced amounts of collagen affect the development of bones and other connective tissues, leading to the characteristic features of Stickler syndrome.Other, as yet unknown, genes may also cause Stickler syndrome because not all individuals with the condition have mutations in one of the three identified genes.
Diagnosis
Types
Genetic changes are related to the following types of Stickler syndrome:
Stickler syndrome, COL2A1 (75% of Stickler cases)
Stickler syndrome, COL11A1
Stickler syndrome, COL11A2(non-ocular)
Stickler syndrome, COL9A1 (recessive variant)
Stickler syndrome, COL9A2 (recessive variant)
Stickler syndrome, COL9A3 (recessive variant)
Stickler Syndrome, LOX3 (Recessive, 7 cases reported)Whether there are two or three types of Stickler syndrome is controversial. Each type is presented here according to the gene involved. The classification of these conditions is changing as researchers learn more about the genetic causes.
Treatment
Many professionals that are likely to be involved in the treatment of those with Sticklers syndrome, include anesthesiologists, oral and maxillofacial surgeons; craniofacial surgeons; ear, nose, and throat specialists, ophthalmologists, optometrists, audiologists, speech pathologists, occupational therapists, physical therapists and rheumatologists.
History
Scientists associated with the discovery of this syndrome include:
B. David (medicine)
Gunnar B. Stickler
G. Weissenbacher
Ernst Zweymüller
See also
Mandy Haberman, invented the Haberman Feeder
Marshall syndrome
Pierre Robin syndrome
References
External links
GeneReviews/NCBI/NIH/UW entry on Stickler Syndrome |
Subsets and Splits