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Nephritic syndrome | Nephritic syndrome is a syndrome comprising signs of nephritis, which is kidney disease involving inflammation. It often occurs in the glomerulus, where it is called glomerulonephritis. Glomerulonephritis is characterized by inflammation and thinning of the glomerular basement membrane and the occurrence of small pores in the podocytes of the glomerulus. These pores become large enough to permit both proteins and red blood cells to pass into the urine (yielding proteinuria and hematuria, respectively). By contrast, nephrotic syndrome is characterized by proteinuria and a constellation of other symptoms that specifically do not include hematuria. Nephritic syndrome, like nephrotic syndrome, may involve low level of albumin in the blood due to the protein albumin moving from the blood to the urine.
Signs and symptoms
Historically, nephritic syndrome has been characterized by blood in the urine (hematuria), high blood pressure (hypertension), decreased urine output <400 ml/day (oliguria), red blood cell casts, pyuria, and mild to moderate proteinuria. If the condition is allowed to progress without treatment, it can eventually lead to azotemia and uremic symptoms. This constellation of symptoms contrasts with the classical presentation of nephrotic syndrome (excessive proteinuria >3.5 g/day, low plasma albumin levels (hypoalbuminemia) <3 g/L, generalized edema, and hyperlipidemia).Signs and symptoms that are consistent with nephritic syndrome include:
Hematuria (red blood cells in the urine)
Proteinuria (protein in the urine) ranging from sub-nephrotic (<3.5 g/day) to >10 g/day, although it is rarely above nephrotic range proteinuria levels.
Hypertension resting blood pressure is persistently at or above 130/80 or 140/90 mmHg.
Blurred vision
Azotemia (increased plasma Urea and Creatinine)
Oliguria (low urine output <400 ml/day)
Red blood cell casts (seen with urinalysis and microscopy)
Pyuria (white blood cells or pus in the urine)
Causes
Nephritic syndrome is caused by extensive inflammatory damage to the glomerulus capillaries, which is associated with a variety of medical conditions that we will discuss. Furthermore, the cause of this inflammation can be infectious, autoimmune, or thrombotic. The causative conditions can be divided conveniently between age groups as follows, though it is important to note that many of the conditions listed in children/adolescents can also occur in adults with lower frequency, and vice versa:
Children/adolescents
IgA nephropathy (Note: Contrast time of onset with Post-streptococcal Glomerulonephritis) - Most commonly diagnosed in children who recently had an upper respiratory tract infection (URI). Symptoms typically present within 1–2 days of a non-specific URI with severe flank/abdominal pain, gross hematuria (characterized by dark brown or red colored urine), and edema of the hands, feet, and/or face.
Post-streptococcal glomerulonephritis (PSGN) - Similar to IgA nephropathy, post-streptococcal glomerulonephritis (PSGN) most often occurs in children who have recently had an upper respiratory infection (URI). In contrast with IgA nephropathy, however, PSGN typically presents 2–3 weeks after recovering from an URI that was caused specifically by a Streptococcus bacteria. The symptoms at onset are very similar to IgA nephropathy and include abdominal pain, hematuria, edema, and oliguria.
Henoch–Schönlein purpura (HSP) - Often considered a systemic form of IgA nephropathy, Henoch–Schönlein purpura (HSP) is a systemic small-vessel vasculitis that is characterized by deposition of IgA antibody immune complexes in different key areas throughout the body. Most often, the condition presents in children with palpable purpura, abdominal pain, and arthritis. When the kidneys are affected, the IgA immune complexes deposit in the glomerulus very similarly to IgA nephropathy and will present in a similar way.
Hemolytic uremic syndrome - Most cases occur immediately following infectious diarrhea caused by a specific type of E. coli (O157:H7). The bacteria produces a toxin that causes widespread inflammation and numerous blood clots in small blood vessels (thrombotic microangiopathy). When the inflammation reaches the kidney, or the by-products of systemic inflammation build up in the kidney, the patient will begin showing signs of nephritic syndrome or potentially acute kidney failure (elevated creatinine, BUN, etc.).
Adults
Goodpasture syndrome - This is a rare autoimmune disease where autoantibodies are produced that target the glomerular basement membrane in both the lungs and the kidneys. The damage to the basement membrane causes bleeding, and the disease often presents in patients as hematuria and haemoptysis (coughing up blood). If not treated promptly with plasmapharesis to remove the autoantibodies, it can lead to permanent damage in the lungs/kidneys.
Systemic Lupus Erythematosus (SLE) - Better known as simply "Lupus", this autoimmune disease can affect nearly every major system in the human body and the kidneys are no exception. Autoantibodies produced in SLE can form immune complexes that deposit along the glomerular basement membrane and cause glomerular inflammation which leads to a nephritic syndrome.
Rapidly progressive glomerulonephritis - This is a syndrome of the kidney that is characterized by rapid loss of kidney function (usually >50% decline in glomerular filtration rate (GFR) within 3 months) with glomerular crescent formation frequently seen on kidney biopsy. Without treatment, it will quickly lead to kidney failure and potentially death within months. This syndrome has numerous underlying causes that can also cause nephritic syndrome, so this may be more of an association than a cause.
Infective endocarditis - Infection that affects the inner lining of the heart (endocardium) and can potentially cause a thrombus to form on one or more heart valves and, if left untreated, can cause septic emboli that can have many systemic effects, including deposition into the glomerulus, causing glomerulonephritis and nephritic syndrome.
Cryoglobulinemia - Antibodies that are sensitive to the cold can become activated in cold conditions and cause an increase in blood viscosity (hyperviscosity syndrome) as well as forming immune complexes that can deposit in the small blood vessels and can cause nephritic syndrome when this occurs in the kidneys.
Membranoproliferative glomerulonephritis (MPGN) - Another type of glomerulonephritis that is caused primarily by immune complex deposition in the glomerular mesangium and glomerular basement membrane thickening, which activates the complement cascade and damages the glomerulus. This damage leads to inflammation in the glomerulus and can present with a nephritic syndrome.
Other ANCA small-vessel vasculitides - The conditions included in this category are eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis, and granulomatosis with polyangiitis.
Pathophysiology
The pathophysiology of nephritic syndrome is dependent on the underlying disease process, which can vary depending on what condition the nephritic syndrome is secondary to. More specifically, different diseases (many of which are mentioned above in the Causes section) affect different segments of the glomerulus and cause disease-specific segments of the glomerulus to become inflamed. Most often, it is dependent on what part of the glomerulus is damaged by antibody-antigen complex (immune complex) deposition. In all cases, however, the inflammatory processes in the glomerulus cause the capillaries to swell and the pores between podocytes become large enough that inappropriate contents in the blood plasma (i.e. red blood cells, protein, etc.) will begin to spill into the urine. This causes a decrease in glomerular filtration rate (GFR) and, if left untreated over time, will eventually produce uremic symptoms and retention of sodium and water in the body, leading to both edema and hypertension.
Diagnosis
The diagnostic approach to nephritic syndrome includes evaluating the patient for any suspected underlying pathology that could cause a nephritic syndrome.
Physical examination
If the person in the office is being examined by a physician, some physical exam findings consistent with nephritic syndrome include the following:
Edema - This could present as generalized edema (anasarca) or specific swelling of the hands, feet, and/or face.
Other signs of fluid overload - Diffuse rales (crackles) may be heard at bilateral lung bases or diffusely in all lung fields on auscultation with a stethoscope. Jugular venous distention (JVD) may also be appreciated when visualizing the veins of the neck on physical exam.
Elevated blood pressure - Measured at least two separate times with at least two minutes between measurements using a sphygmomanometer or equivalent method.
Abnormal heart sounds - If the underlying cause is cardiac in nature (such as infective endocarditis), then you may appreciate abnormal heart sounds during auscultation of the heart.
Laboratory testing
If the physician is suspicious of a possible nephritic syndrome, then he/she may order some common lab tests including:
Serum electrolytes - The kidney is one of the main regulators of electrolytes in the human body and measuring the different electrolyte levels using either a basic metabolic panel (BMP) or comprehensive metabolic panel (CMP) can be a useful indicator of the underlying pathology.
Serum creatinine - Also measured using a BMP or CMP, creatinine is one of the most important indicators of current kidney function and is used to calculate the glomerular filtration rate (GFR). An elevated creatinine level is considered abnormal and may indicate decreased kidney function.
Blood urea nitrogen (BUN) - Also measured using a BMP or CMP, blood urea nitrogen is an indicator of how much nitrogen is in the blood at the time of the phlebotomy. The kidney is responsible for excreting nitrogenous substances in the urine, so an elevated BUN usually indicates that the kidney is not functioning appropriately.
Urine Analysis (Urinalysis) - After the patient provides a urine specimen, it is sent to the lab for analysis using a variety of methods including urine dipstick testing and microscopic examination. Because the kidney is responsible for making urine, analyzing the urine directly can provide crucial data that can help the physician diagnose nephritic syndrome. Some findings on urinalysis that are consistent with nephritic syndrome include red blood cells (hematuria), red blood cell casts, proteinuria, and possibly white blood cells (pyuria).If nephritic syndrome is identified and diagnosed, then it is important for the physician to determine the underlying cause. To do this, he/she may order any of a large variety of relevant lab tests, some of which are included here:
Blood culture - This is the process where a sample of the patients blood is sent to the microbiology lab to attempt to isolate and grow any bacteria that may be circulating in the blood, in order to identify the pathogen. This is helpful if the physician suspects infection as the underlying cause of the nephritic syndrome.
Antinuclear antibody (ANA) titer - ANA is commonly positive in patients who have an underlying autoimmune disease, so this test is useful if the physician suspects an underlying autoimmune disease (refer to the Causes section above for examples) as the cause of the presenting nephritic syndrome. If positive, then the physician may order additional tests to determine which autoimmune condition is the cause and how best to treat it.
Antiglomerular basement membrane (anti-GBM) antibody - If positive, this is highly indicative of Goodpastures syndrome and can be used to guide treatment.
Antineutrophil cytoplasmic antibody (ANCA) - If positive, this indicates that there is likely an underlying vasculitis that may be causing the acute nephritic syndrome.
Serum complement (C3 and C4) - Complement factors bind to antibodies to form immune complexes and a decreased serum complement level could indicate that the complement is being consumed at a higher rate due to the formation of immune complexes leading to deposition in the glomerulus of the kidney.
Invasive testing
A kidney biopsy will provide a fully definitive diagnosis of nephritic syndrome and may also reveal the underlying cause of the nephritic syndrome depending on the underlying pathological process. On biopsy, a patient with nephritic syndrome would show inflammation of numerous glomeruli.
Treatment
When a patient is confirmed to have nephritic syndrome, the main goal of treatment (regardless of the underlying cause) is to control elevated blood pressures and reduce active inflammation in the kidney itself. Most often, the patient will need to be admitted to the hospital for close monitoring to ensure the efficacy of treatment and make adjustments as needed. Some treatment modalities commonly used to meet these goals include:
Bed rest during the recovery process to ensure administration of optimal medical therapy with as low of a risk as possible for any exacerbating factors (falls, infection, etc.).
Fluid restriction to minimize the risk of edema (if not already present) or to reduce any active edema that may be present.
A special diet during the hospital stay that restricts sodium, potassium, and fluids in conjunction with the previously mentioned fluid restriction in an attempt to control symptoms of fluid overload.
Administration of diuretics if patient is showing signs of fluid overload. This will cause excess fluids to be excreted in the urine and may lessen the workload placed on the kidney, allowing it to recover from the inflammatory damage.
Administration of antihypertensives to alleviate hypertension and maintain a normal blood pressure during the recovery process.
Administration of anti-inflammatory medications (such as steroids or NSAIDs) to reduce active inflammation in the kidney.
If the patient is showing signs of kidney failure or end-organ damage, the treatment team may opt to utilize kidney dialysis temporarily (or permanently, in some severe cases) to decrease stress on the kidneys and allow for optimal recovery.Once the acute phase of the nephritic syndrome is controlled, it is crucial to determine the underlying pathology that caused the onset of the acute nephritic syndrome and to treat that condition. If the underlying cause is not determined and treated appropriately, it increases the risk of a recurrence of nephritic syndrome or chronic kidney disease (CKD) in the future.
Prognosis
Because nephritic syndrome is a syndrome and not a disease, the prognosis depends on the underlying cause. Generally, the prognosis of nephritic syndrome in children is better than it is in adults.
Epidemiology
According to the CDC, nephritis/nephrosis/nephritic syndrome was the 9th leading cause of death in the United States in 2017. It was listed as the cause of death for 50,633 out of the total 2,813,503 deaths reported in 2017.
Geography
The southeast region of the United States reported a significantly higher death rate due to kidney disease than any other region in 2017. Mississippi reported the highest death rate due to kidney disease (21.7), followed by Louisiana (20.6) and Arkansas (19.7). Although Vermont reported the lowest death rate due to kidney disease (3.3), the western United States reported the lowest regional average death rate due to kidney disease in 2017.
Gender
Out of the 1,374,392 female deaths reported in the US in 2017, kidney disease was listed as the cause of death for 24,889 women and was reported as the 9th overall cause of death for women in 2017.Out of the 1,439,111 male deaths reported in the US in 2017, kidney disease was not listed in the top 10 causes of death.
Race and ethnicity
Out of the 2,378,385 deaths reported in individuals who identified as White, kidney disease was ranked 10th overall (39,105 deaths) in causes of death in the US in 2017.Out of the 340,644 deaths reported in individuals who identified as Black or African American, kidney disease was ranked 8th overall (9,609 deaths) in causes of death in the US in 2017.Out of the 74,094 deaths reported in individuals who identified as Asian or Pacific Islander, kidney disease was ranked 9th overall (1,563 deaths) in causes of death in the US in 2017.Out of the 197,249 deaths reported in individuals who identified as Hispanic or Latino, kidney disease was ranked 10th overall (3,928 deaths) in causes of death in the US 2017.
Other countries of world
In a review of Romanian cases, a 10-year review yielded that upon biopsy, nephritic syndrome was the second most common clinical syndrome at 21.9% (nephrotic syndrome was 52.3%)
References
Further reading
Crutchlow, Eileen M.; Dudac, Pamela J.; MacAvoy, Suzanne; Madara, Bernadette R. (2002-01-01). Pathophysiology. Jones & Bartlett Learning. ISBN 9781556425653.
Schrier, Robert W. (2014-05-13). Manual of Nephrology. Lippincott Williams & Wilkins. ISBN 9781469887364.
== External links == |
Interstitial granulomatous dermatitis with arthritis | Interstitial granulomatous dermatitis with arthritis (IGDA) or Ackerman dermatitis syndrome is a skin condition that most commonly presents with symmetrical round-to-oval red or violet plaques on the flanks, armpits, inner thighs, and lower abdomen.
See also
Skin lesion
References
== External links == |
Cross syndrome | Cross–McKusick–Breen syndrome (also known as "Cross syndrome", "hypopigmentation and microphthalmia", and "oculocerebral-hypopigmentation syndrome") is an extremely rare disorder characterized by white skin, blond hair with yellow-gray metallic sheen, small eyes with cloudy corneas, jerky nystagmus, gingival fibromatosis and severe intellectual disability and physical retardation.: 867–8 It was characterized in 1967.
See also
Oculocerebrocutaneous syndrome
List of cutaneous conditions
References
External links
http://www.whonamedit.com/synd.cfm/1387.html |
Mineral deficiency | Mineral deficiency is a lack of the dietary minerals, the micronutrients that are needed for an organisms proper health. The cause may be a poor diet, impaired uptake of the minerals that are consumed, or a dysfunction in the organisms use of the mineral after it is absorbed. These deficiencies can result in many disorders including anemia and goitre. Examples of mineral deficiency include, zinc deficiency, iron deficiency, and magnesium deficiency.
Individual Mineral Deficiency
See also
Mineral (nutrient)
Micronutrient deficiency
Vitamin deficiency
References
== External links == |
Congenital cataract | Congenital cataracts refers to a lens opacity which is present at birth. Congenital cataracts cover a broad spectrum of severity: whereas some lens opacities do not progress and are visually insignificant, others can produce profound visual impairment.
Congenital cataracts may be unilateral or bilateral. They can be classified by morphology, presumed or defined genetic cause, presence of specific metabolic disorders, or associated ocular anomalies or systemic findings.
Signs and symptoms
Congenital cataracts occur in a variety of morphologic configurations, including lamellar, polar, sutural, coronary, cerulean, nuclear, capsular, complete, membranous.
Cause
In general, approximately one-third of congenital cataracts are a component of a more extensive syndrome or disease (e.g., cataract resulting from congenital rubella syndrome), one-third occur as an isolated inherited trait, and one-third result from undetermined causes. Metabolic diseases tend to be more commonly associated with bilateral cataracts.
Genetics
Approximately 50% of all congenital cataract cases may have a genetic cause which is quite heterogeneous. It is known that different mutations in the same gene can cause similar cataract patterns, while the highly variable morphologies of cataracts within some families suggest that the same mutation in a single gene can lead to different phenotypes. More than 25 loci and genes on different chromosomes have been associated with congenital cataract. Mutations in distinct genes, which encode the main cytoplasmic proteins of human lens, have been associated with cataracts of various morphologies, including genes encoding crystallins (CRYA, CRYB, and CRYG), lens specific connexins (Cx43, Cx46, and Cx50), major intrinsic protein (MIP) or Aquaporin, cytoskeletal structural proteins, paired-like homeodomain transcription factor 3 (PITX3), avian musculoaponeurotic fibrosarcoma (MAF), and heat shock transcription factor 4 (HSF4).
Diagnosis
All newborns should have screening eye examinations, including an evaluation of the red reflexes.
The red reflex test is best performed in a darkened room and involves shining a bright direct ophthalmoscope into both eyes simultaneously from a distance of 1– 2 ft. This test can be used for routine ocular screening by nurses, pediatricians, family practitioners, and optometrists.
Retinoscopy through the childs undilated pupil is helpful for assessing the potential visual significance of an axial lens opacity in a pre-verbal child. Any central opacity or surrounding cortical distortion greater than 3 mm can be assumed to be visually significant.
Laboratory Tests : In contrast to unilateral cataracts, bilateral congenital cataracts may be associated with many systemic and metabolic diseases. A basic laboratory evaluation for bilateral cataracts of unknown cause in apparently healthy children includes:- Urine test for reducing substance, galactose 1-phosphate uridyltransferase, galactokinase, amino acids
- Infectious diseases: TORCH and varicella titers, VDRL
- Serum calcium, phosphorus, glucose and ferritin
Treatment
Surgery
In general, the younger the child, the greater the urgency in removing the cataract, because of the risk of amblyopia. For optimal visual development in newborns and young infants, a visually significant unilateral congenital cataract should be detected and removed before age 6 weeks, and visually significant bilateral congenital cataracts should be removed before age 10 weeks.Some congenital cataracts are too small to affect vision, therefore no surgery or treatment will be done. If they are superficial and small, an ophthalmologist will continue to monitor them throughout a patients life. Commonly, a patient with small congenital cataracts that do not affect vision will eventually be affected later in life; generally this will take decades to occur.
Epidemiology
Congenital cataract are responsible for nearly 10% of all vision loss in children worldwide.
Congenital cataract are one of the most common treatable causes of visual impairment and blindness during infancy, with an estimated prevalence of 1 to 6 cases per 10,000 live births.
References
== External links == |
Intracranial hemorrhage | Intracranial hemorrhage (ICH), also known as intracranial bleed, is bleeding within the skull. Subtypes are intracerebral bleeds (intraventricular bleeds and intraparenchymal bleeds), subarachnoid bleeds, epidural bleeds, and subdural bleeds. More often than not it ends in a lethal outcome.
Intracerebral bleeding affects 2.5 per 10,000 people each year.
Signs and symptoms
Intracranial hemorrhage is a serious medical emergency because the buildup of blood within the skull can lead to increases in intracranial pressure, which can crush delicate brain tissue or limit its blood supply. Severe increases in intracranial pressure (ICP) can cause brain herniation, in which parts of the brain are squeezed past structures in the skull.
Causes
Trauma is the most common cause of intracranial hemorrhage. It can cause epidural hemorrhage, subdural hemorrhage, and subarachnoid hemorrhage. Other condition such as hemorrhagic parenchymal contusion and cerebral microhemorrhages can also be caused by trauma.Non-traumatic causes of hemorrhage includes: hypertension, cerebral amyloid angiopathy, hemorrhagic conversion of ischemic infarction, cerebral aneurysms, dural arteriovenous fistulae, cerebral venous sinus thrombosis, cerebral vasculitis and mycotic aneurysm.More than half of all cases of intracranial hemorrhage are the result of hypertension.
Diagnosis
CT scan (computed tomography) of the brain (without any iodinated contrast), is the initial imaging choice because of its high speed, good accessibility in hospitals, high sensitivity in detecting brain injuries or brain diseases, thus helping to triage patients in emergency department in a timely manner and urgent neurosurgical intervention can be administered. Examples of brain diseases that require urgent intervention are: large volume hemorrhage, brain herniation, and cerebral infarction. Other advantages of CT over MRI scan are ability to detect bony fractures, vascular injury, and cerebrospinal fluid (CSF) leak. It also does not need to screen for MRI safety of implants/foreign body especially for penetrating or blast injuries.However, MRI has higher sensitivity than CT scan for the detection of epidural hemorrhage, subdural hemorrhage, subarachnoid hemorrhage, nonhemorrhagic cortical contusions, hemorrhagic parenchymal contusions, brainstem injuries, and white matter axonal injuries. If CT scan shows normal findings, but the subject has persistent neurological symptoms, MRI is also indicated. However, MRI safety concerns on metallic foreign bodies, limited availability, longer imaging time, high sensitivity to motion, and higher cost limits the usefulness of MRI.Swirl sign on CT scan (areas of low densities with surrounding areas of high densities) is indicative of active intracranial bleeding, high chance of death within one month, and poor subjects function in three months if the subject is still alive.When ICP is increased the heart rate may be decreased.
Traumatic
Types of intracranial hemorrhage are roughly grouped into intra-axial and extra-axial. Intra-axial hemorrhage is bleeding within the brain itself, or cerebral hemorrhage. This category includes intraparenchymal hemorrhage, or bleeding within the brain tissue, and intraventricular hemorrhage, bleeding within the brains ventricles (particularly of premature infants). Intra-axial hemorrhages are more dangerous and harder to treat than extra-axial bleeds. Hemorrhagic parenchymal contusions and cerebral microhemorrhages are examples of traumatic intra-axial bleeds.Extra-axial hemorrhage, bleeding that occurs within the skull but outside of the brain tissue, falls into three subtypes: epidural hematoma, subdural hematoma, and subarachnoid hemorrhage.
Hemorrhagic parenchymal contusion
This condition most commonly occurred in those with significant head movement or head impact. It is caused by injuries of small arterial or venous vessels, causing hemorrhage within the brain parenchyma, and give rise to hyperdense lesion on CT scan. MRI is more sensitive than CT scan in detecting such small hemorrhagic contusions, with the use of gradient echo sequence. Contusions are more commonly seen in the brain parenchyma near base of the skull such as inferior frontal lobes and temporal lobes as a result of Coup contrecoup injury. Those with parenchymal contusion would require frequent follow-up imaging because such contusions may grow large enough to become hemorrhage and exerts significant mass effect on the brain.Cerebral microhemorrhages is a smaller form of hemorrhagic parenchymal contusion and are typically found in white matter. Such microhemorrhages are difficult to be detected on CT scan, but easily detected on gradient echo and susceptibility weighted imaging on MRI scan as hypointense susceptibility blooming. Such microhemorrhages are frequently associated with diffuse axonal injury and located near the grey-white matter junction.
Epidural hemorrhage
Epidural hemorrhage (extradural hemorrhage, EDH) which occur between the dura mater (the outermost meningeal layer) and the skull, is caused by trauma. It does not cross the suture lines of the skull because the superifical dural layer is attached tightly to the skull along the suture lines. Unless rarely, fracture involves the suture lines (more common in children), then epidural hematoma may cross the suture lines. As the blood accumulated in the epidural space is confined within suture lines, accumulation of additional blood will cause bulging in this space, and thus resulting in a typical "biconvex" appearance on CT scans. EDH can be due to arterial or venous rupture depending on the locations. Arterial injuries results in more rapidly growing hematoma when compared to venous injuries. At the pterion region, middle meningeal artery is most commonly affected. When fracture is crossing areas where dural venous sinuses resides, venous hemorrhage can occur such as falx cerebri, tentorium cerebelli, and vertex (where superior sagittal sinus resides). Anterior temporal EDH is usually caused by sphenoparietal sinus. Such EDH is limited and does not require surgery because its extension is confined within sphenosquamosal suture and orbital fissure. In 20 to 50% of epidural hemorrhage cases, there is a lucid interval where a person regained consciousness after being knocked unconscious and then followed by deterioration of consciousness after that.When the epidural hematoma is large enough, it will cause mass effect on contralateral brain which lead to midline, subfalcine (below the falx cerebri), and trans-tentorial (crossing tentorium cerebelli) herniations. This phenomenon can cause the subject to lose consciousness and eventually death. Therefore, large EDH requires emergent surgical clot evacuation. Embolisation of middle meningeal artery is performed if the hemorrhage is medium or small.
Subdural hemorrhage
Subdural hemorrhage (SDH) results from tearing of the bridging veins in the subdural space between the dura and arachnoid mater. It can cross the suture lines, but not across dural reflections such as falx cerebri or tentorium cerebelli. Therefore, subdural hematoma always limited to one side of the brain. Density of SDH reduces as it progresses from acute to chronic forms. However, areas with low density may not represent chronic SDH entirely as unclotted blood products that are due to active bleed can also give low density appearance on CT scans especially those with coagulopathy. Those with SDH that have same density with brain parenchyma may represent acute bleed such as those with anemia, arachnoid tear, and the mixing of hemorrhage and CSF. SDH usually have high or mixed densities during first two days of trauma, followed by isodensity at 11 days after trauma, and hypodensity after 14 days of trauma. Membranes with granulation tissue can rupture within SDH, and give high density appearance on CT scan. Over a prolonged period of time, calcifications can form. SDH can be treated with burr hole drainage, craniotomy or port system placement for blood clot evacuation, or middle meningeal artery embolisation.Subdural hematoma maybe less acute than epidural hematoma due to slower blood accumulation, but it still has the potential to cause brain herniation that may require surgical evacuation. Clinical features depend on the site of injury and severity of injury. Patients may have a history of loss of consciousness but they recover and do not relapse. Clinical onset occurs over hours. Complications include focal neurologic deficits depending on the site of hematoma and brain injury, increased intracranial pressure leading to herniation of brain and ischemia due to reduced blood supply and seizures.
Subarachnoid hemorrhage
A subarachnoid hemorrhage (SAH) is bleeding into the subarachnoid space—the area between the arachnoid membrane and the pia mater surrounding the brain. Trauma can also cause SAH when the arteries and veins coursing through the subarachnoid space are ruptured. It is usually located at the cerebral sulci near the vertex of the head and spare the basal cisterns on CT scan. Severe trauma can cause SAH in all parts of the brain. When the SAH volume is large, rarely it can cause cerebral infarction a few days after trauma due to arterial vasospasm. Although CT scan is performed more often than MRI to detect SAH, MRI is more sensitive than CT in this aspect. SAH shows hyperintense signal of Fluid-attenuated inversion recovery (FLAIR) sequence and blooming artifact on susceptibility weighted imaging (SWI).Computed tomography angiography (CT angiography) or Magnetic resonance angiography (MR angiography) should be done if fracture involves the carotid canal, because in such cases, posttraumatic vasospasm can occur, thus cutting blood supply to the brain. Besides, intracranial hemorrhage that are atypical for trauma should also be investigated further with CT or MR angiography to look for other causes of intracranial bleeds apart from trauma causes. Such atypical patterns includes: isolated SAH in the basal cisterns, isolated large-volume SAH in the Sylvian fissure, and isolated SAH in the anterior interhemispheric fissure. These cases warrants investigations to look for aneurysms that can cause such bleeding.
Non-traumatic
Hypertensive bleed
Intracranial bleed in hypertensive subjects usually occurs at 50 to 60 years of life with 30 to 50% chance of death. Such hemorrhages are typically located in the basal ganglia, cerebellum, or occipital lobes. Other location such as bleed within the cerebral cortex and intracranial bleed in people younger than 50 years should prompt further investigations on other causes of bleed such as brain tumour or cerebral arteriovenous malformation. The bleed can be very small without any significant effect on surrounding brain or large hemorrhage that exerts mass effecct on adjacent brain. Follow up CT scan is recommended. Those with extension of bleed into the ventricular system, expansion of bleeding, or increasing cerebral oedema on CT scan gives poorer prognosis. CT angiography (CTA) of brain can be performed to investigate the source of bleeding. An image during the delayed phase of the CTA may be taken to look for pooling of contrast that signifies active bleeding (known as "Spot sign"). Presence of "Spot sign" signifies poor clinical outcome for the subject.
Cerebral amyloid angiopathy
Cerebral amyloid angiopathy (CAA) is the deposition of Amyloid beta peptide protein within the brain. Accumulation of such peptide proteins within the walls of the arteries can cause weakening of the walls and causes microhemorrhages, SAH within the cerebral sulci or large cerebral intraparenchymal bleed. SAH in CAA can be differentiated from vasculitis by its presentations. SAH in CAA usually occurs in those who age more than 60 years, temporary motor and sensory deficits, and intracranial bleed in white matter adjacent to cerebral cortex. Basal ganglia, posterior fossa, and brainstem are spared. Boston criteria is used to determine the likelihood of a cerebral hemorrhage due to CAA. Definitive diagnosis of CAA is by performing brain biopsyCT scan may show hyperdense intra-axial hemorrhage in the subcortical region. Diffuse white matter hypodensities in both cerebral hemispheres may represents microangiopathic changes. On MRI these lesions will be presented as blooming artifact on gradient echo and susceptibility weighted imaging.
Hemorrhagic conversion of ishemic infarction
43% of those with infarcted brain tissue will develop hemorrhagic conversion. Risk of hemorrhagic is further increased with recanalisation of veins or arteries. Several types of hemorrhages can occur such as petechial hemorrhages around the infarcted margin (HI1), confluent petechial hemorrhages within the infarcted tissue (HI2), hematoma occupying less than 30% of the infarcted tissue (PH1), hematoma involving greater than 30% of infarcted tissue with small mass effect (PH2), and hematoma involving greater than 30% of the infarcted tissue with significant mass effect. However, only PH2 is clinically significant. Those who has infarction should be monitored frequently with CT brains to access hemorrhagic conversions or worsening vasogenic oedema that may require neurosurgical decompression. Dual energy CT scan maybe useful to differentiate the high densities caused by reperfusion hemorrhage (bleeding after endovascular stroke treatment) and high density due to iodinated contrast administered during cerebral angiography.
Cerebral aneurysm
Besides from head injury, it may occur spontaneously, usually from a ruptured cerebral aneurysm (focal outpouchings with weakened walls on the arteries on the brain surface that are prone to rupture). Symptoms of SAH include a severe headache with a rapid onset (thunderclap headache), vomiting, confusion or a lowered level of consciousness, and sometimes seizures. CT scan has 100% sensitivity of detecting SAH at 6 to 24 hours after symptoms onset. The diagnosis is generally confirmed with a CT scan of the head. If CT scan is normal but SAH is still strongly suspected, lumbar puncture can be done at six to twelfth hours after the onset of headache. This is determine the presence of blood within the cerebrospinal fluid (CSF). Those with SAH will have blood and bilirubin within CSF because of degradation red blood cells. Meanwhile, those who has blood within CSF due to traumatic lumbar puncture will not have bilirubin within CSF. SAH is generally located within basal cisterns, extends diffusely to all subarachnoid spaces (cerebral sulci) or into the ventricular system, or brain parenchyma. Modified Fisher scale is used to describe the volume and distribution of SAH, just predicting the probability of cerebral artery vasospasm after SAH.Treatment is by prompt neurosurgery or radiologically guided interventions with medications and other treatments to help prevent recurrence of the bleeding and complications. Since the 1990s, many aneurysms are treated by a minimal invasive procedure known as endovascular coiling, which is carried out by instrumentation through large blood vessels. However, this procedure has higher recurrence rates than the more invasive craniotomy with clipping.
Cerebral ateriovenous malformation
Cerebral ateriovenous malformation (Cerebral AVM) is characterised by abnormal shunting between cerebral arteries and veins without going through capillaries. Instead the blood goes through a collection of small vessels from arteries to veins. These collection of abnormal small vessels is termed as "nidus". This condition happens in 0.1% of the population has a risk of 2 to 4% per year for intracranial bleeding. Once ruptured, it results in intraparenchymal hemorrhage, intraventricular hemorrhage and SAH. Rupture of cerebral AVM often occurs in young people and children. Cerebral AVM can be diagnosed by computed tomography angiography (CTA) brain, magnetic resonance angiography (MRA) brain, or digital subtraction angiography (DSA). DSA is important to determine whether there is nidal or perinidal aneurysm.
Dural arteriovenous fistulae
Dural arteriovenous fistulae (DAVF) is the direct connection between dural or cerebral arteries with dural venous sinuses or cortical veins. It accounts for 10 to 15% of intracranial arteriovenous shunts. DAVF lacks a nidus. Signs and symptoms of DAVF are: headache, tinnitus, neurological deficits involving cranial nerves, and increased intracranial pressure. DAVF once ruptured, will produce intraparenchymal hemorrhage or SAH. Increase in number of vessels near dural venous sinuses as seen on CTA is suggestive of DVAF. 4DCT may increase the sensitivity of detecting DAVF. In MRI scans, susceptibility weighted imaging (SWI) and arterial spin labelling sequences (labelling protons in blood without the use of contrast media to determine blood flow) are useful in evaluating DAVF. The patterns of draining veins from the fistula determines the risk of DAVF rupture. Increased pressure within the dural venous sinuses causes backpressure into the cortical veins, thus making cortical veins more prone to rupture. The risk of hemorrhage is graded by Cognard and Borden grading systems. These grading systems are based upon the DSA.
Cortical venous/cerebral venous sinus thrombosis
Dural venous sinus thrombosis (DVST) and cortical venous thrombosis (CVT) commonly presents with headache, increased intracranial pressure, or seizures. DVST is more common than CVT. DVST are frequently caused by infections in the skull base, dehydration, thrombophilia, meningioma, and other dural tumours. On CT scans, brain parenchymal hemorrhage that does not confined to specific arterial territory along with hyperdense appearance on dural venous sinuses raises the suspicion of DVST. Further evaluation with CT venography, MR venography, and post gadolinium MRI provides accurate diagnosis of venous thrombosis and follow-up after treatment. These studies demonstrate thrombus as filling defect or lack of signal.
Vasculitis/vasculopathy
Those with vasculitis may be presented with headache, behavioural changes, neurological deficits, or intracranial bleeding. Sulcal SAH is the most common form of intracranial bleed caused by vasculitis. On CT scans, sulcal SAH is seen as hyperdensity within the cerebral sulcus, while on MRI, it is seen as hyperintensity on FLAIR sequence, and hypointensity on GRE/SWI sequence. DSA is important in making the diagnosis of vasculitis or vasculopathy.
Mycotic aneurysm
It is arterial outpouchings arise from distal cerebral arteries. These are pseudoaneurysm, caused by thrombus clogging the distal arteries, which results in inflammation and small tears at the site of occlusion. These inflammation and thrombis can caused by infective endocarditis, artificial heart valve or other heart problems. Similar to vasculitis, rupture of mycotic aneurysm also causes SAH in cerebral sulci, mostly located in the vertex. If mycotic aneurysm is located more proximally, it will produce diffuse SAH pattern. CTA or MRA would produce focal outpouching or increase in diameter of the vessel. Meanwhile, GRE/SWI MRI sequence would produce focal hypointensity. Small mycotic aneurysms are difficult to be seen on CT or MRI. Thus, DSA is useful in identifying these lesions.
Management
For those who is already on blood thinners such as aspirin or clopidogrel for prevention of myocardial infarction or stroke, traumatic intracranial hemorrhage should prompt the use of platelet function assays (PFA-100) to assess the effect of these antiplalelet agents. After that, plateletpheresis can be started to increase the aggregation of platelets, thus stopping the intracranial bleed. In those with impaired kidney functions, desmopressin or cryoprecipitate can be used instead.From limited observational data, it may be relatively safe to restart blood thinners after an ICH as it is asscoated with reduced thromboembolic complications with similar risk of recurrent hemorrhage when compared to those did not start blood thinners after an ICH.
Comparison
References
Further reading
Shepherd S. 2004. "Head Trauma." Emedicine.com.
Vinas FC and Pilitsis J. 2004. "Penetrating Head Trauma." Emedicine.com.
Julian A. Mattiello, M.D., Ph.D. Michael Munz, M.D. 2001. "Four Types of Acute Post-Traumatic Intracranial Hemorrhage" The New England Journal of Medicine
== External links == |
Pretibial myxedema | Pretibial myxedema (myxoedema in British English, also known as Graves dermopathy, thyroid dermopathy, Jadassohn-Dösseker disease or myxoedema tuberosum) is an infiltrative dermopathy, resulting as a rare complication of Graves disease, with an incidence rate of about 1–5%.
Signs and symptoms
Pretibial myxedema is almost always preceded by the ocular signs found in Graves disease.
It usually presents itself as a waxy, discolored induration of the skin—classically described as having a so-called peau dorange (orange peel) appearance—on the anterior aspect of the lower legs, spreading to the dorsum of the feet, or as a non-localised, non-pitting edema of the skin in the same areas. In advanced cases, this may extend to the upper trunk (torso), upper extremities, face, neck, back, chest and ears.
The lesions are known to resolve very slowly. Application of petroleum jelly on the affected area could relieve the burning sensation and the itching. It occasionally occurs in non-thyrotoxic Graves disease, Hashimotos thyroiditis, and stasis dermatitis. The serum contains circulating factors which stimulate fibroblasts to increase synthesis of glycosaminoglycans.
Risk factors
There are suggestions in the medical literature that treatment with radioactive iodine for Graves hyperthyroidism may be a trigger for pretibial myxedema which would be consistent with radioiodine ablation causing or aggravating ophthalmopathy, a condition which commonly occurs with pretibial myxedema and is believed to have common underlying features.Other known triggers for ophthalmopathy include thyroid hormone imbalance, and tobacco smoking, but there has been little research attempting to confirm these are also risk factors for pretibial myxedema.
Diagnosis
A biopsy of the affected skin reveals mucin in the mid- to lower- dermis. There is no increase in fibroblasts. Over time, secondary hyperkeratosis may occur, which may become verruciform. Many of these patients may also have co-existing stasis dermatitis. Elastic stains will reveal a reduction in elastic tissue.
Management
Many cases of pretibial myxedema, particularly cases that are mild, can be managed without specific pharmacologic treatment; approximately 50% of mild cases achieve complete remission without treatment after several years. When pharmacologic treatment is considered, topical, locally injected, or systemic corticosteroids may be used.
References
== External links == |
Psychotic depression | Psychotic depression, also known as depressive psychosis, is a major depressive episode that is accompanied by psychotic symptoms. It can occur in the context of bipolar disorder or major depressive disorder. It can be difficult to distinguish from schizoaffective disorder, a diagnosis that requires the presence of psychotic symptoms for at least two weeks without any mood symptoms present. Unipolar psychotic depression requires that the psychotic features occur only during episodes of major depression. Diagnosis using the DSM-5 involves meeting the criteria for a major depressive episode, along with the criteria for "mood-congruent or mood-incongruent psychotic features" specifier.
Signs and symptoms
Individuals with psychotic depression experience the symptoms of a major depressive episode, along with one or more psychotic symptoms, including delusions and/or hallucinations. Delusions can be classified as mood congruent or incongruent, depending on whether or not the nature of the delusions is in keeping with the individuals mood state. Common themes of mood congruent delusions include guilt, persecution, punishment, personal inadequacy, or disease. Half of patients experience more than one kind of delusion. Delusions occur without hallucinations in about one-half to two-thirds of patients with psychotic depression. Hallucinations can be auditory, visual, olfactory (smell), or haptic (touch), and are congruent with delusional material. Affect is sad, not flat. Severe anhedonia, loss of interest, and psychomotor retardation are typically present.
Cause
Psychotic symptoms tend to develop after an individual has already had several episodes of depression without psychosis. However, once psychotic symptoms have emerged, they tend to reappear with each future depressive episode. The prognosis for psychotic depression is not considered to be as poor as for schizoaffective disorders or primary psychotic disorders. Still, those who have experienced a depressive episode with psychotic features have an increased risk of relapse and suicide compared to those without psychotic features, and they tend to have more pronounced sleep abnormalities.Family members of those who have experienced psychotic depression are at increased risk for both psychotic depression and schizophrenia.Most patients with psychotic depression report having an initial episode between the ages of 20 and 40. As with other depressive episodes, psychotic depression tends to be episodic, with symptoms lasting for a certain amount of time and then subsiding. While psychotic depression can be chronic (lasting more than 2 years), most depressive episodes last less than 24 months. A study conducted by Kathleen S. Bingham found that patients receiving appropriate treatment for psychotic depression went into "remission". They reported a quality of life similar to that of people without PD.
Pathophysiology
There are a number of biological features that may distinguish psychotic depression from non-psychotic depression. The most significant difference may be the presence of an abnormality in the hypothalamic pituitary adrenal axis (HPA). The HPA axis appears to be dysregulated in psychotic depression, with dexamethasone suppression tests demonstrating higher levels of cortisol following dexamethasone administration (i.e. lower cortisol suppression). Those with psychotic depression also have higher ventricular-brain ratios than those with non-psychotic depression.
Diagnosis
Differential diagnosis
Psychotic symptoms are often missed in psychotic depression, either because patients do not think their symptoms are abnormal or they attempt to conceal their symptoms from others. On the other hand, psychotic depression may be confused with schizoaffective disorder. Due to overlapping symptoms, differential diagnosis includes also dissociative disorders.
Treatment
Several treatment guidelines recommend pharmaceutical treatments that include either the combination of a second-generation antidepressant and atypical antipsychotic or tricyclic antidepressant monotherapy or electroconvulsive therapy (ECT) as the first-line treatment for unipolar psychotic depression.There is no evidence for or against the use of mifepristone.
Combined antidepressant and antipsychotic medications
There is some evidence indicating that combination therapy with an antidepressant plus an antipsychotic is more effective in treating psychotic depression than either antidepressant treatment alone or placebo. In the context of psychotic depression, the following are the most well-studied antidepressant/antipsychotic combinations:
First-generation
Amitriptyline/perphenazine
Amitriptyline/haloperidolSecond-generation
Venlafaxine/quetiapine
Olanzapine/fluoxetine
Olanzapine/sertraline
Antidepressant medications
There is insufficient evidence to determine if treatment with an antidepressant alone is effective. Tricyclic antidepressants may be particularly dangerous, because overdosing has the potential to cause fatal cardiac arrhythmias.
Antipsychotic medications
There is insufficient evidence to determine if treatment with antipsychotic medications alone is effective. Olanzapine may be an effective monotherapy in psychotic depression, although there is evidence that it is ineffective for depressive symptoms as a monotherapy; and olanzapine/fluoxetine is more effective. Quetiapine monotherapy may be particularly helpful in psychotic depression since it has both antidepressant and antipsychotic effects and a reasonable tolerability profile compared to other atypical antipsychotics. The current drug-based treatments of psychotic depression are reasonably effective but can cause side effects, such as nausea, headaches, dizziness, and weight gain.
Electroconvulsive therapy (ECT)
In modern practice of ECT a therapeutic clonic seizure is induced by electric current via electrodes placed on a person under general anesthesia. Despite much research the exact mechanism of action of ECT is still not known. ECT carries the risk of temporary cognitive deficits (e.g., confusion, memory problems), in addition to the burden of repeated exposures to general anesthesia.
Research
Efforts are made to find a treatment which targets the proposed specific underlying pathophysiology of psychotic depression. A promising candidate was mifepristone, which by competitively blocking certain neuro-receptors, renders cortisol less able to directly act on the brain and was thought to therefore correct an overactive HPA axis. However, a Phase III clinical trial, which investigated the use of mifepristone in PMD, was terminated early due to lack of efficacy.Transcranial magnetic stimulation (TMS) is being investigated as an alternative to ECT in the treatment of depression. TMS involves the administration of a focused electromagnetic field to the cortex to stimulate specific nerve pathways.
Research has shown that psychotic depression differs from non-psychotic depression in a number of ways: potential precipitating factors, underlying biology, symptomatology beyond psychotic symptoms, long-term prognosis, and responsiveness to psychopharmacological treatment and ECT.
Prognosis
The long-term outcome for psychotic depression is generally poorer than for non-psychotic depression.
== References == |
Angel-shaped phalango-epiphyseal dysplasia | Angel-shaped phalango-epiphyseal dysplasia, also known as peripheral dysostosis, is a rare type of osteochondrodysplasia which is characterized by angel-shaped middle phalanges of the fingers and generalized metaphyseal dysplasia/delayed osseous age. Additional findings include joint hypermobility, hypodontia, and hip osteoarthritis. According to OMIM, 10 cases from multiple families have been described in medical literature. It is thought to be inherited in an autosomal dominant manner. According to ORPHA, 20 cases have been reported.
Presentation
The middle phalanges (often those of the 2nd, 3rd and 5th digits of the hands) angel shape is caused by an abnormal development of the epiphysis, metaphysis, and diaphysis of said phalanges; the wings are formed by an abnormal dyaphysis, the angels skirt is from a cone-shaped epiphysis, and the head is formed by an abnormal distal pseudoepophysis.
Genetics
This disorder is thought to be caused by autosomal dominant mutations in the GDF5 gene, in chromosome 20.
History
This condition was first discovered in 1967, by Bachman et al. when he described a "hereditary peripheral dysostosis" on one woman and 2 of her children.
Eponym
This disorders name comes from the fact that Bachman et al. (the researchers who originally described the disorder) and Giedion et al. missed a characteristic feature that the people diagnosed with the disorder shared: a middle phalange that had a striking resemblance to the shape of decorative angels of small size that are often put in Christmas trees.
== References == |
Renal glycosuria | Renal glycosuria is a rare condition in which the simple sugar glucose is excreted in the urine despite normal or low blood glucose levels. With normal kidney (renal) function, glucose is excreted in the urine only when there are abnormally elevated levels of glucose in the blood. However, in those with renal glycosuria, glucose is abnormally elevated in the urine due to improper functioning of the renal tubules, which are primary components of nephrons, the filtering units of the kidneys.
Signs and symptoms
In most affected individuals, the condition causes no apparent symptoms (asymptomatic) or serious effects. When renal glycosuria occurs as an isolated finding with otherwise normal kidney function, the condition is thought to be inherited as an autosomal recessive trait.
Genetics
It is associated with SLC5A2, coding the sodium-glucose cotransporter 2.
Diagnosis
A doctor normally can diagnose renal glycosuria when a routine urine test (Urinalysis) detects glucose in the urine, while a blood test indicates that the blood glucose level is normal.
Treatment
The cause of glycosuria determines whether the condition is chronic or acute. However, the presence of glucose in urine is not necessarily a serious or life-threatening condition.Managing diabetes, hyperthyroidism and regular kidney function tests can help in reducing excretion of sugars in urine.Drugs like dapagliflozin and canagliflozin have recently been approved for lowering blood sugar levels in patients with type 2 diabetes mellitus.
See also
Sodium-glucose transport proteins
References
External links
Media related to Renal glycosuria at Wikimedia Commons |
Radicular pain | Radicular pain, or radiculitis, is pain "radiated" along the dermatome (sensory distribution) of a nerve due to inflammation or other irritation of the nerve root (radiculopathy) at its connection to the spinal column. A common form of radiculitis is sciatica – radicular pain that radiates along the sciatic nerve from the lower spine to the lower back, gluteal muscles, back of the upper thigh, calf, and foot as often secondary to nerve root irritation from a spinal disc herniation or from osteophytes in the lumbar region of the spine. Radiculitis indicates inflammation of the spinal nerve root, which may lead to pain in that nerves distribution without weakness as opposed to radiculopathy. When the radiating pain is associated with numbness or weakness, the diagnosis is radiculopathy if the lesion is at the nerve root and myelopathy if at the spinal cord itself.
See also
Intervertebral disc
Sciatica
Spinal disc herniation
References
== External links == |
Prurigo gestationis | Prurigo gestationis is an eruption consisting of pruritic, excoriated papules of the proximal limbs and upper trunk, most often occurring between the 20th and 34th week of gestation.The exact etiology is unknown, but it is considered likely to be a flareup of atopic dermatitis during pregnancy.It is sometimes considered to be a term encompassing Besniers prurigo gestationis and other conditions.It is sometimes considered a diagnosis of exclusion.
See also
Dermatoses of pregnancy
Ernest Henri Besnier
List of cutaneous conditions
== References == |
Pyomyositis | Pyomyositis is a bacterial infection of the skeletal muscles which results in an abscess. Pyomyositis is most common in tropical areas but can also occur in temperate zones.
Diagnosis
Diagnosis is done via the following manner:
Pus discharge culture and sensitivity
X ray of the part to rule out osteomyelitis
Creatinine phosphokinase (more than 50,000 units)
MRI is useful
Ultrasound guided aspiration
Treatment
The abscesses within the muscle must be drained surgically (not all patient require surgery if there is no abscess). Antibiotics are given for a minimum of three weeks to clear the infection.
Epidemiology
Pyomyositis is most often caused by the bacterium Staphylococcus aureus. The infection can affect any skeletal muscle, but most often infects the large muscle groups such as the quadriceps or gluteal muscles.Pyomyositis is mainly a disease of children and was first described by Scriba in 1885. Most patients are aged 2 to 5 years, but infection may occur in any age group. Infection often follows minor trauma and is more common in the tropics, where it accounts for 4% of all hospital admissions. In temperate countries such as the US, pyomyositis was a rare condition (accounting for 1 in 3000 pediatric admissions), but has become more common since the appearance of the USA300 strain of MRSA.Gonococcal pyomyositis is a rare infection caused by Neisseria gonorrhoeae.
Additional images
References
Maravelas R, Melgar TA, Vos D, Lima N, Sadarangani S (2020). "Pyomyositis in the United States 2002-2014". J Infect. 80(5):497-503. doi:10.1016/j.jinf.2020.02.005. PMID 32147332.
== External links == |
Tooth pathology | Tooth pathology is any condition of the teeth that can be congenital or acquired. Sometimes a congenital tooth diseases are called tooth abnormalities. These are among the most common diseases in humans The prevention, diagnosis, treatment and rehabilitation of these diseases are the base to the dentistry profession, in which are dentists and dental hygienists, and its sub-specialties, such as oral medicine, oral and maxillofacial surgery, and endodontics. Tooth pathology is usually separated from other types of dental issues, including enamel hypoplasia and tooth wear.
Examples
Congenital
Anodontia
Acquired
Dental caries—Dental caries are known as cavities or tooth decay Bacteria in the mouth use foods that contain sugar or starch to produce acids which eat away at the tooth’s structure causing destruction to the enamel of the teeth. Meanwhile, the minerals in saliva (calcium and phosphate) together with fluoride are repairing the enamel. Dental caries is a chronic disease that can be prevented and show strongly in 6- to 11-year-old children and 12- to 19-year-old adolescents. 9 out of 10 adults are affected with some type of tooth decay. Prevention includes good oral hygiene that consists of brushing twice daily, flossing, eating nutritious meals and limiting snacking, and visiting the dentist on a regular basis. Fluoride treatments benefit the teeth by strengthening while sealants help chewing surfaces to not decay. Severe cases can lead to tooth extraction and dentures.
Dental abscess—A dental abscess is a collection of pus that accumulates in teeth or gums as a result of bacterial infection, giving rise to a severe throbbing pain at the site of the abscess. It is caused by consuming sugary or starchy food and poor dental hygiene and is treated by a dentist by draining the pus and, possibly, removing the infected tooth/teeth altogether.
See also
Oral medicine
Oral and maxillofacial pathology
Tongue disease
References
External links
"10 dental myths exploded". NHS Choices. Retrieved 2013-12-30.
"Oral Health". National Institute of Dental and Craniofacial Research. Retrieved 2013-12-30. |
Dipygus | Dipygus is a severe congenital deformity where the body axis forks left and right partway along the torso with the posterior end (pelvis and legs) duplicated.
Myrtle Corbin was a dipygus; she married and had five children. In human cases, the inner two of the four hindquarters develop much smaller than normal. This is a type of "teras catadidymum" ("monster twinned below"). Another sort of deformity with extra legs can happen from a degenerated conjoined twin, as may have happened with Frank Lentini with his third leg.
Signs
Dipygus manifests as duplicated lower limbs and could include additional organs or bodily structures.
Causes
Dipygus is caused by genetic, environmental, or teratogenic factors. It occurs early in intrauterine life.
== References == |
Paroophoron | The paroophoron (of Johnson) consists of a few scattered rudimentary tubules, best seen in the child, situated in the broad ligament between the epoöphoron and the uterus. Named for the Welsh anatomist David Johnson who originally described the structure at the University of Wales, Aberystwyth.
It is a remnant of the mesonephric tubules.
See also
Epoophoron
References
External links
figures/chapter_35/35-8.HTM: Basic Human Anatomy at Dartmouth Medical School
Swiss embryology (from UL, UB, and UF) ugenital/genitinterne05 |
Sanfilippo syndrome | Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is a rare autosomal recessive lysosomal storage disease that primarily affects the brain and spinal cord. It is caused by a buildup of large sugar molecules called glycosaminoglycans (AKA GAGs, or mucopolysaccharides) in the bodys lysosomes.
Affected children generally do not show any signs or symptoms at birth, although some early indicators can be respiratory issues at birth, large head size, and umbilical hernia. In early childhood, they begin to develop developmental disability and loss of previously learned skills. In later stages of the disorder, they may develop seizures and movement disorders. Patients with Sanfilippo syndrome usually live into adolescence or early adulthood.
Signs and symptoms
The disease manifests in young children. Symptoms usually begin to appear between two and six years of age. Affected infants appear normal, although some mild facial dysmorphism may be noticeable. Of all of the MPS diseases, Sanfilippo syndrome produces the fewest physical abnormalities.
After an initial symptom-free interval, patients usually present with a slowing of development and/or behavioral problems, followed by progressive intellectual decline resulting in severe dementia and progressive motor disease. Acquisition of speech is often slow and incomplete.The disease progresses to increasing behavioral disturbance including temper tantrums, hyperactivity, destructiveness, aggressive behavior, pica, difficulties with toilet training, and sleep disturbance. As affected children initially have normal muscle strength and mobility, the behavioral disturbances may be difficult to manage. The disordered sleep in particular presents a significant problem to care providers.In the final phase of the illness, children become increasingly immobile and unresponsive, often require wheelchairs, and develop swallowing difficulties and seizures. The life-span of an affected child does not usually extend beyond late teens to early twenties.Individuals with MPS type III tend to have mild skeletal abnormalities; osteonecrosis of the femoral head may be present in patients with the severe form. Optic nerve atrophy, deafness, and otitis can be seen in moderate to severe individuals. Other characteristics include coarse facial features, thick lips, synophrys, and stiff joints.It is difficult to clinically distinguish differences among the four types of Sanfilippo syndrome. However, type A is usually the most severe subtype, characterized by earliest onset, rapid clinical progression with severe symptoms, and short survival. The median age of death for children afflicted with type A is 15.4 ± 4.1 years.It is important that simple and treatable conditions such as ear infections and toothaches not be overlooked because of behavior problems that make examination difficult. Children with MPS type III often have an increased tolerance to pain. Bumps, bruises, or ear infections that would be painful for other children often go unnoticed in children with MPS type III. Some children with MPS type III may have a blood-clotting problem during and after surgery.
Genetics
Mutations in four different genes can lead to Sanfilippo syndrome. This disorder is inherited in an autosomal recessive pattern. People with two working copies of the gene are unaffected. People with one working copy are genetic carriers of Sanfilippo syndrome. They have no symptoms but may pass down the defective gene to their children. People with two defective copies will suffer from Sanfilippo syndrome.
Mechanism
Glycosaminoglycans (GAGs) are chains of sugar molecules. They are found in the extracellular matrix and the cell membrane, or stored in the secretory granules. GAGs are stored in the cell lysosome, and are degraded by enzymes such as glycosidases, sulfatases, and acetyltransferases. Deficiency in these enzymes lead to the four subtypes of MPS III.
Diagnosis
Sanfilippo syndrome types A, B, C, and D are considered to be clinically indistinguishable, although mutations in different genes are responsible for each disease. The following discussion is therefore applicable to all four conditions.A urinalysis can show elevated levels of heparan sulfate in the urine. All four types of Sanfilippo syndrome show increased levels of GAGs in the urine; however, this is less true of Sanfilippo syndrome than other MPS disorders. Additionally, urinary GAG levels are higher in infants and toddlers than in older children. In order to avoid a false negative urine test due to dilution, it is important that a urine sample be taken first thing in the morning.The diagnosis may be confirmed by enzyme assay of skin fibroblasts and white blood cells. The enzyme assay is considered to be the most credible diagnostic tool because it detects whether or not the enzymes that are normally present in the cellular pathway that is responsible for breaking down heparan sulfate are present or not, thereby providing a definitive answer. This test is also ideal for younger patients in which collecting a viable urine sample is difficult or impossible. Another diagnostic tool can be gene sequencing. However, if the genetic mutation they carry has never been seen or recorded, the patient would receive a false negative.Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis.
Treatments
Treatment remains largely supportive. The behavioral disturbances of MPS-III respond poorly to medication. If an early diagnosis is made, bone marrow replacement may be beneficial. Although the missing enzyme can be manufactured and given intravenously, it cannot penetrate the blood–brain barrier and therefore cannot treat the neurological manifestations of the disease. Along with many other lysosomal storage diseases, MPS-III exists as a model of a monogenetic disease involving the central nervous system.Several promising therapies are in development. The French company Lysogene is conducting a phase II/III clinical trial of a gene therapy-based treatment. Other potential therapies include chemical modification of deficient enzymes to allow them to penetrate the blood–brain barrier, stabilisation of abnormal but active enzyme to prevent its degradation, and implantation of stem cells strongly expressing the missing enzyme. For any future treatment to be successful, it must be administered as early as possible. Currently MPS-III is mainly diagnosed clinically, by which stage it is probably too late for any treatment to be very effective. Neonatal screening programs would provide the earliest possible diagnosis.The flavonoid genistein decreases the accumulation of GAGs. In vitro, animal studies and clinical experiments suggest that the symptoms of the disease may be alleviated by an adequate dose of genistein. Despite its reported beneficial properties, genistein also has toxic side effects.Several support and research groups have been established to speed the development of new treatments for Sanfilippo syndrome.Participants in the first-ever "Caregiver Preference Study for Sanfilippo Syndrome" advocated for clinical trials that shift focus from primary cognitive outcomes to other multisystem endpoints, and perceptions of non-curative therapies revealed a preference for treatment options that stop or slow the disorder progression to maintain the child’s current function to ensure quality of life; thus, parents express high risk tolerance and a desire for broader inclusion criteria for trials.
Prognosis
According to a study of patients with Sanfilippo syndrome, the median life expectancy varies depending on the subtype. In Sanfilippo syndrome type A, the mean age at death (± standard deviation) was 15.22 ± 4.22 years. For type B, it was 18.91 ± 7.33 years, and for type C it was 23.43 ± 9.47 years. The mean life expectancy for type A has increased since the 1970s.
Epidemiology
Incidence of Sanfilippo syndrome varies geographically, with approximately 1 case per 280,000 live births in Northern Ireland, 1 per 66,000 in Australia, and 1 per 50,000 in the Netherlands.The Australian study estimated the following incidence for each subtype of Sanfilippo syndrome:
History
The condition is named after Sylvester Sanfilippo, the pediatrician who first described the disease in 1963.
Caregiver impact
Caregivers for children with Sanfilippo syndrome face a unique set of challenges because of the diseases complex nature. There is little understanding among clinicians of the family experience of caring for patients with Sanfilippo and how a caregivers experiences change and evolve as patients age. The burden and impact on caregivers quality of life is poorly defined and best-practice guidance for clinicians is lacking.A best-practice guidance to help clinicians understand the challenges caregivers face was published July 2019 in the Orphanet Journal of Rare Diseases by a group of international clinical advisors with expertise in the care of pediatric patients with Sanfilippo, lysosomal storage disorders, and life as a caregiver to a child with Sanfilippo.The group reviewed key aspects of caregiver burden associated with Sanfilippo B by identifying and quantifying the nature and impact of the disease on patients and caregivers. Recommendations were based on findings from qualitative and quantitative research.The articles authors reported, "Providing care for patients with Sanfilippo B impinges on all aspects of family life, evolving as the patient ages and the disease progresses. Important factors contributing toward caregiver burden include sleep disturbances, impulsive and hyperactive behavior, and communication difficulties ... Caregiver burden remained high throughout the life of the patient and, coupled with the physical burden of daily care, had a cumulative impact that generated significant psychological stress."Additionally, the authors call for changing the narrative associated with Sanfilippo: "The panel agreed that the perceived aggressive behavior of the child may be better described as physical impulsiveness and is often misunderstood by the general public. Importantly, the lack of intentionality of the child’s behavior is recognized and shared by parents and panel members ... Parents may seek to protect their child from public scrutiny and avoid situations that many engender criticism of their parenting skills."
Society and culture
The community of Sanfilippo families, foundations, scientists and researchers, and industry partners and collaborators around the world have dedicated November 16 as World Sanfilippo Awareness Day. World Sanfilippo Awareness Day is about spreading awareness and sparking conversations globally about Sanfilippo syndrome. This day of awareness is in honor of the children around the world living with Sanfilippo syndrome today, and those who have died. It also honors the families of the children with Sanfilippo syndrome. November 16, 2019, was the first year observing World Sanfilippo Awareness Day.
See also
Mucopolysaccharidosis
Hurler syndrome (MPS I)
Hunter syndrome (MPS II)
Morquio syndrome (MPS IV)
List of neurological conditions and disorders
References
External links
Media related to Sanfilippo syndrome at Wikimedia Commons |
Tillaux fracture | A Tillaux fracture is a Salter–Harris type III fracture through the anterolateral aspect of the distal tibial epiphysis. It occurs in older adolescents between the ages of 12 and 15 when the medial epiphysis had closed but before the lateral side has done so, due to an avulsion of the anterior inferior tibiofibular ligament, at the opposite end to a Wagstaffe-Le Fort avulsion fracture
Mechanism
The fracture commonly results from an abduction-external rotation force, causing the anterior tibiofibular ligament to avulse the anterolateral corner of the distal tibial epiphysis resulting in a Salter Harris Type III fracture.
Pathology
It occurs in older children at the end of growth. Variability in fracture pattern is due to progression of physeal closure as anterolateral part of distal tibial physis is the last to close. When the lateral physis is the only portion not fused, external rotation may lead to Tillaux or Triplane fractures.
Treatment
If the displacement at fracture is less than 2 mm, it may be managed conservatively. However, displacement requires open reduction and internal fixation, especially when displacement is over 2 mm.
Epidemiology
It occurs commonly in adolescents and older children. However, it does occur rarely in adults though it may be under reported because of difficulty in diagnosis.
Etymology
This fracture pattern is named after Paul Jules Tillaux, a French Anatomist and Surgeon (1834-1904).
See also
Ankle fracture
References
== External links == |
L1 syndrome | L1 syndrome is a group of mild to severe X-linked recessive disorders that share a common genetic basis. The spectrum of L1 syndrome disorders includes X-linked complicated corpus callosum dysgenesis, spastic paraplegia 1, MASA syndrome, and X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS). It is also called L1CAM syndrome (for the disorders causative gene) and CRASH syndrome, an acronym for its primary clinical features: corpus callosum hypoplasia, retardation (intellectual disability), adducted thumbs, spasticity, and hydrocephalus.L1 syndrome can be caused by different variants in L1CAM, the gene that provides the information that allows the body to produce L1 cell adhesion molecule (sometimes called the L1 protein). The L1 cell adhesion molecule is a surface protein found on the surface of all neurons. It allows neurons to bind to one another and create synapses (connections where information is passed on from the axons of one neuron to the dendrites and cell body of another). As a result, L1 cell adhesion molecule is essential for the structural development of the brain and contributes to the ability to think, move, and develop memories. The type and severity of L1CAM variant causing L1 syndrome in a particular person is directly related to the severity of symptoms and functional impairment that they experience.There is no cure for L1 syndrome, and prognosis is often poor. Life expectancy for people with L1 syndrome can vary dramatically depending on the severity of the condition, with some dying shortly after birth and others reaching adulthood. Treatment for people with L1 syndrome is supportive and aims to improve quality of life and minimize functional impairment.
Signs and symptoms
L1 syndrome presents as a spectrum ranging from mild to severe features. There is a genotype -phenotype correlation across the L1 spectrum, meaning that the specific genetic variant causing an L1-spectrum disorder in a patient determines the severity of the L1 syndrome in that patient. Patients with truncating (loss-of-function) variants in L1CAM, which prevent the full synthesis of L1 (protein) experience more severe features than patients with missense variants in L1CAM, which may result in an abnormal protein but do not prevent its synthesis. Illustrating this difference in L1 syndrome severity, up to 50% of infants born with L1 syndrome caused by a truncating mutation will die before the age of 3 years despite provision of best available medical treatment. In comparison, roughly 10% of infants born with L1 syndrome caused by a missense mutation will die before the age of 3 years.Despite its presentation on a continuous spectrum, L1 syndrome is loosely divided into four discrete phenotypes.
Societal Implications Based on Symptoms
People diagnosed with L1 syndrome often experience issues with respect to societal roles and interactions due to the severe physical and mental disabilities associated with the disorder. These issues can vary depending on the symptoms that manifest in a specific individual and the severity of those symptoms, which is ultimately determined based on where the individual is situated on the L1 syndrome spectrum.Spasticity is one of the most common signs of L1 syndrome and is seen in all four major clinical phenotypes. It is characterized as the continuous contraction of certain muscles, leading to muscle stiffness which can interfere with normal movement and speech. In three of the major phenotypes (except HSAS), this spasticity is presented as spastic paraplegia, where the muscles of the lower limbs are stiff and continuously contracted. This spastic paraplegia often manifests itself as a gait (walking motion) disorder, specifically shuffling gait in MASA syndrome patients, which acts as a source of impairment and stress due to postural instability, and leads to poor quality of life and increased mortality.Aphasia is also a common disorder, especially in people with MASA syndrome (a disorder on the L1 syndrome spectrum) and describes a range of language impairments with respect to syntax (structure), semantics (meaning), phonology (sound), morphology (structure), and/or pragmatics in language comprehension or expression. People with aphasia, as well as their family members, often experience a poor quality of life due to the social isolation and depression caused by this language impairment and therefore may seek therapy to enable functional and socially relevant communication. Therapy services to address aphasia in MASA syndrome patients include one-on-one sessions with a clinician, group therapy, or even computer-based therapy, which is becoming more popular given its accessibility.Intellectual disabilities also contribute to the social difficulties faced by people with L1 syndrome, and can range from mild to severe depending on the persons location on the L1 syndrome spectrum. People with mild intellectual disability usually have an IQ around 50-70 (100 is the average) and are slower in all developmental areas, but they have no unusual physical characteristics and are able to blend in socially. Moderate intellectual disability characteristics include being able to maintain self-care with some support from other, travel to familiar places in the community, communicate in simple ways, and having an IQ around 35–50. Severe intellectual disability is often seen in people with X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) (on the L1 syndrome spectrum) and has several key characteristics including: the ability to understand speech but otherwise having very limited communication skills; the ability to learn daily routines and simple self-care, but need direct supervision in social settings and need family support to live in a supervised home setting. Depending on the severity of the intellectual disability, people with L1 syndrome will have varying levels of difficulty in adapting to their social environments and may need considerable support from others to complete day-to-day tasks.
X-linked hydrocephalus with stenosis of the aqueduct of Sylvius
X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) is the most severe phenotype on the L1 spectrum and is predominantly known for its major feature: profound hydrocephalus, typically beginning before birth. Due to its prenatal onset (i.e. before the bones of the skull have fused together), hydrocephalus associated with HSAS results in progressive macrocephaly (abnormal enlargement of the skull) due to markedly increased intracranial pressure. The signs and symptoms of hydrocephalus can vary depending on severity and age of onset, however irritability (due to pain) and vomiting are common amongst infants with the condition. Without treatment, congenital hydrocephalus can be fatal in infancy. In less severe cases of untreated hydrocephalus, a child may progress beyond infancy but often experiences nausea and vomiting, missed developmental milestones (both physical and cognitive/social), diplopia (double vision), and papilledema (swelling of the optic disc) which can progress to permanent visual impairment due to increased intracranial pressure if definitive treatment is withheld. Neurological damage, caused by both hydrocephalus and poor neuronal development because of defects in the L1 cell adhesion molecule, results in nearly all people with HSAS experiencing severe intellectual disability.People living with HSAS will also frequently experience spasticity, a condition causing some muscles to be continuously contracted, thereby causing stiffness of the body and challenges with walking and speaking. Spasticity is also known to cause difficulty in performing activities of daily living such as bathing and showering, dressing, and self-feeding.Despite HSAS frequently being considered an isolated disorder of the central nervous system, its genetic basis also causes musculoskeletal defects that result in more than half of males with HSAS displaying thumbs that are adducted (clasped, or brought inwards towards the palm). Specifically, this abnormal presentation of the hand is due to congenital malformations in the extensor pollicis brevis and/or extensor pollicis longus muscle of forearm.
MASA syndrome
MASA syndrome is named after its four principle features: mental retardation, adducted thumbs (clasped, or brought inwards towards the palm), shuffling gait, and aphasia (a language disability affecting the comprehension and production of speech as well as reading and writing abilities).
Diagnosis
A healthcare provider, usually a medical geneticist (a physician with special training in diagnosing and managing genetic disorders) can provide a clinical diagnosis of L1 syndrome by examining a patient and ordering certain imaging studies, however the presence of L1 syndrome can only be confirmed when a molecular diagnosis has been made through genetic testing.Often, the diagnostic odyssey for a person with L1 syndrome begins prenatally (before they are born) when prenatal ultrasounds reveal non-specific brain abnormalities, ventriculomegaly, or a non-existent or underdeveloped corpus callosum. Fetuses with X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) will typically have hydrocephalus severe enough to be discovered upon routine fetal ultrasound as early as 18–20 weeks gestation. After birth, in the presence of suggestive features (such as macrocephaly), hydrocephalus can be confirmed with noninvasive imaging including head magnetic resonance imaging, computed tomography, or ultrasound showing ventriculomegaly, or direct measurement of intracranial pressure through invasive techniques such as lumbar puncture. Further, the spasticity found in patients with HSAS can be easily demonstrated by examining the deep tendon reflexes and the extensor plantar reflex (which will both be abnormally brisk and strong due to damage to the cortex and internal capsule of the brain).
There are various types of genetic testing that can be used to confirm an L1 syndrome diagnosis in a patient. After birth, genetic tests carry a low-risk of physical complications and are minimally-painful: for the patient, the process requires a small amount of blood being drawn from the arm using a needle. However, prenatal genetic testing carries significant risks for both the fetus and mother due to the need to remove genetic material from the fetus while it is still in utero. In order to conduct prenatal genetic testing, the mother and fetus must undergo either amniocentesis (the surgical puncturing of the amniotic sac, which holds the fetus in the womb) or, less frequently, chorionic villus sampling. Amniocentesis provides a sample of amniotic fluid that can be used to screen for sequence variants or chromosomal variants, whereas samples obtained through chorionic villus sampling can only be used to detect major chromosomal abnormalities (such as trisomy 21), making chorionic villous sampling less relevant in the context of diagnosing L1 syndrome (which is often caused by sequence variants). Amniocentesis (typically performed between 15 and 18 weeks of pregnancy) has a 1% risk of complications for mother and fetus, including miscarriage, while chorionic villus sampling (typically performed between 10 and 12 weeks of pregnancy) has a 2% risk of complications including miscarriage. Mothers carrying a fetus with suspected L1 syndrome will often elect to undergo amniocentesis despite its risk, rather than waiting to pursue lower-risk genetic testing after their child is born, because prenatal diagnostic results can inform considerations to terminate the pregnancy.For any child born with multiple physical abnormalities, the first-line diagnostic test is chromosomal microarray.
Management
To know the extent of the disease and the required needs of an individual diagnosed with L1 syndrome, some tests are recommended, including: Head imaging study, Complete neurologic evaluation, Developmental evaluation, Evaluation for Hirschsprung disease if there is a history of constipation, Consultation with a clinical geneticist and/or genetic counselor. A proper management of the manifestations of the L1 syndrome involves a multidisciplinary(involving a team specialized in more than one medical fields) approach involving a team that works within these fields: pediatrics, child neurology, neurosurgery, rehabilitation, and clinical genetics. To prevent secondary complications(conditions that occur in the course of a disease as a result), physiotherapy is recommended. Prior to birth recognition of an affected fetus during pregnancy requires a plan involving multiple medical disciplines for a safe delivery for both mother and infant and to allow for an evaluation and possible treatment for hydrocephalus shortly after birth.Hydrocephalus: Surgery should be performed as needed, to shunt cerebrospinal fluid (CSF) in order to reduce pressure inside the head (intracranial pressure). Intellectual Disability: The development of the individual should be monitored since the development outcomes are variable among affected individuals, educational programs are needed for these individuals. Adducted Thumbs: Surgical procedures are generally not required, a splint may reduce the degree of the adduction, and in milder cases tendon transfer may improve the thumb function.Spastic paraplegia: Currently there are no specific treatments to prevent or reduce neural degeneration. Treatments aim to reduce symptoms and improving balance, strength, and agility. Individuals should be evaluated periodically by a neurologist and physiatrist to evaluate progress made and to develop treatment strategies to maximize walking ability and reduce symptoms. The General guidelines for follow-up and treatment can be followed while monitoring the neurologic features of the condition. Treatment for spastic paraplegia usually involves exercise to: (1) improve and maintain cardiovascular fitness (The hearts ability to supply oxygen to the tissues) (2) reverse the reduced functional capacity (3) improve the mechanics of walking, and gait in general (4) Improve the individuals independence and sense of control. Orthotics can be used to reduce the extension of the feet (toe down), which causes dragging and falling, to be noted that orthotics are usually used along with medications that decrease spasticity, such as Botox.
References
== External links == |
Hutchinsons teeth | Hutchinsons teeth is a sign of congenital syphilis. Affected people have teeth that are smaller and more widely spaced than normal and which have notches on their biting surfaces. It is named after Sir Jonathan Hutchinson, an English surgeon and pathologist, who first described it.Hutchinsons teeth form part of Hutchinsons triad.
See also
List of cutaneous conditions
References
External links
Hutchinsons teeth at Who Named It? |
Vertiginous epilepsy | Vertiginous epilepsy is infrequently the first symptom of a seizure, characterized by a feeling of vertigo. When it occurs, there is a sensation of rotation or movement that lasts for a few seconds before full seizure activity. While the specific causes of this disease are speculative there are several methods for diagnosis, the most important being the patients recall of episodes. Most times, those diagnosed with vertiginous seizures are left to self-manage their symptoms or are able to use anti-epileptic medication to dampen the severity of their symptoms.Vertiginous epilepsy has also been referred to as epileptic vertigo, vestibular epilepsy, vestibular seizures, and vestibulogenic seizures in different cases, but vertiginous epilepsy is the preferred term.
Signs and Symptoms
The signs of vertiginous epilepsy often occur without a change in the subject’s consciousness so that they are still aware while experiencing the symptoms. It is often described as a sudden onset of feeling like one is turning in one direction, typically lasting several seconds. Although subjects are aware during an episode, they often cannot remember specific details due to disorientation, discomfort, and/or partial cognitive impairment. This sensation of rotational movement in the visual and auditory planes is also known as a vertiginous aura (symptom), which can precede a seizure or may constitute a seizure itself. Auras are a “portion of the seizure that occur before consciousness is lost and for which memory is retained afterwards.” Auras can be focused in different regions of the brain and can thus affect different functions. Some such symptoms that may accompany vertiginous epilepsy include:
Auditory hallucination
Cognitive impairment
Motor activity
Ictal behavior
Limbic aurasMany people tend to mistake dizziness as vertigo, and although they sound similar, dizziness is not considered a symptom of vertiginous epilepsy. Dizziness is the sensation of imbalance or floating, impending loss of consciousness, and/or confusion. This is different from vertigo which is characterized by the illusion of rotational movement caused by the “conflict between the signals sent to the brain by balance- and position-sensing systems of the body”.
Mechanism
Although a specific cause has not been identified to always induce vertiginous epilepsy there have been a number of supported hypotheses to how these seizures come about, the most common being traumatic injury to the head. Other causes include tumor or cancers in the brain, stroke with loss of blood flow to the brain, and infection. A less tested hypothesis that some believe may play a larger role in determining who is affected by this disease is a genetic mutation that predisposes the subject for vertiginous epilepsy. This hypothesis is supported by occurrences of vertiginous epilepsy in those with a family history of epilepsy.
Vertiginous epilepsies are included in the category of the partial epilepsy in which abnormal electrical activity in the brain is localized. With current research, it is presumed that the most likely cause to produce vertigo are epilepsies occurring in the lateral temporal lobe. These abnormal electrical activities can either originate from within the temporal lobe or may propagate from an epilepsy in a neighboring region of the brain. Epilepsies in the parietal and occipital lobes commonly propagate into the temporal lobe inducing a vertiginous state. This electrical propagation across the brain explains why so many different symptoms may be associated with the vertiginous seizure. The strength of the electrical signal and its direction of propagation in the brain will also determine which associated symptoms are noticeable.
Diagnosis
The most important factor in diagnosing a patient with vertiginous epilepsy is the subject’s detailed description of the episode. However, due to the associated symptoms of the syndrome a subject may have difficulty remembering the specifics of the experience. This makes it difficult for a physician to confirm the diagnosis with absolute certainty. A questionnaire may be used to help patients, especially children, describe their symptoms. Clinicians may also consult family members for assistance in diagnosis, relying on their observations to help understand the episodes. In addition to the description of the event, neurological, physical and hematologic examinations are completed to assist in diagnosis. For proper diagnosis, an otological exam (examination of the ear) should also be completed to rule out disorders of the inner ear, which could also be responsible for manifestations of vertigo. This may include an audiological assessment and vestibular function test. During diagnosis, history-taking is essential in determining possible causes of vertiginous epilepsy as well as tracking the progress of the disorder over time.Other means used in diagnosis of vertiginous epilepsy include:
Electroencephalography (EEG)
Magnetic resonance imaging (MRI)
Positron emission tomography (PET)
Neuropsychological testingThe EEG measures electrical activity in the brain, allowing a physician to identify any unusual patterns. While EEGs are good for identifying abnormal brain activity is it not helpful in localizing where the seizure originates because they spread so quickly across the brain. MRIs are used to look for masses or lesions in the temporal lobe of the brain, indicating possible tumors or cancer as the cause of the seizures. When using a PET scan, a physician is looking to detect abnormal blood flow and glucose metabolism in the brain, which is visible between seizures, to indicate the region of origin.
Management
There is no real way to prevent against vertiginous episodes out of the means of managing the disease. As head trauma is a major cause for vertiginous epilepsy, protecting the head from injury is an easy way to avoid possible onset of these seizures. With recent advances in science it is also possible for an individual to receive genetic screening, but this only tells if the subject is predisposed to developing the condition and will not aid in preventing the disease.There are a range of ways to manage vertiginous epilepsy depending on the severity of the seizures. For simple partial seizures medical treatment is not always necessary. To the comfort of the patient, someone ailed with this disease may be able to lead a relatively normal life with vertiginous seizures. If, however, the seizures become too much to handle, antiepileptic medication can be administered as the first line of treatment. There are several different types of medication on the market to deter epileptic episodes but there is no support to show that one medication is more effective than another. In fact, research has shown that simple partial seizures do not usually respond well to medication, leaving the patient to self-manage their symptoms. A third option for treatment, used only in extreme cases when seizure symptoms disrupt daily life, is surgery wherein the surgeon will remove the epileptic region.
Epidemiology
Vertiginous epilepsy onset can happen between the ages of 4–50, although typically symptoms will begin occurring in adolescence or young adulthood. Research studies have shown no inclination for this disease between sexes.
History
Caloric reflex testing was developed and used for testing vestibular function of deaf children and in diagnosis of childhood vertigo. A man named Barany (1902) published the first monograph on vestibular nystagmus that recognized the clinical usefulness of caloric responses. Baranys theory of production of the vestibulo-ocular reflex in caloric testing remains as the accepted explanation along with the description of nystagmus created by rotation in both adults and infants. Baranys work would later influence a researcher named Galebsky that would help him conclude that semicircular canals were functional at birth for both calorization and rotation. His work would also confirm that the eyelid of a newborn is raised in response to a vestibular as well as an auditory stimulus.In the late 19th century and early 20th century, Hughlings Jackson and W.R. Gowers recognized that episodes of dizziness were a symptom of epilepsy. During this time, when epileptic symptoms were brought to the forefront of study, there was no distinction between dizziness and vertigo. Sir George Frederick (1868–1941), known for his work in pediatric rheumatoid arthritis referred to as Still’s disease, was the first to publish a description of episodic vertigo in children within the broad category of ‘headaches in children’ in 1924. Until recently, it was not widely recognized that episodes of suspected dizziness might be caused by epilepsy.
Research
There have been early and consistent strategies for measurement to better understand vertiginous epilepsy including caloric reflex test, posture and gait, or rotational experimentation.In Japan, Kaga et al prepared a longitudinal study of rotation tests comparing congenital deafness and children with delayed acquisition of motor system skills. They were able to demonstrate the development of post-rotation nystagmus response from the frequency of beat and duration period from birth to six years to compare to adult values. Overall, the study demonstrated that some infants from the deaf population had impaired vestibular responses related to head control and walking age. A side interpretation included the evaluation of the vestibular system in reference to matching data with age.Research in this area of medicine is limited due to its lacking need for urgent attention. But, the American Hearing Research Foundation (AHRF) conducts studies in which they hope to make new discoveries to help advance treatment of the disease and possibly one day prevent vertiginous seizures altogether.
== References == |
Spinocerebellar ataxia type 6 | Spinocerebellar ataxia type 6 (SCA6) is a rare, late-onset, autosomal dominant disorder, which, like other types of SCA, is characterized by dysarthria, oculomotor disorders, peripheral neuropathy, and ataxia of the gait, stance, and limbs due to cerebellar dysfunction. Unlike other types, SCA 6 is not fatal. This cerebellar function is permanent and progressive, differentiating it from episodic ataxia type 2 (EA2) where said dysfunction is episodic. In some SCA6 families, some members show these classic signs of SCA6 while others show signs more similar to EA2, suggesting that there is some phenotypic overlap between the two disorders. SCA6 is caused by mutations in CACNA1A, a gene encoding a calcium channel α subunit. These mutations tend to be trinucleotide repeats of CAG, leading to the production of mutant proteins containing stretches of 20 or more consecutive glutamine residues; these proteins have an increased tendency to form intracellular agglomerations. Unlike many other polyglutamine expansion disorders expansion length is not a determining factor for the age that symptoms present.
Signs and symptoms
SCA6 is typified by progressive and permanent cerebellar dysfunction. These cerebellar signs include ataxia and dysarthria, likely caused by cerebellar atrophy. Prior to diagnosis and the onset of major symptoms, patients often report a feeling of "wooziness" and momentary imbalance when turning corners or making rapid movements. The age at which symptoms first occur varies widely, from age 19 to 71, but is typically between 43 and 52. Other major signs of SCA6 are the loss of vibratory and proprioceptive sensation and nystagmus.While most patients present with these severe progressive symptoms, others, sometimes within the same family, display episodic non-progressive symptoms more similar to episodic ataxia. Still others present with symptoms common to both SCA6 and familial hemiplegic migraine.
Pathophysiology
Most cases of SCA6 are a result of CAG repeat expansion beyond the normal range, i.e., more than 19 repeats, in the Cav2.1 calcium channel encoding gene CACNA1A. This gene has two splice forms, "Q-type" and "P-type", and the polyglutamine coding CAG expansion occurs in the P-type splice form. This form is expressed heavily in the cerebellum where it is localized in Purkinje cells. In Purkinje cells from SCA6 patients, mutant Cav2.1 proteins form ovular intracellular inclusions, or aggregations, similar in many ways to those seen in other polyglutamine expansion disorders such as Huntingtons disease. In cell culture models of the disease, this leads to early apoptotic cell death.Mutant channels that are able to traffic properly to the membrane have a negatively shifted voltage-dependence of inactivation. The result of this is that the channels are active for a shorter amount of time and, consequently, cell excitability is decreased.There are also a number of point mutations resulting in patients with phenotypes reminiscent of episodic ataxia and SCA6 (C271Y, G293R and R1664Q) or familial hemiplegic migraine and SCA6 (R583Q and I1710T). C287Y and G293R are both located in the pore region of domain 1 and are present in a single family each. Expression of these mutant channels results in cells with drastically decreased current density compared to wild-type expressing cells. In cell-based assays, it was found that these mutant channels aggregate in the endoplasmic reticulum, not dissimilar from that seen in the CAG expansion mutants above. R1664Q is in the 4th transmembrane spanning segment of domain 4 and, presumably, affects the channels voltage dependence of activation. Little is known about the point mutations resulting in overlapping phenotypes of familial hemiplegic migraine and episodic ataxia. R583Q is present in the 4th transmembrane spanning region of domain 2 while the I1710T mutation is segment 5 of domain 4.
Diagnosis
Spinocerebellar Ataxia Diagnosis is done via genetic testing. Your Neurologist can administer the test.
Spinocerebellar Ataxia is often misdiagnosed as other diseases such as ALC or Parkinsons Disease.
Screening
There is no known prevention of spinocerebellar ataxia. Those who are believed to be at risk can have genetic sequencing of known SCA loci performed to confirm inheritance of the disorder.
Treatment
There are no drug based treatments currently available for SCA Type 6, however, there are supportive treatments that may be useful in managing symptoms.
Physical Therapy, Speech Pathology can help patients manage the symptoms.
Epidemiology
The prevalence of SCA6 varies by culture. In Germany, SCA6 accounts for 10-25% of all autosomal dominant cases of SCA (SCA itself having a prevalence of 1 in 100,000). This prevalence in lower in Japan, however, where SCA6 accounts for only ~6% of spinocerebellar ataxias. In Australia, SCA6 accounts for 30% of spinocerebellar ataxia cases while 11% in the Dutch.
See also
Calcium channel
Cerebellum
Episodic ataxia
Familial hemiplegic migraine
Huntingtons disease
Spinocerebellar ataxia
References
External links
sca6 at NIH/UW GeneTests |
Erotic asphyxiation | Erotic asphyxiation (variously called asphyxiophilia, hypoxyphilia or breath control play) is the intentional restriction of oxygen to the brain for the purposes of sexual arousal. The term autoerotic asphyxiation is used when the act is done by a person to themselves. Colloquially, a person engaging in the activity is sometimes called a gasper. Erotic asphyxiation can lead to accidental death due to asphyxia.
The erotic interest in asphyxiation is classified as a paraphilia in the Diagnostic and Statistical Manual of the American Psychiatric Association.
Physiology
Concerning hallucinogenic states brought about by chronic hypoxia, Dr. E. L. Lloyd notes that they may be similar to the hallucinations experienced by climbers at altitude. He further notes that no such state occurs in hypoxia brought about by sudden aircraft decompression at altitude. These findings suggest to him that they do not arrive purely from a lack of oxygen. Upon examining the studies on hypoxia he found that "abnormalities in the cerebral neurochemistry involving one or more of the interconnected neurotransmitters, dopamine, serotonin, and beta-endorphin had been reported in all the conditions associated with hallucinations."
History
Historically, the practice of autoerotic asphyxiation has been documented since the early 17th century. It was first used as a treatment for erectile dysfunction. The idea for this most likely came from subjects who were executed by hanging. Observers at public hangings noted that male victims developed an erection, sometimes remaining after death (a death erection), and occasionally ejaculated when being hanged.
Practice
Various methods are used to achieve the level of oxygen depletion needed, such as a hanging, suffocation with a plastic bag over the head, self-strangulation such as with a ligature, gas or volatile solvents, chest compression, or some combination of these. Complicated devices (such as hydraulics) are sometimes used to produce the desired effects. The practice can be dangerous even if performed with care and has resulted in a significant number of accidental deaths. Uva (1995) writes "Estimates of the mortality rate of autoerotic asphyxia range from 250 to 1000 deaths per year in the United States." Cases have also been reported in Scandinavia and Germany. Swedish police reported in 1994 that the number of autoerotic asphyxiation fatalities in the Stockholm area (c. 1.7 million inhabitants) were at least five annually, but the number of unrecorded cases was assumed to be high. Autoerotic asphyxiation may often be mistaken for suicide, which is a major cause of death in teenagers.
Accidental death
Deaths often occur when the loss of consciousness caused by partial asphyxia leads to loss of control over the means of strangulation, resulting in continued asphyxia and death. While often asphyxiophilia is incorporated into sex with a partner, others enjoy this behaviour by themselves, making it potentially more difficult to get out of dangerous situations.In some fatality cases, the body of the asphyxiophilic individual is discovered naked or with genitalia in hand, with pornographic material or sex toys present, or with evidence of having orgasmed prior to death. Bodies found at the scene of an accidental death often show evidence of other paraphilic activities, such as fetishistic cross-dressing and masochism. In cases involving teenagers at home, families may disturb the scene by "sanitizing" it, removing evidence of paraphilic activity. This can have the consequence of making the death appear to be a deliberate suicide, rather than an accident.The great majority of known erotic asphyxial deaths are male; among all known cases in Ontario and Alberta from 1974 to 1987, only 1 out of 117 cases was female. Some individual cases of women with erotic asphyxia have been reported. The main age of accidental death is mid-20s, but deaths have been reported in adolescents and in men in their 70s.Autoerotic asphyxiation has at times been incorrectly diagnosed as murder and especially so when a partner is present.Lawyers and insurance companies have brought cases to the attention of clinicians because some life insurance claims are payable in the event of accidental death, but not suicide.
In fiction
The sensational nature of erotic asphyxiation often makes it the subject of urban legends. It has also been mentioned specifically in a number of works of fiction.
In the Marquis de Sades famous novel Justine, or The Misfortunes of the Virtue, Justine is subjected to this by one of her captors. She survives the encounter.
In the Guts short story in Chuck Palahniuks novel Haunted, one the characters discusses parents who discover the accidental deaths of their sons to autoerotic asphyxiation. They are said to cover up the deaths before police or coroners arrive to save the family from shame.
In the novel (and later movie adaptation) Rising Sun, death as a result of this type of sexual arousal is explained when it is offered as a possible cause for a murder victims death.
In the film Worlds Greatest Dad, the protagonists teenage son accidentally kills himself with asphyxiation whilst sexually aroused. The protagonist then stages his sons death as a suicide, which gives him the opportunity to rise to infamy through a literary hoax.
In the film Ken Park a character named Tate practices autoerotic asphyxia.
Autoerotic asphyxiation occurs in the cold open of Six Feet Under episode Back to the Garden.
Kenny from South Park dies from suffocating while wearing a Batman costume and practicing autoerotic asphyxia in the episode "Sexual Healing".
In the season four episode of Californication, titled "Monkey Business", the character Zig Semetauer is found dead in his bathroom by Hank, Charlie and Stu after suffocating due to autoerotic asphyxia, to which Hank quips "Im not averse to the occasional choke-n-stroke, but this is a prime example of why one must always use a buddy system."
A character in the film Knocked Up offers to be a "spotter" for a friend if he intends on performing autoerotic asphyxiation.
Bruce Robertson, the main character in the 1998 Irvine Welsh novel, Filth, engages in the practice. This is also depicted in the 2013 film adaptation.
In the sixth episode, season two of BoJack Horseman, autoerotic asphyxiation and celebrity deaths are recurrent discussions.
In the episode, "Clyde Bruckmans Final Repose" of the TV series The X-Files, a psychic implies that special agent Fox Mulder will die by autoerotic asphyxiation.
See also
Cerebral hypoxia
Choke hold
Choking game
Facesitting
Hypoxia
Self-bondage
Sexual fetishism
References
Further reading
Robert R. Hazelwood, Park Elliot Dietz, Ann Wolbert Burgess: Autoerotic Fatalities. Lexington, Mass.: LexingtonBooks, 1983.
Sergey Sheleg, Edwin Ehrlich: Autoerotic Asphyxiation: Forensic, Medical, and Social Aspects, Wheatmark (15 August 2006), trade paperback, 208 pages ISBN 1587366045 ISBN 978-1587366048
John Money, Gordon Wainwright and David Hingsburger: The Breathless Orgasm: A Lovemap Biography of Asphyxiophilia. Buffalo, New York: Prometheus Books, 1991.
External links
Well Hung: Death By Orgasm
Turvey B. "An Objective Overview of Autoerotic Fatalities"
The Medical Realities of Breath Control Play By Jay Wiseman
Is there a safe way to perform autoerotic asphyxiation? - Slate Magazine i |
Preauricular sinus and cyst | Preauricular sinuses and preauricular cysts are two common congenital malformations. Each involves the external ear. The difference between them is that a cyst does not connect with the skin, but a sinus does. Frequency of preauricular sinus differs depending the population: 0.1–0.9% in the US, 0.9% in the UK, and 4–10% in Asia and parts of Africa.Preauricular sinuses are inherited features, and frequently appear next to both ears. Preauricular sinuses can be associated with other defects that are not visible, one example being branchio-oto-renal syndrome.
Presentation
Complications
Occasionally a preauricular sinus or cyst can become infected. Most preauricular sinuses are asymptomatic, and remain untreated unless they become infected too often. Preauricular sinuses can be excised surgically, but often present a high risk of recurrence.
Causes
Preauricular sinuses and cysts result from developmental defects of the first and second pharyngeal arches. This and other ear malformations are sometimes associated with renal anomalies. In rare circumstances these pits may be seen in genetic conditions such as branchio-oto-renal syndrome; however these conditions are always concurrent with other health concerns.
Treatment
Courses of treatment typically include the following:
Surgical excision is indicated with recurrent fistular infections, preferably after significant healing of the infection. In case of a persistent infection, infection drainage is performed during the excision operation. The operation is generally performed by an appropriately trained specialist surgeon e.g. an otolaryngologist or a pediatric Surgeon.
The fistula can be excised as a cosmetic operation even though no infection appeared. The procedure is considered an elective operation in the absence of any associated complications.
See also
Branchial cleft cyst
Thyroglossal cyst
Lachiewicz Sibley syndrome
List of cutaneous conditions
References
Bibliography
Further reading
== External links == |
Congenital pulmonary airway malformation | Congenital pulmonary airway malformation (CPAM), formerly known as congenital cystic adenomatoid malformation (CCAM), is a congenital disorder of the lung similar to bronchopulmonary sequestration. In CPAM, usually an entire lobe of lung is replaced by a non-working cystic piece of abnormal lung tissue. This abnormal tissue will never function as normal lung tissue. The underlying cause for CPAM is unknown. It occurs in approximately 1 in every 30,000 pregnancies.In most cases the outcome of a fetus with CPAM is very good. In rare cases, the cystic mass grows so large as to limit the growth of the surrounding lung and cause pressure against the heart. In these situations, the CPAM can be life-threatening for the fetus. CPAM can be separated into five types, based on clinical and pathologic features. CPAM type 1 is the most common, with large cysts and a good prognosis. CPAM type 2 (with medium-sized cysts) often has a poor prognosis, owing to its frequent association with other significant anomalies. Other types are rare.
Signs and symptoms
Three quarters of affected patients are asymptomatic. However, 25% develop cyanosis, pneumothorax, and show signs of increased breathing difficulty (tachypnoea and intercostal retractions).At examination, they may show hyper-resonance at percussion, diminished vesicular murmur and an asymmetrical thorax.
Cause
The cause of CPAM is unknown.
Diagnosis
CPAMs are often identified during routine prenatal ultrasonography. Identifying characteristics on the sonogram include: an echogenic (bright) mass appearing in the chest of the fetus, displacement of the heart from its normal position, a flat or everted (pushed downward) diaphragm, or the absence of visible lung tissue.CPAMs are classified into three different types based largely on their gross appearance. Type I has a large (>2 cm) multiloculated cysts. Type II has smaller uniform cysts. Type III is not grossly cystic, referred to as the "adenomatoid" type. Microscopically, the lesions are not true cysts, but communicate with the surrounding parenchyma. Some lesions have an abnormal connection to a blood vessel from an aorta and are referred to as "hybrid lesions."
Imaging
The earliest point at which a CPAM can be detected is by prenatal ultrasound. The classic description is of an echogenic lung mass that gradually disappears over subsequent ultrasounds. The disappearance is due to the malformation becoming filled with fluid over the course of the gestation, allowing the ultrasound waves to penetrate it more easily and rendering it invisible on sonographic imaging. When a CPAM is rapidly growing, either solid or with a dominant cyst, they have a higher incidence of developing venous outflow obstruction, cardiac failure and ultimately hydrops fetalis. If hydrops is not present, the fetus has a 95% chance of survival. When hydrops is present, risk of fetal demise is much greater without in utero surgery to correct the pathophysiology. The greatest period of growth is during the end of the second trimester, between 20–26 weeks.A measure of mass volume divided by head circumference, termed cystic adenomatoid malformation volume ratio (CVR) has been developed to predict the risk of hydrops. The lung mass volume is determined using the formula (length × width × anteroposterior diameter ÷ 2), divided by head circumference. With a CVR greater than 1.6 being considered high risk. Fetuses with a CVR less than 1.6 and without a dominant cyst have less than a 3% risk of hydrops. After delivery, if the patient is symptomatic, resection is mandated. If the infant is asymptomatic, the need for resection is a subject of debate, though it is usually recommended. Development of recurrent infections, rhabdomyosarcoma, adenocarcinomas in situ within the lung malformation have been reported.
Treatment
In most cases, a fetus with CPAM is closely monitored during pregnancy and the CPAM is removed via surgery after birth. Most babies with a CPAM are born without complication and are monitored during the first few months. Many patients have surgery, typically before their first birthday, because of the risk of recurrent lung infections associated with CPAMs. Some pediatric surgeons can safely remove these lesions using very tiny incisions using minimally invasive surgical techniques (thoracoscopy). However, some CPAM patients live a full life without any complication or incident. It is hypothesized that there are thousands of people living with an undetected CPAM. Through ultrasound testing employed in recent years, many more patients are aware that they live with this condition. Rarely, long standing CPAMs have been reported to become cancerous.Very large cystic masses might pose a danger during birth because of the airway compression. In this situation, a special surgical type of delivery called the EXIT procedure may be used.
In rare extreme cases, where fetuss heart is in danger, fetal surgery can be performed to remove the CPAM. If non-immune hydrops fetalis develop, there is a near universal mortality of the fetus without intervention. Fetal surgery can improve the chances of survival to 50-60%. Recently, several studies found that a single course of prenatal steroids (betamethasone) may increase survival in hydropic fetuses with microcystic CPAMs to 75-100%. These studies indicate that large microcystic lesions may be treated prenatally without surgical intervention. Large macrocyst lesions may require in utero placement of a Harrison thoracoamniotic shunt.
References
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Enteritis | Enteritis is inflammation of the small intestine. It is most commonly caused by food or drink contaminated with pathogenic microbes, such as serratia, but may have other causes such as NSAIDs, radiation therapy as well as autoimmune conditions like Crohns disease and celiac disease. Symptoms include abdominal pain, cramping, diarrhea, dehydration, and fever. Related diseases of the gastrointestinal system include inflammation of the stomach and large intestine.
Duodenitis, jejunitis and ileitis are subtypes of enteritis which are localised to a specific part of the small intestine. Inflammation of both the stomach and small intestine is referred to as gastroenteritis.
Signs and symptoms
Signs and symptoms of enteritis are highly variable and vary based on the specific cause and other factors such as individual variance and stage of disease.
Symptoms may include abdominal pain, cramping, diarrhea, dehydration, fever, nausea, vomiting and weight loss.
Causes
Autoimmune
Crohns disease – also known as regional enteritis, it can occur along any surface of the gastrointestinal tract. In 40% of cases, it is limited to the small intestine.Coeliac disease – caused by an autoimmune reaction to gluten by genetically predisposed individuals.Eosinophilic enteropathy – a condition where eosinophils build up in the gastrointestinal tract and blood vessels, leading to polyp formation, necrosis, inflammation and ulcers. It is most commonly seen in patients with a history of atopy, however is overall relatively uncommon.
Infectious enteritis
In Germany, 90% of cases of infectious enteritis are caused by four pathogens, Norovirus, Rotavirus, Campylobacter and Salmonella. Other common causes of infectious enteritis include bacteria such as Shigella and E. coli, as well as viruses such as adenovirus, astrovirus and calicivirus. Other less common pathogens include Bacillus cereus, Clostridium perfringens, Clostridium difficile and Staphylococcus aureus.Campylobacter jejuni is one of the most common sources of infectious enteritis, and the most common bacterial pathogen found in 2 year old and smaller children with diarrhoea. It has been linked to consumption of contaminated water and food, most commonly poultry and milk. The disease tends to be less severe in developing countries, due to the constant exposure which people have with the antigen in the environment, leading to early development of antibodies.Rotavirus is responsible for infecting 140 million people and causing 1 million deaths each year, mostly in children younger than 5 years. This makes it the most common cause of severe childhood diarrhoea and diarrhea-related deaths in the world. It selectively targets mature enterocytes in the small intestine, causing malabsorption, as well as inducing secretion of water. It has also been observed to cause villus ischemia, and increase intestinal motility. The net result of these changes is induced diarrhoea.
Enteritis necroticans is an often fatal illness, caused by β-toxin of Clostridium perfringens. This causes inflammation and segments of necrosis throughout the gastrointestinal tract. It is most common in developing countries, however has also been documented in post-World War II Germany. Risk factors for enteritis necroticans include decreased trypsin activity, which prevent intestinal degradation of the toxin, and reduced intestinal motility, which increases likelihood of toxin accumulation.
Vascular disease
Ischemic enteritis is uncommon compared to ischemic colitis due to the highly vascularised nature of the small intestine, allowing for sufficient blood flow in most situations. It develops due to circulatory shock of mesenteric vessels in the absence of major vessel occlusion, often associated with an underlying condition such as hypertension, arrhythmia or diabetes. Thus it has been considered to be associated with atherosclerosis. Surgical treatment is usually required due to the likelihood of stenosis or complete occlusion of the small intestine. Ischemic damage can range from mucosal infarction, which is limited only to the mucosa; mural infarction of the mucosa and underlying submucosa; to transmural infarction of the full thickness of the gastrointestinal wall. Mucosal and mural infarcts in and of themselves may not be fatal, however may progress further to a transmural infarct. This has the potential for perforation of the wall, leading to peritonitis.
Radiation enteritis
Inflammation of the gastrointestinal tract is common after treatment with radiation therapy to the abdomen or pelvis. It is classified as early if it manifests within the first 3 months, and delayed if it manifests 3 months after treatment. Early radiation enteritis is caused by cell death of the crypt epithelium and subsequent mucosal inflammation, however usually subsides after the course of radiation therapy is completed. Delayed radiation enteritis is a chronic disease which has a complex pathogenesis involving changes in the majority of the intestinal wall.
Diagnosis
Diagnosis may be simple in cases where the patients signs and symptoms are idiopathic to a specific cause. However, this is generally not the case, considering that many pathogens which cause enteritis may exhibit similar symptoms, especially early in the disease. In particular, campylobacter, shigella, salmonella and many other bacteria induce acute self-limited colitis, an inflammation of the lining of the colon which appears similar under the microscope.A medical history, physical examination and tests such as blood counts, stool cultures, CT scans, MRIs, PCRs, colonoscopies and upper endoscopies may be used in order to perform a differential diagnosis. A biopsy may be required to obtain a sample for histopathology.
Treatment
Mild cases usually do not require treatment and will go away after a few days in healthy people. In cases where symptoms persist or when it is more severe, specific treatments based on the initial cause may be required.In cases where diarrhea is present, replenishing fluids lost is recommended, and in cases with prolonged or severe diarrhoea which persists, intravenous rehydration therapy or antibiotics may be required. A simple oral rehydration therapy (ORS) can be made by dissolving one teaspoon of salt, eight teaspoons of sugar and the juice of an orange into one litre of clean water. Studies have shown the efficacy of antibiotics in reducing the duration of the symptoms of infectious enteritis of bacterial origin, however antibiotic treatments are usually not required due to the self-limiting duration of infectious enteritis.
Etymology
The word enteritis () uses combining forms of entero- and -itis, both New Latin from Greek, respectively from ἑντερον (enteron, small intestine) and -ιτις (-itis, inflammation).
See also
Enteropathy
Staphylococcal enteritis
References
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Nitrogen dioxide poisoning | Nitrogen dioxide poisoning is the illness resulting from the toxic effect of nitrogen dioxide (NO2). It usually occurs after the inhalation of the gas beyond the threshold limit value.
Nitrogen dioxide is reddish-brown with a very harsh smell at high concentrations, at lower concentrations it is colorless but may still have a harsh odour. Nitrogen dioxide poisoning depends on the duration, frequency, and intensity of exposure.
Nitrogen dioxide is an irritant of the mucous membrane linked with another air pollutant that causes pulmonary diseases such as obstructive lung disease, asthma, chronic obstructive pulmonary disease and sometimes acute exacerbation of COPD and in fatal cases, deaths.
Its poor solubility in water enhances its passage and its ability to pass through the moist oral mucosa of the respiratory tract.
Like most toxic gases, the dose inhaled determines the toxicity on the respiratory tract. Occupational exposures constitute the highest risk of toxicity and domestic exposure is uncommon. Prolonged exposure to low concentration of the gas may have lethal effects, as can short-term exposure to high concentrations like chlorine gas poisoning. It is one of the major air pollutants capable of causing severe health hazards such as coronary artery disease as well as stroke.
Nitrogen dioxide is often released into the environment as a byproduct of fuel combustion but rarely released by spontaneous combustion. Known sources of nitrogen dioxide gas poisoning include automobile exhaust and power stations.
The toxicity may also result from non-combustible sources such as the one released from anaerobic fermentation of food grains and anaerobic digestion of biodegradable waste.The World Health Organization (WHO) developed a global recommendation limiting exposures to less than 20 parts per billion for chronic exposure and value less 100 ppb for one hour for acute exposure, using nitrogen dioxide as a marker for other pollutants from fuel combustion.
There is a significant association between indoor NO2 levels and increased respiratory symptoms such as wheeze, chest tightness and severity of infections among children with asthma.
Historically, some cities in the United States including Chicago and Los Angeles have higher levels of nitrogen dioxide than the EPA maximum exposure limits of 100 ppb for a one-hour exposure and less than 53 ppb for chronic exposure.
Signs and symptoms
Nitrogen dioxide poisoning is harmful to all forms of life just like chlorine gas poisoning and carbon monoxide poisoning. It is easily absorbed through the lungs and its inhalation can result in heart failure and sometimes death in severe cases.
Individuals and races may differ in nitrogen dioxide tolerance level and individual tolerance level for the gas may be altered by several factors, such as metabolic rate, barometric pressure, and hematological disorders but significant exposure may result in fatal conditions that could lead to shorter lifespan due to heart failure.
Acute poisoning
Exposure to high level of nitrogen dioxide may lead to inflammation of the mucous membrane and the lower and upper respiratory tracts.
The symptoms of acute nitrogen dioxide poisoning is non-specific and have a semblance with ammonia gas poisoning, chlorine gas poisoning, and carbon monoxide poisoning. The symptoms also resembles that of pneumonia or viral infection and other inhalational injuries but common symptoms includes rhinitis wheezing or coughing, conjunctivitis, headache, throat irritation and dyspnea which may progress to nasal fissures, ulcerations, or perforation.
The patient is usually ill-appearing and presents with hypoxemia coupled with shallow rapid breathing.
Therapy is supportive and includes removal from further nitrogen dioxide exposure.
Systemic symptoms include fever and anorexia. Electrocardiography and chest radiography can help in revealing diffuse, bilateral alveolar infiltrates.
Chest radiography may be used in diagnosis and the baseline could be established with pulmonary function testing.
There is no specific laboratory diagnostic test for acute nitrogen dioxide poisoning but analysis of arterial blood gas level,
methemoglobin level, complete blood count, glucose test, lactate threshold measurement and r peripheral blood smear may be helpful in the diagnosis of nitrogen dioxide poisoning.
The determination of nitrogen dioxide in urine or tissue does not establish the diagnosis, and there are technical and interpretive problems with these tests.
Chronic poisoning
Prolonged exposure to high levels of nitrogen dioxide can have an inflammatory effect that principally targets the respiratory tracts leading to chronic nitrogen dioxide poisoning which can occur within days or weeks after the threshold limit value is excessively exceeded.This condition causes fever, rapid breathing coupled with rapid heart rate, labored breathing and severe shortness of breath. Other effects include diaphoresis, chest pain, and persistent dry cough, all of which may result in weight loss, anorexia and may also lead to right-side heart enlargement and heart disease in advanced cases.
Prolonged exposure to relatively low levels of nitrogen (II) oxide may cause persistent headaches and nausea.
Like chlorine gas poisoning, symptoms usually resolve themselves upon removal from further nitrogen dioxide exposure, unless there had been an episode of severe acute poisoning.
Treatment and management vary with symptoms. Patients are often observed for hypoxemia for a minimum of 12 hours if there are no initial symptoms and if the patient is hypoxemic, oxygen may be administered but high-dose steroids are recommended for patients with pulmonary manifestations. Patients may also be hospitalized for 12 to 24 hours or longer for observation if the gaseous exchange is impaired.
In a case where gaseous exchange is impaired, mechanical ventilation and intubation may be necessary and if bronchiolitis obliterans develop within 2 to 6 weeks of nitrogen dioxide exposure, corticosteroid therapy or anticholinergic medications may be required for 6 to 12 months to lower the body overreaction to nitrogen dioxide gas.
Cause
Occupational exposures constitute the highest risk of toxicity and it is often high for farmers especially those that deal with food grains. It is equally high for firefighters and military personnel, especially those officers that deal in explosives. The risk is also high for arc welders, traffic officers, aerospace staffs and miners as well as those people whose occupations are connected with the nitric acid. Silo-fillers disease is a consequence of exposure to nitrogen dioxide poisoning by farmers dealing with silos. Food grains such as corn and millet, as well as grasses such as alfalfa and some other plant material, produces nitrogen dioxide within hours due to anaerobic fermentation. The threshold concentrations of nitrogen dioxide are often attained within 1 to 2 days and begin to decline gradually after 10 to 14 days but if the silos is well sealed, the gas may remain in there for weeks. Heavily fertilized silage, particularly the ones produced from immature plants, generate a higher concentration of the gas within the silo.
Nitrogen dioxide is about 1.5 times heavier than air and during silage storage, nitrogen dioxide remains in the silage material.
Improper ventilation may result in exposure during the leveling of the silage.
Pathophysiology
Nitrogen dioxide is sparingly soluble in water and on inhalation, it diffuses into the lung and slowly hydrolyzes to nitrous and nitric acid which causes pulmonary edema and pneumonitis leading to the inflammation of the bronchioles and pulmonary alveolus resulting from lipid peroxidation and oxidative stress.
Mucous membrane is primarily affected along with type I pneumocyte and the respiratory epithelium. The generation of free radicals from lipid peroxidation results in irritation of the bronchioles and alveoli that causes rapid destruction of the respiratory epithelial cells.
The overall reaction results in the release of fluid that causes pulmonary edema.Nitrogen dioxide poisoning may alter macrophage activity and immune function leading to susceptibility of the body to a wide range of infections, and overexposure to the gas may also lead to methemoglobinemia, a disorder characterized by a higher than normal level of methemoglobin (metHb, i.e., ferric [Fe3+] rather than ferrous [Fe2+] haemoglobin) in the blood.
Methemoglobinemia prevents the binding of oxygen to haemoglobin causing oxygen depletion that could lead to severe hypoxia.If nitrogen dioxide poisoning is untreated, fibrous granulation tissue is likely to develop within the alveolar ducts, tiny ducts that connect the respiratory bronchioles to alveolar sacs, each of which contains a collection of alveoli (small mucus-lined pouches made of flattened epithelial cells). The overall reaction may cause an obstructive lung disease. Meanwhile, proliferative bronchiolitis is a secondary effect of nitrogen dioxide poisoning.
Epidemiology
The EPA have some regulations and guidelines for monitoring nitrogen dioxide levels. Historically, some states in the U.S including Chicago, Northeast corridor and L.A have had high levels of nitrogen dioxide.
In 2006, the WHO estimated that over 2 million deaths result annually from air pollution in which nitrogen dioxide constitute one of the pollutants. While over 50% of the disease that results from these pollutants are common in developing countries and the effects in developed countries is also significant. An EPA survey in the U.S. suggests that 16 percent of United States housing units are sited close to an airport, highway or railroad increasing in the United States the exposure risk of approximately 48 million people.
A feasibility study of the ozone formed from the oxidation of nitrogen dioxide in ambient air reported by the WHO suggested that daily deaths of 1 to 2% is attributed to exposure to ozone concentration above 47.3 ppb and exposure above 75.7ppb is attributed to 3 to 5% increase in daily mortality. A level of 114 ppb was attributed to 5 to 9% increase daily mortality.
Silo fillers disease is pervasive during the harvest seasons of food grains.In May 2015, the National Green Tribunal directed Delhi and other states in India to ban diesel vehicles over 10 years old as a measure to reduce nitrogen dioxide emission that may result in nitrogen dioxide poisoning. In 2008, the report of United Kingdom Committee on the Medical Effects of Air Pollutants (COMEAP) suggested that air pollution is the cause of about 29,000 deaths in UK. The WHO urban air quality database estimated Delhis mean annual PM 10 levels in 2010 as 286 μg /m3 and London as 23 μg /m3. In 2014, the database estimated Delhis annual mean PM 2.5 particulate matter levels in 2013 as 156 μg /m3 whereas, London have only 8 μg /m3 in 2010 but the nitrogen dioxide in London breach the European Unions standard. In 2013, the annual mean nitrogen dioxide level in London was estimated as 58 μg /m3 but the save and "threshold limit value" is 40 μg /m3. In March 2015, Brussels took the United Kingdom into court for breaching emissions limits of nitrogen dioxide at its coal-fired Aberthaw power stations in Wales. The plant operated under a permit allowing emissions of 1200 mg/Nm3, which is more than twice the 5 mg/Nm3 limit specified in the EUs large combustion plant directive.
Prognosis
Generally, long-term prognosis is helpful to survival of initial exposure to nitrogen dioxide. Some cases of nitrogen dioxide poisoning resolves with no observable symptoms and patient may be determined by pulmonary function testing. If chronic exposure causes lung damage, it could take several days or months for the pulmonary function to improve. Meanwhile, permanent mild dysfunction may result from bronchiolitis obliterans and could manifest as abnormal flow at 50 to 70 percent of vital capacity. It may also manifest as mild hyperinflammation, airway obstruction and in that case, patient may be subject to steroid treatment to treat deconditioning.
Complications from prolong exposure includes bronchiolitis obliterans and other secondary infections such as pneumonia due to injuries on the mucous membrane from pulmonary edema and inhibition of immune system by nitrogen dioxide. Nitrogen dioxide inhalation can result in short and long-term morbidity or death depending on the extent of exposure and inhaled concentration and the exposure time.
Illness resulting from acute exposure is usually not fatal although some exposure may cause bronchiolitis obliterans, pulmonary edema as well as rapid asphyxiation.
If the concentration of exposure is excessively high, the gas may displace oxygen resulting in fatal asphyxiation.Generally, patients and workers should be educated by medical personnel on how to identify the signs and symptoms of Nitrogen dioxide poisoning.
Farmers and other farm workers should be educated on the proper way of food grain storage to prevent silo fillers disease.
Biochemical effects
Chronic exposure to high level of nitrogen dioxide results in the allosteric inhibition of glutathione peroxidase and glutathione S-transferase, both of which are important enzymes found in the mucous membrane antioxidant defense system, that catalyse nucleophilic attack by reduced glutathione (GSH) on non-polar compounds that contain an electrophilic carbon and nitrogen. These inhibition mechanisms generates free radicals that causes peroxidation from the lipids in the mucous membrane leading to increased peroxidized erythrocyte lipids, a reaction that proceeds by a free radical chain reaction mechanism that result in oxidative stress. The oxidative stress on the mucous membrane causes the dissociation of the GSTp-JNK complex, oligomerization of GSTP and induction of the JNK pathway, resulting in apoptosis or inflammation of the bronchioles and pulmonary alveolus in mild cases.
On migrating to the bloodstream, nitrogen dioxide poisoning results in an irreversible inhibition of the erythrocyte membrane acetylcholinesterase which may lead to muscular paralysis, convulsions, bronchoconstriction, the narrowing of the airways in the lungs (bronchi and bronchioles) and death by asphyxiation.
It also causes a decrease in glucose-6-phosphate dehydrogenase which may results in glucose-6-phosphate dehydrogenase deficiency known as favism, a condition that predisposes to hemolysis (spontaneous destruction of red blood cells).
Acute and chronic exposure also reduces glutathione reductase, an enzyme that catalyzes the reduction of glutathione disulfide (GSSG) to the sulfhydryl form glutathione (GSH), which is a critical molecule in resisting oxidative stress and maintaining the reducing environment of the cell.
Reproductive effects
Exposure to nitrogen dioxide has a significant effect on the male reproductive system by inhibiting the production of Sertoli cells, the "nurse" cells of the testicles that are part of a seminiferous tubule and help in the process of spermatogenesis.
These effects consequently retard the production of sperm cells.
The effects of nitrogen dioxide poisoning on female reproduction may be linked with the effects of oxidative stress on female reproduction.
Nitrogen dioxide poisoning disrupts the balance of reactive oxygen species (ROS), which results in oxidative stress, leading to significant effects on the female reproductive lifespan. ROS play a significant role in body physiology, from oocyte production, development and maturation to fertilization, development of the embryo and gestation.
Exposure to nitrogen dioxide causes ovulation-induced oxidative damage to the DNA of ovarian epithelium.
There is a growing body of literature on the pathological effects of ROS on female reproduction as evidenced by free-radical-induced birth defects, abortions, hydatidiform moles and pre-eclampsia. ROS also play a significant role in the etiopathogenesis of endometriosis, a disease in which tissue that normally grows inside the uterus grows outside of it.
Oxidative stress causes defective placentation, which is likely to lead to placental hypoxia, shortage of oxygen in the placental as well as reperfusion injury resulting from ischemia, which may lead to endothelial cell dysfunction.
Increased oxidative stress caused by nitrogen dioxide poisoning may result in ovarian epithelium inflammation and potentially to cancer in the most severe cases.
References
== External links == |
Cardiac amyloidosis | Cardiac amyloidosis is a subcategory of amyloidosis where there is depositing of the protein amyloid in the cardiac muscle and surrounding tissues. Amyloid, a misfolded and insoluble protein, can become a deposit in the hearts atria, valves, or ventricles. These deposits can cause thickening of different sections of the heart, leading to decreased cardiac function. The overall decrease in cardiac function leads to a plethora of symptoms. This multisystem disease was often misdiagnosed, with diagnosis previously occurring after death during autopsy. However, recent advancements of technologies have increased the diagnosis of the disease. Cardiac amyloidosis has multiple sub-types including light chain, familial, and senile. One of the most studied types is light chain cardiac amyloidosis. Prognosis depends on the extent of the deposits in the body and the type of amyloidosis. New treatment methods are actively being researched in regards to the treatment of heart failure and specific cardiac amyloidosis problems.
Types
The multiple subtypes of cardiac amyloidosis have varying epidemiological, diagnostic, and prognostic characteristics.
Light chain (AL-CM)
This relatively rare form of cardiac amyloidosis occurs in an estimated six to ten cases per 1,000,000 people. This sub- type usually affects males over the age of 60 and is rapidly progressive. Pathogenesis of this form is due to the aggregation of immunoglobulin lambda light chains. These chains are created by an abnormal expansion of plasma cells. Over time, these light chains deposit into the interstitial tissue within the myocardium. Diagnostic tests includes serum and urine electrophoresis, laboratory testing for the determination of elevated levels of troponin and BNP, and ECGs showing low QRS voltages.
Familial (ATTRm-CM)
This type is caused by mutations of proteins involved in amyloid formation, including transthyretin (TTR), fibrinogen, apolipoprotein A1, or apolipoprotein A2. Due to the multiple number of potential genetic causes the incidence of this form is variable. The vast majority of familial cardiac amyloidosis still present after the age of 60. A common mutation is the TTR gene mutation Val122Ile. It is estimated that 3.5–4% of African Americans in The United States have the Val 122lle mutation. This type of amyloidosis can be identified by genetic testing for protein mutation. For the diagnosis of familial cardiac amyloidosis to be made a biopsy with histological evaluation must be obtained. In this histological evaluation special stains are utilized to visualize the amyloid deposits. One such stain is Congo Red, which binds specifically to the amyloid deposit and can be characterized by various lighting methods. Under polarized light, the amyloid deposits while show pathognomonic apple green birefringence, and under plain light the deposits will appear a light salmon pink color. Familial amyloidosis symptoms are centered around neuropathological and cardiac problems. Cardiac manifestations of the TTR mutation present more often in The United States.
Wild-type (ATTRwt-CM)
This type is considered the wild-type mutation which leads to the development of TTR deposits. It usually affects males over 70 years with the manifestation of carpal tunnel syndrome. Similar to the other subtypes of cardiac amyloidosis, a biopsy is required for diagnosis. However, formal diagnosis of Senile cardiac amyloidosis is a diagnosis of exclusion. Biopsy with histological evaluation can rule out Light chain and Familial subtypes, leaving the diagnosis of Senile. This type is often misdiagnosed, however, greater use of cardiac magnetic resonance has increased the rate of diagnosis The severity of the disease tends to be less than the Light chain and Familial variants. This is due to the amount of time that it takes to accumulate the amyloid depositions being longer in the Senile variant.
Symptoms and signs
Symptoms of cardiac amyloidosis are a combination of heart failure and amyloid deposition in various other organs. Amyloid deposition in the heart causes restrictive diastolic heart failure that progresses to systolic heart failure.Cardiac manifestations include:
Dyspnea on exertion
Peripheral edema and ascites
Pericardial effusion
Arrhythmias (secondary to disruption of the normal electrical system of the heart)
Atrial arrhythmias (such as atrial fibrillation)
First/second degree heart blocks
Syncope
Elevated neck veins and jugular venous pressure
Myocardial ischemia/Angina (secondary to amyloid deposition in the small arteries of the heart)Myocardial oxygen demand is increased in patients with cardiac amyloidosis, regardless of changes to coronary perfusion.For patients with light-chain amyloidosis, there can be depositions of amyloid into numerous different organs. Deposition of amyloid into other organs makes the diagnosis of cardiac amyloidosis difficult as these extracardiac manifestations mask the diagnosis. Extracardiac manifestations include:
Macroglossia
Periorbital bruising
Loss of the third and fourth heart sound
Thromboembolisms
Symmetric sensory neuropathy (such as bilateral carpal tunnel)
Postural hypotension (secondary to autonomic neuropathy)
Nephrotic syndrome (secondary to free light chain damage to the kidneys/deposition of amyloid in the kidneys)
Cause
The general cause of cardiac amyloidosis is the misfolding of a specific protein precursor depending on the amyloidosis type. Protein precursors include immunoglobulin-derived light chains and transthyretin mutations. The misfolding of the protein causes it to have insoluble beta-pleated sheets, creating an amyloid. Amyloid, the aggregation, or clumping, of proteins, is resistant to degradation by the body. Amyloids are mostly fibrils, while also containing a P component, apolipoprotein, collagen, fibronectin, and laminin. The P component, a pentameric protein, stabilizes the fibrils of the amyloid, which reduces their clearance from the body. Deposits of the amyloids can occur throughout the body, including the heart, liver, kidneys, spleen, adrenal glands, and bones. Deposits in the extracellular cardiac space can stiffen the heart, resulting in restriction of the ventricles. This restriction in ventricular motion results in a decreased ability for the heart to pump efficiently, leading to the various symptoms associated with cardiac amyloidosis.
Diagnosis
Echocardiography
Echocardiography is a safe and non-invasive method that can be used to assess the structural and functional disease of the heart. Amyloidosis presents with ventricle and valvular thickening, biatrial enlargement, restrictive filling pattern, with normal to mildly reduced systolic function and decreased diastolic filling. An echo can be used to evaluate for prognosis of the disease, measuring the different strains within the heart. Cardiac amyloidosis produces specific alterations to the functionality of the heart. Echocardiography can be utilized to detect this specific pattern (relative preservation of the apical myocardium with decreased longitudinal strain in the mid and basal sections), which is 90–95% sensitive and 80–85% specific for cardiac amyloidosis. Echocardiography can be used to help physicians with diagnosis, however, it can only be used for the suggestion of the disease, not the confirmation, unless it is late stage amyloidosis.
ECG/EKG
ECGs of patients with cardiac amyloidosis usually show a low voltage in the limb leads, with an unusual extreme right axis. There is usually a normal P-wave, however, it can be slightly prolonged. For patients with light-chain amyloidosis, the QRS complex pattern is skewed, with poor R-waves of the chest leads.Holter ECGs can be used to identify asymptomatic arrhythmias.EKG changes may be present, showing low voltage and conduction abnormalities like atrioventricular block or sinus node dysfunction.
Laboratory Tests
Laboratory tests including urea and creatinine levels, liver enzymes, glucose, thyroid function, full blood count, and clotting tests. The analysis of serum and urine for presence of monoclonal immunoglobulin is also done through immunofixation for detection of the monoclonal band. Presence of the monoclonal band would be consistent with light chain amyloidosis. For light chain amyloidosis, serum immunoglobulin free light chain assay can be used for diagnosis and following of the amyloidosis. In light-chain amyloidosis, a low paraprotein level can be present.
Cardiac biomarkers
There are two main cardiac biomarkers used in the assessment of cardiac amyloidosis, troponin and N-terminal proBNP. As expected, with cardiac damage and dysfunction, there can be an elevation of these markers in patients with cardiac amyloidosis. These markers have been incorporated into the various staging/scoring systems used by physicians to determine severity of the disease and prognosis.
Biopsies
Extracardiac biopsies of tissues of the kidney, liver, peripheral nerve, or abdominal fat can be used to confirm the presence of amyloid deposits. Amyloid deposits in biopsy samples are confirmed through the use of Congo red dye, which produces a green birefringence when viewed under polarized light. Sirius red staining or electron microscopy examination can also be done. The determination of the type of amyloid can be done by immunohisto-labeling techniques as well as immunofluorescence staining.For light-chain amyloidosis patients, bone marrow biopsies could be conducted to determine the baseline percentage of plasma cells and to rule out multiple myeloma.
Catheterization
Right heart catheterization is the test used to test for elevated diastolic ventricular pressures. This test is more invasive and would be performed after inconclusive endomyocardial biopsy samples.
Cardiac magnetic resonance imaging
Cardiac magnetic resonance (CMR) is capable of measuring the thickness of different areas of the heart. This can be used for quantification of the deposits in the heart. CMR also shows the characterization of myocardial tissue through patterns of gadolinium enhancements. However, none of the CMR technique is able to differentiate ATTR-CM and AL-CM definitely.For AL-CM, 68% of them have symmetrical and concentric left ventricular hypertrophy. On the other hand, for ATTR-CM, 79% of them have asymmetrical left ventricular hypertrophy and 18% of them have symmetrical and concentric left ventricular hypertrophy.In T1-weighted imaging, edema in the heart can be detected with a high T1 signal. Meanwhile, enlargement of heart cells will reduce the T1 signal. Using T1 signal, Extracellular volume (ECV) is useful to determine the degree of amyloid deposition around the heart cells and detect the regression of amyloid deposits after treatment. ECV is higher in ATTR-CM than in AL-CM.In T2-weighted imaging, the T2 signal is increased in acute myocarditis (inflammation of heart muscles), and myocardial infarction (heart attack). T2 signal is also increased in AL-CM and ATTR-CM but the signal is greater in AL-CM before starting chemotherapy.Late gadolinum enhancement (LGE) can determine the severity of deposition of amyloid in heart tissue. The higher the LGE signal, the more severe the heart involvement. It can be divided into three stages: no LGE, subendocardial LGE, and full-thickness (transmural) LGE.
Scintigraphy/radionuclide imaging
Scintigraphy can be used to measure the extent and distribution of the amyloid throughout the body, including the liver, kidney, spleen, and heart. A radiolabelled serum amyloid P component can be administered to a patient intravenously and the P component pools to the amyloid deposit proportional to the size of the deposit. The labeling of the P component can then be pictured by a gamma camera.Technetium radionuclide scans can now reliably diagnosis cardiac amyloidosis, with certain scanning methods having greater than 99% sensitivity (but only 91% specific for amyloidosis). In this method of imaging, radiolabeled technetium is injected into the body where it binds to cardiac amyloid deposits. A subsequent scan is taken to determine where the tracer stays, therefore highlighting the amyloid deposition in the heart. This method allows for a noninvasive definitive diagnosis of cardiac amyloidosis (as in the past an endomyocardial biopsy was required)
Mass spectrometry
Mass spectrometry can be used to determine whether the protein is light-chain or familial amyloidosis by identifying the protein subunit.
Treatments
Treatments differ according to the type of amyloidosis present. The majority of treatment is aimed at preserving heart function and treating heart failure symptoms.Light chain (AL-CM) Treatment: Since the cause of this subtype of cardiac amyloidosis is the excessive production of free light chains, the major goal of treatment is the reduction in concentration of light chains. For light-chain amyloidosis, the use of FLC assays and NT-proBNP levels can be used to monitor the progression of amyloidosis and any response to treatments. One of the major routes to decrease the production of these excess light chains is to kill the abnormal cells that are producing them. Chemotherapeutic agents such as melphalan or bortezomib can be used to kill off the abnormal cell line that is producing the free light chains. Following chemotherapy, a bone marrow transplant can be utilized to restore the normal cell lines. There are newer medications (ixazomib, carfilzomib, daratumumab, elotuzumab) under research for the treatment of multiple myeloma that can help to decrease the production of free light chains. New data suggests that orthotopic heart transplant followed by melphalan and stem cell transplant produces results similar to non cardiac amyloidosis indicated heart transplant. To treat complications, medications can be prescribed including midodrine for autonomic neuropathy, amiodarone for patients with atrial fibrillation to prevent arrhythmias, and warfarin used after a cardioembolic episode. Beta-blockers should be avoided due to the usual symptom of hypotension.Familial (ATTRm-CM) Treatment: In recent years there have been developments in the treatment of Familial/Transthyretin cardiac amyloidosis including methods to suppress transthyretin production, stabilize amyloid fibrils, and medications that can destroy already existing fibrils. For familial amyloidosis, ACE-inhibitors and beta-blockers can be prescribed if there is no autonomic neuropathy.
Suppression of transthyretin production: liver transplantation and medications that decreases the activity of the transthyretin genes (patisiran and inotersen). In patients with familial transthyretin mutations, liver transplantation can provide the body with a source of normal transthyretin. By changing the source of transthyretin from the original liver that contains the mutated transthyretin to a healthy liver, there will be no more production of the abnormal protein. However, liver transplant does not reverse the disease. The goal of liver transplant is to prevent additional amyloid deposition and prevent new symptoms/complications from happening. These medications bind to the mRNA of transthyretin and prevent the production of the transthyretin protein, thus decreasing the overall amount of transthyretin that can accumulate in the body.
Stabilization of abnormal transthyretin: There are medications that can stabilize the normally folded transthyretin, preventing misfolding and subsequent amyloid deposition. These medications include Tafamidis, the NSAID Diflunisal, and AG10. Tafamidis is a medication that binds to transthyretin and keeps it in its normal shape, stopping it from aggregating into amyloid fibrils. Diflunisal and AG10 work in a similar manner to Tafamidis in their ability to bind to and stabilize Transthyretin.
Destruction of existing amyloid fibrils: There are multiple medications that show amyloid destroying properties, Doxycycline, Tauro-ursodeoxy-cholic acid (TUDCA), and monoclonal antibodies.The use of pacemakers (both right ventricular pacing and biventricular pacing) or implantable cardioverter defibrillators remains questionable in cardiac amyloidosis.In 2012, Craig Lewis, a 55 year old Texan, presented at the Texas Heart Institute with a severe case of amyloidosis. He was given an experimental continuous-flow artificial heart transplant which saved his life. Lewis died 5 weeks later of liver failure after slipping into a coma due to the amyloidosis.
Prognosis
Overall prognosis is dependent on the extent of cardiac dysfunction. Worse outcomes have been seen when echocardiography shows left ventricular wall thickness, poor systolic function and severe diastolic dysfunction.Light chain (AL-CM) Prognosis: For light-chain amyloidosis early detection leads to best possibility of therapies prolonging the period of remission. Well treated light chain cardiac amyloidosis has a 4-year survival rate of around 90%. In patients that undergo stem cell transplant the average survival time increases to 10 years. Staging systems have been developed to stratify severity of the disease, including the Mayo Biomarker Stage, which utilizes various biomarkers such as troponin I, troponin T, BNP, and NT-proBNP, and Free light chain concentrations.Familial (ATTRm-CM) Prognosis: Due to the extensive number of variables involved in this subtype, prognosis varies depending on the specific type of familial cardiac amyloidosis. Variables involve mutant vs wild type transthyretin mutation and age of onset of symptoms. In comparison to light chain amyloidosis, the familial subtype is slower to progress and has a more favorable prognosis. However, the Val 122lle mutation (most common cause of familial cardiac amyloidosis) has a 4-year survival rate of 16% with an average length of 26 months. A delay in recognition plays a major factor in this reduced survival rate.
== References == |
Polio | Poliomyelitis, commonly shortened to polio, is an infectious disease caused by the poliovirus. Approximately 70% of cases are asymptomatic; mild symptoms which can occur include sore throat and fever; in a proportion of cases more severe symptoms develop such as headache, neck stiffness, and paresthesia. These symptoms usually pass within one or two weeks. A less common symptom is permanent paralysis, and possible death in extreme cases. Years after recovery, post-polio syndrome may occur, with a slow development of muscle weakness similar to that which the person had during the initial infection.Polio occurs naturally only in humans. It is highly infectious, and is spread from person to person either through fecal-oral transmission (e.g. poor hygiene, or by ingestion of food or water contaminated by human feces), or via the oral-oral route. Those who are infected may spread the disease for up to six weeks even if no symptoms are present. The disease may be diagnosed by finding the virus in the feces or detecting antibodies against it in the blood.Poliomyelitis has existed for thousands of years, with depictions of the disease in ancient art. The disease was first recognized as a distinct condition by the English physician Michael Underwood in 1789, and the virus that causes it was first identified in 1909 by the Austrian immunologist Karl Landsteiner. Major outbreaks started to occur in the late 19th century in Europe and the United States, and in the 20th century, it became one of the most worrying childhood diseases. Following the introduction of polio vaccines in the 1950s polio incidence declined rapidly.
Once infected, there is no specific treatment. The disease can be prevented by the polio vaccine, with multiple doses required for lifelong protection. There are two broad types of polio vaccine; an injected vaccine using inactivated poliovirus and an oral vaccine containing attenuated (weakened) live virus. Through the use of both types of vaccine, incidence of wild polio has decreased from an estimated 350,000 cases in 1988 to 6 confirmed cases in 2021, confined to just three countries. There are rare incidents of disease transmission and/or of paralytic polio associated with the attenuated oral vaccine and for this reason the injected vaccine is preferred.
Signs and symptoms
The term "poliomyelitis" is used to identify the disease caused by any of the three serotypes of poliovirus. Two basic patterns of polio infection are described: a minor illness which does not involve the central nervous system (CNS), sometimes called abortive poliomyelitis, and a major illness involving the CNS, which may be paralytic or nonparalytic. Adults are more likely to develop symptoms, including severe symptoms, than children.In most people with a normal immune system, a poliovirus infection is asymptomatic. In about 25% of cases, the infection produces minor symptoms which may include sore throat and low fever. These symptoms are temporary and full recovery occurs within one or two weeks.In about 1 percent of infections the virus can migrate from the gastrointestinal tract into the central nervous system (CNS). Most patients with CNS involvement develop nonparalytic aseptic meningitis, with symptoms of headache, neck, back, abdominal and extremity pain, fever, vomiting, stomach pain, lethargy, and irritability. About one to five in 1000 cases progress to paralytic disease, in which the muscles become weak, floppy and poorly controlled, and, finally, completely paralyzed; this condition is known as acute flaccid paralysis. The weakness most often involves the legs, but may less commonly involve the muscles of the head, neck, and diaphragm. Depending on the site of paralysis, paralytic poliomyelitis is classified as spinal, bulbar, or bulbospinal. In those who develop paralysis, between 2 and 10 percent die as the paralysis affects the breathing muscles.Encephalitis, an infection of the brain tissue itself, can occur in rare cases, and is usually restricted to infants. It is characterized by confusion, changes in mental status, headaches, fever, and, less commonly, seizures and spastic paralysis.
Cause
Poliomyelitis is caused by infection with a member of the genus Enterovirus known as poliovirus (PV). This group of RNA viruses colonize the gastrointestinal tract – specifically the oropharynx and the intestine. The incubation time (form the first signs and symptoms) ranges from three to 35 days, with a more common span of six to 20 days. PV does not affect any species other than humans. Its structure is quite simple, composed of a single (+) sense RNA genome enclosed in a protein shell called a capsid. In addition to protecting the virus genetic material, the capsid proteins enable poliovirus to infect certain types of cells. Three serotypes of poliovirus have been identified – wild poliovirus type 1 (WPV1), type 2 (WPV2), and type 3 (WPV3) – each with a slightly different capsid protein. All three are extremely virulent and produce the same disease symptoms. PV1 is the most commonly encountered form, and the one most closely associated with paralysis. WPV2 was certified as eradicated in 2015 and WPV3 certified as eradicated in 2019.Individuals who are exposed to the virus, either through infection or by immunization via polio vaccine, develop immunity. In immune individuals, IgA antibodies against poliovirus are present in the tonsils and gastrointestinal tract and able to block virus replication; IgG and IgM antibodies against PV can prevent the spread of the virus to motor neurons of the central nervous system. Infection or vaccination with one serotype of poliovirus does not provide immunity against the other serotypes, and full immunity requires exposure to each serotype.A rare condition with a similar presentation, nonpoliovirus poliomyelitis, may result from infections with enteroviruses other than poliovirus.The oral polio vaccine contains weakened viruses that can replicate. On rare occasions, these may be transmitted from the vaccinated person to other people, who may display symptoms of polio. In communities with good vaccine coverage transmission is limited, and the virus dies out. In communities with low vaccine coverage, this weakened virus may continue to circulate. Polio arising from this cause is referred to as circulating vaccine-derived polio (cVDPV) in order to distinguish it from the natural or "wild" poliovirus (WPV).
Transmission
Poliomyelitis is highly contagious via the fecal–oral (intestinal source) and the oral–oral (oropharyngeal source) routes. In endemic areas, wild polioviruses can infect virtually the entire human population. It is seasonal in temperate climates, with peak transmission occurring in summer and autumn. These seasonal differences are far less pronounced in tropical areas. The time between first exposure and first symptoms, known as the incubation period, is usually 6 to 20 days, with a maximum range of 3 to 35 days. Virus particles are excreted in the feces for several weeks following initial infection. The disease is transmitted primarily via the fecal–oral route, by ingesting contaminated food or water. It is occasionally transmitted via the oral–oral route, a mode especially visible in areas with good sanitation and hygiene. Polio is most infectious between 7 and 10 days before and after the appearance of symptoms, but transmission is possible as long as the virus remains in the saliva or feces.Factors that increase the risk of polio infection or affect the severity of the disease include immune deficiency, malnutrition, physical activity immediately following the onset of paralysis, skeletal muscle injury due to injection of vaccines or therapeutic agents, and pregnancy. Although the virus can cross the maternal-fetal barrier during pregnancy, the fetus does not appear to be affected by either maternal infection or polio vaccination. Maternal antibodies also cross the placenta, providing passive immunity that protects the infant from polio infection during the first few months of life.
Pathophysiology
Poliovirus enters the body through the mouth, infecting the first cells with which it comes in contact – the pharynx and intestinal mucosa. It gains entry by binding to an immunoglobulin-like receptor, known as the poliovirus receptor or CD155, on the cell membrane. The virus then hijacks the host cells own machinery, and begins to replicate. Poliovirus divides within gastrointestinal cells for about a week, from where it spreads to the tonsils (specifically the follicular dendritic cells residing within the tonsilar germinal centers), the intestinal lymphoid tissue including the M cells of Peyers patches, and the deep cervical and mesenteric lymph nodes, where it multiplies abundantly. The virus is subsequently absorbed into the bloodstream.Known as viremia, the presence of a virus in the bloodstream enables it to be widely distributed throughout the body. Poliovirus can survive and multiply within the blood and lymphatics for long periods of time, sometimes as long as 17 weeks. In a small percentage of cases, it can spread and replicate in other sites, such as brown fat, the reticuloendothelial tissues, and muscle. This sustained replication causes a major viremia, and leads to the development of minor influenza-like symptoms. Rarely, this may progress and the virus may invade the central nervous system, provoking a local inflammatory response. In most cases, this causes a self-limiting inflammation of the meninges, the layers of tissue surrounding the brain, which is known as nonparalytic aseptic meningitis. Penetration of the CNS provides no known benefit to the virus, and is quite possibly an incidental deviation of a normal gastrointestinal infection. The mechanisms by which poliovirus spreads to the CNS are poorly understood, but it appears to be primarily a chance event – largely independent of the age, gender, or socioeconomic position of the individual.
Paralytic polio
In around one percent of infections, poliovirus spreads along certain nerve fiber pathways, preferentially replicating in and destroying motor neurons within the spinal cord, brain stem, or motor cortex. This leads to the development of paralytic poliomyelitis, the various forms of which (spinal, bulbar, and bulbospinal) vary only with the amount of neuronal damage and inflammation that occurs, and the region of the CNS affected.
The destruction of neuronal cells produces lesions within the spinal ganglia; these may also occur in the reticular formation, vestibular nuclei, cerebellar vermis, and deep cerebellar nuclei. Inflammation associated with nerve cell destruction often alters the color and appearance of the gray matter in the spinal column, causing it to appear reddish and swollen. Other destructive changes associated with paralytic disease occur in the forebrain region, specifically the hypothalamus and thalamus. The molecular mechanisms by which poliovirus causes paralytic disease are poorly understood.
Early symptoms of paralytic polio include high fever, headache, stiffness in the back and neck, asymmetrical weakness of various muscles, sensitivity to touch, difficulty swallowing, muscle pain, loss of superficial and deep reflexes, paresthesia (pins and needles), irritability, constipation, or difficulty urinating. Paralysis generally develops one to ten days after early symptoms begin, progresses for two to three days, and is usually complete by the time the fever breaks.The likelihood of developing paralytic polio increases with age, as does the extent of paralysis. In children, nonparalytic meningitis is the most likely consequence of CNS involvement, and paralysis occurs in only one in 1000 cases. In adults, paralysis occurs in one in 75 cases. In children under five years of age, paralysis of one leg is most common; in adults, extensive paralysis of the chest and abdomen also affecting all four limbs – quadriplegia – is more likely. Paralysis rates also vary depending on the serotype of the infecting poliovirus; the highest rates of paralysis (one in 200) are associated with poliovirus type 1, the lowest rates (one in 2,000) are associated with type 2.
Spinal polio
Spinal polio, the most common form of paralytic poliomyelitis, results from viral invasion of the motor neurons of the anterior horn cells, or the ventral (front) grey matter section in the spinal column, which are responsible for movement of the muscles, including those of the trunk, limbs, and the intercostal muscles. Virus invasion causes inflammation of the nerve cells, leading to damage or destruction of motor neuron ganglia. When spinal neurons die, Wallerian degeneration takes place, leading to weakness of those muscles formerly innervated by the now-dead neurons. With the destruction of nerve cells, the muscles no longer receive signals from the brain or spinal cord; without nerve stimulation, the muscles atrophy, becoming weak, floppy and poorly controlled, and finally completely paralyzed. Maximum paralysis progresses rapidly (two to four days), and usually involves fever and muscle pain. Deep tendon reflexes are also affected, and are typically absent or diminished; sensation (the ability to feel) in the paralyzed limbs, however, is not affected.The extent of spinal paralysis depends on the region of the cord affected, which may be cervical, thoracic, or lumbar. The virus may affect muscles on both sides of the body, but more often the paralysis is asymmetrical. Any limb or combination of limbs may be affected – one leg, one arm, or both legs and both arms. Paralysis is often more severe proximally (where the limb joins the body) than distally (the fingertips and toes).
Bulbar polio
Making up about two percent of cases of paralytic polio, bulbar polio occurs when poliovirus invades and destroys nerves within the bulbar region of the brain stem. The bulbar region is a white matter pathway that connects the cerebral cortex to the brain stem. The destruction of these nerves weakens the muscles supplied by the cranial nerves, producing symptoms of encephalitis, and causes difficulty breathing, speaking and swallowing. Critical nerves affected are the glossopharyngeal nerve (which partially controls swallowing and functions in the throat, tongue movement, and taste), the vagus nerve (which sends signals to the heart, intestines, and lungs), and the accessory nerve (which controls upper neck movement). Due to the effect on swallowing, secretions of mucus may build up in the airway, causing suffocation. Other signs and symptoms include facial weakness (caused by destruction of the trigeminal nerve and facial nerve, which innervate the cheeks, tear ducts, gums, and muscles of the face, among other structures), double vision, difficulty in chewing, and abnormal respiratory rate, depth, and rhythm (which may lead to respiratory arrest). Pulmonary edema and shock are also possible and may be fatal.
Bulbospinal polio
Approximately 19 percent of all paralytic polio cases have both bulbar and spinal symptoms; this subtype is called respiratory or bulbospinal polio. Here, the virus affects the upper part of the cervical spinal cord (cervical vertebrae C3 through C5), and paralysis of the diaphragm occurs. The critical nerves affected are the phrenic nerve (which drives the diaphragm to inflate the lungs) and those that drive the muscles needed for swallowing. By destroying these nerves, this form of polio affects breathing, making it difficult or impossible for the patient to breathe without the support of a ventilator. It can lead to paralysis of the arms and legs and may also affect swallowing and heart functions.
Diagnosis
Paralytic poliomyelitis may be clinically suspected in individuals experiencing acute onset of flaccid paralysis in one or more limbs with decreased or absent tendon reflexes in the affected limbs that cannot be attributed to another apparent cause, and without sensory or cognitive loss.A laboratory diagnosis is usually made based on the recovery of poliovirus from a stool sample or a swab of the pharynx. Antibodies to poliovirus can be diagnostic, and are generally detected in the blood of infected patients early in the course of infection. Analysis of the patients cerebrospinal fluid (CSF), which is collected by a lumbar puncture ("spinal tap"), reveals an increased number of white blood cells (primarily lymphocytes) and a mildly elevated protein level. Detection of virus in the CSF is diagnostic of paralytic polio but rarely occurs.If poliovirus is isolated from a patient experiencing acute flaccid paralysis, it is further tested through oligonucleotide mapping (genetic fingerprinting), or more recently by PCR amplification, to determine whether it is "wild type" (that is, the virus encountered in nature) or "vaccine type" (derived from a strain of poliovirus used to produce polio vaccine). It is important to determine the source of the virus because for each reported case of paralytic polio caused by wild poliovirus, an estimated 200 to 3,000 other contagious asymptomatic carriers exist.
Prevention
Passive immunization
In 1950, William Hammon at the University of Pittsburgh purified the gamma globulin component of the blood plasma of polio survivors. Hammon proposed the gamma globulin, which contained antibodies to poliovirus, could be used to halt poliovirus infection, prevent disease, and reduce the severity of disease in other patients who had contracted polio. The results of a large clinical trial were promising; the gamma globulin was shown to be about 80 percent effective in preventing the development of paralytic poliomyelitis. It was also shown to reduce the severity of the disease in patients who developed polio. Due to the limited supply of blood plasma gamma globulin was later deemed impractical for widespread use and the medical community focused on the development of a polio vaccine.
Vaccine
Two types of vaccine are used throughout the world to combat polio. Both types induce immunity to polio, efficiently blocking person-to-person transmission of wild poliovirus, thereby protecting both individual vaccine recipients and the wider community (so-called herd immunity).The first candidate polio vaccine, based on one serotype of a live but attenuated (weakened) virus, was developed by the virologist Hilary Koprowski. Koprowskis prototype vaccine was given to an eight-year-old boy on 27 February 1950. Koprowski continued to work on the vaccine throughout the 1950s, leading to large-scale trials in the then Belgian Congo and the vaccination of seven million children in Poland against serotypes PV1 and PV3 between 1958 and 1960.The second polio virus vaccine was developed in 1952 by Jonas Salk at the University of Pittsburgh, and announced to the world on 12 April 1955. The Salk vaccine, or inactivated poliovirus vaccine, is based on poliovirus grown in a type of monkey kidney tissue culture (vero cell line), which is chemically inactivated with formalin. After two doses of inactivated poliovirus vaccine (given by injection), 90 percent or more of individuals develop protective antibody to all three serotypes of poliovirus, and at least 99 percent are immune to poliovirus following three doses.Subsequently, Albert Sabin developed another live, oral polio vaccine. It was produced by the repeated passage of the virus through nonhuman cells at subphysiological temperatures. The attenuated poliovirus in the Sabin vaccine replicates very efficiently in the gut, the primary site of wild poliovirus infection and replication, but the vaccine strain is unable to replicate efficiently within nervous system tissue. A single dose of Sabins oral polio vaccine produces immunity to all three poliovirus serotypes in about 50 percent of recipients. Three doses of live-attenuated oral vaccine produce protective antibody to all three poliovirus types in more than 95 percent of recipients. Human trials of Sabins vaccine began in 1957, and in 1958 it was selected, in competition with the live vaccines of Koprowski and other researchers, by the US National Institutes of Health. Licensed in 1962, it rapidly became the only polio vaccine used worldwide.
Because the oral polio vaccine is inexpensive, easy to administer, and produces excellent immunity in the intestine (which helps prevent infection with wild virus in areas where it is endemic), it has been the vaccine of choice for controlling poliomyelitis in many countries. On very rare occasions (about one case per 750,000 vaccine recipients), the attenuated virus in the oral polio vaccine reverts into a form that can paralyze. In 2017, cases caused by vaccine-derived poliovirus (cVDPV) outnumbered wild poliovirus cases for the first time, due to wild polio cases hitting record lows. Most industrialized countries have switched to inactivated polio vaccine, which cannot revert, either as the sole vaccine against poliomyelitis or in combination with oral polio vaccine.
Treatment
There is no cure for polio, but there are treatments. The focus of modern treatment has been on providing relief of symptoms, speeding recovery and preventing complications. Supportive measures include antibiotics to prevent infections in weakened muscles, analgesics for pain, moderate exercise and a nutritious diet. Treatment of polio often requires long-term rehabilitation, including occupational therapy, physical therapy, braces, corrective shoes and, in some cases, orthopedic surgery.Portable ventilators may be required to support breathing. Historically, a noninvasive, negative-pressure ventilator, more commonly called an iron lung, was used to artificially maintain respiration during an acute polio infection until a person could breathe independently (generally about one to two weeks). Today, many polio survivors with permanent respiratory paralysis use modern jacket-type negative-pressure ventilators worn over the chest and abdomen.Other historical treatments for polio include hydrotherapy, electrotherapy, massage and passive motion exercises, and surgical treatments, such as tendon lengthening and nerve grafting.Sister Elizabeth Kennys Kenny regimen is now the hallmark for the treatment of paralytic polio.
Prognosis
Patients with abortive polio infections recover completely. In those who develop only aseptic meningitis, the symptoms can be expected to persist for two to ten days, followed by complete recovery. In cases of spinal polio, if the affected nerve cells are completely destroyed, paralysis will be permanent; cells that are not destroyed, but lose function temporarily, may recover within four to six weeks after onset. Half the patients with spinal polio recover fully; one-quarter recover with mild disability, and the remaining quarter are left with severe disability. The degree of both acute paralysis and residual paralysis is likely to be proportional to the degree of viremia, and inversely proportional to the degree of immunity. Spinal polio is rarely fatal.Without respiratory support, consequences of poliomyelitis with respiratory involvement include suffocation or pneumonia from aspiration of secretions. Overall, 5 to 10 percent of patients with paralytic polio die due to the paralysis of muscles used for breathing. The case fatality rate (CFR) varies by age: 2 to 5 percent of children and up to 15 to 30 percent of adults die. Bulbar polio often causes death if respiratory support is not provided; with support, its CFR ranges from 25 to 75 percent, depending on the age of the patient. When intermittent positive pressure ventilation is available, the fatalities can be reduced to 15 percent.
Recovery
Many cases of poliomyelitis result in only temporary paralysis. Generally in these cases, nerve impulses return to the paralyzed muscle within a month, and recovery is complete in six to eight months. The neurophysiological processes involved in recovery following acute paralytic poliomyelitis are quite effective; muscles are able to retain normal strength even if half the original motor neurons have been lost. Paralysis remaining after one year is likely to be permanent, although some recovery of muscle strength is possible up to 18 months after infection.One mechanism involved in recovery is nerve terminal sprouting, in which remaining brainstem and spinal cord motor neurons develop new branches, or axonal sprouts. These sprouts can reinnervate orphaned muscle fibers that have been denervated by acute polio infection, restoring the fibers capacity to contract and improving strength. Terminal sprouting may generate a few significantly enlarged motor neurons doing work previously performed by as many as four or five units: a single motor neuron that once controlled 200 muscle cells might control 800 to 1000 cells. Other mechanisms that occur during the rehabilitation phase, and contribute to muscle strength restoration, include myofiber hypertrophy – enlargement of muscle fibers through exercise and activity – and transformation of type II muscle fibers to type I muscle fibers.In addition to these physiological processes, the body can compensate for residual paralysis in other ways. Weaker muscles can be used at a higher than usual intensity relative to the muscles maximal capacity, little-used muscles can be developed, and ligaments can enable stability and mobility.
Complications
Residual complications of paralytic polio often occur following the initial recovery process. Muscle paresis and paralysis can sometimes result in skeletal deformities, tightening of the joints, and movement disability. Once the muscles in the limb become flaccid, they may interfere with the function of other muscles. A typical manifestation of this problem is equinus foot (similar to club foot). This deformity develops when the muscles that pull the toes downward are working, but those that pull it upward are not, and the foot naturally tends to drop toward the ground. If the problem is left untreated, the Achilles tendons at the back of the foot retract and the foot cannot take on a normal position. People with polio that develop equinus foot cannot walk properly because they cannot put their heels on the ground. A similar situation can develop if the arms become paralyzed.In some cases the growth of an affected leg is slowed by polio, while the other leg continues to grow normally. The result is that one leg is shorter than the other and the person limps and leans to one side, in turn leading to deformities of the spine (such as scoliosis). Osteoporosis and increased likelihood of bone fractures may occur. An intervention to prevent or lessen length disparity can be to perform an epiphysiodesis on the distal femoral and proximal tibial/fibular condyles, so that limbs growth is artificially stunted, and by the time of epiphyseal (growth) plate closure, the legs are more equal in length. Alternatively, a person can be fitted with custom-made footwear which corrects the difference in leg lengths. Other surgery to re-balance muscular agonist/antagonist imbalances may also be helpful. Extended use of braces or wheelchairs may cause compression neuropathy, as well as a loss of proper function of the veins in the legs, due to pooling of blood in paralyzed lower limbs. Complications from prolonged immobility involving the lungs, kidneys and heart include pulmonary edema, aspiration pneumonia, urinary tract infections, kidney stones, paralytic ileus, myocarditis and cor pulmonale.
Post-polio syndrome
Between 25 percent and 50 percent of individuals who have recovered from paralytic polio in childhood can develop additional symptoms decades after recovering from the acute infection, notably new muscle weakness and extreme fatigue. This condition is known as post-polio syndrome (PPS) or post-polio sequelae. The symptoms of PPS are thought to involve a failure of the oversized motor units created during the recovery phase of the paralytic disease. Contributing factors that increase the risk of PPS include aging with loss of neuron units, the presence of a permanent residual impairment after recovery from the acute illness, and both overuse and disuse of neurons. PPS is a slow, progressive disease, and there is no specific treatment for it. Post-polio syndrome is not an infectious process, and persons experiencing the syndrome do not shed poliovirus.
Orthotics
Paralysis, length differences and deformations of the lower extremities can lead to a hindrance when walking with compensation mechanisms that lead to a severe impairment of the gait pattern. In order to be able to stand and walk safely and to improve the gait pattern, orthotics can be included in the therapy concept. Today, modern materials and functional elements enable the orthosis to be specifically adapted to the requirements resulting from the patients gait. Mechanical stance phase control knee joints may secure the knee joint in the early stance phases and release again for knee flexion when the swing phase is initiated. With the help of an orthotic treatment with a stance phase control knee joint, a natural g |
Polio | ait pattern can be achieved despite mechanical protection against unwanted knee flexion. In these cases, locked knee joints are often used, which have a good safety function, but do not allow knee flexion when walking during swing phase. With such joints, the knee joint remains mechanically blocked during the swing phase. Patients with locked knee joints must swing the leg forward with the knee extended even during the swing phase. This only works if the patient develops compensatory mechanisms, e.g. by raising the bodys center of gravity in the swing phase (Duchenne limping) or by swinging the orthotic leg to the side (circumduction).
Epidemiology
Eradication
Following the widespread use of poliovirus vaccine in the mid-1950s, new cases of poliomyelitis declined dramatically in many industrialized countries. A global effort to eradicate polio - the Global Polio Eradication Initiative - began in 1988, led by the World Health Organization, UNICEF, and The Rotary Foundation. Polio is one of only two diseases currently the subject of a global eradication program, the other being Guinea worm disease. So far, the only diseases completely eradicated by humankind are smallpox, declared eradicated in 1980, and rinderpest, declared eradicated in 2011. In April 2012, the World Health Assembly declared that the failure to completely eradicate polio would be a programmatic emergency for global public health, and that it "must not happen."These efforts have hugely reduced the number of cases; from an estimated 350,000 cases in 1988 to a low of 483 cases in 2001, after which it remained at a level of about 1,000–2000 cases per year for a number of years.By 2015, polio was believed to remain naturally spreading in only two countries, Pakistan and Afghanistan, although it continued to cause outbreaks in other nearby countries due to hidden or reestablished transmission. Between 2016 and 2020 worldwide cases of wild polio (mostly in these countries) remained below 200 per year, with only 6 confirmed cases in 2021.
Circulating vaccine-derived polioviruses
The oral polio vaccine, while highly effective, has the disadvantage that it comprises a live virus which has been attenuated so that it cannot cause severe illness. The vaccine virus is excreted in the stool, and in under-immunized communities it can spread from person to person. This is known as circulating vaccine-derived poliovirus (cVDPV).
With prolonged transmission of this kind the weakened virus can mutate and revert to a form that causes illness and paralysis. Cases of cVDPV now exceed wild-type cases, making it desirable to discontinue the use of the oral polio vaccine as soon as safely possible and instead use other types of polio vaccines.
Afghanistan and Pakistan
The last remaining region with wild polio cases are the South Asian countries Afghanistan and Pakistan.
During 2011, the CIA ran a fake hepatitis vaccination clinic in Abbottabad, Pakistan in an attempt to locate Osama bin Laden. This destroyed trust in vaccination programs in the region. There were attacks and deaths among vaccination workers; 66 vaccinators were killed in 2013 and 2014. In Afghanistan, the Taliban banned house-to-house polio vaccination between 2018 and 2021. These factors have set back efforts to eliminate polio by means of vaccination in these countries.In Afghanistan, 80 cases of polio were reported from 35 districts during 2011. Incidence over the subsequent 10 years has declined to just 4 cases in 2 districts during 2021.In Pakistan, cases dropped by 97 percent from 2014 to 2018; reasons include 440 million dirham support from the United Arab Emirates to vaccinate more than ten million children, changes in the military situation, and arrests of some of those who attacked polio workers. During 2021 only one case of wild polio was detected in Pakistan.
Americas
The Americas were declared polio-free in 1994. The last known case was a boy in Peru in 1991. The US Centers for Disease Control and Prevention recommends polio vaccination boosters for travelers and those who live in countries where the disease is endemic.In July 2022, the US state of New York reported a polio case for the first time in almost a decade in the country. Health officials said the person, an unvaccinated young adult who had not recently travelled abroad, first showed symptoms a month earlier and eventually developed paralysis. The New York State Health Commissioner subsequently attributed this to a vaccine-derived strain of the virus. This strain had also had been detected in wastewater in New York City. As of September 13, 2022 vaccine-derived polio is confirmed to be circulating locally in Rockland County and may be circulating locally in Orange County and may be circulating locally.
Western Pacific
In 2000, polio was declared to have been officially eliminated in 37 Western Pacific countries, including China and Australia.Despite eradication ten years earlier, an outbreak was confirmed in China in September 2011, involving a strain common in Pakistan.In September 2019, the Department of Health of the Philippines declared a polio outbreak in the country after a single case in a 3-year-old girl. The outbreak was declared to be ended during June 2021. In December 2019, acute poliomyelitis was confirmed in an infant in Sabah state, Borneo, Malaysia. Subsequently, a further three polio cases were reported, with the last case reported in January 2020. Prior to this, Malaysia had been declared polio-free in 2000. WHO declared an end to the outbreak in September 2021. Both outbreaks were found to be linked instances of vaccine-derived poliomyelitis.
Europe
Europe was declared polio-free in 2002.
Southeast Asia
The last case of polio in the region was in India (part of the WHOs South-East Asia Region) in January 2011. Since January 2011, there have been no reported cases of the wild polio infections in India, and in February 2012 the country was taken off the WHO list of polio endemic countries.On 27 March 2014, the WHO announced the eradication of poliomyelitis in the South-East Asia Region, which includes eleven countries: Bangladesh, Bhutan, North Korea, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand and Timor-Leste. With the addition of this region, 80 per cent of the world population was considered to be living in polio-free regions.
Middle East
In Syria difficulties in executing immunization programs in the ongoing civil war led to a return of polio, probably in 2012, acknowledged by the WHO in 2013. 15 cases were confirmed among children in Syria between October and November 2013 in Deir Ezzor. Later, two more cases, one each in rural Damascus and Aleppo, were identified. It was the first outbreak in Syria since 1999. Doctors and international public health agencies report more than 90 cases of polio in Syria, with fears of contagion in rebel areas from lack of sanitation and safe-water services. A vaccination campaign in Syria operated literally under fire and led to the deaths of several vaccinators, but returned vaccination coverage to pre-war levels.An outbreak of vaccine-derived polio was confirmed in 2017 in eastern Syria. Syria is currently free of polio, but is consider "at risk".
Africa
In 2003 in northern Nigeria – a country which at that time was considered provisionally polio free – a fatwa was issued declaring that the polio vaccine was designed to render children sterile. Subsequently, polio reappeared in Nigeria and spread from there to several other countries. In 2013, nine health workers administering polio vaccine were targeted and killed by gunmen on motorcycles in Kano, but this was the only attack. Local traditional and religious leaders and polio survivors worked to revive the campaign, and Nigeria was removed from the polio-endemic list in September 2015 after more than a year without any cases, only to be restored to the list in 2016 when two cases were detected.Africa was declared free of wild polio in August 2020, although cases of circulating vaccine-derived poliovirus type 2 continue to appear in several countries.A single case of wild polio which was detected in Malawi in February 2022, and another in Mozambique in May 2022 were both of a strain imported from Pakistan and do not affect the African regions wild poliovirus-free certification status.
History
The effects of polio have been known since prehistory; Egyptian paintings and carvings depict otherwise healthy people with withered limbs, and young children walking with canes. The first clinical description was provided by the English physician Michael Underwood in 1789, where he refers to polio as "a debility of the lower extremities". The work of physicians Jakob Heine in 1840 and Karl Oskar Medin in 1890 led to it being known as Heine–Medin disease. The disease was later called infantile paralysis, based on its propensity to affect children.
Before the 20th century, polio infections were rarely seen in infants before six months of age, most cases occurring in children six months to four years of age. Poorer sanitation of the time resulted in constant exposure to the virus, which enhanced a natural immunity within the population. In developed countries during the late 19th and early 20th centuries, improvements were made in community sanitation, including better sewage disposal and clean water supplies. These changes drastically increased the proportion of children and adults at risk of paralytic polio infection, by reducing childhood exposure and immunity to the disease.Small localized paralytic polio epidemics began to appear in Europe and the United States around 1900. Outbreaks reached pandemic proportions in Europe, North America, Australia, and New Zealand during the first half of the 20th century. By 1950, the peak age incidence of paralytic poliomyelitis in the United States had shifted from infants to children aged five to nine years, when the risk of paralysis is greater; about one-third of the cases were reported in persons over 15 years of age. Accordingly, the rate of paralysis and death due to polio infection also increased during this time. In the United States, the 1952 polio epidemic became the worst outbreak in the nations history. Of the nearly 58,000 cases reported that year, 3,145 died and 21,269 were left with mild to disabling paralysis. Intensive care medicine has its origin in the fight against polio. Most hospitals in the 1950s had limited access to iron lungs for patients unable to breathe without mechanical assistance. Respiratory centers designed to assist the most severe polio patients, first established in 1952 at the Blegdam Hospital of Copenhagen by Danish anesthesiologist Bjørn Ibsen, were the precursors of modern intensive care units (ICU). (A year later, Ibsen would establish the worlds first dedicated ICU.)The polio epidemics not only altered the lives of those who survived them, but also brought profound cultural changes, spurring grassroots fund-raising campaigns that would revolutionize medical philanthropy, and giving rise to the modern field of rehabilitation therapy. As one of the largest disabled groups in the world, polio survivors also helped to advance the modern disability rights movement through campaigns for the social and civil rights of the disabled. The World Health Organization estimates that there are 10 to 20 million polio survivors worldwide. In 1977, there were 254,000 persons living in the United States who had been paralyzed by polio. According to doctors and local polio support groups, some 40,000 polio survivors with varying degrees of paralysis were living in Germany, 30,000 in Japan, 24,000 in France, 16,000 in Australia, 12,000 in Canada and 12,000 in the United Kingdom in 2001. Many notable individuals have survived polio and often credit the prolonged immobility and residual paralysis associated with polio as a driving force in their lives and careers.The disease was very well publicized during the polio epidemics of the 1950s, with extensive media coverage of any scientific advancements that might lead to a cure. Thus, the scientists working on polio became some of the most famous of the century. Fifteen scientists and two laymen who made important contributions to the knowledge and treatment of poliomyelitis are honored by the Polio Hall of Fame, which was dedicated in 1957 at the Roosevelt Warm Springs Institute for Rehabilitation in Warm Springs, Georgia, US. In 2008 four organizations (Rotary International, the World Health Organization, the U.S. Centers for Disease Control and UNICEF) were added to the Hall of Fame.World Polio Day (24 October) was established by Rotary International to commemorate the birth of Jonas Salk, who led the first team to develop a vaccine against poliomyelitis. Use of this inactivated poliovirus vaccine and subsequent widespread use of the oral poliovirus vaccine developed by Albert Sabin led to establishment of the Global Polio Eradication Initiative (GPEI) in 1988. Since then, GPEI has reduced polio worldwide by 99 percent.
Etymology
The term derives from the Ancient Greek poliós (πολιός), meaning "grey", myelós (µυελός "marrow"), referring to the grey matter of the spinal cord, and the suffix -itis, which denotes inflammation, i.e., inflammation of the spinal cords grey matter, although a severe infection can extend into the brainstem and even higher structures, resulting in polioencephalitis, resulting in inability to breathe, requiring mechanical assistance such as an iron lung.
Research
The Poliovirus Antivirals Initiative was launched in 2007 with the aim of developing antiviral medications for polio, but while several promising candidates were identified, none have progressed beyond Phase II clinical trials. Pocapavir (a capsid inhibitor) and V-7404 (a protease inhibitor) may speed up viral clearance and are being studied for this purpose.
References
Further reading
Kluger Jefferey (2004). Splendid Solution: Jonas Salk and the Conquest of Polio. New York: G. P. Putnams Sons. ISBN 978-0-399-15216-0.
Oshinsky DM (2005). Polio: An American story. Oxford: Oxford University Press. ISBN 978-0-19-515294-4. polio.
Shaffer MM, Bernard S (2005). The death of a disease: a history of the eradication of poliomyelitis. New Brunswick, NJ: Rutgers University Press. ISBN 978-0-8135-3677-4.
Shell M (2005). Polio and its aftermath: the paralysis of culture. Cambridge: Harvard University Press. ISBN 978-0-674-01315-5. polio.
Wilson DJ (2005). Living with polio: the epidemic and its survivors. Chicago: University of Chicago Press. ISBN 978-0-226-90103-9.
Wilson DJ, Silver J (2007). Polio voices: an oral history from the American polio epidemics and worldwide eradication efforts. New York: Praeger. ISBN 978-0-275-99492-1.
External links
Media related to Polio at Wikimedia Commons
Quotations related to Polio at Wikiquote
The dictionary definition of polio at Wiktionary
Polio at Curlie |
Amaurosis | Amaurosis (Greek meaning darkening, dark, or obscure) is vision loss or weakness that occurs without an apparent lesion affecting the eye. It may result from either a medical condition or excess acceleration, as in flight. The term is the same as the Latin gutta serena, which means, in Latin, drop clear (or drop bright). Gutta serena is a condition of partial or complete blindness with a transparent, clear pupil. This term contrasts with suffusio nigra which means, in Latin, suffusion dark, indicating partial or complete blindness with a dark pupil, e.g., a cataract. Milton, already totally blind for twelve years (some scholars think from retinal detachment; others have diagnosed glaucoma) by the time he published Paradise Lost, refers to these terms in Book 3, lines 25–26.
Types
Lebers congenital amaurosis is an inherited disease resulting in optic atrophy and secondary severe vision loss or blindness. It was first described by Theodore Leber in the 19th century.Amaurosis fugax (Latin: fugax meaning fleeting) is a temporary loss of vision in one eye caused by decreased blood flow (ischemia) to the retina.
It may also be caused by embolization from atherosclerotic plaques in the ipsilateral (same side) internal carotid artery. It is a type of transient ischaemic attack (TIA). Those experiencing amaurosis usually experience complete symptom resolution within a few minutes. In a small minority of those who experience amaurosis, stroke or permanent vision loss results. Diabetes, hypertension and smoking are factors known to increase the risks of suffering this condition. It also can be the result of surgical repair to the mitral valve, when very small emboli may break away from the site of the repair, while the patients tissue grows to cover the plastic annuloplasty band.Quinidine toxicity can lead to cinchonism and also to quinine amaurosis.
Management
Those experiencing amaurosis are usually advised to consult a physician immediately as any form of vision loss, even if temporary, is a symptom that may indicate the presence of a serious ocular or systemic problem.
In animals
This condition can also occur in ruminants suffering from a vitamin B1 (thiamine) deficiency due to thiamine-related cerebrocortical necrosis (CCN).
== References == |
Perforated eardrum | A perforated eardrum (tympanic membrane perforation) is a hole in the eardrum. It can be caused by infection (otitis media), trauma, overpressure (loud noise), inappropriate ear clearing, and changes in middle ear pressure. An otoscope can be used to view the eardrum to diagnose a perforation. Perforations may heal naturally, or require surgery.
Presentation
A perforated eardrum leads to conductive hearing loss, which is usually temporary. Other symptoms may include tinnitus, ear pain, vertigo, or a discharge of mucus. Nausea and/or vomiting secondary to vertigo may occur.
Causes
A perforated eardrum can have one of many causes, such as:
infection (otitis media). This infection may then spread through the middle ear, and may reoccur.
trauma. This may be caused by trying to clean ear wax with sharp instruments. It may also occur due to surgical complications.
overpressure (loud noise or shockwave from an explosion).
inappropriate ear clearing.
flying with a severe cold, due to changes in air pressure and blocked Eustachian tubes resulting from the cold. This is especially true on landing.
Diagnosis
An otoscope can be used to look at the ear canal. This gives a view of the ear canal and eardrum, so that a perforated eardrum can be seen. Tympanometry may also be used.
Treatment
Conservative management
A perforated eardrum often heals naturally. It may heal in a few weeks, or may take up to a few months.
Surgery
Some perforations require surgical intervention. This may take the form of a paper patch to promote healing (a simple procedure by an ear, nose and throat specialist), or surgery (tympanoplasty). However, in some cases, the perforation can last several years and will be unable to heal naturally. For patients with persistent perforation, surgery is usually undertaken to close the perforation. The objective of the surgery is to provide a platform of sort to support the regrowth and healing of the tympanic membrane in the two weeks post surgery period. There are two ways of doing the surgery:
Traditional tympanoplasty, usually using the microscope and performed through a 10 cm incision behind the ear lobe. This technique was introduced by Wullstien and Zollner and popularized by the Jim Sheehy at the House Ear Institute.
Endoscopic tympanoplasty, usually using the endoscope through the ear canal without the need for incision. This technique was introduced and popularized by Professor Tarabichi of TSESI: Tarabichi Stammberger Ear and Sinus Institute.The success of surgery is variable based on the cause of perforation and the technique being used. Predictors of success include traumatic perforation, dry ear, and central perforations. Predictors of failure includes young age and poor eustachian tube function. The use of minimally invasive endoscopic technique does not reduce the chance of successful outcome. Hearing is usually recovered fully, but chronic infection over a long period may lead to permanent hearing loss. Those with more severe ruptures may need to wear an ear plug to prevent water contact with the ear drum.
References
== External links == |
Oppositional defiant disorder | Oppositional defiant disorder (ODD) is listed in the DSM-5 under Disruptive, impulse-control, and conduct disorders and defined as "a pattern of angry/irritable mood, argumentative/defiant behavior, or vindictiveness". This behavior is usually targeted toward peers, parents, teachers, and other authority figures. Unlike conduct disorder (CD), those with ODD do not show patterns of aggression towards people or animals, destruction of property, theft, or deceit. It has certain links to attention deficit hyperactivity disorder (ADHD), and as many as one half of children with ODD also fulfill the diagnostic criteria for ADHD.
History
Oppositional defiant disorder was first defined in the DSM-III (1980). Since the introduction of ODD as an independent disorder, the field trials to inform its definition have included predominantly male subjects. Some clinicians have debated whether the diagnostic criteria would be clinically relevant for use with females, and furthermore, some have questioned whether gender-specific criteria and thresholds should be included. Additionally, some clinicians have questioned the preclusion of ODD when conduct disorder is present. According to Dickstein, the DSM-5 attempts to:
"redefine ODD by emphasizing a persistent pattern of angry and irritable mood along with vindictive behavior, rather than DSM-IVs focus exclusively on negativistic, hostile, and defiant behavior. Although DSM-IV implied, but did not mention, irritability, DSM-5 now includes three symptom clusters, one of which is angry/irritable mood—defined as loses temper, is touchy/easily annoyed by others, and is angry/resentful. This suggests that the process of clinically relevant research driving nosology, and vice versa, has ensured that the future will bring greater understanding of ODD."
Epidemiology
ODD is a pattern of negative, defiant, disobedient, and hostile behavior, and it is one of the most prevalent disorders from preschool age to adulthood. This can include frequent temper tantrums, excessive arguing with adults, refusing to follow rules, purposefully upsetting others, getting easily irked, having an angry attitude, and acting vindictive. Children with ODD usually begin showing symptoms around 6 to 8, although the disorder can emerge in younger children too. Symptoms can last throughout teenage years. The pooled prevalence is 3.6% up to age 18 (Ezpeleta, et al. 2019). While adults can be affected by ODD, they often go undiagnosed if they were not diagnosed as children. There has been research to support that ODD is more common in boys than girls with a 2:1 ratio.Oppositional defiant disorder has a prevalence of 1% to 11%. The average prevalence is approximately 3.3%. Gender and age play an important role in the rate of the disorder. ODD gradually develops and becomes apparent in preschool years, often before the age of eight years old. However, it is very unlikely to emerge following early adolescence. There is a difference in prevalence between boys and girls, with a ratio of 1.4 to 1 before adolescence. However, girls prevalence tends to increase after puberty. Researchers have found that the general prevalence of ODD throughout cultures remains constant. However, the difference in ODD prevalence between sexes is only significant in Western cultures. It is possible that there is a decreased prevalence of ODD in boys or an increased prevalence of ODD in girls in non-Western cultures, but it is also possible that the disorder is either over- or under-diagnosed in boys or girls, respectively, in Western cultures. Other factors can influence the prevalence of the disorder. Youths living in families of low socioeconomic status have a higher prevalence. Another factor is based on the criteria used to diagnose an individual. When the disorder was first included in the DSM-III, the prevalence was 25% higher than when the DSM-IV revised the criteria of diagnosis. The DSM-V made more changes to the criteria, grouping certain characteristics together in order to demonstrate that ODD display both emotional and behavioral symptomatology. In addition, criteria were added to help guide clinicians in diagnosis because of the difficulty found in identifying whether the behaviors or symptoms are directly related to the disorder or simply a phase in a childs life. Consequently, future studies may obtain results indicating a decline in prevalence between the DSM-IV and the DSM-V.
Signs and symptoms
The fourth revision of the Diagnostic and Statistical Manual (DSM-IV-TR) (now replaced by DSM-5) states that a person must exhibit four out of the eight signs and symptoms to meet the diagnostic threshold for ODD. These symptoms include:
Often loses temper
Is often touchy or easily annoyed
Is often angry and resentful
Often argues with authority figures or, for children and adolescents, with adults
Often actively defies or refuses to comply with requests from authority figures or with rules
Often deliberately annoys others
Often blames others for their mistakes or misbehavior
Has been spiteful or vindictive at least twice within the past six monthsThese behaviors are mostly directed towards an authority figure such as a teacher or a parent. Although these behaviors can be typical among siblings, they must be observed with individuals other than siblings for an ODD diagnosis. Children with ODD can be verbally aggressive. However, they do not display physical aggressiveness, a behavior observed in conduct disorder. Furthermore, they must be perpetuated for longer than six months and must be considered beyond a normal childs age, gender and culture to fit the diagnosis. For children under five years of age, they must occur on most days over a period of six months. For children over five years of age, they must occur at least once a week for at least six months. If symptoms are confined to only one setting, most commonly home, it is considered mild in severity. If it is observed in two settings, it is characterized as moderate, and if the symptoms are observed in three or more settings, it is considered severe.These patterns of behavior result in impairment at school or other social venues.
Etiology
There is no specific element that has yet been identified as directly causing ODD. Research looking precisely at the etiological factors linked with ODD is limited. The literature often examines common risk factors linked with all disruptive behaviors, rather than ODD specifically. Symptoms of ODD are also often believed to be the same as CD, even though the disorders have their own respective set of symptoms. When looking at disruptive behaviors such as ODD, research has shown that the causes of behaviors are multi-factorial. However, disruptive behaviors have been identified as being mostly due either to biological or environmental factors.
Genetic influences
Research indicates that parents pass on a tendency for externalizing disorders to their children that may be displayed in multiple ways, such as inattention, hyperactivity, or oppositional and conduct problems. Research has also shown that there is a genetic overlap between ODD and other externalizing disorders. Heritability can vary by age, age of onset, and other factors. Adoption and twin studies indicate that 50% or more of the variance causing antisocial behavior is attributable to heredity for both males and females. ODD also tends to occur in families with a history of ADHD, substance use disorders, or mood disorders, suggesting that a vulnerability to develop ODD may be inherited. A difficult temperament, impulsivity, and a tendency to seek rewards can also increase the risk of developing ODD. New studies into gene variants have also identified possible gene-environment (G x E) interactions, specifically in the development of conduct problems. A variant of the gene that encodes the neurotransmitter metabolizing enzyme monoamine oxidase-A (MAOA), which relates to neural systems involved in aggression, plays a key role in regulating behavior following threatening events. Brain imaging studies show patterns of arousal in areas of the brain that are associated with aggression in response to emotion-provoking stimuli.
Prenatal factors and birth complications
Many pregnancy and birth problems are related to the development of conduct problems. Malnutrition, specifically protein deficiency, lead poisoning or exposure to lead, and mothers use of alcohol or other substances during pregnancy may increase the risk of developing ODD. In numerous research, substance use prior to birth has also been associated with developing disruptive behaviors such as ODD. Although pregnancy and birth factors are correlated with ODD, strong evidence of direct biological causation is lacking.
Neurobiological factors
Deficits and injuries to certain areas of the brain can lead to serious behavioral problems in children. Brain imaging studies have suggested that children with ODD may have hypofunction in the part of the brain responsible for reasoning, judgment, and impulse control. Children with ODD are thought to have an overactive behavioral activation system (BAS), and an underactive behavioral inhibition system (BIS). The BAS stimulates behavior in response to signals of reward or non-punishment. The BIS produces anxiety and inhibits ongoing behavior in the presence of novel events, innate fear stimuli, and signals of non-reward or punishment. Neuroimaging studies have also identified structural and functional brain abnormalities in several brain regions in youths with conduct disorders. These brain regions are the amygdala, prefrontal cortex, anterior cingulate, and insula, as well as interconnected regions.
Social-cognitive factors
As many as 40 percent of boys and 25 percent of girls with persistent conduct problems display significant social-cognitive impairments. Some of these deficits include immature forms of thinking (such as egocentrism), failure to use verbal mediators to regulate his or her behavior, and cognitive distortions, such as interpreting a neutral event as an intentional hostile act.
Children with ODD have difficulty controlling their emotions or behaviors. In fact, students with ODD have limited social knowledge that is based only on individual experiences, which shapes how they process information and solve problems cognitively.
This information can be linked with the social information processing model (SIP) that describes how children process information to respond appropriately or inappropriately in social settings. This model explains that children will go through five stages before displaying behaviors: encoding, mental representations, response accessing, evaluation, and enactment.
However, children with ODD have cognitive distortions and impaired cognitive processes.
This will therefore directly impact their interactions and relationship negatively. It has been shown that social and cognitive impairments result in negative peer relationships, loss of friendship, and an interruption in socially engaging in activities.
Children learn through observational learning and social learning. Therefore, observations of models have a direct impact and greatly influence childrens behaviors and decision-making processes. Children often learn through modeling behavior. Modeling can act as a powerful tool to modify childrens cognition and behaviors.
Environmental factors
Negative parenting practices and parent–child conflict may lead to antisocial behavior, but they may also be a reaction to the oppositional and aggressive behaviors of children. Factors such as a family history of mental illnesses and/or substance use disorders as well as a dysfunctional family and inconsistent discipline by a parent or guardian can lead to the development of behavior disorders. Parenting practices not providing adequate or appropriate adjustment to situations as well as a high ratio of conflicting events within a family are causal factors of risk for developing ODD.Insecure parent–child attachments can also contribute to ODD. Often little internalization of parent and societal standards exists in children with conduct problems. These weak bonds with their parents may lead children to associate with delinquency and substance use. Family instability and stress can also contribute to the development of ODD. Although the association between family factors and conduct problems is well established, the nature of this association and the possible causal role of family factors continues to be debated.School is also a significant environmental context besides family that strongly influences a childs maladaptive behaviors. Studies indicate that child and adolescent externalizing disorders like ODD are strongly linked to peer network and teacher response. Children with ODD present hostile and defiant behavior toward authority including teachers which makes teachers less tolerant toward deviant children. The way in which a teacher handles disruptive behavior has a significant influence on the behavior of children with ODD. Negative relationships from the socializing influences and support network of teachers and peers increases the risk of deviant behavior. This is because the child consequently gets affiliated with deviant peers that reinforce antisocial behavior and delinquency. Due to the significant influence of teachers in managing disruptive behaviors, teacher training is a recommended intervention to change the disruptive behavior of ODD children. In a number of studies, low socioeconomic status has also been associated with disruptive behaviors such as ODD.Other social factors such as neglect, abuse, parents that are not involved, and lack of supervision can also contribute to ODD.Externalizing problems are reported to be more frequent among minority-status youth, a finding that is likely related to economic hardship, limited employment opportunities, and living in high-risk urban neighborhoods. Studies have also found that the state of being exposed to violence was a contribution factor for externalizing behaviors to occur.
Diagnosis
For a child or adolescent to qualify for a diagnosis of ODD, behaviors must cause considerable distress for the family or interfere significantly with academic or social functioning. Interference might take the form of preventing the child or adolescent from learning at school or making friends or placing him or her in harmful situations. These behaviors must also persist for at least six months. Effects of ODD can be greatly amplified by other disorders in comorbidity such as ADHD. Other common comorbid disorders include depression and substance use disorders. Adults who were diagnosed with ODD as children tend to have a higher chance of being diagnosed with other mental illness in their lifetime, as well as being at higher risk of developing social and emotional problems.
Management
Approaches to the treatment of ODD include parent management training, individual psychotherapy, family therapy, cognitive behavioral therapy, and social skills training. According to the American Academy of Child and Adolescent Psychiatry, treatments for ODD are tailored specifically to the individual child, and different treatment techniques are applied for pre-schoolers and adolescents.Children with oppositional defiant disorder tend to exhibit problematic behavior that can be very difficult to control. An occupational therapist can recommend family based education referred to as Parent Management Training (PMT) in order to encourage positive parents and child relationships and reduce the childs tantrums and other disruptive behaviors. Since ODD is a neurological disorder that has biological correlates, an occupational therapist can also provide problem solving training to encourage positive coping skills when difficult situations arise, as well as offer cognitive behavioral therapy.
Psychopharmacological treatment
Psychopharmacological treatment is the use of prescribed medication in managing oppositional defiant disorder. Prescribed medications to control ODD include mood stabilizers, anti-psychotics, and stimulants. In two controlled randomized trials, it was found that between administered lithium and the placebo group, administering lithium decreased aggression in children with conduct disorder in a safe manner. However, a third study found the treatment of lithium over a period of two weeks invalid. Other drugs seen in studies include haloperidol, thioridazine, and methylphenidate which also is effective in treating ADHD, as it is a common comorbidity.
The effectiveness of drug and medication treatment is not well established. Effects that can result from taking these medications include hypotension, extrapyramidal symptoms, tardive dyskinesia, obesity, and increase in weight. Psychopharmacological treatment is found to be most effective when paired with another treatment plan, such as individual intervention or multimodal intervention.In one case, a 16-year-old boy was given estrogen at an L. A. juvenile jail due to allegedly having ODD due to somewhat elevated testosterone levels, developing gynecomastia and requiring breast reduction surgery as a result.
Individual interventions
Individual interventions are focused on child-specific individualized plans. These interventions include anger control/stress inoculation, assertiveness training, a child-focused problem-solving skills training program, and self-monitoring skills.Anger control and stress inoculation help prepare the child for possible upsetting situations or events that may cause anger and stress. They include a process of steps the child may go through.
Assertiveness training educates individuals in keeping a balance between passivity and aggression. It aims to help the child respond in a controlled and fair manner.
A child-focused problem-solving skills training program aims to teach the child new skills and cognitive processes that teach how to deal with negative thoughts, feelings, and actions.
Parent and family treatment
According to randomized trials, evidence shows that parent management training is most effective. It has strong influences over a long period of time and in various environments.Parent-child interaction training is intended to coach the parents while involving the child. This training has two phases; the first phase is child-directed interaction, where the focus is to teach the child non-directive play skills. The second phase is parent-directed interaction, where the parents are coached on aspects including clear instruction, praise for compliance, and time-out for noncompliance. The parent-child interaction training is best suited for elementary-aged children.Parent and family treatment has a low financial cost, which can yield an increase in beneficial results.
Multimodal intervention
Multimodal intervention is an effective treatment that looks at different levels including family, peers, school, and neighborhood. It is an intervention that concentrates on multiple risk factors. The focus is on parent training, classroom social skills, and playground behavior programs. The intervention is intensive and addresses barriers to individuals improvement such as parental substance use or parental marital conflict.An impediment to treatment includes the nature of the disorder itself, whereby treatment is often not complied with and is not continued or stuck with for adequate periods of time.
Comorbidity
Oppositional defiant disorder can be described as a term or disorder with a variety of pathways in regard to comorbidity. High importance must be given to the representation of ODD as a distinct psychiatric disorder independent of conduct disorder.In the context of oppositional defiant disorder and comorbidity with other disorders, researchers often conclude that ODD co-occurs with an attention deficit hyperactivity disorder (ADHD), anxiety disorders, emotional disorders as well as mood disorders. Those mood disorders can be linked to major depression or bipolar disorder. Indirect consequences of ODD can also be related or associated with a later mental disorder. For instance, conduct disorder is often studied in connection with ODD. Strong comorbidity can be observed within those two disorders, but an even higher connection with ADHD in relation to ODD can be seen. For instance, children or adolescents who have ODD with coexisting ADHD will usually be more aggressive and have more of the negative behavioral symptoms of ODD, which can inhibit them from having a successful academic life. This will be reflected in their academic path as students.Other conditions that can be predicted in children or people with ODD are learning disorders in which the person has significant impairments with academics and language disorders, in which problems can be observed related to language production and/or comprehension.
See also
Attention deficit hyperactivity disorder (ADHD)
Antisocial personality disorder
Disruptive mood dysregulation disorder (DMDD)
Pathological demand avoidance
References
Further reading
External links
ODD Resource Center – American Academy of Child and Adolescent Psychiatry |
Vanishing twin | A vanishing twin, also known as twin resorption, is a fetus in a multigestation pregnancy that dies in utero and is then partially or completely reabsorbed. In some instances, the dead twin is compressed into a flattened, parchment-like state known as fetus papyraceus.Vanishing twins occur in up to one of every eight multifetus pregnancies and may not even be known in most cases. "High resorption rates, which cannot be explained on the basis of the expected abortion rate, suggest intense fetal competition for space, nutrition, or other factors during early gestation, with frequent loss or resorption of the other twin(s)."In pregnancies achieved by in vitro fertilization, "it frequently happens that more than one amniotic sac can be seen in early pregnancy, whereas a few weeks later there is only one to be seen and the other has vanished."
See also
Chimera (genetics)
Mosaicism
Parasitic twin
References
Further reading
External links
Vanishing twin at eMedicine.com
50 articles about vanishing twin phenomenon in PubMed |
Plasma cell gingivitis | Plasma cell gingivitis is a rare condition, appearing as generalized erythema (redness) and edema (swelling) of the attached gingiva, occasionally accompanied by cheilitis (lip swelling) or glossitis (tongue swelling). It is called plasma cell gingivitis where the gingiva (gums) are involved, plasma cell cheilitis, where the lips are involved, and other terms such as plasma cell orifacial mucositis, or plasma cell gingivostomatitis where several sites in the mouth are involved. On the lips, the condition appears as sharply outlined, infiltrated, dark red plaque with a lacquer-like glazing of the surface of the involved oral area.
Signs and symptoms
Plasma cell gingivitis appears as mild gingival enlargement and may extend from the free marginal gingiva on to the attached gingiva. Sometimes it is blended with a marginal, plaque induced gingivitis, or it does not involve the free marginal gingiva. It may also be found as a solitude red area within the attached gingiva (pictures). In some cases the healing of a plaque-induced gingivitis or a periodontitis resolves a plasma cell gingivitis situated a few mm from the earlier plaque-infected marginal gingiva. In case of one or few solitary areas of plasma cell gingivitis, no symptoms are reported from the patient. Most often solitary entities are therefore found by the dentist.The gums are red, friable, or sometimes granular, and sometimes bleed easily if traumatised. The normal stippling is lost. There is not usually any loss of periodontal attachment. In a few cases a sore mouth can develop, and if so pain is sometimes made worse by toothpastes, or hot or spicy food. The lesions can extend to involve the palate.Plasma cell cheilitis appears as well defined, infiltrated, dark red plaque with a superficial lacquer-like glazing. Plasma cell cheilitis usually involves the lower lip. The lips appear dry, atrophic and fissured. Angular cheilitis is sometimes present.Where the condition involves the tongue, there is an erythematous enlargement with furrows, crenation and loss of the normal dorsal tongue coating.
Causes
Plasma cell gingivitis and plasma cell cheilitis are thought to be hypersensitivity reactions to some antigen. Possible sources of antigens include ingredients in toothpastes, chewing gum, mints, pepper, or foods. Specifically, cinnamonaldehyde and cinnamon flavoring are often to blame. However, the exact cause in most is unknown.
Diagnosis
Histologically plasma cell gingivitis shows mainly plasma cells. The differential diagnosis is with acute leukemia and multiple myeloma. Hence, blood tests are often involved in ruling out other conditions. A biopsy is usually taken, and allergy testing may also be used. The histopathologic appearance is characterized by diffuse, sub-epithelial plasma cell inflammatory infiltration into the connective tissue. The epithelium shows spongiosis. Some consider that plasmoacanthoma (solitary plasma cell tumor) is part of the same spectrum of disease as plasma cell cheilitis.
Classification
Depending upon the site of involvement, this condition could be considered a type of gingivitis (or gingival enlargement); a type of cheilitis; glossitis; or stomatitis. Sometimes the lips, the gums and the tongue can simultaneously be involved, and some authors have described this triad as a syndrome ("plasma-cell gingivostomatitis"). The mucous membranes of the genitals can also be involved by a similar condition, termed "plasma cell balanitis" or "plasma cell vulvitis".Other synonyms for this condition not previously mentioned include atypical gingivitis, allergic gingivitis, plasmacytosis of the gingiva, idiopathic gingivostomatitis, and atypical gingivostomatitis. Some of these terms are largely historical.
Plasma cell gingivitis has been subclassified into 3 types based upon the cause; namely, allergic, neoplastic and of unknown cause.
Treatment
Preventing exposure to the causative antigen leads to resolution of the condition. Tacrolimus or clobetasol propionate have also been used to treat plasma cell cheilitis.
Epidemiology
Plasma cell gingivitis is rare, and plasma cell cheilitis is very rare. Most people with plasma cell cheilitis have been elderly.
History
Plasma cell gingivitis was first described in the late 1960-early 1970s. A wave of cases occurred during this period, thought to be caused by allergic reactions to a component in chewing gum. Since, the number of cases has decreased, but they are still occasionally reported.
See also
Desquamative gingivitis
References
== External links == |
Neural tube defect | Neural tube defects (NTDs) are a group of birth defects in which an opening in the spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal side of the embryo begin to change shape and form the neural tube. When the neural tube does not close completely, an NTD develops.
Specific types include: spina bifida which affects the spine, anencephaly which results in little to no brain, encephalocele which affects the skull, and iniencephaly which results in severe neck problems.NTDs are one of the most common birth defects, affecting over 300,000 births each year worldwide. For example, spina bifida affects approximately 1,500 births annually in the United States, or about 3.5 in every 10,000 (0.035% of US births), which has decreased from around 5 per 10,000 (0.05% of US births) since folate fortification of grain products was started. The number of deaths in the US each year due to neural tube defects also declined from 1,200 before folate fortification was started to 840.
Types
There are two classes of NTDs: open, which are more common, and closed. Open NTDs occur when the brain and/or spinal cord are exposed at birth through a defect in the skull or vertebrae (spinal column). Open NTDs include anencephaly, encephaloceles, hydranencephaly, iniencephaly, schizencephaly, and the most common form, spina bifida. Closed NTDs occur when the spinal defect is covered by skin. Types of closed NTDs include lipomeningocele, lipomyelomeningocele, and tethered cord.
Anencephaly
Anencephaly (without brain) is a severe neural tube defect that occurs when the anterior-most end of the neural tube fails to close, usually during the 23rd and 26th days of pregnancy. This results in an absence of a major portion of the brain and skull. Infants born with this condition lack the main part of the forebrain and are usually blind, deaf and display major craniofacial anomalies. The lack of a functioning cerebrum will prevent the infant from even gaining consciousness. Infants are either stillborn or usually die within a few hours or days after birth. For example, anencephaly in humans can result from mutations in the NUAK2 kinase.
Encephaloceles
Encephaloceles are characterized by protrusions of the brain through the skull that are sac-like and covered with membrane. They can be a groove down the middle of the upper part of the skull, between the forehead and nose, or the back of the skull. Due to the range in its location, encephaloceles are classified by the location as well as the type of defect it causes. Subtypes include occipital encephalocele, encephalocele of the carnival vault, and nasal encephaloceles (frontoethmoidal encephaloceles and basal encephaloceles), with approximately 80% of all encephaloceles occurring in the occipital area. Encephaloceles are often obvious and diagnosed immediately. Sometimes small encephaloceles in the nasal and forehead are undetected. Despite the wide range in its implications, encephaloceles are most likely to be caused by improper separation of the surface ectoderm and the neuroectoderm after the closure of the neural folds in the fourth week of gastrulation.
Hydranencephaly
Hydranencephaly is a condition in which the cerebral hemispheres are missing and instead filled with sacs of cerebrospinal fluid. People are born with hydranencephaly, but most of the time, the symptoms appear in a later stage. Newborns with hydrancephaly can swallow, cry, sleep and their head is in proportion to their body. However, after a few weeks, the infants develop increased muscle tone and irritability. After a few months, the brain start to fill with cerebrospinal fluid (hydrocephalus). This has several consequences. Infants start to develop problems with seeing, hearing, growing, and learning. The missing parts of the brain and the amount of cerebrospinal fluid can also lead to seizures, spasm, problems with regulating their body temperature, and breathing and digestion problems. Besides problems in the brain, hydranencephaly can also be seen on the outside of the body. Hydrocephalus leads to more cerebrospinal fluid in the brain, which can result in an enlarged head.The cause of hydranencephaly is not clear. Hydranencephaly is a result of an injury of the nervous system or an abnormal development of the nervous system. The neural tube closes in the sixth week of the pregnancy, so hydranencephaly develops during these weeks of the pregnancy. The cause of these injuries/development is not clear.
Theories regarding the causes of hydrancephaly include:
blockage in the carotid artery: some researchers think that a blockage of the carotid artery leads to the under-/no development of the brain. The carotid artery is the most important blood supplier of the brain. With a blockage, the brain barely receives blood. Blood is necessary for development and keeping intact of the brain.
inherited condition.
infections: during the pregnancy, a woman can develop an infection in the uterus what can lead to problems with the neural tube.
environmental toxins: during the pregnancy, a woman can be exposed to environmental toxins what can have effect on the health of the infant.
Iniencephaly
Iniencephaly is a rare neural tube defect that results in extreme bending of the head to the spine. The diagnosis can usually be made on antenatal ultrasound scanning, but if not will undoubtedly be made immediately after birth because the head is bent backwards and the face looks upwards. Usually the neck is absent. The skin of the face connects directly to the chest and the scalp connects to the upper back. Individuals with iniencephaly generally die within a few hours after birth.
Spina bifida
Spina bifida is further divided into two subclasses, spina bifida cystica and spina bifida occulta.
Spina bifida cystica includes meningocele and myelomeningocele. Meningocele is less severe and is characterized by herniation of the meninges, but not the spinal cord, through the opening in the spinal canal. Myelomeningocele involves herniation of the meninges as well as the spinal cord through the opening.
Spina bifida occulta means hidden split spine. In this type of neural tube defect, the meninges do not herniate through the opening in the spinal canal. The most frequently seen form of spina bifida occulta is when parts of the bones of the spine, called the spinous process, and the neural arch appear abnormal on a radiogram, without involvement of the spinal cord and spinal nerves. The risk of recurrence in those who have a first degree relative (a parent or sibling) is 5–10 times greater compared to the general population.
Causes
Folate deficiency
Inadequate levels of folate (vitamin B9) and vitamin B12 during pregnancy have been found to lead to increased risk of NTDs. Although both are part of the same biopathway, folate deficiency is much more common and therefore more of a concern. Folate is required for the production and maintenance of new cells, for DNA synthesis and RNA synthesis. Folate is needed to carry one carbon groups for methylation and nucleic acid synthesis. It has been hypothesized that the early human embryo may be particularly vulnerable to folate deficiency due to differences of the functional enzymes in this pathway during embryogenesis combined with high demand for post translational methylations of the cytoskeleton in neural cells during neural tube closure. Failure of post-translational methylation of the cytoskeleton, required for differentiation has been implicated in neural tube defects. Vitamin B12 is also an important receptor in the folate biopathway such that studies have shown deficiency in vitamin B12 contributes to risk of NTDs as well. There is substantial evidence that direct folic supplementation increases blood serum levels of bioavailable folate even though at least one study have shown slow and variable activity of dihydrofolate reductase in human liver. A diet rich in natural folate (350 μg/d) can show as much increase in plasma folate as taking low levels of folic acid (250 μg/d) in individuals However a comparison of general population outcomes across many countries with different approaches to increasing folate consumption has found that only general food fortification with folic acid reduces neural tube defects. While there have been concerns about folic acid supplementation being linked to an increased risk for cancer, a systematic review in 2012 shows there is no evidence except in the case of prostate cancer which indicates a modest reduction in risk.There have been studies showing the relationship between NTDs, folate deficiency and the difference of skin pigmentation within human populations across different latitudes. There are many factors that would influence the folate levels in human bodies: (i) the direct dietary intake of folic acid through fortified products, (ii) environmental agents such as UV radiation. In concern with the latter, the UV radiation-induced folate photolysis has been shown via in vitro and in vivo studies to decrease the folate level and implicate in etiology of NTDs not only in humans but other amphibian species. Therefore, a protection against the UV radiation-induced photolysis of folate is imperative for the evolution of human populations living in tropical regions where the exposure to UV radiation is high over the year. One body natural adaptation is to elevate the concentration of melanin inside the skin. Melanin works as either an optical filter to disperse the incoming UV radiation rays or free radical to stabilize the hazardous photochemical products. Multiple studies have demonstrated the highly melanized integument as a defense against folate photolysis in Native Americans or African Americans correlates with lower occurrence of NTDs in general.
Genetic deficiencies
As reported by Bruno Reversade and colleagues, the inactivation of the NUAK2 kinase in humans leads to anencephaly. This fatal birth defect is believed to arise as a consequence of impaired HIPPO signalling. Other genes such as TRIM36 have also been associated with anencephaly in humans.
Gene-environment interaction
A deficiency of folate itself does not cause neural tube defects. The association seen between reduced neural tube defects and folic acid supplementation is due to a gene-environment interaction such as vulnerability caused by the C677T methylenetetrahydrofolate reductase (MTHFR) variant. Supplementing folic acid during pregnancy reduces the prevalence of NTDs by not exposing this otherwise sub-clinical mutation to aggravating conditions. Other potential causes can include folate antimetabolites (such as methotrexate), mycotoxins in contaminated corn meal, arsenic, hyperthermia in early development, and radiation. Maternal obesity has also been found to be a risk factor for NTDs. Studies have shown that both maternal cigarette smoking and maternal exposure to secondhand smoke increased the risk for neural tube defects in offspring. A mechanism by which maternal exposure to cigarette smoke could increase NTD risk in offspring is suggested by several studies that show an association between cigarette smoking and elevations of homocysteine levels. Cigarette smoke during pregnancy, including secondhand exposure, can increase the risk of neural tube defects. All of the above may act by interference with some aspect of normal folic acid metabolism and folate linked methylation related cellular processes as there are multiple genes of this type associated with neural tube defects.
Other
Folic acid supplementation reduces the prevalence of neural tube defects by approximately 70% of neural tube defects indicating that 30% are not folate-dependent and are due to some cause other than alterations of methylation patterns. Multiple other genes related to neural tube defects exist which are candidates for folate insensitive neural tube defects. There are also several syndromes such as Meckel syndrome, and triploid syndrome which are frequently accompanied by neural tube defects that are assumed to be unrelated to folate metabolism
Diagnosis
Tests for neural tube defects include ultrasound examination and measurement of maternal serum alpha-fetoprotein (MSAFP). Second trimester ultrasound is recommended as the primary screening tool for NTDs, and MSAFP as a secondary screening tool. This is due to increased safety, increased sensitivity and decreased false positive rate of ultrasound as compared to MSAFP. Amniotic fluid alpha-fetoprotein (AFAFP) and amniotic fluid acetylcholinesterase (AFAChE) tests are also used to confirming if ultrasound screening indicates a positive risk. Often, these defects are apparent at birth, but acute defects may not be diagnosed until much later in life. An elevated MSAFP measured at 16–18 weeks gestation is a good predictor of open neural tube defects, however the test has a very high false positive rate, (2% of all women tested in Ontario, Canada between 1993 and 2000 tested positive without having an open neural tube defect, although 5% is the commonly quoted result worldwide) and only a portion of neural tube defects are detected by this screen test (73% in the same Ontario study). MSAFP screening combined with routine ultrasonography has the best detection rate although detection by ultrasonography is dependent on operator training and the quality of the equipment.
Prevention
Incidence of neural tube defects has been shown to decline through maintenance of adequate folic acid levels prior to and during pregnancy. This is achieved through dietary sources and supplementation of folic acid. In 1996, the United States Food and Drug Administration published regulations requiring the addition of folic acid to enriched breads, cereals, flour and other grain products. Similar regulations made it mandatory to fortify selected grain products with folic acid in Canada by 1998. It is important to note that during the first four weeks of pregnancy (when most people do not even realize that they are pregnant), adequate folate intake is essential for proper operation of the neurulation process. Therefore, any individuals who could become pregnant are advised to eat foods fortified with folic acid or take supplements in addition to eating folate-rich foods to reduce the risks of serious birth defects. In Canada, mandatory fortification of selected foods with folic acid had been shown to reduce the incidence of neural tube defects by 46% compared to incidence prior to mandatory fortification. However, relying on eating a folate-rich diet alone is not recommended for preventing neural tube defects when trying to conceive because a regular diet usually does not contain enough folate to reach pregnancy requirements. All individuals who have the ability to become pregnant are advised to get 400 micrograms of folic acid daily. This daily 400 mcg dose of folic acid can be found in most multivitamins advertised as for women. Higher doses can be found in pre-natal multivitamins but those doses may not be necessary for everyone. Individuals who have previously given birth to a child with a neural tube defect and are trying to conceive again may benefit from a supplement containing 4.0 mg daily, following advice provided by their doctor. In Canada, guidelines on folic acid intake when trying to conceive is based on a risk assessment of how likely they are to experience a neural tube defect during pregnancy. Risk is divided into high, moderate, and low risk categories. High risk would include those that had a past experience with neural tube defects, either themselves or during another pregnancy. Medium risk individuals are those with certain conditions that put them at higher risk for experiencing a neural tube defect. These include having a first or second degree relative or partner with a history of neural tube defects, having a gastrointestinal condition that affects normal absorption patterns, advanced kidney disease, kidney dialysis, alcohol over-use, or had another pregnancy resulting in a congenital abnormality that was folate sensitive. Medium risk individuals would also include those taking medications that can interfere with folate absorption such as anticonvulsants, metformin, sulfasalazine, triamterene, and trimethoprim. Low risk would include everyone else that do not fall into either medium or high risk categories. Recommendations on when to start folic acid supplementation for all individuals looking to become pregnant is at least 3 months preconception. If an individual is in the high risk category, the recommended dose is 4–5 mg of folic acid daily until 12 weeks gestation and then decrease to 0.4–1 mg until 4–6 weeks postpartum or for however long breastfeeding lasts. If an individual is in the medium risk category, the recommended dose is 1 mg of folic acid daily until 12 weeks gestation and then they can either continue at 1 mg or decrease to 0.4 mg daily until 4–6 weeks postpartum or however long breastfeeding lasts. If the pregnancy is low risk to develop a neural tube defect then the recommendation for that individual is 0.4 mg daily until 4–6 weeks postpartum or however long breastfeeding lasts. All dose recommendations and risk assessment should be done with the advice of a qualified health care provider.
Treatment
As of 2008, treatments of NTDs depends on the severity of the complication. No treatment is available for anencephaly and infants usually do not survive more than a few hours. Aggressive surgical management has improved survival and the functions of infants with spina bifida, meningoceles and mild myelomeningoceles. The success of surgery often depends on the amount of brain tissue involved in the encephalocele. The goal of treatment for NTDs is to allow the individual to achieve the highest level of function and independence. Fetal surgery in utero before 26 weeks gestation has been performed with some hope that there is benefit to the outcome including a reduction in Arnold–Chiari malformation and thereby decreases the need for a ventriculoperitoneal shunt but the procedure is very high risk for both mother and baby and is considered extremely invasive with questions that the positive outcomes may be due to ascertainment bias and not true benefit. Further, this surgery is not a cure for all problems associated with a neural tube defect. Other areas of research include tissue engineering and stem cell therapy but this research has not been used in humans.
Epidemiology
Neural tube defects resulted in 71,000 deaths globally in 2010. It is unclear how common the condition is in low income countries.Prevalence rates of NTDs at birth used to be a reliable measure for the actual number of children affected by the diseases. However, due to advances in technology and the ability to diagnose prenatally, the rates at birth are no longer reliable. Measuring the number of cases at birth may be the most practical way, but the most accurate way would be to include stillbirths and live-births. Most studies that calculate prevalence rates only include data from live births and stillborn children and normally exclude the data from abortions and miscarriages. Abortions are a huge contributing factor to the prevalence rates; one study found that in 1986 only a quarter of the pregnancies with an identified NTD were aborted, but that number had already doubled by 1999. Through this data, it is clear that excluding data from abortions could greatly affect the prevalence rates. This could also possibly explain why prevalence rates have appeared to drop. If abortions are not being included in the data but half of the identified cases are being aborted, the data could show that prevalence rates are dropping when they actually are not. However, it is unclear how much of an impact these could have on prevalence rates due to the fact that abortion rates and advances in technology vary greatly by country.There are many maternal factors that also play a role in prevalence rates of NTDs. These factors include things like maternal age and obesity all the way to things like socioeconomic status along with many others. Maternal age has not been shown to have a huge impact on prevalence rates, but when there has been a relationship identified, older mothers along with very young mothers are at an increased risk. While maternal age may not have a huge impact, mothers that have a body mass index greater than 29 double the risk of their child having an NTD. Studies have also shown that mothers with three or more previous children show moderate risk for their next child having an NTD.
References
External links
"Neural Tube Defects". MedlinePlus. U.S. National Library of Medicine.
Preventing Neural Tube Birth Defects: A Prevention Model and Resource Guide: Centers for Disease Control and Prevention (CDC) |
Erythromelalgia | Erythromelalgia or Mitchells disease (after Silas Weir Mitchell) is a rare vascular peripheral pain disorder in which blood vessels, usually in the lower extremities or hands, are episodically blocked (frequently on and off daily), then become hyperemic and inflamed. There is severe burning pain (in the small fiber sensory nerves) and skin redness. The attacks are periodic and are commonly triggered by heat, pressure, mild activity, exertion, insomnia or stress. Erythromelalgia may occur either as a primary or secondary disorder (i.e. a disorder in and of itself or a symptom of another condition). Secondary erythromelalgia can result from small fiber peripheral neuropathy of any cause, polycythemia vera, essential thrombocytosis, hypercholesterolemia, mushroom or mercury poisoning, and some autoimmune disorders. Primary erythromelalgia is caused by mutation of the voltage-gated sodium channel α-subunit gene SCN9A.
In 2004 erythromelalgia became the first human disorder in which it has been possible to associate an ion channel mutation with chronic neuropathic pain, when its link to the SCN9A gene was initially published in the Journal of Medical Genetics. Later that year, in an article in The Journal of Neuroscience, Cummins et al., demonstrated, using voltage clamp recordings, that these mutations enhanced the function of NaV1.7 sodium channels, which are preferentially expressed within peripheral neurons. One year later, in an article in Brain, Dib-Hajj et al., demonstrated that NaV1.7 mutants channels, from families with inherited erythromelalgia (IEM), make dorsal root ganglion (DRG, peripheral and sensory), neurons hyper excitable, thereby demonstrating the mechanistic link between these mutations and pain, thereby firmly establishing NaV1.7 gain-of-function mutations as the molecular basis for IEM. Conversely, in December 2006 a University of Cambridge team reported an SCN9A mutation that resulted in a complete lack of pain sensation in a Pakistani street performer and some of his family members. He felt no pain, walked on hot coals and stabbed himself to entertain crowds. By 2013, nearly a dozen gain-of-function mutations of NaV1.7 had been linked to IEM. The multi-decades search which identified gene SCN9A as the cause of inherited erythomelalgia is documented in a book by Stephen Waxman, Chasing Men on Fire: The Story of the Search for a Pain Gene.
Classification
Primary erythromelalgia may be classified as either familial or sporadic, with the familial form inherited in an autosomal dominant manner. Both of these may be further classified as either juvenile or adult onset. The juvenile onset form occurs prior to age 20 and frequently prior to age 10. While the genetic cause of the juvenile and sporadic adult onset forms is often known, this is not the case for the adult onset familial form.In rural areas of southern China, outbreaks of erythromelalgia have occurred during winter and spring at 3-5 year intervals among secondary school students. This epidemic form of erythromelalgia has been viewed as a different form of non-inherited primary erythromelalgia and affects mainly teenage girls in middle schools. The disease is characterized by burning pain in the toes and soles of the feet, accompanied by foot redness, congestion, and edema; a few patients may have fever, palpitations, headache, and joint pain. In the 1987 epidemic in Hubei, 60.6% of patients had a common cold before the onset of erythromelalgia and 91.2% had pharyngitis.
Billing codes systems and other systems
Erythromelalgia can be found in several billing codes systems and other systems. Erythromelalgia is generally classified as a disease of the circulatory system, falling under the class of other peripheral vascular disease, as the following two billing code systems will show:
ICD-9-CM According to the ICD-9-CM database (International Classification of Diseases, Ninth Revision, Clinical Modification), Erythromelalgia is listed under Diseases of the Circulatory System and is identified by number 443.82.
ICD-10-CM According to the ICD-10-CM database (International Classification of Diseases, Tenth Revision, Clinical Modification), Erythromelalgia is listed under Diseases of the circulatory system and is identified by I73.81.
Mesh According to the MESH database (Medical Subject Headings), Erythromelalgia is classified under the unique ID number of D004916.
OMIM According to the OMIM database (NCBI - Online Mendelian Inheritance in Man), Primary Erythromelalgia is listed under the number: 133020.
Symptoms and signs
The most prominent symptoms of erythromelalgia are episodes of erythema, swelling, a painful deep-aching of the soft tissue (usually either radiating or shooting) and tenderness, along with a painful burning sensation primarily in the extremities. These symptoms are often symmetric and affect the lower extremities more frequently than the upper extremities. Symptoms may also affect the ears and face. For secondary erythromelalgia, attacks typically precede and are precipitated by the underlying primary condition. For primary erythromelalgia, attacks can last from an hour to months at a time and occur infrequently to frequently with multiple times daily. Attacks most frequently occur at night, thus having the potential to greatly interfere with sleep. Common triggers for daytime episodes are exertion, heating of the affected extremities, and alcohol or caffeine consumption, and any pressure applied to the limbs. In some patients sugar and even melon consumption have also been known to provoke attacks. Many of those with primary erythromelalgia avoid wearing shoes or socks as the heat this generates is known to produce erythromelalgia attacks. The coexistence of erythromelalgia and Raynauds phenomenon is rare, but case studies of patients with both diagnoses have been reported in medical journals. Symptoms may present gradually and incrementally, sometimes taking years to become intense enough for patients to seek medical care. In other cases symptoms emerge full blown with onset.Epidemic erythromelalgia is characterized by burning pain in the toes and soles of the feet, accompanied by foot redness, congestion, and edema; a few patients may have fever, palpitations, headache, and joint pain. In the 1987 epidemic in Hubei, 60.6% of patients had a common cold before the onset of erythromelalgia and 91.2% had pharyngitis.
Cause
In general, erythromelalgia seems to consist of neuropathological and microvascular alterations. How this occurs in secondary erythromelalgia is poorly understood and may be specific to the underlying primary condition. Primary conditions that have been shown to elicit erythromelalgia are listed in diagnosis, below.Primary erythromelalgia is a better understood autosomal dominant disorder. The neuropathological symptoms of primary erythromelalgia arise from hyperexcitability of C-fibers in the dorsal root ganglion. Specifically, nociceptors (neurons responsible for the sensation and conduction of painful stimuli) appear to be the primarily affected neurons in these fibers. This hyperexcitability results in the severe burning pain experienced by patients. While the neuropathological symptoms are a result of hyperexcitability, microvascular alterations in erythromelalgia are due to hypoexcitability. The sympathetic nervous system controls cutaneous vascular tone and altered response of this system to stimuli such as heat likely results in the observed microvascular symptoms. In both cases, these changes in excitability are typically due to mutation of the sodium channel NaV1.7. These differences in excitability alterations between the sympathetic nervous system and nociceptors is due to different expression of sodium channels other than NaV1.7 in them.What causes epidemic erythromelalgia in southern China remains unknown although several erythromelalgia-associated poxviruses were isolated from throat swabs of several patients at different counties and from two different seasons.
Side effect of medication
Several medications, including verapamil and nifedipine, as well as ergot derivatives such as bromocriptine and pergolide, have been associated with medication-induced erythromelalgia.
Mushroom poisoning
The consumption of two species of related fungi, Clitocybe acromelalga from Japan, and Clitocybe amoenolens from France, has led to several cases of mushroom-induced erythromelalgia which lasted from 8 days to 5 months.
Possible infectious cause
An epidemic form of this syndrome occurs in secondary school students in rural areas of China. A large epidemic erythromelalgia was occurred in Hubei province of China in 1987 and the disease was characterized by burning pain in the toes and soles of the feet, accompanied by foot redness, congestion, and edema; a few patients had fever, palpitations, headache, and joint pain. 60.6% of patients had a common cold before the onset of erythromelalgia and 91.2% had pharyngitis. Subsequently, a virus - erythromelalgia-related poxvirus (ERPV) - was repeatedly isolated from throat swabs of six separate patients from two different counties and Wuhan city in Hubei province. The genome of this virus has been sequenced and it appears that this virus is related to a strain of mousepox. Serological characterization can easily distinguish human ERPV from ectromelia virus and vaccinia virus by cross-neutralization and plaque reduction assays Since this virus has not yet been isolated from other outbreaks in other parts of southern China to date this putative association needs to be further investigated. The finding of the specific antibody conversion to ATIs of ERPV in patients paired sera strengthens the evidence for a possible aetiological role of human ERPV in epidemic erythromelalgia.
Pathophysiology
There are 10 known mutations in the voltage-gated sodium channel α-subunit NaV1.7 encoding gene, SCN9A. This channel is expressed primarily in nociceptors of the dorsal root ganglion and the sympathetic ganglion neurons. Nine of these mutations have received further study and they have all shown to result in similar biophysical alterations, Table 1. As can be seen from table 1, the primary effect of erythromelalgia mutations is NaV1.7 channels that activate at more hyperpolarized potentials. NaV1.7 channels act largely as threshold sensors and initiate action potentials. Consequently, this shift in their activation profile results in channels that open closer to the resting membrane potential. In many mutations, this shift of activation is accompanied by shifts in the voltage sensitivity of fast and/or slow inactivation, often in the depolarized direction. This results in channels that are open for a longer of period of time, producing larger and more prolonged changes in membrane potential.Some of these mutant channels have been expressed in dorsal root ganglion (DRG) or sympathetic neurons. In DRG neurons expressing the F1449V mutation, a lower threshold is required for action potential creation (93.1 ± 12.0 pA) than those expressing wild-type channels (124.1 ± 7.4 pA). Furthermore, while DRG neurons expressing wild-type channels only respond with a few action potentials, those expressing F1449V channels respond with a high-frequency train of action potentials. There is a similar effect in DRG neurons expressing the L858H and A863P mutants. Here, there is also a notable change in resting membrane potential, being depolarized by 4-7 mV versus wild-type channel expressing cells. The situation is different, however, in sympathetic neurons expressing the L858H mutation. While L858H expressing sympathetic ganglion are depolarized ~5mV relative to wild-type expressing neurons, their threshold for action potential initiation is notably higher. Furthermore, while current injection of 40pA for 950ms provokes an average of 6 action potentials in sympathetic neurons expressing wild-type channels this stimulation evokes only approximately 2 action potentials with reduced overshoots in sympathetic neurons expressing L858H mutant channels. Further investigation has demonstrated that the differences in response between DRG and sympathetic neurons is due to expression of NaV1.8 in the former. Consequently, expression of NaV1.8 channels in sympathetic neurons also expressing L858H mutant NaV1.7 results in neurons with a depolarized resting membrane potential that nevertheless have a normal action potential threshold and overshoot.An effective, though not recommended, treatment for erythromelalgia symptoms is cooling of the affected area. Activation of wild-type channels is unaffected by cooling. L858F mutant channels, however, are activated at more depolarized potentials when cooled than at normal body temperature. At 16 °C the activation V½ of the mutant channel is only 4.6mV more hyperpolarized that wild-type versus 9.6mV more hyperpolarized at 35 °C. Fast inactivation is affected in a similar manner in both wild-type and L858F mutant channel and is, thus, unlikely to contribute to symptom resolution due to cooling. While such cooling is unlikely to affect neuronal cell bodies, axons and termini express NaV1.7 and are present in the skin.
Diagnosis
Erythromelalgia is a difficult condition to diagnose as there are no specific tests available. However, reduced capillary density has been observed microscopically during flaring; and reduced capillary perfusion is noted in the patient. Another test that can be done is to have the patient elevate their legs, and note the reversal (from red to pale) in skin color. Tests done at universities include quantitative sensory nerve testing, laser evoked potentials, sweat testing and epidermal sensory nerve fiber density test (which is an objective test for small fiber sensory neuropathy). Due to the aforementioned factors, patients may face delays in diagnosis.Once it has been established that it is not secondary erythromelalgia — see below — a programme of management can be put in place.Some diseases present with symptoms similar to erythromelalgia. Complex regional pain syndrome (CRPS), for instance, presents with severe burning pain and redness except these symptoms are often unilateral (versus symmetric) and may be proximal instead of purely or primarily distal. Furthermore, attacks triggered by heat and resolved by cooling are less common with CRPS.Erythromelalgia is sometimes caused by other disorders. A partial list of diseases known to precipitate erythromelalgia is below.
Myeloproliferative disease
Hypercholesterolemia
Autoimmune disorder
Small fiber peripheral neuropathy
Fabrys disease
Mercury poisoning
Mushroom poisoning
Obstructive Sleep Apnea
Sciatica
Some medications, such as fluoroquinolones, bromocriptine, pergolide, verapamil, and ticlopidine
Treatment
For secondary erythromelalgia, treatment of the underlying primary disorder is the most primary method of treatment. Although aspirin has been thought to reduce symptoms of erythromelalgia, it is rare to find evidence that this is effective. Mechanical cooling of the limbs by elevating them can help or managing the ambient environment frequently is often necessary constantly as flares occur due to sympathetic autonomic dysfunction of the capillaries. The pain that accompanies it is severe and treated separately (the pain is similar to CRPS, phantom limb or thalamic pain syndrome). Patients are strongly advised not to place the affected limbs in cold water to relieve symptoms when flaring occurs. It may seem a good idea, but it precipitates problems further down the line causing damage to the skin and ulceration often intractable due to the damaged skin. A possible reduction in skin damage may be accomplished by enclosing the flaring limb in a commonly available, thin, heat transparent, water impermeable, plastic food storage bag. The advice of a physician is advised depending on specific circumstances.Primary erythromelalgia management is symptomatic, i.e. treating painful symptoms only. Specific management tactics include avoidance of attack triggers such as: heat, change in temperature, exercise or over exertion, alcohol and spicy foods. This list is by no means comprehensive as there are many triggers to set off a flaring episode that are inexplicable. Whilst a cool environment is helpful in keeping the symptoms in control, the use of cold water baths is strongly discouraged. In pursuit of added relief sufferers can inadvertently cause tissue damage or death, i.e. necrosis. See comments at the end of the preceding paragraph regarding possible effectiveness of plastic food storage bags to avoid/reduce negative effects of submersion in cold water baths.One clinical study has demonstrated the efficacy of IV lidocaine or oral mexilitine, though differences between the primary and secondary forms were not studied. Another trial has shown promise for misoprostol, while other have shown that gabapentin, venlafaxine and oral magnesium may also be effective, but no further testing was carried out as newer research superseded this combination.Strong anecdotal evidence from EM patients shows that a combination of drugs such as duloxetine and pregabalin is an effective way of reducing the stabbing pains and burning sensation symptoms of erythromelalgia in conjunction with the appropriate analgesia. In some cases, antihistamines may give some relief. Most people with erythromelalgia never go into remission and the symptoms are ever present at some level, whilst others get worse, or the EM is eventually a symptom of another disease such as systemic scleroderma.Some suffering with EM are prescribed ketamine topical creams as a way of managing pain on a long-term basis. Feedback from some EM patients has led to reduction in usage as they believe it is only effective for short periods.Living with erythromelalgia can result in a deterioration in quality of life resulting in the inability to function in a work place, lack of mobility, depression, and is socially alienating; much greater education of medical practitioners is needed. As with many rare diseases, many people with EM end up taking years to get a diagnosis and to receive appropriate treatment.Research into the genetic mutations continues but there is a paucity of clinical studies focusing on living with erythromelalgia. There is much urgency within pharmaceutical companies to provide a solution to those who suffer with pain such as that with erythromelalgia.
Pain relief
Patients find relief by cooling the skin. All patients must be notified to not apply ice directly on to the skin, since this can cause maceration of the skin, nonhealing ulcers, infection, necrosis, and even amputation in severe cases.Mild sufferers may find sufficient pain relief with tramadol or amitriptyline. Sufferers of more severe and widespread EM symptoms, however, may obtain relief only from opioid drugs. Opana ER has been found to be effective for many in the US, whilst in the UK slow-release morphine has proved to be effective. These powerful and potentially-addictive drugs may be prescribed to patients only after they have tried almost every other type of analgesia to no avail. (This delay in appropriate pain management can be a result of insurer-mandated or legally-required step therapy, or merely overly-cautious prescribing on the part of sufferers doctors.)The combination of Cymbalta (duloxetine) and Lyrica (pregabalin) has also proven to be useful in controlling pain, but many EM patients have found this combination has side effects that they are unable to tolerate.
Epidemiology
Only a small number of studies that have investigated the prevalence of EM, with four studies conducted to date.
The mean of all the studies combined results in an EM estimation incidence of 4.7/100,000 with a mean of 1 : 3.7 of the male to female ratio, respectively.In 1997 there was a study conducted in Norway that estimated that the annual incidence of 2/100,000, with a 1 : 2.4 male to female ratio in this study
population, respectively. In 2009 there was a population-based study of EM in the USA (Olmsted County, Minnesota), that reported that the annual incidence was 1.3/100,000, with a 1 : 5.6 male to female ratio in this study population, respectively.
The incidence in this study of primary and secondary EM was 1.1 : 0.2 per 100 000 people per year, respectively.
A study of a single centre in the south of Sweden in 2012, showed the overall annual population-based incidence was 0.36/100,000.
In New Zealand (Dunedin) a study estimated that in 2013 the incidence of EM is 15/100,000, with a 1 : 3 male to female ratio in this study
population, respectively. This last study has an estimation that is at least ten times higher than the prevalence previously reported. This study recruited individuals based on self-identification of symptoms (after self-identification, patients were invited for an assessment of an EM diagnosis), instead of participants that are identified through secondary and tertiary referrals as in the other studies.
Prevalence in China
Epidemic EM appears quite common in female middle school students of southern China, most likely due to a sharp decline in temperature following by a rapid increase of temperature. It has been postulated that epidemic erythromelalgia might be related to a poxvirus (ERPV) infection. The disease was characterized by burning pain in the toes and soles of the feet, accompanied by foot redness, congestion, and edema; a few patients had fever, palpitations, headache, and joint pain. 60.6% of patients had a common cold before the onset of erythromelalgia and 91.2% had pharyngitis. For temperature-related theory, the acral (foot and hand) small superficial arteries intensely constrict and dilate during the sharp decline of temperature, whereas a sharp increase of temperature, the intense expansion of capillaries irritate the nerve endings around, and thus lead to syndromes including (first and second degree) burning pain, increased temperature, erythema and swelling.
History
The first reported case was in 1878 by Silas Weir Mitchell who suggested the term erythromelalgia to describe a syndrome of red congestion and burning pain in the hands and feet.
He distinguished it from the painful red limbs seen in some patients with gout or rheumatoid arthritis. It is derived from the Greek words erythros ("red"), melos ("limb") and algos ("pain").Some confusion was introduced when Smith and Allen suggested changing the name to erythermalgia in order to emphasise the symptoms of painful inflammation and warmth. In their paper they showed for the first time that when their patients used aspirin, this promptly relieved the burning pain for about three days. They also suggested a distinction between primary (idiopathic) erythromelalgia and secondary erythromelalgia (due to underlying neurologic, hematologic, or vascular problems).In 1994 Drenth, van Genderen and Michiels distinguished between erythromelalgia and erythermalgia on the basis of responsiveness to aspirin. They established three categories: erythromelalgia (platelet-mediated and aspirin-sensitive), primary erythermalgia, and secondary erythermalgia.Because of the confusion in terminology, Norton and Zager and Grady classified erythromelalgia in 1998 as either: primary/idiopathic erythromelalgia or secondary erythromelalgia. The primary/idiopathic form of erythromelalgia is not associated with any other disease process and can be either early onset (in children) or adult onset. In their paper they described secondary erythromelalgia as being associated with another disease, often related to a myeloproliferative disorder and has also seen cases of: hypertension, diabetes mellitus, rheumatoid arthritis, gout, systemic lupus erythematosus, multiple sclerosis, astrocytoma of the brain, vasculitis, and pernicious anemia.The following table shows the history of the nomenclature of Erythromelalgia:
Amputation
Because of the severity of the pain in erythromelalgia, and the lack of good pain medication then, there have been reports dating back to 1903 of amputation of the affected limb. In 1903 H. Batty Shaw reported that in three cases the pain was so severe, and that the affected extremities are so useless, that amputation was performed.
Differences with Raynauds disease
Back in 1899 Thomas Barlow had already summarized with great detail the contrast between erythromelalgia and Raynauds disease as following: Dependence produces considerable increase of the dusky red or violaceous tint of the extremity affected; the arteries in this position of the limb may pulsate forcibly; pain is common, sometimes constant, and more especially when the limb is dependent or parts pressed upon; in wintry weather, or on the application of cold, the conditions are relieved; on the other hand, warmth and summer weather increases pain; there is no loss of sensation, but there may be increased sensitiveness; the local temperature of the affected parts may be raised or lowered; gangrene does not occur; the affection is asymmetrical; there is a certain amount of swelling, sometimes allowing pitting on pressure, sometimes not; incisions over such swelling, even down to the bone, have proved useless; excessive pain on pressure upon the nerves supplying the parts affected is not found; muscular wasting is found, but explainable by the disuse of the limb, and is not at all as severe as in cases of disease of the peripheral nerves; a reaction of degeneration in the nerves of the affected parts has not been found; the deep reflexes, with few exceptions, are not reduced.
Footnotes
== External links == |
Locked-in syndrome | Locked-in syndrome (LIS), also known as pseudocoma, is a condition in which a patient is aware but cannot move or communicate verbally due to complete paralysis of nearly all voluntary muscles in the body except for vertical eye movements and blinking. The individual is conscious and sufficiently intact cognitively to be able to communicate with eye movements.Electroencephalography results are normal in locked-in syndrome.
Total locked-in syndrome, or completely locked-in state (CLIS), is a version of locked-in syndrome wherein the eyes are paralyzed as well. Fred Plum and Jerome B. Posner coined the term for this disorder in 1966.
Signs and symptoms
Locked-in syndrome is usually characterized by quadriplegia (loss of limb function) and the inability to speak in otherwise cognitively intact individuals. Those with locked-in syndrome may be able to communicate with others through coded messages by blinking or moving their eyes, which are often not affected by the paralysis. The symptoms are similar to those of sleep paralysis. Patients who have locked-in syndrome are conscious and aware, with no loss of cognitive function. They can sometimes retain proprioception and sensation throughout their bodies. Some patients may have the ability to move certain facial muscles, and most often some or all of the extraocular muscles. Individuals with the syndrome lack coordination between breathing and voice. This prevents them from producing voluntary sounds, though the vocal cords themselves may not be paralysed.
Causes
Unlike persistent vegetative state, in which the upper portions of the brain are damaged and the lower portions are spared, locked-in syndrome is essentially the opposite, caused by damage to specific portions of the lower brain and brainstem, with no damage to the upper brain. Injuries to the pons are the most common cause of locked-in syndrome.
Possible causes of locked-in syndrome include:
Poisoning cases – More frequently from a krait bite and other neurotoxic venoms, as they cannot usually cross the blood–brain barrier
Brainstem stroke
Diseases of the circulatory system
Medication overdose
Damage to nerve cells, particularly destruction of the myelin sheath, caused by disease or osmotic demyelination syndrome (formerly designated central pontine myelinolysis) secondary to excessively rapid correction of hyponatremia [>1 mEq/L/h])
A stroke or brain hemorrhage, usually of the basilar artery
Traumatic brain injury
Result from lesion of the brain-stemCurare poisoning mimics a total locked-in syndrome by causing paralysis of all voluntarily controlled skeletal muscles. The respiratory muscles are also paralyzed, but the victim can be kept alive by artificial respiration.
Diagnosis
Locked-in syndrome can be difficult to diagnose. In a 2002 survey of 44 people with LIS, it took almost three months to recognize and diagnose the condition after it had begun. Locked-in syndrome may mimic loss of consciousness in patients, or, in the case that respiratory control is lost, may even resemble death. People are also unable to actuate standard motor responses such as withdrawal from pain; as a result, testing often requires making requests of the patient such as blinking or vertical eye movement.Brain imaging may provide additional indicators of locked-in syndrome, as brain imaging provides clues as to whether or not brain function has been lost. Additionally, an EEG can allow the observation of sleep-wake patterns indicating that the patient is not unconscious but simply unable to move.
Similar conditions
Amyotrophic lateral sclerosis (ALS)
Bilateral brainstem tumors
Brain death (of the whole brain or the brain stem or other part)
Coma (deep or irreversible)
Guillain–Barré syndrome
Myasthenia gravis
Poliomyelitis
Polyneuritis
Vegetative state (chronic or otherwise)
Treatment
Neither a standard treatment nor a cure is available. Stimulation of muscle reflexes with electrodes (NMES) has been known to help patients regain some muscle function. Other courses of treatment are often symptomatic. Assistive computer interface technologies such as Dasher, combined with eye tracking, may be used to help people with LIS communicate with their environment.
Prognosis
It is extremely rare for any significant motor function to return, with the majority of locked-in syndrome patients never regaining motor control. However, some people with the condition continue to live for extended periods of time, while in exceptional cases, like that of Kerry Pink, Gareth Shepherd, Jacob Haendel, Kate Allatt, and Jessica Wegbrans, a near-full recovery may be achieved with intensive physical therapy.
Research
New brain–computer interfaces (BCIs) may provide future remedies. One effort in 2002 allowed a fully locked-in patient to answer yes-or-no questions. In 2006, researchers created and successfully tested a neural interface which allowed someone with locked-in syndrome to operate a web browser. Some scientists have reported that they have developed a technique that allows locked-in patients to communicate via sniffing.
For the first time in 2020, a 34- year-old German patient, paralyzed since 2015 (later also the eyeballs) managed to communicate through an implant capable of reading brain activity.
See also
Akinetic mutism
List of people with locked-in syndrome
The Diving Bell and the Butterfly: memoirs of journalist Jean-Dominique Bauby about his life with the condition
Johnny Got His Gun, novel about a soldier who loses all of his limbs and senses after being wounded fighting in WWI
References
25. Injuries to the pons are the most common cause of locked-in syndrome,Harrison’s principles of internal medicine 21st edition vol 2 page 3332.
Further reading
Piotr Kniecicki (2014). An Art of Graceful Dying. Lukasz Swiderski ISBN 978-0-9928486-0-6 (Autobiography, written with residual wrist movements and specially adapted computer)
== External links == |
Genetic disorder | A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development (a de novo mutation), or it can be inherited from two parents who are carriers of a faulty gene (autosomal recessive inheritance) or from a parent with the disorder (autosomal dominant inheritance). When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA (due to their size).There are well over 6,000 known genetic disorders, and new genetic disorders are constantly being described in medical literature. More than 600 genetic disorders are treatable. Around 1 in 50 people are affected by a known single-gene disorder, while around 1 in 263 are affected by a chromosomal disorder. Around 65% of people have some kind of health problem as a result of congenital genetic mutations. Due to the significantly large number of genetic disorders, approximately 1 in 21 people are affected by a genetic disorder classified as "rare" (usually defined as affecting less than 1 in 2,000 people). Most genetic disorders are rare in themselves.Genetic disorders are present before birth, and some genetic disorders produce birth defects, but birth defects can also be developmental rather than hereditary. The opposite of a hereditary disease is an acquired disease. Most cancers, although they involve genetic mutations to a small proportion of cells in the body, are acquired diseases. Some cancer syndromes, however, such as BRCA mutations, are hereditary genetic disorders.
Single-gene
A single-gene disorder (or monogenic disorder) is the result of a single mutated gene. Single-gene disorders can be passed on to subsequent generations in several ways. Genomic imprinting and uniparental disomy, however, may affect inheritance patterns. The divisions between recessive and dominant types are not "hard and fast", although the divisions between autosomal and X-linked types are (since the latter types are distinguished purely based on the chromosomal location of the gene). For example, the common form of dwarfism, achondroplasia, is typically considered a dominant disorder, but children with two genes for achondroplasia have a severe and usually lethal skeletal disorder, one that achondroplasics could be considered carriers for. Sickle cell anemia is also considered a recessive condition, but heterozygous carriers have increased resistance to malaria in early childhood, which could be described as a related dominant condition. When a couple where one partner or both are affected or carriers of a single-gene disorder wish to have a child, they can do so through in vitro fertilization, which enables preimplantation genetic diagnosis to occur to check whether the embryo has the genetic disorder.Most congenital metabolic disorders known as inborn errors of metabolism result from single-gene defects. Many such single-gene defects can decrease the fitness of affected people and are therefore present in the population in lower frequencies compared to what would be expected based on simple probabilistic calculations.
Autosomal dominant
Only one mutated copy of the gene will be necessary for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent.: 57 The chance a child will inherit the mutated gene is 50%. Autosomal dominant conditions sometimes have reduced penetrance, which means although only one mutated copy is needed, not all individuals who inherit that mutation go on to develop the disease. Examples of this type of disorder are Huntingtons disease,: 58 neurofibromatosis type 1, neurofibromatosis type 2, Marfan syndrome, hereditary nonpolyposis colorectal cancer, hereditary multiple exostoses (a highly penetrant autosomal dominant disorder), tuberous sclerosis, Von Willebrand disease, and acute intermittent porphyria. Birth defects are also called congenital anomalies.
Autosomal recessive
Two copies of the gene must be mutated for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene and are referred to as genetic carriers. Each parent with a defective gene normally do not have symptoms. Two unaffected people who each carry one copy of the mutated gene have a 25% risk with each pregnancy of having a child affected by the disorder. Examples of this type of disorder are albinism, medium-chain acyl-CoA dehydrogenase deficiency, cystic fibrosis, sickle cell disease, Tay–Sachs disease, Niemann–Pick disease, spinal muscular atrophy, and Roberts syndrome. Certain other phenotypes, such as wet versus dry earwax, are also determined in an autosomal recessive fashion. Some autosomal recessive disorders are common because, in the past, carrying one of the faulty genes led to a slight protection against an infectious disease or toxin such as tuberculosis or malaria. Such disorders include cystic fibrosis, sickle cell disease, phenylketonuria and thalassaemia.
X-linked dominant
X-linked dominant disorders are caused by mutations in genes on the X chromosome. Only a few disorders have this inheritance pattern, with a prime example being X-linked hypophosphatemic rickets. Males and females are both affected in these disorders, with males typically being more severely affected than females. Some X-linked dominant conditions, such as Rett syndrome, incontinentia pigmenti type 2, and Aicardi syndrome, are usually fatal in males either in utero or shortly after birth, and are therefore predominantly seen in females. Exceptions to this finding are extremely rare cases in which boys with Klinefelter syndrome (44+xxy) also inherit an X-linked dominant condition and exhibit symptoms more similar to those of a female in terms of disease severity. The chance of passing on an X-linked dominant disorder differs between men and women. The sons of a man with an X-linked dominant disorder will all be unaffected (since they receive their fathers Y chromosome), but his daughters will all inherit the condition. A woman with an X-linked dominant disorder has a 50% chance of having an affected fetus with each pregnancy, although in cases such as incontinentia pigmenti, only female offspring are generally viable.
X-linked recessive
X-linked recessive conditions are also caused by mutations in genes on the X chromosome. Males are much more frequently affected than females, because they only have the one X chromosome necessary for the condition to present. The chance of passing on the disorder differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected (since they receive their fathers Y chromosome), but his daughters will be carriers of one copy of the mutated gene. A woman who is a carrier of an X-linked recessive disorder (XRXr) has a 50% chance of having sons who are affected and a 50% chance of having daughters who are carriers of one copy of the mutated gene. X-linked recessive conditions include the serious diseases hemophilia A, Duchenne muscular dystrophy, and Lesch–Nyhan syndrome, as well as common and less serious conditions such as male pattern baldness and red–green color blindness. X-linked recessive conditions can sometimes manifest in females due to skewed X-inactivation or monosomy X (Turner syndrome).
Y-linked
Y-linked disorders are caused by mutations on the Y chromosome. These conditions may only be transmitted from the heterogametic sex (e.g. male humans) to offspring of the same sex. More simply, this means that Y-linked disorders in humans can only be passed from men to their sons; females can never be affected because they do not possess Y-allosomes.
Y-linked disorders are exceedingly rare but the most well-known examples typically cause infertility. Reproduction in such conditions is only possible through the circumvention of infertility by medical intervention.
Mitochondrial
This type of inheritance, also known as maternal inheritance, is the rarest and applies to the 13 genes encoded by mitochondrial DNA. Because only egg cells contribute mitochondria to the developing embryo, only mothers (who are affected) can pass on mitochondrial DNA conditions to their children. An example of this type of disorder is Lebers hereditary optic neuropathy.
It is important to stress that the vast majority of mitochondrial diseases (particularly when symptoms develop in early life) are actually caused by a nuclear gene defect, as the mitochondria are mostly developed by non-mitochondrial DNA. These diseases most often follow autosomal recessive inheritance.
Multifactorial disorder
Genetic disorders may also be complex, multifactorial, or polygenic, meaning they are likely associated with the effects of multiple genes in combination with lifestyles and environmental factors. Multifactorial disorders include heart disease and diabetes. Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a persons risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. Studies that aim to identify the cause of complex disorders can use several methodological approaches to determine genotype–phenotype associations. One method, the genotype-first approach, starts by identifying genetic variants within patients and then determining the associated clinical manifestations. This is opposed to the more traditional phenotype-first approach, and may identify causal factors that have previously been obscured by clinical heterogeneity, penetrance, and expressivity.
On a pedigree, polygenic diseases do tend to "run in families", but the inheritance does not fit simple patterns as with Mendelian diseases. This does not mean that the genes cannot eventually be located and studied. There is also a strong environmental component to many of them (e.g., blood pressure). Other factors include:
asthma
autoimmune diseases such as multiple sclerosis
cancers
ciliopathies
cleft palate
diabetes
heart disease
hypertension
inflammatory bowel disease
intellectual disability
mood disorder
obesity
refractive error
infertility
Chromosomal disorder
A chromosomal disorder is a missing, extra, or irregular portion of chromosomal DNA. It can be from an atypical number of chromosomes or a structural abnormality in one or more chromosomes. An example of these disorders is trisomy 21 (Down syndrome), in which there is an extra copy of chromosome 21.
Diagnosis
Due to the wide range of genetic disorders that are known, diagnosis is widely varied and dependent of the disorder. Most genetic disorders are diagnosed pre-birth, at birth, or during early childhood however some, such as Huntingtons disease, can escape detection until the patient is well into adulthood.
The basic aspects of a genetic disorder rests on the inheritance of genetic material. With an in depth family history, it is possible to anticipate possible disorders in children which direct medical professionals to specific tests depending on the disorder and allow parents the chance to prepare for potential lifestyle changes, anticipate the possibility of stillbirth, or contemplate termination. Prenatal diagnosis can detect the presence of characteristic abnormalities in fetal development through ultrasound, or detect the presence of characteristic substances via invasive procedures which involve inserting probes or needles into the uterus such as in amniocentesis.
Prognosis
Not all genetic disorders directly result in death; however, there are no known cures for genetic disorders. Many genetic disorders affect stages of development, such as Down syndrome, while others result in purely physical symptoms such as muscular dystrophy. Other disorders, such as Huntingtons disease, show no signs until adulthood. During the active time of a genetic disorder, patients mostly rely on maintaining or slowing the degradation of quality of life and maintain patient autonomy. This includes physical therapy and pain management.
Treatment
The treatment of genetic disorders is an ongoing battle, with over 1,800 gene therapy clinical trials having been completed, are ongoing, or have been approved worldwide. Despite this, most treatment options revolve around treating the symptoms of the disorders in an attempt to improve patient quality of life.
Gene therapy refers to a form of treatment where a healthy gene is introduced to a patient. This should alleviate the defect caused by a faulty gene or slow the progression of the disease. A major obstacle has been the delivery of genes to the appropriate cell, tissue, and organ affected by the disorder. Researchers have investigated how they can introduce a gene into the potentially trillions of cells that carry the defective copy. Finding an answer to this has been a roadblock between understanding the genetic disorder and correcting the genetic disorder.
Epidemiology
Around 1 in 50 people are affected by a known single-gene disorder, while around 1 in 263 are affected by a chromosomal disorder. Around 65% of people have some kind of health problem as a result of congenital genetic mutations. Due to the significantly large number of genetic disorders, approximately 1 in 21 people are affected by a genetic disorder classified as "rare" (usually defined as affecting less than 1 in 2,000 people). Most genetic disorders are rare in themselves. There are well over 6,000 known genetic disorders, and new genetic disorders are constantly being described in medical literature.
History
The earliest known genetic condition in a hominid was in the fossil species Paranthropus robustus, with over a third of individuals displaying amelogenesis imperfecta.
See also
FINDbase (the Frequency of Inherited Disorders database)
Genetic epidemiology
List of genetic disorders
Population groups in biomedicine
Mendelian error
References
External links
Public Health Genomics at CDC
OMIM — Online Mendelian Inheritance in Man, a catalog of human genes and genetic disorders
Genetic and Rare Diseases Information Center (GARD) Office of Rare Diseases (ORD), National Institutes of Health (NIH)
CDC’s National Center on Birth Defects and Developmental Disabilities
Genetic Disease Information from the Human Genome Project
Global Genes Project, Genetic and Rare Diseases Organization
List of Genetic Disorders - Genome.gov |
Premature ventricular contraction | A premature ventricular contraction (PVC) is a common event where the heartbeat is initiated by Purkinje fibers in the ventricles rather than by the sinoatrial node. PVCs may cause no symptoms or may be perceived as a "skipped beat" or felt as palpitations in the chest. PVCs do not usually pose any danger.The electrical events of the heart detected by the electrocardiogram (ECG) allow a PVC to be easily distinguished from a normal heart beat. However, very frequent PVCs can be symptomatic of an underlying heart condition (such as arrhythmogenic right ventricular cardiomyopathy). Furthermore, very frequent (over 20% of all heartbeats) PVCs are considered a risk factor for arrhythmia-induced cardiomyopathy, in which the heart muscle becomes less effective and symptoms of heart failure may develop. Ultrasound of the heart is therefore recommended in people with frequent PVCs.
If PVCs are frequent or troublesome, medication (beta blockers or certain calcium channel blockers) may be used. Very frequent PVCs in people with dilated cardiomyopathy may be treated with radiofrequency ablation.
Signs and symptoms
Although there are many possible symptoms associated with PVCs, PVCs may also have no symptoms at all. PVCs may be perceived as a skipped heart beat, a strong beat, palpitations, or lightheadedness. They may also cause chest pain, a faint feeling, fatigue, or hyperventilation after exercise. Symptoms may be more pronounced at times of stress. Women may be more aware of PVCs at the time of the menstrual period.Premature ventricular contractions may be associated with underlying heart disease, and certain characteristics are therefore elicited routinely: the presence of signs of heart disease or a known history of heart disease (e.g. previous myocardial infarction), as well as heart disease or sudden cardiac death in close relatives. PVCs and palpitation associated with syncope (transient loss of consciousness) or provoked by exertion are also concerning. Physical examination is focused on identifying evidence of underlying heart disease.
Causes
Premature ventricular contractions occur in healthy persons of any age, but are more prevalent in the elderly and in men. In a very significant proportion of people they occur spontaneously with no known cause.Some possible underlying causes of PVCs include:
Non-cardiac causes
Adrenaline excess
Anemia
Catecholamine excess
Certain medicines such as tricyclic antidepressants, digoxin, sympathomimetics, aminophylline
Chemical (electrolyte) abnormalities in the blood (for example hypokalemia (low blood potassium), which can occur in those taking diuretics ("water pills") and hypomagnesaemia (magnesium deficiency)).
Contact with the carina (trachea/bronchi) when performing medical suctioning stimulates vagus nerve
Drugs/substances such as:Amphetamines
Alcohol
Caffeine
Cocaine
Nicotine
Theobromine
Hypercapnia (CO2 poisoning)
Hypertension (high blood pressure)
Hyperthyroidism
High blood calcium
Hypoxia and/or hypercapnia
Lack of sleep/exhaustion
Sarcoidosis
Smoking
Stress
Anxiety
Cardiac causes
Any structural heart disease which alters electrical conduction pathways due to tissue alterations
Cardiomyopathy, hypertrophic or dilated
Myocardial infarction
Myocarditis
Myocardial contusion
Mitral valve prolapse
Pathophysiology
Normally, impulses pass through both ventricles almost at the same time and the depolarization waves of the two ventricles partially cancel each other out in the ECG. However, when a PVC occurs the impulse nearly always travels through only one bundle fiber, so there is no neutralization effect; this results in the high voltage QRS wave in the electrocardiograph.
There are three main physiological explanations for premature ventricular contractions: enhanced ectopic nodal automaticity, re-entry signaling, and toxic/reperfusion triggered.
Ectopic enhanced nodal automaticity suggests foci of sub-pulmonic valvular pacemaker cells that have a subthreshold potential for firing. The basic rhythm of the heart raises these cells to threshold, which precipitates an ectopic beat. This process is the underlying mechanism for arrhythmias due to excess catecholamines and some electrolyte deficiencies, particularly low blood potassium, known as hypokalemia.
Reentry occurs when an area of 1-way block in the Purkinje fibers and a second area of slow conduction are present. This condition is frequently seen in patients with underlying heart disease that creates areas of differential conduction and recovery due to myocardial scarring or ischemia. During ventricular activation, one bundle tracts area of slow conduction activates the other tracts bundle fibers post block after the rest of the ventricle has recovered. This resulting in an extra beat. Reentry can produce single ectopic beats, or it can trigger paroxysmal tachycardia.
Triggered beats are considered to be due to after-depolarizations triggered by the preceding action potential. These are often seen in patients with ventricular arrhythmias due to digoxin toxicity and reperfusion therapy after myocardial infarction (MI).
This ectopy of the ventricles when associated with a structurally normal heart most commonly occurs from the right ventricular outflow tract (RVOT) under the pulmonic valve. The mechanism behind this is thought to be enhanced automaticity versus triggered activity.
Molecular basis
There are a number of different molecular explanations for PVCs.
calcium excess: One explanation is most basically due to an increased amount of cyclic AMP(cAMP) in the muscle cells of the hearts ventricles leading to increased flow of calcium ions into the cell. This may happen for the following reasons:Activation of the sympathetic nervous system, due to anxiety and/or physiological stress, for example hypovolemia caused by dehydration or bleeding. This activation can cause a release of catecholamines such as epinephrine (adrenaline) which can bind to beta-1 adrenergic receptor (β1 receptors) on cardiac myocytes, activating a type of guanosine nucleotide-binding protein called Gs protein. This type of protein stimulates the production of cAMP, ultimately increasing the flow of calcium ions from the extracellular space and from the sarcoplasmic reticulum into the cytosol. This has the effect of (1) increasing the strength of contraction (inotropy) and (2) depolarizing the myocyte more rapidly (chronotropy). The ventricular myocytes are therefore more irritable than usual, and may depolarize spontaneously before the SA node depolarizes. Other sympathomimetic molecules such as amphetamines and cocaine will also cause this effect.
Phosphodiesterase inhibitors such as caffeine directly affect the G-coupled signal transduction cascade by inhibiting the enzyme that catalyzes the breakdown of cAMP, again leading to the increased concentration of calcium ions in the cytosol.potassium deficiency: Potassium ion concentrations are a major determinant in the magnitude of the electrochemical potential of cells, and hypokalemia makes it more likely that cells will depolarize spontaneously. Hypercalcemia has a similar effect, although clinically it is of less concern.
magnesium deficiency: Magnesium ions affect the flow of calcium ions, and they affect the function of the Na+/K+ ATPase, and are necessary for maintaining potassium levels. Low blood magnesium therefore also makes spontaneous depolarization more likely.
myocardium damage: Existing damage to the myocardium can also provoke PVCs. The myocardial scarring that occurs in myocardial infarction and also in the surgical repair of congenital heart disease can disrupt the conduction system of the heart and may also irritate surrounding viable ventricular myocytes, make them more likely to depolarize spontaneously. Inflammation of the myocardium (as occurs in myocarditis) and systemic inflammation cause surges of cytokines, which can affect the electrical properties of myocytes and may be ultimately responsible for causing irritability of myocytes.
Diagnosis
PVCs may be found incidentally on cardiac tests such as a 12-lead electrocardiogram (ECG/EKG) performed for another reason. In those with symptoms suggestive of premature ventricular complexes, the ECG/EKG is the first investigation that may identify PVCs as well as other cardiac rhythm issues that may cause similar symptoms. If symptoms are infrequent, other forms of continuous heart beat recording may be used, such as a 24 or 48-hour Holter monitor or even 14- to 30-day recorders if the symptoms are very occasional. The advantage of these monitors is that they allow a quantification of the amount of abnormal beats ("burden") and ensure that there are no heart arrhythmias present that might require attention, such as ventricular tachycardia. If symptoms are associated with exercise, a supervised cardiac stress test may be required to reproduce the abnormality. Specifically, if this shows exercise-induced ventricular tachycardia this would require specific treatment. If PVCs are suppressed by exercise, this is an encouraging finding.On electrocardiography (ECG or Holter) premature ventricular contractions have a specific appearance of the QRS complexes and T waves, which are different from normal readings. By definition, a PVC occurs earlier than the regular normally conducted beat. Subsequently, the time between the PVC and the next normal beat is longer as the result of a compensatory pause. PVCs can be distinguished from premature atrial contractions because the compensatory pause is longer following premature ventricular contractions, in addition to a difference in QRS appearance.In some people, PVCs occur in a predictable pattern. Two PVCs in a row are called doublets and three PVCs in a rows are triplets. Depending whether there are one, two, or three normal (sinus) beats between each PVC, the rhythm is called bigeminy, trigeminy, or quadrigeminy. If 3 or more consecutive PVCs occur in a row it may be called ventricular tachycardia. The precise shape of the QRS can give an indication as to where precisely in the heart muscle the abnormal electrical activity arises. If someone has PVCs that all have the same appearance, they are considered "monofocal", if PVC’s have different appearance, they are considerevole “multifocal”.
Treatment
Isolated PVCs with benign characteristics and no underlying heart disease require no treatment, especially if there are limited symptoms.The most effective treatment is the elimination of triggers (particularly stopping the use of substances such as caffeine and certain drugs, like tobacco). If frequent, it’s possible to use:
Medications
Antiarrhythmics: these agents alter the electrophysiologic mechanisms responsible for PVCs. In CAST study of survivors of myocardial infarction encainide and flecainide, it was shown that, though those drugs could suppress PVC, they also increased the risk of death. However, while moricizine increased the death rate when used with diuretics, it reduced the frequency of deaths when it was used alone.
Beta blockers: do not directly affect or reduce the occurrence of PVCs, but reduce cardiac contractility which makes PVCs less obvious to a person; possibly reduce catecholamine induced PVCs (in catecholamine-sensitive people) due to adrenaline not reaching sinus node as much.
Calcium channel blockers
Electrolytes replacement
Magnesium supplements (e.g. magnesium citrate, orotate, Maalox, etc.)
Potassium supplements (e.g. chloride potassium with citrate ion)
Radiofrequency catheter ablation treatment. It is advised for people with ventricular dysfunction and/or tachyarrythmia or very frequent PVC (>20% in 24 h) and normal ventricular function. This procedure is a way to destroy the area of the heart tissue that is causing the irregular contractions characteristic of PVCs using radio frequency energy.
Implantable cardioverter-defibrillator
Lifestyle modification
Frequently stressed individuals should consider therapy, or joining a support group.
Prognosis
PVCs are harmless, but frequent PVCs may increase the risk of developing cardiomyopathy, which can greatly impair heart function. On a more serious and severe scale, very frequent PVCs can accompany underlying heart disease.People who do not have heart disease (with ejection fractions greater than 40%) have the same long-term prognoses as the minorance of people without PVCs on the 24 hours. Emerging data also suggest that very frequent ventricular ectopy may be associated with cardiomyopathy through a mechanism thought to be similar to that of chronic right ventricular pacing associated cardiomyopathy. For patients with underlying chronic structural heart disease and complex ectopy, mortality is significantly increased.In meta-analysis of 11 studies, people with frequent PVCs (≥ once during a standard electrocardiographic recording or ≥30 times over a 1-hour recording) had risk of cardiac death twice as great as that of participants with occasional PVCs. Although most researchers attempted to exclude high-risk subjects, such as those with histories of cardiovascular disease, they did not test participants for underlying structural heart disease.In a study of 239 people with frequent PVCs (>1000 beats/day) and without structural heart disease (i.e. in the presence of normal heart function) there were no serious cardiac events through 5.6 years on average, but there was correlation between PVC prevalence and decrease of ejection fraction and increase of left ventricular diastolic dimension. In this study absence of heart of disease was established by echocardiography, cardiac magnetic resonance imaging in 63 persons and Holter monitoring.Another study has suggested that in the absence of structural heart disease even frequent (> 60/h or 1/min) and complex PVCs are associated with a benign prognosis. It was study of 70 people followed by 6.5 years on average. Healthy status was verified by extensive noninvasive cardiologic examination, although cardiac catheterization of a subgroup disclosed serious coronary artery disease in 19%. Overall survival was better than expected.On the other hand, the Framingham Heart Study reported that frequent PVCs in healthy people were associated with a twofold increase in the risk of all-cause mortality, myocardial infarction and cardiac death. In men with coronary heart disease and in women with or without coronary heart disease, complex or frequent arrhythmias were not associated with an increased risk. The at-risk people might have subclinical coronary disease. These Framingham results have been criticized for the lack of rigorous measures to exclude the potential confounder of underlying heart disease.In the ARIC study of 14,783 people followed for 15 to 17 years those with detected PVC during 2 minute ECG, and without hypertension or diabetes on the beginning, had risk of stroke increased by 109%. Hypertension or diabetes, both risk factors for stroke, did not change significantly risk of stroke for people with PVCs. It is possible that PVCs identified those at risk of stroke with blood pressure and impaired glucose tolerance on a continuum of risk below conventional diagnostic thresholds for hypertension and diabetes. Those in ARIC study with any PVC had risk of heart failure increased by 63% and were > twice as likely to die from coronary heart disease (CHD). Risk was also higher for people with or without baseline CHD.In the Niigata study of 63,386 people with a 10-year follow-up period, subjects with PVC during a 10-second recording had triple the risk of atrial fibrillation of those without PVCs, independently of these risk factors: age; male sex; high simple body mass index (a possible signifier of obesity); hypertension (systolic and diastolic blood pressure within certain abnormal limits); and diabetes.Reducing very frequent PVC (>20%) by antiarrhythmic drugs or by catheter ablation significantly improves heart performance.Recent studies have shown that those subjects with extremely frequent PVCs (several thousand a day) can develop dilated cardiomyopathy. In these cases, if the PVCs are reduced or removed (for example, via ablation therapy) the cardiomyopathy regresses.
Epidemiology
Single PVCs are common in healthy persons. When 24-hour ambulatory monitoring is used, up to 80 percent of apparently healthy people have occasional PVCs. Rates vary by age with extremely rare for those under the age of 11 and extremely common in those older than 75 years. These differences may be due to rates of high blood pressure and atherosclerosis, which are more easy to find in older persons. In 101 people free of heart disease during 24 hours Holter monitoring, 39 had at least 1 PVC, and 4 at least 100. Heart disease was excluded after physical examination, chest x-ray, ECG, echocardiography, maximal exercise stress test, right- and left-heart catheterization and coronary angiography. In 122,043 United States Air Force flyers and cadet applicants during approximately 48 seconds of ECG 0.78% (952 males) had PVC within all age groups, but with increased incidence with increasing age. Ventricular ectopy is more prevalent in men than in women of the same age data from large, population-based studies indicate that the prevalence is less for young white women without heart disease and greater for older African American individuals with hypertension.
References
Further reading
== External links == |
Agenesis of the corpus callosum | Agenesis of the corpus callosum (ACC) is a rare birth defect in which there is a complete or partial absence of the corpus callosum. It occurs when the development of the corpus callosum, the band of white matter connecting the two hemispheres in the brain, in the embryo is disrupted. The result of this is that the fibers that would otherwise form the corpus callosum are instead longitudinally oriented along the ipsilateral ventricular wall and form structures called Probst bundles.
In addition to agenesis, other degrees of callosal defects exist, including hypoplasia (underdevelopment or thinness), hypogenesis (partial agenesis) or dysgenesis (malformation).ACC is found in many syndromes and can often present alongside hypoplasia of the cerebellar vermis. When this is the case, there can also be an enlarged fourth ventricle or hydrocephalus; this is called Dandy–Walker malformation.
Signs and symptoms
Signs and symptoms of ACC and other callosal disorders vary greatly among individuals. However, some characteristics common in individuals with callosal disorders include vision impairments, low muscle tone (hypotonia), poor motor coordination, delays in motor milestones such as sitting and walking, delayed toilet training and dysautonomic symptoms such as low perception of pain or chewing and swallowing difficulties.Laboratory research has demonstrated that individuals with ACC have difficulty transferring more complex information from one hemisphere to the other. They also have been shown to have some cognitive disabilities (difficulty in complex problem solving) and social difficulties (missing subtle social cues), even when their intelligence quotient is normal. Recent research suggests that specific social difficulties may be a result of impaired face processing. The unusual social behavior in childhood often resembles that of an autism spectrum disorder.Other characteristics sometimes associated with callosal disorders include seizures, spasticity, early feeding difficulties and/or gastric reflux, hearing impairments, abnormal head and facial features, and intellectual disability.
Associated brain anomalies
Brain anomalies that can sometimes occur in syndromes that cause callosal disorders include:
Aplasia of the cerebellar vermis
Chiari malformation
Colpocephaly
Dandy–Walker syndrome
Holoprosencephaly
Hydrocephalus
Neuronal migration disorders such as grey matter heterotopia
Schizencephaly
Associated syndromes and conditions
Some syndromes that frequently include ACC are:
Acrocallosal syndrome
Aicardi syndrome
Andermann syndrome
Donnai–Barrow syndrome
Dwarfism
FG syndrome
L1CAM syndrome
Microcephalic osteodysplastic primordial dwarfism type II
Mowat–Wilson syndrome
Oculocerebrocutaneous syndrome
Saal Bulas syndrome
Septo-optic dysplasia (optic nerve hypoplasia)
Shapiro syndrome
Vici syndromeSome conditions that can sometimes be associated with ACC or other callosal disorders include:
1p36 deletion syndrome
13q deletion syndrome
CDK13-related disorder
Craniofacial abnormalities and other oral and maxillofacial pathologies
Fetal alcohol syndrome
Fetal warfarin syndrome
Genitopatellar syndrome
Gomez-Lopez-Hernandez syndrome
Joubert syndrome
Lujan–Fryns syndrome
Marden–Walker syndrome
Maternal nutritional deficiencies or infections
Metabolic disorders
Okamoto syndrome
Opitz G/BBB syndrome
Pascual-Castroviejo syndrome
Pitt–Hopkins syndrome
Sensenbrenner syndrome
Strømme syndrome
Triploid syndrome
Trisomy 9
Xia-Gibbs syndrome
Causes
Agenesis of the corpus callosum is caused by disruption to development of the fetal brain between the 3rd and 12th weeks of pregnancy. In most cases, it is not possible to know what caused an individual to have ACC or another callosal disorder. However, research suggests that some possible causes may include chromosome errors, inherited genetic factors, prenatal infections or injuries, prenatal toxic exposures, structural blockage by cysts or other brain abnormalities and metabolic disorders.
Ciliopathies: rare genetic disorders
Until recently, the medical literature did not indicate a connection among many genetic disorders, both genetic syndromes and genetic diseases, that are now being found to be related. As a result of new genetic research, some of these are, in fact, highly related in their root cause despite the widely varying symptoms apparent on clinical examination. Agenesis of the corpus callosum is one such disease, part of an emerging class of diseases called ciliopathies. The underlying cause may be a dysfunctional molecular mechanism in the primary cilia structures of the cell organelles that are present in many cellular types throughout the human body. The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development and thus offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases. Known ciliopathies include primary ciliary dyskinesia, Bardet–Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Alström syndrome, Meckel–Gruber syndrome and some forms of retinal degeneration.
Cocaine and other street drugs
In utero exposure to cocaine, heroin, amphetamines and phenylpropanolamine can lead to agenesis of corpus callosum.
Diagnosis
Callosal disorders can be diagnosed through brain imaging studies or during autopsy. They may be diagnosed through an MRI, CT scan, Sonography, prenatal ultrasound, or prenatal MRI.
Treatment
There are currently no specific medical treatments for callosal disorders, but individuals with ACC and other callosal disorders may benefit from a range of developmental therapies, educational support, and services. It is important to consult with a variety of medical, health, educational, and social work professionals. Such professionals include neurologists, neuropsychologists, occupational therapists, physical therapists, speech and language pathologists, pediatricians, recreation therapists, music therapists, geneticists, social workers, special educators, early childhood intervention specialists, and caregivers for adults.
Prognosis
Prognosis varies depending on the type of callosal abnormality and associated conditions or syndromes. It is not possible for the corpus callosum to regenerate. Neuropsychological testing reveals subtle differences in higher cortical function compared to individuals of the same age and education without ACC,
although some individuals with callosal disorders have average intelligence and live normal lives.
Culture
Kim Peek, inspiration for the film Rain Man and renowned for his savant abilities, was born with agenesis of the corpus callosum, along with macrocephaly and damage to the cerebellum.
Notes
== External links == |
Coprophilia | Coprophilia (from Greek κόπρος, kópros excrement and φιλία, philía liking, fondness), also called scatophilia or scat (Greek: σκατά, skatá feces), is the paraphilia involving sexual arousal and pleasure from feces.
Research
In the Diagnostic and Statistical Manual of Mental Disorders (DSM), published by the American Psychiatric Association, it is classified under 302.89—Paraphilia NOS (Not Otherwise Specified) and has no diagnostic criteria other than a general statement about paraphilias that says "the diagnosis is made if the behavior, sexual urges, or fantasies cause clinically significant distress or impairment in social, occupational, or other important areas of functioning". Furthermore, the DSM-IV-TR notes, "Fantasies, behaviors, or objects are paraphilic only when they lead to clinically significant distress or impairment (e.g. are obligatory, result in sexual dysfunction, require participation of nonconsenting individuals, lead to legal complications, interfere with social relationships)".
Although there may be no connection between coprophilia and sadomasochism (SM), the limited data on the former comes from studies of the latter. A 1999 study of 164 males in Finland from two SM clubs found that 18.2% had engaged in coprophilia; 3% as a sadist only, 6.1% as a masochist only, and 9.1% as both. In the study pool 18% of heterosexuals and 17% of homosexuals had tried coprophilia, showing no statistically significant difference between heterosexuals and homosexuals. In a separate article analyzing 12 men who engaged in bestiality, an additional analysis of an 11-man subgroup revealed that six had engaged in coprophilic behavior, compared with only one in the matched control group consisting of 12 SM-oriented males who did not engage in bestiality.
Society and culture
American musician Chuck Berry recorded videos of himself urinating on and engaging in coprophilia with women. In one video, a woman defecates on him after he says "Now its time for my breakfast." He was also sued for videotaping dozens of women in the restroom of a restaurant he owned, which has been identified as being motivated by his coprophilia fetish.The Cleveland steamer is a colloquial term for a form of coprophilia, where someone defecates on their partners chest. The term received news attention through its use in a U.S. Congress staff hoax email and being addressed by the United States Federal Communications Commission. Hot Karl (also Hot Sasser) is sexual slang referring to one of several purported acts involving feces. It variously means an act of defecating on ones sexual partner, defecating on someone who is asleep, or defecating on someones face while covered in plastic wrap. According to psychologist Anil Aggrawal, it is a synonym for a Cleveland steamer and is part of a coprophilia vocabulary that also includes the Dirty Sanchez. The term was adopted as a name by rapper Hot Karl. Dirty Sanchez is a purported sex act which consists of feces purposely being smeared onto a partners upper lip. Sex-advice columnist Dan Savage dismissed the act as completely fictional. Brian Bouldrey in Dirty Words: A Literary Encyclopedia of Sex says the act is an urban legend. The New Partridge Dictionary of Slang and Unconventional English says, "This appears to have been contrived with the intention to provoke shock rather than actually as a practice, although, no doubt, some have or will experiment." Columnist Gustavo Arellano of ¡Ask a Mexican! contends the term evokes the stereotypical mustache of a Mexican. The term for the sex act entered British gay cant Polari in the 1960s.A Chicago sunroof is a fictional act, popularized in American crime drama series Better Call Saul, a spinoff of Breaking Bad. In the series, the titular character Jimmy McGill (Bob Odenkirk) defecates through an open sunroof as part of a revenge plan. As he (falsely) points out, “Its a real thing. I didnt make it up. Im not the first person to do it. Theres a name for it.” Series creator Peter Gould clarified in an interview that the "Chicago sunroof" is not real.
See also
2 Girls 1 Cup
Anilingus
Ass to mouth—removing the penis from the passive partners anus followed by its immediate insertion into the mouth
Coprophagia—the consumption of feces
Flatulence fetishism
Sadomasochism
Scatology
Urolagnia (also known as urophilia)—a paraphilia involving sexual pleasure from urine
References
Further reading
Fritscher, Jack (1978). "Review of END PRODUCT: THE FIRST TABOO by Dan Sabbath and Mandel Hall, Preface by Abby Rockefeller. URIZEN BOOKS, N.Y., 1977. 287 pp" (PDF). Drummer. No. 22. Retrieved December 28, 2018.
Xavier CM (June 1955). "Coprophilia; a clinical study". Br J Med Psychol. 28 (2–3): 188–90. doi:10.1111/j.2044-8341.1955.tb00893.x. PMID 14389628.
External links
The dictionary definition of coprophilia at Wiktionary
Media related to Coprophilia at Wikimedia Commons
Quotations related to Coprophilia at Wikiquote |
Hydrocarbon keratosis | A hydrocarbon keratosis (also known as "pitch keratosis", "tar keratosis", and "tar wart") is a precancerous keratotic skin lesion that occurs in people who have been occupationally exposed to polycyclic aromatic hydrocarbons.: 728
== References == |
Lymphedema praecox | Lymphedema praecox is a condition characterized by swelling of the soft tissues in which an excessive amount of lymph has accumulated, and generally develops in females between the ages of nine and twenty-five. This is the most common form of primary lymphedema, accounting for about 80% of the patients.: 848
See also
Lymphedema
Lymphedema-distichiasis syndrome
Aagenaes syndrome
List of cutaneous conditions
References
== External links == |
Ocular myasthenia | Ocular myasthenia gravis (MG) is a disease of the neuromuscular junction resulting in hallmark variability in muscle weakness and fatigability. MG is an autoimmune disease where anomalous antibodies are produced against the naturally occurring acetylcholine receptors in voluntary muscles. MG may be limited to the muscles of the eye (ocular MG), leading to abrupt onset of weakness/fatigability of the eyelids or eye movement. MG may also involve other muscle groups (generalized MG).
Signs and symptoms
Although these blocking antibodies may be confined to one of the larger muscles responsible for moving the face or appendages or for breathing, about 90% of MG patients eventually have eye involvement. The most common symptoms are double vision (diplopia) and eyelid drooping (ptosis), whereas the pupil is always spared. Diplopia occurs when MG affects a single extraocular muscle in one eye, limiting eye movement and leading to double vision when the eye is turned toward the affected muscle. Ptosis occurs when the levator palpebrae superioris (the muscle responsible for eyelid elevation) is affected on one or both sides, leading to eyelid drooping. Although these symptoms may not be readily apparent in well-rested patients, weakness can usually be induced with exercise of the commonly affected muscles (e.g. by having the patient look upward for about 60 seconds).
In 75% of MG cases, the initial manifestation is in the eye. Within 2 years, 80% of patients with ocular onset of MG will progress to involve other muscle groups, thereby developing generalized MG. If MG is confined to the ocular muscles for more than 3 years, there is a 94% likelihood that the symptoms will not worsen or generalize.Aside from asymmetric ptosis (which becomes worse with fatigue, sustained upgaze, and at the end of the day) and variable limitation of extraocular muscles/diplopia, other clinical signs of ocular MG include gaze-evoked nystagmus (rapid, involuntary, oscillatory motion of the eyeball) and Cogan’s lid twitch (upper lid twitch present when patient looks straight ahead after looking down for 10–15 seconds).
Pathophysiology
Normally, muscle contraction is a result of electrical signals sent from the central nervous system to muscle fibers via nerve impulses. At the neuromuscular junction, this electrical message is converted into a chemical message as acetylcholine is released from nerve fibers and attaches to corresponding receptors on the muscle fiber.
In MG, antibodies are produced that block acetylcholine receptors, preventing the molecule from binding to the receptor and leading to a breakdown in communication between the nervous system and the muscle, resulting in muscle fatigue, and sometimes paralysis. Autoantibodies against acetylcholine receptors are detectable in 70–90% of patients with generalized MG, but only 50% in ocular MG.
Predilection for eye muscles
The precise reasons for the preferential involvement of eye muscles in MG is not well understood, but there are several lines of thought.
Functional hypotheses propose that although multiple muscles may be affected, a deficit may be more readily apparent in the eyes for several reasons. Slight weakness in a limb may be tolerated, but slight weakness in the extraocular muscles would lead to misalignment of the two eyes, even a small degree of which could lead to diplopia. Eyes may also be less able to adapt to variable weakness, because extraocular muscles use visual rather than proprioceptive (body position-sensing) cues for fine-tuning.
Immunologic hypotheses proposes that there may be differences in the antibodies in ocular MG versus generalized MG that may favor the muscles responsible for eye movement and eyelid elevation.
Physiologic hypotheses propose that it is the unique structure and function of extraocular muscles that predispose them to weakness in MG. Compared to extremity muscles, extraocular muscles are smaller, served by more nerve fibers, and are among the fastest contracting muscles in the body. This higher level of activity may predispose them to fatigue in MG. Additionally, some reports indicate that there may be fewer acetylcholine receptors in extraocular muscles versus limb muscles.
Diagnosis
The variable course of MG may make the diagnosis difficult. In brief, the diagnosis of MG relies mostly on the patients history and physical findings, with particular attention to neurologic, eye motility, and eyelid exams. Frequently, patients will describe experiencing alternating ptosis (lid droop in one eye that gets better, then is followed by ptosis in the other eye), as well as diplopia that worsens during the day (with increasing extraocular muscle fatigue).
A tensilon (edrophonium chloride) test can be used, which temporarily blocks the breakdown of acetylcholine, and briefly relieves weakness; however, false-negative results are common. Single-fiber electromyography can be used to electrically stimulate single muscle fibers to determine if there is muscle weakness present. The diagnosis of MG can also be confirmed with blood work that measures the amount of blocking antibody present, but only 70% of ocular MG patients have detectable antibody levels. Additional lab and image tests for commonly associated thyroid, thymus and autoimmune diseases are also advisable.
Treatment
The prognosis tends to be good for patients with MG. It is often best not to treat mild cases of MG. Management necessitates avoidance of medications that can worsen neuromuscular transmission, such as aminoglycoside antibiotics, quinolone antibiotics, beta-blockers, chloroquine, anti-arrhythmics, calcium channel blockers, some anticonvulsants and intravenous iodinated contrast should be avoided.
MG is characteristically variable in course, with the frequency of diplopia and ptosis affected by environmental, emotional and physical factors such as bright sunlight, stress, viral illness, menstruation, pregnancy, etc. Spontaneous remission can occur in any patient and remain for years. In a study of the natural history of generalized MG among 168 patients (with an average follow-up of 12 years), 14% experienced complete remission.
Patients with mild-to-moderate ocular myasthenia are usually treated initially with oral anticholinesterase agents, Mestinon (pyridostigmine) being the most commonly employed. There have not been any randomized clinical trials conducted with these agents, and this treatment is often unsuccessful, particularly in resolving diplopia. Immunosuppressive therapy is then started and the agent of choice is usually prednisone. In a small controlled study this drug demonstrated greater efficacy than pyridostigmine. Steroid therapy is controversial, but in another study the results suggested that prednisone does decrease progression to generalized MG. There is no single recommended dosing regimen in light of the side effects commonly associated with chronic corticosteroid therapy, and the difficulty in weaning patients from steroids without exacerbation of symptoms. Response to prednisone therapy is variable.
Additionally, MG patients should be examined for thymomas, and if found, should undergo surgery to address this condition. A prophylactic thymectomy is controversial, but has been shown to be helpful in young MG patients with acute disease within 3 years of disease onset, in patients with enlarged thymus glands and for whom surgery is low-risk, and patients with generalized MG who are unresponsive to medical treatment.
The symptoms of ocular MG can also be addressed by non-medicinal means. Ptosis can be corrected with placement of crutches on eyeglasses and with ptosis tape to elevate eyelid droop. Diplopia can be addressed by occlusion with eye patching, frosted lens, occluding contact lens, or by simply placing opaque tape over a portion of eyeglasses. Also, plastic prisms (Fresnel prisms) can be attached to eyeglasses of a diplopic patient, allowing for alignment of vision from both eyes in the affected direction, but are often problematic if the degree of muscle weakness, and therefore ocular misalignment, fluctuates frequently.
Epidemiology
In contrast to generalized MG, purely ocular MG occurs equally among females and males, has a higher incidence in persons of Korean descent, and is likely associated with thyroid disease, thymomas (20% incidence), and other autoimmune diseases such as scleroderma, systemic lupus erythematosus, rheumatoid arthritis, Hashimotos thyroiditis, multiple sclerosis, and thyroid ophthalmopathy.
Notes
== References == |
Dissociation (psychology) | Dissociation, as a concept that has been developed over time, is any of a wide array of experiences, ranging from a mild emotional detachment from the immediate surroundings, to a more severe disconnection from physical and emotional experiences. The major characteristic of all dissociative phenomena involves a detachment from reality, rather than a loss of reality as in psychosis.The phenomena are diagnosable under the DSM-5 as a group of disorders as well as a symptom of other disorders through various diagnostic tools. Its cause is believed to be related to neurobiological mechanisms, trauma, anxiety, and psychoactive drugs. Research has further related it to suggestibility and hypnosis, and it is inversely related to mindfulness, which is a potential treatment.
History
French philosopher and psychologist Pierre Janet (1859–1947) is considered to be the author of the concept of dissociation. Contrary to some conceptions of dissociation, Janet did not believe that dissociation was a psychological defense.Psychological defense mechanisms belong to Sigmund Freuds theory of psychoanalysis, not to Janetian psychology. Janet claimed that dissociation occurred only in persons who had a constitutional weakness of mental functioning that led to hysteria when they were stressed. Although it is true that many of Janets case histories described traumatic experiences, he never considered dissociation to be a defense against those experiences. Quite the opposite: Janet insisted that dissociation was a mental or cognitive deficit. Accordingly, he considered trauma to be one of many stressors that could worsen the already-impaired "mental deficiency" of a hysteric, thereby generating a cascade of hysterical (in todays language, "dissociative") symptoms.Although there was great interest in dissociation during the last two decades of the nineteenth century (especially in France and England), this interest rapidly waned with the coming of the new century. Even Janet largely turned his attention to other matters.
There was a sharp peak in interest in dissociation in America from 1890 to 1910, especially in Boston as reflected in the work of William James, Boris Sidis, Morton Prince, and William McDougall. Nevertheless, even in America, interest in dissociation rapidly succumbed to the surging academic interest in psychoanalysis and behaviorism.
For most of the twentieth century, there was little interest in dissociation. Despite this, a review of 76 previously published cases from the 1790s to 1942 was published in 1944, describing clinical phenomena consistent with that seen by Janet and by therapists today. In 1971, Bowers and her colleagues presented a detailed, and still quite valid, treatment article. The authors of this article included leading thinkers of their time – John G. Watkins (who developed ego-state therapy) and Zygmunt A. Piotrowski (famed for his work on the Rorschach test). Further interest in dissociation was evoked when Ernest Hilgard (1977) published his neodissociation theory in the 1970s. During the 1970s and 1980s an increasing number of clinicians and researchers wrote about dissociation, particularly multiple personality disorder.Carl Jung described pathological manifestations of dissociation as special or extreme cases of the normal operation of the psyche. This structural dissociation, opposing tension, and hierarchy of basic attitudes and functions in normal individual consciousness is the basis of Jungs Psychological Types. He theorized that dissociation is a natural necessity for consciousness as well.Attention to dissociation as a clinical feature has been growing in recent years as knowledge of post-traumatic stress disorder (PTSD) increased, due to interest in dissociative identity disorder (DID), and as neuroimaging research and population studies show its relevance.Historically the psychopathological concept of dissociation has also another different root: the conceptualization of Eugen Bleuler that looks into dissociation related to schizophrenia.
Diagnosis
Dissociation is commonly displayed on a continuum. In mild cases, dissociation can be regarded as a coping mechanism or defense mechanism in seeking to master, minimize or tolerate stress – including boredom or conflict. At the non-pathological end of the continuum, dissociation describes common events such as daydreaming. Further along the continuum are non-pathological altered states of consciousness.More pathological dissociation involves dissociative disorders, including dissociative fugue and depersonalization disorder with or without alterations in personal identity or sense of self. These alterations can include: a sense that self or the world is unreal (depersonalization and derealization), a loss of memory (amnesia), forgetting identity or assuming a new self (fugue), and separate streams of consciousness, identity and self (dissociative identity disorder, formerly termed multiple personality disorder) and complex post-traumatic stress disorder. Although some dissociative disruptions involve amnesia, other dissociative events do not. Dissociative disorders are typically experienced as startling, autonomous intrusions into the persons usual ways of responding or functioning. Due to their unexpected and largely inexplicable nature, they tend to be quite unsettling.
Dissociative disorders are sometimes triggered by trauma, but may be preceded only by stress, psychoactive substances, or no identifiable trigger at all. The ICD-10 classifies conversion disorder as a dissociative disorder. The Diagnostic and Statistical Manual of Mental Disorders groups all dissociative disorders into a single category and recognizes dissociation as a symptom of acute stress disorder, posttraumatic stress disorder, and borderline personality disorder.Misdiagnosis is common among people who display symptoms of dissociative disorders, with an average of seven years to receive proper diagnosis and treatment. Research is ongoing into etiologies, symptomology, and valid and reliable diagnostic tools. In the general population, dissociative experiences that are not clinically significant are highly prevalent with 60% to 65% of the respondents indicating that they have had some dissociative experiences.
Diagnostic and Statistical Manual of Mental Disorders
Diagnoses listed under the DSM-5 are dissociative identity disorder, dissociative amnesia, depersonalization/derealization disorder, other specified dissociative disorder and unspecified dissociative disorder. The list of available dissociative disorders listed in the DSM-5 changed from the DSM-IV-TR, as the authors removed the diagnosis of dissociative fugue, classifying it instead as a subtype of dissociative amnesia. Furthermore, the authors recognized derealization on the same diagnostic level of depersonalization with the opportunity of differentiating between the two.The DSM-IV-TR considers symptoms such as depersonalization, derealization and psychogenic amnesia to be core features of dissociative disorders. The DSM-5 carried these symptoms over and described symptoms as positive and negative. Positive symptoms include unwanted intrusions that alter continuity of subjective experiences, which account for the first two symptoms listed earlier with the addition of fragmentation of identity. Negative symptoms include loss of access to information and mental functions that are normally readily accessible, which describes amnesia.
Peritraumatic dissociation
Peritraumatic dissociation is considered to be dissociation that is experienced during and immediately following a traumatic event. Research is on-going related to its development, its importance, and its relationship to trauma, dissociative disorders, and predicting the development of PTSD.
Measurements
Two of the most commonly used screening tools in the community are the Dissociative Experiences Scale and the Multiscale Dissociation Inventory. Meanwhile, the Structured Clinical Interview for DSM-IV – Dissociative Disorders (SCID-D) and its second iteration, the SCID-D-R, are both semi-structured interviews and are considered psychometrically strong diagnostic tools.Other tools include the Office Mental Status Examination (OMSE), which is used clinically due to inherent subjectivity and lack of quantitative use. There is also the Dissociative Disorders Interview Schedule (DDSI), which lacks substantive clarity for differential diagnostics.Peritraumatic dissociation is measured through the Peritraumatic Dissociative Scale.
Etiology
Neurobiological mechanism
Preliminary research suggests that dissociation-inducing events, drugs like ketamine, and seizures generate slow rhythmic activity (1–3 Hz) in layer 5 neurons of the posteromedial cortex in humans (retrosplenial cortex in mice). These slow oscillations disconnect other brain regions from interacting with the posteromedial cortex, which may explain the overall experience of dissociation.
Trauma
Dissociation has been described as one of a constellation of symptoms experienced by some victims of multiple forms of childhood trauma, including physical, psychological, and sexual abuse. This is supported by studies which suggest that dissociation is correlated with a history of trauma.Dissociation appears to have a high specificity and a low sensitivity to having a self-reported history of trauma, which means that dissociation is much more common among those who are traumatized, yet at the same time there are many people who have suffered from trauma but who do not show dissociative symptoms.Adult dissociation when combined with a history of child abuse and otherwise interpersonal violence-related posttraumatic stress disorder has been shown to contribute to disturbances in parenting behavior, such as exposure of young children to violent media. Such behavior may contribute to cycles of familial violence and trauma.Symptoms of dissociation resulting from trauma may include depersonalization, psychological numbing, disengagement, or amnesia regarding the events of the abuse. It has been hypothesized that dissociation may provide a temporarily effective defense mechanism in cases of severe trauma; however, in the long term, dissociation is associated with decreased psychological functioning and adjustment.Other symptoms sometimes found along with dissociation in victims of traumatic abuse (often referred to as "sequelae to abuse") include anxiety, PTSD, low self-esteem, somatization, depression, chronic pain, interpersonal dysfunction, substance abuse, self-harm and suicidal ideation or actions. These symptoms may lead the victim to present the symptoms as the source of the problem.Child abuse, especially chronic abuse starting at early ages, has been related to high levels of dissociative symptoms in a clinical sample, including amnesia for abuse memories. It has also been seen that girls who suffered abuse during their childhood had higher reported dissociation scores than did boys who reported dissociation during their childhood. A non-clinical sample of adult women linked increased levels of dissociation to sexual abuse by a significantly older person prior to age 15, and dissociation has also been correlated with a history of childhood physical and sexual abuse. When sexual abuse is examined, the levels of dissociation were found to increase along with the severity of the abuse.A 2012 review article supports the hypothesis that current or recent trauma may affect an individuals assessment of the more distant past, changing the experience of the past and resulting in dissociative states.
Psychoactive substances
Psychoactive drugs can often induce a state of temporary dissociation. Substances with dissociative properties include ketamine, nitrous oxide, alcohol, tiletamine, amphetamine, dextromethorphan, MK-801, PCP, methoxetamine, salvia, muscimol, atropine, ibogaine, and minocycline.
Correlations
Hypnosis and suggestibility
There is evidence to suggest that dissociation is correlated with hypnotic suggestibility, specifically with dissociative symptoms related to trauma. However, the relationship between dissociation and hypnotic suggestibility appears to be complex and indicates further research is necessary.Aspects of hypnosis include absorption, dissociation, suggestibility, and willingness to receive behavioral instruction from others. Both hypnotic suggestibility and dissociation tend to be less mindful, and hypnosis is used as a treatment modality for dissociation, anxiety, chronic pain, trauma, and more. Difference between hypnosis and dissociation: one is suggested, imposed by self or other, meaning dissociation is generally more spontaneous altering of awareness.
Mindfulness and meditation
Mindfulness and meditation have shown an inverse relationship specifically with dissociation related to re-experiencing trauma due to the lack of present awareness inherent with dissociation. The re-experiencing episodes can include anything between illusions, distortions in perceived reality, and disconnectedness from the present moment. It is believed that the nature of dissociation as an avoidance coping or defense mechanism related to trauma inhibits resolution and integration.Mindfulness and meditation also can alter the state of awareness to the present moment; however, unlike dissociation, it is clinically used to bring greater awareness to an individuals present state of being. It achieves this through increased abilities to self-regulate attention, emotion, and physiological arousal, maintain continuity of consciousness, and adopt an approach to the present experience that is open and curious. In practice, non-judgmental awareness has displayed a positive relationship with lower symptoms of PTSD avoidance, which can relate to greater opportunities for success with exposure therapy and lowering PTSD symptoms of hypervigilance, re-experiencing, and overgeneralization of fears.When using mindfulness and meditation with people expressing trauma symptoms, it is crucial to be aware of potential trauma triggers, such as the focus on the breath. Often, a meditation session will begin with focused attention and move into open monitoring. With severe trauma symptoms, it may be important to start the meditation training and an individual session at the peripheral awareness, such as the limbs. Moreover, trauma survivors often report feeling numb as a protection against trauma triggers and reminders, which are often painful, making it good practice to start all trainings at the limbs as a gradual exposure to body sensations. Doing so will also increase physical attachment to the present moment and the sense of grounding, thereby increasing tolerance to trauma reminders and decreasing the need and use of dissociation.
Treatment
When receiving treatment, patients are assessed to discover their level of functioning. Some patients might be higher functioning than others. This is taken into account when creating a patients potential treatment targets. To start off treatment, time is dedicated to increasing a patients mental level and adaptive actions in order to gain a balance in both their mental and behavioral action. Once this is achieved, the next goal is to work on removing or minimizing the phobia made by traumatic memories, which is causing the patient to dissociate. The final step of treatment includes helping patients work through their grief in order to move forward and be able to engage in their own lives. This is done with the use of new coping skills attained through treatment. One coping skill that can improve dissociation is mindfulness due to the introduction of staying in present awareness while observing non-judgmentally and increasing the ability to regulate emotions. Specifically in adolescents, mindfulness has been shown to reduce dissociation after practicing mindfulness for three weeks.
See also
References
External links
International Society for the Study of Trauma and Dissociation
The official journal of the International Society for the Study of Dissociation (ISSD), published between 1988 and 1997 |
Eosinopenia | Eosinopenia is a form of agranulocytosis where the number of eosinophil granulocytes is lower than expected. Leukocytosis with eosinopenia can be a predictor of bacterial infection. It can be induced by stress reactions, Cushings syndrome, or the use of steroids. Pathological causes include burns and acute infections.
See also
Eosinophilia
Hypereosinophilia
References
Further reading
Krause JR, Boggs DR (1987). "Search for eosinopenia in hospitalized patients with normal blood leukocyte concentration". Am. J. Hematol. 24 (1): 55–63. doi:10.1002/ajh.2830240108. PMID 3799595. S2CID 20021710.
== External links == |
Inverted nipple | An inverted nipple (occasionally invaginated nipple) is a condition where the nipple, instead of pointing outward, is retracted into the breast. In some cases, the nipple will be temporarily protruded if stimulated. Both women and men can have inverted nipples.
Causes
The most common causes of nipple inversion include:
Born with condition
Trauma which can be caused by conditions such as fat necrosis, scars, or a result of surgery
Breast sagging, drooping or ptosis
Breast cancer
Breast carcinoma
Pagets disease
Inflammatory breast cancer
Breast infections or inflammations
Mammary duct ectasia
Breast abscess
Mastitis
Genetic variant of nipple shape, such as:
Weaver syndrome
Congenital disorder of glycosylation type 1A and 1 L
Kennerknecht-Sorgo-Oberhoffer syndrome
Gynecomastia
Recurrent infections
TuberculosisMost common nipple variations that women are born with are caused by short ducts or a wide areola muscle sphincter.
Inverted nipples can also occur after sudden and major weight loss.
Grading system
The three grades of inverted nipples are defined on how easily the nipple may be protracted and the degree of fibrosis existent in the breast, as well as the damage it has caused on the milk ducts.
Inverted nipple grade 1 refers to nipples that can easily be pulled out, by using finger pressure around the areola. The grade-1 inverted nipple maintains its projections and rarely retracts. Also, grade-1 inverted nipples may occasionally pop up without manipulation or pressure. Milk ducts are usually not compromised and breast feeding is possible. These are "shy nipples". It is believed to have minimal or no fibrosis. There is no soft-tissue deficiency of the nipple. The lactiferous duct should be normal without any retraction.Inverted nipple grade 2 is the nipple which can be pulled out, though not as easily as the grade 1, but which retracts after pressure is released. Breast feeding is usually possible, though it is more likely to be hard to get the baby to latch comfortably in the first weeks after birth; extra help may be needed. Grade 2 nipples have a moderate degree of fibrosis. The lactiferous ducts are mildly retracted, but do not need to be cut for the release of fibrosis. On histological examination, these nipples have rich collagenous stromata with numerous bundles of smooth muscle.
Inverted nipple grade 3 describes a severely inverted and retracted nipple which can rarely be pulled out physically and which requires surgery to be protracted. Milk ducts are often constricted, and breast feeding is difficult, but not necessarily impossible. With good preparation and help, babies often can drink at the breast, and milk production is not affected; after breastfeeding, nipples often are less or no longer inverted. Women with grade-3 inverted nipples may also struggle with infections, rashes, or problems with nipple hygiene. The fibrosis is remarkable and lactiferous ducts are short and severely retracted. The bulk of soft tissue is markedly insufficient in the nipple. Histologically, atrophic terminal duct lobular units and severe fibrosis are seen.
Pregnancy and breastfeeding
Women with inverted nipples may find that their nipples protract (come out) temporarily or permanently during pregnancy, or as a result of breastfeeding. Most women with inverted nipples who give birth are able to breastfeed without complication, but inexperienced mothers may experience higher than average pain and soreness when initially attempting to breastfeed. When a mother uses proper breastfeeding technique, the infant latches onto the areola, not the nipple, so women with inverted nipples are actually able to breastfeed without any problem. An infant that latches on well may be able to slush out an inverted nipple. The use of a breast pump or other suction device immediately before a feeding may help to draw out inverted nipples. A hospital grade electric pump may be used for this purpose. Some women also find that using a nipple shield can help facilitate breastfeeding. Frequent stimulation such as sexual intercourse and foreplay (such as nipple sucking) also helps the nipple protract.
Piercing
Another method of protracting inverted nipples is to have the nipple pierced. This method will only be effective if the nipple can be temporarily protracted. If pierced when protracted, the jewellery may prevent the nipple from returning to its inverted state. The success of both of these methods, from a cosmetic standpoint, is mixed. The piercing may actually correct the overly taut connective tissue to allow the nipple to become detached from underlying connective tissue and resume a more typical appearance.
Other corrective strategies
Other strategies for protracting inverted nipples include regularly stimulating the nipples to a protruding state, in an attempt to gradually loosen the nipple tissue. Some sex toys designed for nipple stimulation, such as suction cups or clamps, may also cause inverted nipples to protract or stay protracted longer. Some special devices are specifically designed to draw out inverted nipples, or a home-made nipple protractor can be constructed out of a 10-ml disposable syringe. These methods are often used in preparation for breastfeeding, which can sometimes cause inverted nipples to become protracted permanently.
Two methods which are now discouraged are breast shells and the Hoffman technique. Breast shells may be used to apply gentle constant pressure to the areola to try to break any adhesions under the skin that are preventing the nipple from being drawn out. The shells are worn inside the bra. The Hoffman technique is a nipple-stretching exercise that may help loosen the adhesions at the base of the nipple when performed several times a day. Although both techniques are heavily promoted, a 1992 study found that not only do shells and the Hoffman technique not promote more successful breastfeeding, but they may also actually disrupt it.
References
External links
Inflammatory Breast Cancer
Inversion of Nipple |
Colon cleansing | Colon cleansing, also known as colon therapy, or colon hydrotherapy, or a colonic, or colonic irrigation encompasses a number of alternative medical therapies claimed to remove unspecified toxins from the colon and intestinal tract by removing supposed accumulations of feces. Colon cleansing in this context should not be confused with an enema which introduces fluid into the colon, often under mainstream medical supervision, for a limited number of purposes including severe constipation and medical imaging.Some forms of colon hydrotherapy use tubes to inject water, sometimes mixed with herbs or with other liquids, into the colon via the rectum using special equipment. Oral cleaning regimes use dietary fiber, herbs, dietary supplements, or laxatives. Those who practice colon cleansing believe in autointoxication, that accumulations of putrefied feces line the walls of the large intestine and that these accumulations harbor parasites or pathogenic gut flora, causing nonspecific symptoms and general ill-health.
Autointoxication, a term coined in 1884 by the French physician Charles Jacques Bouchard, is a hypothesis based on medical beliefs of the ancient Egyptians and Greeks and was discredited in the early 20th century. Nonetheless, during the 2000s Internet marketing and infomercials of oral supplements supposedly for colon cleansing increased.There is no scientific evidence for the alleged benefits of colon cleansing. Certain enema preparations have been associated with heart attacks and electrolyte imbalances, and improperly prepared or used equipment can cause infection or damage to the bowel. Frequent colon cleansing can lead to dependence on enemas to defecate and some herbs may reduce the effectiveness of, or increase the risks associated with the use of prescription medications.
Effectiveness and risks
The symptoms that are attributed to autointoxication—headache, fatigue, loss of appetite and irritability—may be caused by mechanical distention within the bowel, such as irritable bowel syndrome, rather than toxins from putrefying food. The benefits anecdotally attributed to colon cleansing are vague and the claims made by manufacturers and practitioners are based on a flawed understanding of the body. There is little evidence of actual benefit to the procedure, and no evidence that it can alleviate the symptoms that are attributed to the theories of colon cleansing.As the colon normally expels waste, colon cleansing is generally unneeded. Colonic irrigation can disrupt the bowels normal flora, and, if done frequently, can result in electrolyte depletion with dehydration. Rare but severe adverse events have been rectal perforation, as well as amoebic infection, from poorly sterilised equipment. Others claim that colon cleansing may impede the colons shedding of dead cells.Excessive use of enemas has also been associated with heart problems, such as heart failure, as well as heart attacks related to electrolyte imbalances when performed as a coffee enema. Frequent enemas or other colon-cleansing tools may lead to dependence and inability to defecate without assistance, as well as potential withdrawal symptoms. Herbs taken orally may modulate the absorption or the activity of prescription medications.Medical doctor Harriet Hall writes that "The colon cleanses itself... The idea that its walls are coated with years-old hamburger residue is preposterous".
Supplement effectiveness
The consumer advocacy news program Marketplace conducted a consumer trial with three women on the effectiveness of two colon supplements versus fiber. The results showed the supplements did not assist in weight loss and provided no additional benefit over a basic fiber supplement. According to the American Cancer Society, "Available scientific evidence does not support claims that colon therapy is effective in treating cancer or any other disease".
Colon hydrotherapy
Colonic irrigation, also known as colon hydrotherapy, colonic hydrotherapy, or a "colonic", is a treatment which is used "to wash out the contents of the large bowel by means of copious enemas using water or other medication."During a cleansing enema, liquid is introduced into the colon and retained for five to fifteen minutes. During a colonic, liquid is introduced into the colon and then it is flushed out and this is repeated until the entire colon is cleared.Colonic irrigation has been described as an "unwise" procedure as it carries the risk of serious harm and has no proven benefit.
Regulation
In the United States, the Food and Drug Administration (FDA) regulates the production of equipment used in colon hydrotherapy but does not regulate their use, or the supplements used in oral colon-cleansing regimens. Manufacturer claims do not require verification or supporting evidence. The contents of the products are also not verified or tested. The FDA has issued several letters warning manufacturers and suppliers of colon hydrotherapy equipment about making false claims of effectiveness, safety issues, and quality control violations.
History
The concept of autointoxication, the idea that food enters the intestine and rots, provides a rationale for colon cleansing. The ancient Egyptians believed that toxins formed as a result of decomposition within the intestines, and moved from there into the circulatory system, causing fever and the development of pus. The Ancient Greeks adopted and expanded the idea, applying their belief in the four humours. In the 19th century, studies in biochemistry and microbiology seemed to support the autointoxication hypothesis, and mainstream physicians promoted the idea.
Daly notes that, historically, "purging was one of the few procedures that a physician could perform with visible, often impressive results and without immediate or obvious dangers".Ilya Ilyich Mechnikov (1845-1916) became the strongest supporter of the idea of colon cleansing; he thought that toxins could shorten the lifespan. Over time, the concept broadened to autointoxication, which supposes that the body cannot fully dispose of its waste products and toxins, which then accumulate in the intestine. In some cases, the concept led to radical surgeries to remove the colon for unrelated symptoms.Autointoxication enjoyed some favor in the medical community in the late 19th and early 20th centuries, but clinicians discarded it as advances in science failed to support its claims.
A 1919 paper entitled "Origin of the so-called auto-intoxication symptom" in the Journal of the American Medical Association marked the beginning of the rejection of the auto-intoxication hypothesis by the medical community.Despite a lack of scientific support, autointoxication persists in the public imagination. In the 1990s the practice of colon cleansing experienced a resurgence in the alternative-medical community, supported by testimonials and anecdotal evidence and promoted by manufacturers of colon-cleansing products.
See also
Mucoid plaque
Whole bowel irrigation
== References == |
Polyp (medicine) | In anatomy, a polyp is an abnormal growth of tissue projecting from a mucous membrane. If it is attached to the surface by a narrow elongated stalk, it is said to be pedunculated; if it is attached without a stalk, it is said to be sessile. Polyps are commonly found in the colon, stomach, nose, ear, sinus(es), urinary bladder, and uterus. They may also occur elsewhere in the body where there are mucous membranes, including the cervix, vocal folds, and small intestine. Some polyps are tumors (neoplasms) and others are non-neoplastic, for example hyperplastic or dysplastic, which are benign. The neoplastic ones are usually benign, although some can be pre-malignant, or concurrent with a malignancy.
The name is of ancient origin, in use in English from about 1400 for a nasal polyp, from Latin polypus through Greek. The animal of similar appearance called polyp is attested from 1742, although the word was earlier used for an octopus.
Digestive polyps
Relative incidences by location:
Colorectal polyp
While colon polyps are not commonly associated with symptoms, occasionally they may cause rectal bleeding, and on rare occasions pain, diarrhea or constipation. They are a concern because of the potential for colon cancer being present microscopically, and the risk of benign colon polyps becoming malignant over time. Since most polyps are asymptomatic, they are usually discovered at the time of colon cancer screening. Common screening methods are occult blood test, colonoscopy with a modern flexible endoscope, sigmoidoscopy (usually with the older rigid endoscope), lower gastrointestinal series (barium enema), digital rectal examination (DRE), virtual colonoscopy or Cologuard. The polyps are routinely removed at the time of colonoscopy, either with a wire loop known as a polypectomy snare (first description by P. Deyhle, Germany, 1970), or with biopsy forceps. If an adenomatous polyp is found, it must be removed, since such a polyp is pre-cancerous and has a propensity to become cancerous. For certainty, all polyps which are found by any diagnostic modality, are removed by a colonoscopy. Although colon cancer is usually not found in polyps smaller than 2.5 cm, all polyps found are removed since their removal reduces the likelihood of future colon cancer. When adenomatous polyps are removed, a repeat colonoscopy is usually performed three to five years later.Most colon polyps can be categorized as sporadic.
Inherited polyposis syndromes
Familial adenomatous polyposis
Peutz–Jeghers syndrome
Turcot syndrome
Juvenile polyposis syndrome
Cowden disease
Bannayan–Riley–Ruvalcaba syndrome (Bannayan–Zonana syndrome)
Gardners syndrome
Serrated polyposis syndrome
Non-inherited polyposis syndromes
Cronkhite–Canada syndrome
Types of colon polyps
Malignant
Hamartomatous
Hyperplastic
Inflammatory: Inflammatory fibroid polyp
Adenomatous polyps
Adenomatous polyps, or adenomas, are polyps that grow on the lining of the colon and which carry a high risk of cancer. The adenomatous polyp is considered pre-malignant, i.e., likely to develop into colon cancer. The other types of polyps that can occur in the colon are hyperplastic and inflammatory polyps, which are unlikely to develop into colorectal cancer.About 5% of people aged 60 will have at least one adenomatous polyp of 1 cm diameter or greater. Multiple adenomatous polyps often result from familial polyposis coli or familial adenomatous polyposis, a condition that carries a very high risk of colon cancer.
Types
Adenomas constitute approximately 10% of digestive polyps. Most polyps (approximately 90%) are small, usually less than 1 cm in diameter, and have a small potential for malignancy. The remaining 10% of adenomas are larger than 1 cm and approach a 10% chance of containing invasive cancer.There are three types of adenomatous polyp:
Tubular adenomas (tube-like shape) are the most common of the adenomatous polyps; they may occur everywhere in the colon and they are the least likely colon polyps to develop into colon cancer
Tubulovillous
Villous adenomas are commonly found in the rectal area and they are normally larger in size than the other two types of adenomas. They tend to be non-pedunculated, velvety, or cauliflower-like in appearance and they are associated with the highest morbidity and mortality rates of all polyps. They can cause hypersecretory syndromes characterized by hypokalemia and profuse mucous discharge, and can harbor carcinoma in situ or invasive carcinoma more frequently than other adenomas.
Risks
The risks of progression to colorectal cancer increase if the polyp is larger than 1 cm and contains a higher percentage of villous component. Also, the shape of the polyps is related to the risk of progression into carcinoma. Polyps that are pedunculated (with a stalk) are usually less dangerous than sessile polyps (flat polyps). Sessile polyps have a shorter pathway for migration of invasive cells from the tumor into submucosal and more distant structures, and they are also more difficult to remove and ascertain. Sessile polyps larger than 2 cm usually contain villous features, have a higher malignant potential, and tend to recur following colonoscopic polypectomy.Although polyps do not carry significant risk of colon cancer, tubular adenomatous polyps may become cancerous when they grow larger. Larger tubular adenomatous polyps have an increased risk of malignancy when larger because then they develop more villous components and may become sessile.It is estimated that an individual whose parents have been diagnosed with an adenomatous polyp has a 50% greater chance to develop colon cancer than individuals with no family history of colonic polyps. As of 2019 there is no way to establish the risks of colon polyps of patients with a family history of them. Overall, nearly 6% of the population, regardless of family history, is at risk of developing colon cancer.
Screening
Screening for colonic polyps as well as preventing them has become an important part of the management of the condition. Medical societies have established guidelines for colorectal screening in order to prevent adenomatous polyps and to minimize the chances of developing colon cancer. It is believed that some changes in the diet might be helpful in preventing polyps from occurring, but there is no other way to prevent the polyps from developing into cancerous growths than detecting and removing them.Colon polyps as they grow can sometimes cause bleeding within the intestine, which can be detected by an occult blood test. According to American Cancer Society guidelines, people over 50 should have an annual occult blood test. People in their 50s are recommended to have flexible sigmoidoscopies performed once every 3 to 5 years to detect any abnormal growth which could be an adenomatous polyp. If adenomatous polyps are detected during this procedure, a colonoscopy is recommended. Medical societies recommend colonoscopies every ten years starting at age 50 as a necessary screening practice for colon cancer. The screening provides an accurate image of the intestine and also allows the removal of the polyp, if found. Once an adenomatous polyp is identified during colonoscopy, there are several methods of removal, including using a snare or a heating device. Colonoscopies are preferred over sigmoidoscopies because they allow the examination of the entire colon and can detect polyps in the upper colon, where more than half of polyps occur.It has been statistically demonstrated that screening programs are effective in reducing the number of deaths caused by colon cancer due to adenomatous polyps. The risk of complications associated with colonoscopies is approximately 0.35 percent, compared to a lifetime risk of developing colon cancer of around 6 percent. As there is a small likelihood of recurrence, surveillance after polyp removal is recommended.
Endometrial polyp
An endometrial polyp or uterine polyp is a polyp or lesion in the lining of the uterus (endometrium) that takes up space within the uterine cavity. Commonly occurring, they are experienced by up to 10% of women. They may have a large flat base (sessile) or be attached to the uterus by an elongated pedicle (pedunculated). Pedunculated polyps are more common than sessile ones. They range in size from a few millimeters to several centimeters. If pedunculated, they can protrude through the cervix into the vagina. Small blood vessels may be present in polyps, particularly large ones.
Cervical polyp
A cervical polyp is a common benign polyp or tumor on the surface of the cervical canal. They can cause irregular menstrual bleeding or increased pain but often show no symptoms.
Nasal polyps
Nasal polyps are polypoidal masses arising mainly from the mucous membranes of the nose and paranasal sinuses. They are overgrowths of the mucosa that frequently accompany allergic rhinitis. They are freely movable and nontender.
Laryngeal polyps
Polyps on the vocal folds can take on many different forms, and can sometimes result from vocal abuse, although this is not always the cause. They can occur on one or both vocal folds, and appear as swelling, a bump (similar to a nodule), a stalk-like growth, or a blister-like lesion. Most polyps are larger than nodules, which are more similar to callouses on the vocal folds. Polyps and nodules can exhibit similar symptoms including hoarseness or breathiness, “rough” or “scratchy” voice, harshness in vocal quality, shooting pain from ear to ear, sensation of having “a lump in the back of the throat”, neck pain, decreased pitch range in the voice, and vocal and bodily fatigue.If an individual experiences symptoms for more than 2 to 3 weeks, they should see a physician. For a diagnosis, a thorough evaluation of the voice should include a physical examination, preferably by an otolaryngologist (ear, nose, and throat doctor) who specializes in voice, a voice evaluation with a speech-language pathologist (SLP), a neurological examination (in certain cases)
The qualities of the voice that will be evaluated include quality, pitch, loudness, and ability to sustain voicing. In some cases, an instrumental examination may be performed with an endoscope into the mouth or nose; this gives a clear look at the vocal folds and larynx in general. In addition to this, a stroboscope (flashing light) may be used to observe the movement of the vocal folds during speech.Polyps may be treated with medical, surgical, or behavioral intervention. Surgical intervention involves removing the polyp from the vocal fold. This approach is only used when the growth(s) are very large or have existed for an extended amount of time. In children, surgical intervention is rare. Existing medical problems may be treated in an effort to reduce the strain and negative impact on the vocal cords. This could include treatment for gastrointestinal reflux disease, allergies, and thyroid problems. Intervention to stop smoking and reduce stress may also be needed. Most people receive behavioral intervention, or vocal therapy, from an SLP. This might involve teaching good vocal hygiene, and reducing or stopping vocal abuse behaviors. Direct voice treatments may be used to alter pitch, loudness, or breathe support to promote good voicing.
Footnotes
External links
National Institutes of Health polyp website
Thorough review of polyposis syndromes by Dr. Ali Nawaz Khan with CME available
"How I Do It" — Removing large or sessile colonic polyps. Dr. Brian Saunders MD FRCP; St. Marks Academic Institute; Harrow, Middlesex, UK. Retrieved April 9, 2008.
FAP Patient Information Sheet |
Posterior cord syndrome | Posterior cord syndrome (PCS), also known as posterior spinal artery syndrome (PSA), is a type of incomplete spinal cord injury. PCS is the least commonly occurring of the six clinical spinal cord injury syndromes, with an incidence rate of less than 1%.
PCS originates from an infarct in the posterior spinal artery and is caused by lesions on the posterior portion of the spinal cord, specifically the posterior column, posterior horn, and posterolateral region of the lateral column. These lesions can be caused by trauma to the neck, occlusion of the spinal artery, tumors, disc compression, vitamin B12 deficiency, syphilis, or multiple sclerosis. Despite these numerous pathological pathways, the result is an interruption in transmission of sensory information and motor commands from the brain to the periphery.
Causes
Trauma to the spinal cord, such as neck hyperflexion injuries, are often the result of car accidents or sports-related injuries. In such injuries, posterior dislocations and extensions occur without the rupture of ligaments. This blunt trauma may be further complicated with subsequent disc compression. In addition to these complications, transient ischemic attacks could occur in the spinal cord during spinal artery occlusion.Common pathological sources of PCS include Friedreichs Ataxia, an autosomal-recessive inherited disease, and tumors such as astrocytoma, ependymoma, meningioma, neurofibroma, sarcoma, and schwannoma.
Cobalamin, commonly known as vitamin B12, plays a crucial role in the synthesis and maintenance of myelin in neurons found in the spinal cord. A deficiency of this essential vitamin results in demyelination, a deterioration of the axons layer of insulation causing interrupted signal transmission, with a currently unknown specificity to the posterior region.PCS may develop with the failure to treat syphilis. Symptoms typically appear during the tertiary phase of the disease, between twenty and thirty years after the initial syphilis infection. Failure to treat syphilis leads to progressive degeneration of the nerve roots and posterior columns. The bacteria Treponema pallidum that causes syphilis results in locomotor ataxia and tabes dorsalis. Further complications from tabes dorsalis include optic nerve damage, blindness, shooting pains, urinary incontinence, and degeneration of the joints.In most cases, lesions present bilaterally. However, in rare cases, lesions have been seen unilaterally. Moreover, general symptoms of posterior spinal artery infarcts include ipsilateral loss of proprioceptive sensation, fine touch, pressure, and vibration below the lesion; deep tendon areflexia; and in severe circumstances, complete paralysis below the portion of the spinal cord affected.
Diagnosis
Complete spinal imaging, X-rays, computed tomography (CT), or magnetic resonance imaging (MRI) can be used to identify infarctions on the dorsal columns. Imaging alone is often inconclusive and does not present a full analysis of the affected columns. Clinical history, blood and cerebral spinal fluid (CSF) tests can also be used to make a full diagnosis.
Treatment
Treatment for patients with posterior cord syndrome depends on the causes and symptoms of the patient, as well as the source of the infraction. The main goal of treatment is to stabilize the spine. Possible treatments include airway adjuncts; the use of ventilators; full spinal precautions and immobilization; and injections of dopamine. While there is no definitive cure for posterior cord syndrome, treatment and supportive care can be provided based on the patients symptoms. Therapy and rehabilitative care including walking aids, physical, occupational, and psychotherapy can help ease the symptoms associated with PCS. Acute therapy can include intensive medical care and analgesia. Corticosteroids are used to reduce any inflammation or swelling. Bracing or surgical repair can be done to stabilize the spinal fracture.
Research
It has been difficult to make any breakthroughs in diagnosis and/or treatment of PCS as symptoms are not specific in nature and can vary based on the exact location of spinal cord lesions. In addition, the demographics of patients with PCS are widespread as the onset of symptoms typically follows a traumatic event. Additionally, research has suffered setbacks because PCS is rare with few documented cases, unlike anterior spinal cord injury.However, ongoing research has helped in differentiating PCS from other brain injuries. Therefore, better therapies for PCS treatment can be developed. For instance, one study suggests that a tissue plasminogen activator (tPA) therapy intervention, commonly used in stroke patients, may aid in treating patients with symptoms of PCS.
References
== External links == |
Notalgia paresthetica | Notalgia paresthetica or Notalgia paraesthetica (NP) (also known as "Hereditary localized pruritus", "Posterior pigmented pruritic patch", and "subscapular pruritus") is a chronic sensory neuropathy. Notalgia paresthetica is a common localized itch, affecting mainly the area between the shoulder blades (especially the T2–T6 dermatomes) but occasionally with a more widespread distribution, involving the shoulders, back, and upper chest.: 402 The characteristic symptom is pruritus (itch or sensation that makes a person want to scratch) on the back, usually on the left hand side below the shoulder blade (mid to upper back). It is occasionally accompanied by pain, paresthesia (pins and needles), or hyperesthesia (unusual or pathologically increased sensitivity of the skin to sensory stimuli, such as pain, heat, cold, or touch), which results in a well circumscribed hyperpigmentation of a skin patch in the affected area.
Causes
The correlation of notalgia paresthetica localization with corresponding degenerative changes in the spine suggests that spinal nerve impingement may be a contributing cause. According to Plete and Massey, "The posterior rami of spinal nerves arising in T2 through T6 are unique in that they pursue a right-angle course through the multifidus spinae muscle, and this particular circumstance may predispose them to harm from otherwise innocuous insults of a varied nature." Patients may have other conditions that predispose them to peripheral neuropathies (nerve damage).The causes of this condition have not yet been completely defined. Patients are usually older persons.
Diagnosis
Treatment
Therapy for notalgia paresthetica is directed at controlling symptoms, as no cure exists for the condition. Available treatments include local anesthetics, topical capsaicin, topical corticosteroids, hydroxyzine, oxcarbazepine, palmitoylethanolamide and gabapentin. Paravertebral nerve block and botulinum toxin injections may also be helpful.
Some patients treated with low concentration topical capsaicin reported pain, burning, or tingling sensations with treatment, and symptoms returned within a month of ceasing treatment. Oxcarbazepine was reported to reduce the severity of symptoms in a few cases. One patient has been treated with "paravertebral nerve blocks, with bupivacaine and methylprednisolone acetate injected into the T3–T4 and T5–T6 intervertebral spaces" Hydroxyzine has also been used with considerable success in some cases as long as the pills are used daily.
High concentration topical capsaicin (8%, Qutenza) have been shown to be highly effective in treating neuropathic itch in some patients (including notalgia paresthetica) as well as in a recent proof-of-concept study.Most recently intradermal injections of botulinum toxin type A (Botox) have been tried with some success. Even though botulinum normally wears off in three to six months, the treatment appears to be long term, and it has been theorised that botulinum type A effects lasting change in pain signaling. Unfortunately, repeated injections have been associated with diminished movement ability of the upper back and arms and its recommendation as a treatment has therefore become less popular.
See also
List of cutaneous conditions
Hereditary neuralgic amyotrophy
References
Pleet, A Bernard and Massey, E Wayne, Notalgia Paresthetica, Neurology, Dec 1978; 28: 1310
Pleet, A Bernard and Massey, E Wayne, Letter to the Editor: Notalgia Paresthetica, Neurology, Vol. 29, Issue 4, 528 April 1, 1979
== External links == |
Angiofibroma | Angiofibroma (AGF) is a descriptive term for a wide range of benign skin or mucous membrane (i.e. the outer membrane lining body cavities such as the mouth and nose) lesions in which individuals have: 1) benign papules, i.e. pinhead-sized elevations that lack visible evidence of containing fluid; 2) nodules, i.e. small firm lumps usually >0.1 cm in diameter; and/or 3) tumors, i.e. masses often regarded as ~0.8 cm or larger. AGF lesions share common macroscopic (i.e. gross) and microscopic appearances. Grossly, AGF lesions consist of multiple papules, one or more skin-colored to erythematous, dome-shaped nodules, or usually just a single tumor. Microscopically, they consist of spindle-shaped and stellate-shaped cells centered around dilated and thin-walled blood vessels in a background of coarse bundles of collagen (i.e. the main fibrous component of connective tissue). Angiofibromas have been divided into different types but commonly a specific type was given multiple and very different names in different studies. The following list gives a brief description of the AFG types and their alternate names.
Cutaneous angiofibroma: These papule, nodule, and/or tumor lesions occur on the: 1) face and are typically termed fibrous papules; 2) penis and are typically termed pearly penile papules; and 3) underneath a fingernail or toenail and are typically termed periungual angiofibromas. Some of these cutaneous AGF lesions occur in individuals with one or more of 3 different genetic diseases: tuberous sclerosis, multiple endocrine neoplasia type 1, and Birt-Hogg-Dube syndrome. The following are examples of these cutaneous angiofibromas and their alternate names.
Fibrous papules are also termed facial angiofibromas and were formerly and incorrectly termed adenoma sebaceum (fibrous papules are unrelated to sebaceous glands). They develop in up to 8% of the general adult population and occur as 1 to 3 pink to red, dome-shaped papules in the central areas of the face, nose, and/or lips. About 75% of individuals with tuberous sclerosis present with fibrous papules in their infancy or early childhood; when associated with this rare disease, the lesions often occur as multiple papules in symmetrical, butterfly-shaped patterns over both cheeks and the nose. Fibrous papules also occur in individuals with multiple endocrine neoplasia type 1 (a study done in Japan found that 43% of individuals with this genetic disease bore facial angiofibromas) and, uncommonly, in individuals with Birt-Hogg-Dube syndrome.
Pearly penile papules are also termed hirsuties coronae glandis, papillae coronae glandis, papillomatosis corona penis, corona capillitii, and hirsutoid papillomas. These lesions develop in up to 30% of males during their puberty or, less commonly, early adulthood. They typically occur as numerous white-colored to skin-colored papules located circumferentially around the corona of the penis or, less commonly, the ventromedial aspect of the corona near the peniss frenulum. (Vestibular papillomatosis, also named hirsutoid vulvar papillomas, vulvar squamous papillomatosis, micropapillomatosis labialis, and squamous vestibular micropapilloma, is the female equivalent of pearly penile papules in men. It has not been formally termed an angiofibroma.)
Periungual angiofibromas are also termed Koenens tumors, periungual fibromas, and subungual fibromas. In addition, these tumors were formerly regarded as a type of acral angiofibroma (see below description). These lesions present as multiple nodules or tumors under multiple finger and/or toe nails of individuals with tuberous sclerosis or in one case the Birt-Hogg-Dube syndrome. Periungual angiofibromas have also been reported to occur in individuals that do not have these genetic diseases. Periungual angiofibromas tumors can be highly mutilating finger/toe-nail lesions.Oral fibromas are also termed irritation fibromas, focal fibrous hyperplasia, and traumatic fibromas. These lesions are nodules that occur on the buccal mucosa (i.e. mucous membranes lining the cheeks and back of the lips) or lateral tongue. They may be irritating or asymptomatic and are the most common tumor-like lesions in the oral cavity. Oral fibromas are not neoplasms; they are hyperplastic (i.e. overgrowth) reactions of fibrous tissue to local trauma or chronic irritation.Nasopharyngeal angiofibromas, also termed juvenile nasopharyngeal angiofibromas, fibromatous hamartomas, or angiofibromatous hamartoma of the nasal cavity, are large benign tumors (average size 5.9 cm in one study) that develop almost exclusively in males aged 9 to 36 years old. They commonly arise in the nasopharynx (i.e. upper part of the throat that lies behind the nose) and typically have attachments to the sphenopalatine foramen, clivus, and/or root of the pterygoid processes of the sphenoid bone. These tumors may expand into various other nearby structures including the cranial cavity. Nasopharyngeal angiofibromas are highly vascularized tumors consisting of fibroblasts (i.e. connective tissue cells) in a dense collagen matrix (i.e. tissue background). Studies have suggested that these tumors are due to the expression of male sex hormones (i.e. androgens and progesterones), genetic factors, molecular alterations (i.e. changes in the normal characteristics of cells that lead to abnormal cell growth), and/or human papillomavirus infection.Angiofibroma of soft tissue is also named angiofibroma, not otherwise specified, by the World Health Organization, 2020. The Organization also classified these lesions as in the category of benign fibroblastic and myofibroblastic tumors. These tumors more often afflict females, typically occur in adults (median age 49 years), have a median size of ~3.5 cm, and develop in a leg near to, and may invade, a large joint. Less uncommonly, they occur in the back, abdominal wall, pelvic cavity, or breast. Angiofibroma of soft tissue tumors consist of uniform, bland, spindle-shaped cells and a prominent vascular network consisting of small thin-walled branching blood vessels in a variably collagenous tissue background. Its tumor cells contain an AHRR-NCOA2 fusion gene in 60% to 80% of cases and a GTF2I-NCOA2 or GAB1-ABL1 fusion gene in rare cases.Cellular angiofibroma is usually a small, slow-growing tumor arising in the vulva-vaginal areas of adult woman and the inguinal-scrotal areas of adult men although some of these tumors, especially in men, can grow up to 25 cm. Affected men are usually older (7th decade) than women (5th decade). Less commonly. cellular angiofibromas have occurred in various other superficial soft tissue areas throughout the body. These tumors are edematous (i.e. abnormally swollen with fluid), highly vascular, spindle-shaped cell lesions with a variable amount of fibrous stroma. In 2020, the World Health Organization classified cellular angiofibroma tumors in the category of benign fibroblastic/myofibroblastic tumors. The tumor cells in these lesions contain chromosome and gene abnormalities including a loss of one of the two RB1 genes. It has been suggested that the loss of this gene contributes to the development of cellular angiofibroma tumors.Acral angiofibromas are also termed superficial acral fibromyxomas, digital fibromyxomas, acquired digital fibrokeratomas, acquired periungual fibrokeratomas, garlic clove fibromas, digital fibromas, and cellular digital fibromas. At one time, periungual angiofibromas were regarded as a type of acral angiofibroma (see above description). Acral refers to distal sites of the ears, nose, hands, fingers, feet, and toes. Acral angifibromeae occur primarily in areas close to the nails of fingers and toes (~80% of cases) or, less commonly, palms of the hands or soles of the feet. The tissues of this tumor consists of bland spindle-shaped and star-shaped cells within a collagen fiber-rich stroma containing prominent blood vessels and mast cells.
See also
List of cutaneous conditions
Tuberous sclerosis
multiple endocrine neoplasia type 1
Birt-Hogg-Dube syndrome
References
== External links == |
Mitochondrial trifunctional protein deficiency | Mitochondrial trifunctional protein deficiency (MTP deficiency or MTPD) is an autosomal recessive fatty acid oxidation disorder that prevents the body from converting certain fats to energy, particularly during periods without food. People with this disorder have inadequate levels of an enzyme that breaks down a certain group of fats called long-chain fatty acids.
Signs and symptoms
The presentation of mitochondrial trifunctional protein deficiency may begin during infancy, features that occur are: low blood sugar, weak muscle tone, and liver problems. Infants with this disorder are at risk for heart problems, breathing difficulties, and pigmentary retinopathy. Signs and symptoms of mitochondrial trifunctional protein deficiency that may begin after infancy include hypotonia, muscle pain, a breakdown of muscle tissue, and a loss of sensation in the extremities called peripheral neuropathy. Some who have MTP deficiency show a progressive course associated with myopathy, and recurrent rhabdomyolysis.
Genetics
The genetics of mitochondrial trifunctional protein deficiency is based on mutations in the HADHA and HADHB genes which cause this disorder. These genes each provide instructions for making part of an enzyme complex called mitochondrial trifunctional protein. This enzyme complex functions in mitochondria, the energy-producing centers within cells: mitochondrial trifunctional protein contains three enzymes that each perform a different function. This enzyme complex is required to metabolize a group of fats called long-chain fatty acids. These fatty acids are stored in the bodys fat tissues and are a major source of energy for the heart and muscles. During periods of fasting, fatty acids are also an important energy source for the liver and other tissues.Mutations in the HADHA or HADHB genes that cause mitochondrial trifunctional protein deficiency disrupt all functions of this enzyme complex. Without enough of this enzyme complex, long-chain fatty acids cannot be metabolized. As a result, these fatty acids are not converted to energy, which can lead to some features of this disorder. Long-chain fatty acids may also build up and damage the liver, heart, and muscles. This abnormal buildup causes other symptoms of mitochondrial trifunctional protein deficiency.The mechanism of this condition indicates that the mitochondrial trifunction protein catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids: long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase, and long-chain thiolase activities. Trifunctional protein deficiency is characterized by decreased activity of all 3 enzymes. Clinically, trifunctional protein deficiency usually results in sudden unexplained infant death, cardiomyopathy, or skeletal myopathy.
Diagnosis
Diagnosis of mitochondrial trifunctional protein deficiency is often confirmed using tandem mass spectrometry. Genetic counseling is available for this condition. Additionally the following exams are available:
CBC
Urine test
Treatment
Management for mitochondrial trifunctional protein deficiency entails the following:
Avoiding factors that might precipitate condition
Glucose
Low fat/high carbohydrate nutrition
See also
Long-chain acyl-CoA dehydrogenase
References
Further reading
Nyhan, William L.; Hoffman, Georg F.; Barshop, Bruce A.; Al-Aqeel, Aida I. (2012). Atlas of Inherited Metabolic Diseases 3E. CRC Press. ISBN 9781444149487.
Thöny, Beat; Duran, Marinus; Gibson, K. Michael; Dionisi-Vici, Carlo (2013). Physicians Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Springer. ISBN 9783642403378.
External links
Media related to Mitochondrial trifunctional protein deficiency at Wikimedia Commons |
Sycosis vulgaris | Sycosis vulgaris is a cutaneous condition characterized by a chronic infection of the chin or bearded region.: 252 The irritation is caused by a deep infection of hair follicles, often by species of Staphylococcus or Propionibacterium bacteria. Asymptomatic or painful and tender erythematous papules and pustules may form around coarse hair in the beard (sycosis barbae) or the back of the neck (sycosis nuchae).
See also
Folliculitis
List of cutaneous conditions
== References == |
Pendred syndrome | Pendred syndrome is a genetic disorder leading to congenital bilateral (both sides) sensorineural hearing loss and goitre with euthyroid or mild hypothyroidism (decreased thyroid gland function). There is no specific treatment, other than supportive measures for the hearing loss and thyroid hormone supplementation in case of hypothyroidism. It is named after Vaughan Pendred (1869–1946), the British doctor who first described the condition in an Irish family living in Durham in 1896. It accounts for 7.5% to 15% of all cases of congenital deafness.
Signs and symptoms
The hearing loss of Pendred syndrome is often, although not always, present from birth, and language acquisition may be a significant problem if deafness is severe in childhood. The hearing loss typically worsens over the years, and progression can be step-wise and related to minor head trauma. In some cases, language development worsens after head injury, demonstrating that the inner ear is sensitive to trauma in Pendred syndrome; this is as a consequence of the widened vestibular aqueducts usual in this syndrome. Vestibular function varies in Pendred syndrome and vertigo can be a feature of minor head trauma. A goitre is present in 75% of all cases.
Genetics
Pendred syndrome is inherited in an autosomal recessive manner, meaning that one would need to inherit an abnormal gene from each parent to develop the condition. This also means that a sibling of a patient with Pendred syndrome has a 25% chance of also having the condition if the parents are unaffected carriers.It has been linked to mutations in the PDS gene, which codes for the pendrin protein (solute carrier family 26, member 4, SLC26A4). The gene is located on the long arm of chromosome 7 (7q31). Mutations in the same gene also cause enlarged vestibular aqueduct syndrome (EVA or EVAS), another congenital cause of deafness; specific mutations are more likely to cause EVAS, while others are more linked with Pendred syndrome.
Pathophysiology
SLC26A4 can be found in the cochlea (part of the inner ear), thyroid and the kidney. In the kidney, it participates in the secretion of bicarbonate. However, Pendred syndrome is not known to lead to kidney problems. It functions as an iodide/chloride transporter. In the thyroid, this leads to reduced organification of iodine (i.e. its incorporation into thyroid hormone).
Diagnosis
People with Pendred syndrome present with a hearing loss either at birth or during childhood. The hearing loss is commonly progressive. In early stages it is usually a mixed hearing loss (both conductive and sensorineural hearing loss) because of a third window effect due to the inner ear malformation (widened vestibular aqueducts). A thyroid goitre may be present in the first decade and is usual towards the end of the second decade. MRI scanning of the inner ear usually shows widened or large vestibular aqueducts with enlarged endolymphatic sacs and may show abnormalities of the cochleae that are known as Mondini dysplasia. Genetic testing to identify the pendrin gene usually establishes the diagnosis. If the condition is suspected, a "perchlorate discharge test" is sometimes performed. This test is highly sensitive, but may also be abnormal in other thyroid conditions. If a goitre is present, thyroid function tests are performed to identify mild cases of thyroid dysfunction even if they are not yet causing symptoms.
Treatment
No specific treatment exists for Pendred syndrome. If thyroid hormone levels are decreased, thyroid hormone supplements may be required. Patients are advised to take precautions against head injury.
References
External links
GeneReviews/NCBI/NIH/UW entry on Pendred Syndrome/DFNB4
NCBI Genes and Diseases |
Platelet | Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby initiating a blood clot. Platelets have no cell nucleus; they are fragments of cytoplasm that are derived from the megakaryocytes of the bone marrow or lung, which then enter the circulation. Circulating inactivated platelets are biconvex discoid (lens-shaped) structures,: 117–18 2–3 µm in greatest diameter. Activated platelets have cell membrane projections covering their surface. Platelets are found only in mammals, whereas in other vertebrates (e.g. birds, amphibians), thrombocytes circulate as intact mononuclear cells.: 3
On a stained blood smear, platelets appear as dark purple spots, about 20% the diameter of red blood cells. The smear is used to examine platelets for size, shape, qualitative number, and clumping. A healthy adult typically has 10 to 20 times more red blood cells than platelets. One major function of platelets is to contribute to hemostasis: the process of stopping bleeding at the site of interrupted endothelium. They gather at the site and, unless the interruption is physically too large, they plug the hole. First, platelets attach to substances outside the interrupted endothelium: adhesion. Second, they change shape, turn on receptors and secrete chemical messengers: activation. Third, they connect to each other through receptor bridges: aggregation. Formation of this platelet plug (primary hemostasis) is associated with activation of the coagulation cascade, with resultant fibrin deposition and linking (secondary hemostasis). These processes may overlap: the spectrum is from a predominantly platelet plug, or "white clot" to a predominantly fibrin, or "red clot" or the more typical mixture. Some would add the subsequent retraction and platelet inhibition as fourth and fifth steps to the completion of the process and still others would add a sixth step, wound repair. Platelets also participate in both innate and adaptive intravascular immune responses. The platelet cell membrane has receptors for collagen. Following the rupture of the blood vessel wall, the platelets are exposed and they adhere to the collagen in the surrounding connective tissue.
Low platelet concentration is called thrombocytopenia, and is due to either decreased production or increased destruction. Elevated platelet concentration is called thrombocytosis, and is either congenital, reactive (to cytokines), or due to unregulated production: one of the myeloproliferative neoplasms or certain other myeloid neoplasms. A disorder of platelet function is called a thrombocytopathy or a platelet function disorder.
Normal platelets can respond to an abnormality on the vessel wall rather than to hemorrhage, resulting in inappropriate platelet adhesion/activation and thrombosis: the formation of a clot within an intact vessel. This type of thrombosis arises by mechanisms different from those of a normal clot: namely, extending the fibrin of venous thrombosis; extending an unstable or ruptured arterial plaque, causing arterial thrombosis; and microcirculatory thrombosis. An arterial thrombus may partially obstruct blood flow, causing downstream ischemia, or may completely obstruct it, causing downstream tissue death.
Measurement
Platelet concentration is measured either manually using a hemocytometer, or by placing blood in an automated platelet analyzer using electrical impedance, such as a Coulter counter. The normal range (99% of population analyzed) for platelets in healthy white people is 150,000 to 450,000 per cubic millimeter (a mm3 equals a microliter). or 150–450 × 109 per liter. The normal range has been confirmed to be the same in the elderly and the population of Spain.The number of platelets varies across individuals. The normal physiologic range is 200,000 to 500,000 per microliter of blood.
Since they contain receptors for thrombopoietin (the protein that facilitates the maturation of megakaryocytes and release of platelets), a higher number of platelets binds more of the protein. Consequently, there is stimulation for more production of thrombopoietin in the liver and kidneys. This is the basis for the production of more thrombopoietin and, as a result, more platelets in the bloodstream during the blood clotting process.
Shape
In a first approximation, the platelet shape can be considered similar to oblate spheroids, with a semiaxis ratio of 2 to 8. This approximation is often used to model the hydrodynamic and optical properties of a platelet population, as well as to restore the geometric parameters of individual measured platelets by flow cytometry. More accurate biophysical models of the platelet surface morphology, which model its shape from first principles, make it possible to obtain a more realistic platelet geometry in a calm and activated state.
Structure
Structurally the platelet can be divided into four zones, from peripheral to innermost:
Peripheral zone – is rich in glycoproteins required for platelet adhesion, activation and aggregation. For example, GPIb/IX/V; GPVI; GPIIb/IIIa.
Sol-gel zone – is rich in microtubules and microfilaments, allowing the platelets to maintain their discoid shape.
Organelle zone – is rich in platelet granules. Alpha granules contain clotting mediators such as factor V, factor VIII, fibrinogen, fibronectin, platelet-derived growth factor, and chemotactic agents. Delta granules, or dense bodies, contain ADP, calcium and serotonin, which are platelet-activating mediators.
Membranous zone – contains membranes derived from megakaryocyte smooth endoplasmic reticulum organized into a dense tubular system which is responsible for thromboxane A2 synthesis. This dense tubular system is connected to the surface platelet membrane to aid thromboxane A2 release.
Development
Megakaryocyte and platelet production is regulated by thrombopoietin, a hormone produced in the kidneys and liver.
Each megakaryocyte produces between 1,000 and 3,000 platelets during its lifetime.
An average of 1011 platelets are produced daily in a healthy adult.
Reserve platelets are stored in the spleen and are released when needed by splenic contraction induced by the sympathetic nervous system.
The average life span of circulating platelets is 8 to 9 days. Life span of individual platelets is controlled by the internal apoptotic regulating pathway, which has a Bcl-xL timer.
Old platelets are destroyed by phagocytosis in the spleen and liver.
Hemostasis
An overview summarizing platelet dynamics, the complex process of converting inactive platelets into a platelet plug, is essential. Complicating any verbal description is the fact that at least 193 proteins and 301 interactions are involved in platelet dynamics. The separation of platelet dynamics into three stages is useful in this regard, but it is artificial: in fact, each stage is initiated in rapid succession, and each continues until the trigger for that stage is no longer present, so there is overlap.
Adhesion
Thrombus formation on an intact endothelium is prevented by nitric oxide, prostacyclin, and CD39.Endothelial cells are attached to the subendothelial collagen by von Willebrand factor (VWF), which these cells produce. VWF is also stored in the Weibel-Palade bodies of the endothelial cells and secreted constitutively into the blood. Platelets store vWF in their alpha granules.
When the endothelial layer is disrupted, collagen and VWF anchor platelets to the subendothelium. Platelet GP1b-IX-V receptor binds with VWF; and GPVI receptor and integrin α2β1 bind with collagen.
Activation
Inhibition
The intact endothelial lining inhibits platelet activation by producing nitric oxide, endothelial-ADPase, and PGI2 (prostacyclin). Endothelial-ADPase degrades the platelet activator ADP.Resting platelets maintain active calcium efflux via a cyclic AMP-activated calcium pump. Intracellular calcium concentration determines platelet activation status, as it is the second messenger that drives platelet conformational change and degranulation (see below). Endothelial prostacyclin binds to prostanoid receptors on the surface of resting platelets. This event stimulates the coupled Gs protein to increase adenylate cyclase activity and increases the production of cAMP, further promoting the efflux of calcium and reducing intracellular calcium availability for platelet activation.ADP on the other hand binds to purinergic receptors on the platelet surface. Since the thrombocytic purinergic receptor P2Y12 is coupled to Gi proteins, ADP reduces platelet adenylate cyclase activity and cAMP production, leading to accumulation of calcium inside the platelet by inactivating the cAMP calcium efflux pump. The other ADP-receptor P2Y1 couples to Gq that activates phospholipase C-beta 2 (PLCB2), resulting in inositol 1,4,5-trisphosphate (IP3) generation and intracellular release of more calcium. This together induces platelet activation. Endothelial ADPase degrades ADP and prevents this from happening. Clopidogrel and related antiplatelet medications also work as purinergic receptor P2Y12 antagonists.
Trigger (induction)
Platelet activation begins seconds after adhesion occurs. It is triggered when collagen from the subendothelium binds with its receptors (GPVI receptor and integrin α2β1) on the platelet. GPVI is associated with the Fc receptor gamma chain and leads via the activation of a tyrosine kinase cascade finally to the activation of PLC-gamma2 (PLCG2) and more calcium release.Tissue factor also binds to factor VII in the blood, which initiates the extrinsic coagulation cascade to increase thrombin production. Thrombin is a potent platelet activator, acting through Gq and G12. These are G protein-coupled receptors and they turn on calcium-mediated signaling pathways within the platelet, overcoming the baseline calcium efflux. Families of three G proteins (Gq, Gi, G12) operate together for full activation. Thrombin also promotes secondary fibrin-reinforcement of the platelet plug. Platelet activation in turn degranulates and releases factor V and fibrinogen, potentiating the coagulation cascade. So, in reality, the process of platelet plugging and coagulation are occurring simultaneously rather than sequentially, with each inducing the other to form the final fibrin-crosslinked thrombus.
Components (consequences)
GPIIb/IIIa activation
Collagen-mediated GPVI signalling increases the platelet production of thromboxane A2 (TXA2) and decreases the production of prostacyclin. This occurs by altering the metabolic flux of platelets eicosanoid synthesis pathway, which involves enzymes phospholipase A2, cyclo-oxygenase 1, and thromboxane-A synthase. Platelets secrete thromboxane A2, which acts on the platelets own thromboxane receptors on the platelet surface (hence the so-called "out-in" mechanism), and those of other platelets. These receptors trigger intraplatelet signaling, which converts GPIIb/IIIa receptors to their active form to initiate aggregation.
Granule secretion
Platelets contain dense granules, lambda granules and alpha granules. Activated platelets secrete the contents of these granules through their canalicular systems to the exterior. Simplistically, bound and activated platelets degranulate to release platelet chemotactic agents to attract more platelets to the site of endothelial injury. Granule characteristics:
α granules (alpha granules) – containing P-selectin, platelet factor 4, transforming growth factor-β1, platelet-derived growth factor, fibronectin, B-thromboglobulin, vWF, fibrinogen, and coagulation factors V and XIII
δ granules (delta or dense granules) – containing ADP or ATP, calcium, and serotonin
γ granules (gamma granules) – similar to lysosomes and contain several hydrolytic enzymes
λ granules (lambda granules) – contents involved in resorption during later stages of vessel repair
Morphology change
As shown by flow cytometry and electron microscopy, the most sensitive sign of activation, when exposed to platelets using ADP, are morphological changes. Mitochondrial hyperpolarization is a key event in initiating changes in morphology. Intraplatelet calcium concentration increases, stimulating the interplay between the microtubule/actin filament complex. The continuous changes in shape from the unactivated to the fully activated platelet is best seen on scanning electron microscopy. Three steps along this path are named early dendritic, early spread and spread. The surface of the unactivated platelet looks very similar to the surface of the brain, with a wrinkled appearance from numerous shallow folds to increase the surface area; early dendritic, an octopus with multiple arms and legs; early spread, an uncooked frying egg in a pan, the "yolk" being the central body; and the spread, a cooked fried egg with a denser central body.
These changes are all brought about by the interaction of the microtubule/actin complex with the platelet cell membrane and open canalicular system (OCS), which is an extension and invagination of that membrane. This complex runs just beneath these membranes and is the chemical motor that literally pulls the invaginated OCS out of the interior of the platelet, like turning pants pockets inside out, creating the dendrites. This process is similar to the mechanism of contraction in a muscle cell. The entire OCS thus becomes indistinguishable from the initial platelet membrane as it forms the "fried egg". This dramatic increase in surface area comes about with neither stretching nor adding phospholipids to the platelet membrane.
Platelet-coagulation factor interactions: coagulation facilitation
Platelet activation causes its membrane surface to become negatively charged. One of the signaling pathways turns on scramblase, which moves negatively charged phospholipids from the inner to the outer platelet membrane surface. These phospholipids then bind the tenase and prothrombinase complexes, two of the sites of interplay between platelets and the coagulation cascade. Calcium ions are essential for the binding of these coagulation factors.
In addition to interacting with vWF and fibrin, platelets interact with thrombin, Factors X, Va, VIIa, XI, IX, and prothrombin to complete formation via the coagulation cascade. Six studies suggested platelets express tissue factor: the definitive study shows they do not. The platelets from rats were conclusively shown to express tissue factor protein and also it was proved that the rat platelets carry both the tissue factor pre-mRNA and mature mRNA.
Aggregation
Aggregation begins minutes after activation, and occurs as a result of turning on the GPIIb/IIIa receptor, allowing these receptors to bind with vWF or fibrinogen. There are around 60,000 of these receptors per platelet. When any one or more of at least nine different platelet surface receptors are turned on during activation, intraplatelet signaling pathways cause existing GpIIb/IIIa receptors to change shape – curled to straight – and thus become capable of binding.Since fibrinogen is a rod-like protein with nodules on either end capable of binding GPIIb/IIIa, activated platelets with exposed GPIIb/IIIa can bind fibrinogen to aggregate. GPIIb/IIIa may also further anchor the platelets to subendothelial vWF for additional structural stabilisation.
Classically it was thought that this was the only mechanism involved in aggregation, but three new mechanisms have been identified which can initiate aggregation, depending on the velocity of blood flow (i.e. shear range).
Wound repair
The blood clot is only a temporary solution to stop bleeding; tissue repair is needed. Small interruptions in the endothelium are handled by physiological mechanisms; large interruptions by the trauma surgeon. The fibrin is slowly dissolved by the fibrinolytic enzyme, plasmin, and the platelets are cleared by phagocytosis.
Immune function
Platelets have central role in innate immunity, initiating and participating in multiple inflammatory processes, directly binding pathogens and even destroying them. This supports clinical data which show that many with serious bacterial or viral infections have thrombocytopenia, thus reducing their contribution to inflammation. Also platelet-leukocyte aggregates (PLAs) found in circulation are typical in sepsis or inflammatory bowel disease, showing the connection between thrombocytes and immune cells.
Immunothrombosis
As hemostasis is a basic function of thrombocytes in mammals, it also has its uses in possible infection confinement. In case of injury, platelets, together with the coagulation cascade, form the first line of defense by forming a blood clot. Thus, hemostasis and host defense were intertwined in evolution. For example, in the Atlantic horseshoe crab (living fossil estimated to be over 400 million years old), the only blood cell type, the amebocyte, facilitates both the hemostatic function and the encapsulation and phagocytosis of pathogens by means of exocytosis of intracellular granules containing bactericidal defense molecules. Blood clotting supports the immune function by trapping the pathogenic bacteria within.Although thrombosis, blood coagulation in intact blood vessels, is usually viewed as a pathological immune response, leading to obturation of lumen of blood vessel and subsequent hypoxic tissue damage, in some cases, directed thrombosis, called immunothrombosis, can locally control the spread of the infection. The thrombosis is directed in concordance of platelets, neutrophils and monocytes. The process is initiated either by immune cells by activating their pattern recognition receptors (PRRs), or by platelet-bacterial binding. Platelets can bind to bacteria either directly through thrombocytic PRRs and bacterial surface proteins, or via plasma proteins that bind both to platelets and bacteria. Monocytes respond to bacterial pathogen-associated molecular patterns (PAMPs), or damage-associated molecular patterns (DAMPs) by activating the extrinsic pathway of coagulation. Neutrophils facilitate the blood coagulation by NETosis. In turn, the platelets facilitate neutrophils NETosis. NETs bind tissue factor, binding the coagulation centres to the location of infection. They also activate the intrinsic coagulation pathway by providing its negatively charged surface to the factor XII. Other neutrophil secretions, such as proteolytic enzymes, which cleave coagulation inhibitors, also bolster the process.In case of imbalance throughout the regulation of immunothrombosis, this process can quickly become aberrant. Regulatory defects in immunothrombosis are suspected to be major factor in causing pathological thrombosis in many forms, such as disseminated intravascular coagulation (DIC) or deep vein thrombosis. DIC in sepsis is a prime example of both dysregulated coagulation process as well as undue systemic inflammatory response resulting in multitude of microthrombi of similar composition to that in physiological immunothrombosis – fibrin, platelets, neutrophils and NETs.
Inflammation
Platelets are rapidly deployed to sites of injury or infection, and potentially modulate inflammatory processes by interacting with leukocytes and by secreting cytokines, chemokines and other inflammatory mediators. Platelets also secrete platelet-derived growth factor (PDGF).
Platelets modulate neutrophils by forming platelet-leukocyte aggregates (PLAs). These formations induce upregulated production of αmβ2 (Mac-1) integrin in neutrophils. Interaction with PLAs also induce degranulation and increased phagocytosis in neutrophils. Platelets are also the largest source of soluble CD40L which induces production of reactive oxygen species (ROS) and upregulate expression of adhesion molecules, such as E-selectin, ICAM-1 and VCAM-1, in neutrophils, activates macrophages and activates cytotoxic response in T and B lymphocytes.Recently, the dogma that mammalian platelets lacking nucleus are unable of autonomous locomotion was broken. In fact, the platelets are active scavengers, scaling walls of blood vessels and reorganising the thrombus. They are able to recognize and adhere to many surfaces, including bacteria. They are even able to fully envelop them in their open canalicular system (OCP), leading to proposed name of the process being "covercytosis", rather than phagocytosis, as OCS is merely an invagination of outer plasma membrane. These platelet-bacteria bundles are then used as an interaction platform for neutrophils which destroy the bacteria using the NETosis and phagocytosis.
Platelets also participate in chronic inflammatory diseases, such as synovitis or rheumatoid arthritis. Platelets are activated by collagen receptor glycoprotein IV (GPVI). Proinflammatory platelet microvesicles trigger constant cytokine secretion from neighboring fibroblast-like synoviocytes, most prominently Il-6 and Il-8. Inflammatory damage to surrounding extracellular matrix continually reveals more collagen, maintaining the microvesicle production.
Adaptive immunity
Activated platelets are able to participate in adaptive immunity, interacting with antibodies. They are able to specifically bind IgG through FcγRIIA, receptor for constant fragment (Fc) of IgG. When activated and bound to IgG opsonised bacteria, the platelets subsequently release reactive oxygen species (ROS), antimicrobial peptides, defensins, kinocidins and proteases, killing the bacteria directly. Platelets also secrete proinflammatory and procoagulant mediators such as inorganic polyphosphates or platelet factor 4 (PF4), connecting innate and adaptive immune responses.
Signs and symptoms of disorders
Spontaneous and excessive bleeding can occur because of platelet disorders. This bleeding can be caused by deficient numbers of platelets, dysfunctional platelets, or very excessive numbers of platelets: over 1.0 million/microliter. (The excessive numbers create a relative von Willebrand factor deficiency due to sequestration.)One can get a clue as to whether bleeding is due to a platelet disorder or a coagulation factor disorder by the characteristics and location of the bleeding.: 815, Table 39-4 All of the following suggest platelet bleeding, not coagulation bleeding: the bleeding from a skin cut such as a razor nick is prompt and excessive, but can be controlled by pressure; spontaneous bleeding into the skin which causes a purplish stain named by its size: petechiae, purpura, ecchymoses; bleeding into mucous membranes causing bleeding gums, nose bleed, and gastrointestinal bleeding; menorrhagia; and intraretinal and intracranial bleeding.
Excessive numbers of platelets, and/or normal platelets responding to abnormal vessel walls, can result in venous thrombosis and arterial thrombosis. The symptoms depend on the site of thrombosis.
Tests of function
Bleeding time
Bleeding time was first developed as a test of platelet function by Duke in 1910. Dukes test measured the time taken for bleeding to stop from a standardized wound in the ear lobe which was blotted every 30 seconds. The normal time for bleeding to stop was less than 3 minutes. More modern techniques are now used. A normal bleeding time reflects sufficient platelet numbers and function, plus normal microvasculature.
Multiple electrode aggregometry
In multiple electrode aggregometry, anticoagulated whole blood is mixed with saline and a platelet agonist in a single-use cuvette with two pairs of electrodes. The increase in impedance between the electrodes as platelets aggregate onto them, is measured and visualized as a curve.
Light transmission aggregometry
In light transmission aggregometry (LTA), platelet-rich plasma is placed between a light source and a photocell. Unaggregated plasma allows relatively little light to pass through. After adding an agonist, the platelets aggregate, resulting in greater light transmission, which is detected by the photocell.
PFA-100
The PFA-100 (Platelet Function Assay - 100) is a system for analysing platelet function in which citrated whole blood is aspirated through a disposable cartridge containing an aperture within a membrane coated with either collagen and epinephrine or collagen and ADP. These agonists induce platelet adhesion, activation and aggregation, leading to rapid occlusion of the aperture and cessation of blood flow termed the closure time (CT). An elevated CT with EPI and collagen can indicate intrinsic defects such as von Willebrand disease, uremia, or circulating platelet inhibitors. The follow-up test involving collagen and ADP is used to indicate if the abnormal CT with collagen and EPI was caused by the effects of acetyl sulfosalicylic acid (aspirin) or medications containing inhibitors.
Disorders
Adapted from:: vii The three broad categories of platelet disorders are "not enough", "dysfunctional", and "too many".: vii
Thrombocytopenia
Immune thrombocytopenias (ITP) – formerly known as immune thrombocytopenic purpura and idiopathic thrombocytopenic purpura
Splenomegaly
Gauchers disease
Familial thrombocytopenia
Chemotherapy
Babesiosis
Dengue fever
Onyalai
Thrombotic thrombocytopenic purpura
HELLP syndrome
Hemolytic–uremic syndrome
Drug-induced thrombocytopenic purpura (five known drugs – most problematic is heparin-induced thrombocytopenia (HIT)
Pregnancy-associated
Neonatal alloimmune associated
Aplastic anemia
Transfusion-associated
Pseudothrombocytopenia
Idiopathic thrombocytopenic purpura
Vaccine induced immune thrombocytopenia
Gilberts syndrome
Altered platelet function (thrombocytopathy)
Congenital
Disorders of adhesion
Bernard–Soulier syndrome
Disorders of activation
Disorders of granule amount or release
Hermansky–Pudlak syndrome
Gray platelet syndrome
ADP receptor defect
Decreased cyclooxygenase activity
Platelet storage pool deficiency
Disorders of aggregation
Glanzmanns thrombasthenia
Wiskott–Aldrich syndrome
Disorders of coagulant activity
COAT platelet defect
Scott syndrome
Acquired
Disorders of adhesion
Paroxysmal nocturnal hemoglobinuria
Asthma
Samters triad (aspirin-exacerbated respiratory disease/AERD)
Cancer
Malaria
Decreased cyclooxygenase activity
Thrombocytosis and thrombocythemia
Reactive
Chronic infection
Chronic inflammation
Malignancy
Hyposplenism (post-splenectomy)
Iron deficiency
Acute blood loss
Myeloproliferative neoplasms – platelets are both elevated and activated
Essential thrombocythemia
Polycythemia vera
Associated with other myeloid neoplasms
Congenital
Drugs affecting
Anti-inflammatory drugs
Some drugs used to treat inflammation have the unwanted side effect of suppressing normal platelet function. These are the non-steroidal anti-inflammatory drugs (NSAIDS). Aspirin irreversibly disrupts platelet function by inhibiting cyclooxygenase-1 (COX1), and hence normal hemostasis. The resulting platelets are unable to produce new cyclooxygenase because they have no DNA. Normal platelet function will not return until the use of aspirin has ceased and enough of the affected platelets have been replaced by new ones, which can |
Platelet | take over a week. Ibuprofen, another NSAID, does not have such a long duration effect, with platelet function usually returning within 24 hours, and taking ibuprofen before aspirin prevents the irreversible effects of aspirin.
Drugs that suppress platelet function
These drugs are used to prevent thrombus formation.
Oral agents
Aspirin
Clopidogrel
Cilostazol
Ticlopidine
Ticagrelor
Prasugrel
Drugs that stimulate platelet production
Thrombopoietin mimetics
Desmopressin
Factor VIIa
Intravenous agents
Abciximab
Eptifibatide
Tirofiban
Others: oprelvekin, romiplostim, eltrombopag, argatroban
Therapy with platelets
Transfusion
Indications
Platelet transfusion is most frequently used to correct unusually low platelet counts, either to prevent spontaneous bleeding (typically at counts below 10×109/L) or in anticipation of medical procedures that will necessarily involve some bleeding. For example, in patients undergoing surgery, a level below 50×109/L is associated with abnormal surgical bleeding, and regional anaesthetic procedures such as epidurals are avoided for levels below 80×109/L. Platelets may also be transfused when the platelet count is normal but the platelets are dysfunctional, such as when an individual is taking aspirin or clopidogrel. Finally, platelets may be transfused as part of a massive transfusion protocol, in which the three major blood components (red blood cells, plasma, and platelets) are transfused to address severe hemorrhage. Platelet transfusion is contraindicated in thrombotic thrombocytopenic purpura (TTP), as it fuels the coagulopathy.
Collection
Platelets are either isolated from collected units of whole blood and pooled to make a therapeutic dose, or collected by platelet apheresis: blood is taken from the donor, passed through a device which removes the platelets, and the remainder is returned to the donor in a closed loop. The industry standard is for platelets to be tested for bacteria before transfusion to avoid septic reactions, which can be fatal. Recently the AABB Industry Standards for Blood Banks and Transfusion Services (5.1.5.1) has allowed for use of pathogen reduction technology as an alternative to bacterial screenings in platelets.Pooled whole-blood platelets, sometimes called "random" platelets, are separated by one of two methods. In the US, a unit of whole blood is placed into a large centrifuge in what is referred to as a "soft spin". At these settings, the platelets remain suspended in the plasma. The platelet-rich plasma (PRP) is removed from the red cells, then centrifuged at a faster setting to harvest the platelets from the plasma. In other regions of the world, the unit of whole blood is centrifuged using settings that cause the platelets to become suspended in the "buffy coat" layer, which includes the platelets and the white blood cells. The "buffy coat" is isolated in a sterile bag, suspended in a small amount of red blood cells and plasma, then centrifuged again to separate the platelets and plasma from the red and white blood cells. Regardless of the initial method of preparation, multiple donations may be combined into one container using a sterile connection device to manufacture a single product with the desired therapeutic dose.
Apheresis platelets are collected using a mechanical device that draws blood from the donor and centrifuges the collected blood to separate out the platelets and other components to be collected. The remaining blood is returned to the donor. The advantage to this method is that a single donation provides at least one therapeutic dose, as opposed to the multiple donations for whole-blood platelets. This means that a recipient is not exposed to as many different donors and has less risk of transfusion-transmitted disease and other complications. Sometimes a person such as a cancer patient who requires routine transfusions of platelets will receive repeated donations from a specific donor to further minimize the risk. Pathogen reduction of platelets using for example, riboflavin and UV light treatments can also be carried out to reduce the infectious load of pathogens contained in donated blood products, thereby reducing the risk of transmission of transfusion-transmitted diseases. Another photochemical treatment process utilizing amotosalen and UVA light has been developed for the inactivation of viruses, bacteria, parasites, and leukocytes that can contaminate blood components intended for transfusion. In addition, apheresis platelets tend to contain fewer contaminating red blood cells because the collection method is more efficient than "soft spin" centrifugation at isolating the desired blood component.
Storage
Platelets collected by either method have a very short shelf life, typically five days. This results in frequent problems with short supply, as testing the donations often requires up to a full day. Since there are no effective preservative solutions for platelets, they lose potency quickly and are best when fresh.
Platelets are stored under constant agitation at 20–24 °C (68–75.2 °F). Units can not be refrigerated as this causes platelets to change shape and lose function. Storage at room temperature provides an environment where any bacteria that are introduced to the blood component during the collection process may proliferate and subsequently cause bacteremia in the patient. Regulations are in place in the United States that require products to be tested for the presence of bacterial contamination before transfusion.
Delivery to recipients
Platelets do not need to belong to the same A-B-O blood group as the recipient or be cross-matched to ensure immune compatibility between donor and recipient unless they contain a significant amount of red blood cells (RBCs). The presence of RBCs imparts a reddish-orange color to the product and is usually associated with whole-blood platelets. An effort is sometimes made to issue type specific platelets, but this is not critical, as it is with RBCs.
Prior to issuing platelets to the recipient, they may be irradiated to prevent transfusion-associated graft versus host disease or they may be washed to remove the plasma if indicated.
The change in the recipients platelet count after transfusion is termed the "increment" and is calculated by subtracting the pre-transfusion platelet count from the post-transfusion platelet count. Many factors affect the increment including the recipients body size, the number of platelets transfused, and clinical features that may cause premature destruction of the transfused platelets. When recipients fail to demonstrate an adequate post-transfusion increment, this is termed platelet transfusion refractoriness.
Platelets, either apheresis-derived or random-donor, can be processed through a volume reduction process. In this process, the platelets are spun in a centrifuge and the excess plasma is removed, leaving 10 to 100 mL of platelet concentrate. Such volume-reduced platelets are normally transfused only to neonatal and pediatric patients when a large volume of plasma could overload the childs small circulatory system. The lower volume of plasma also reduces the chances of an adverse transfusion reaction to plasma proteins. Volume reduced platelets have a shelf life of only four hours.
Wound therapy
Platelets release platelet-derived growth factor (PDGF), a potent chemotactic agent; and TGF beta, which stimulates the deposition of extracellular matrix; fibroblast growth factor, insulin-like growth factor 1, platelet-derived epidermal growth factor, and vascular endothelial growth factor. Local application of these factors in increased concentrations through platelet-rich plasma (PRP) is used as an adjunct in wound healing.
Other animals
Instead of having platelets, non-mammalian vertebrates have nucleated thrombocytes, which resemble B lymphocytes in morphology. They aggregate in response to thrombin, but not to ADP, serotonin, nor adrenaline, as platelets do.
History
George Gulliver in 1841 drew pictures of platelets using the twin lens (compound) microscope invented in 1830 by Joseph Jackson Lister. This microscope improved resolution sufficiently to make it possible to see platelets for the first time.
William Addison in 1842 drew pictures of a platelet-fibrin clot.
Lionel Beale in 1864 was the first to publish a drawing showing platelets.
Max Schultze in 1865 described what he called "spherules", which he noted were much smaller than red blood cells, occasionally clumped, and were sometimes found in collections of fibrin material.
Giulio Bizzozero in 1882 studied the blood of amphibians microscopically in vivo. He named Schultzes spherules (It.) piastrine: little plates. An article in Scientific American suggests Bizzozero proposed the name Blutplattchen.
William Osler observed platelets and, in published lectures in 1886, called them a third corpuscle and a blood plaque; and described them as "a colorless protoplasmic disc".
James Wright examined blood smears using the stain named for him, and used the term plates in his 1906 publication but changed to platelets in his 1910 publication which has become the universally accepted term.The term thrombocyte (clot cell) came into use in the early 1900s and is sometimes used as a synonym for platelet; but not generally in the scientific literature, except as a root word for other terms related to platelets (e.g. thrombocytopenia meaning low platelets).: v3 The term thrombocytes are proper for mononuclear cells found in the blood of non-mammalian vertebrates: they are the functional equivalent of platelets, but circulate as intact cells rather than cytoplasmic fragments of bone marrow megakaryocytes.: 3 In some contexts, the word thrombus is used interchangeably with the word clot, regardless of its composition (white, red, or mixed). In other contexts it is used to contrast a normal from an abnormal clot: thrombus arises from physiologic hemostasis, thrombosis arises from a pathologic and excessive quantity of clot. In a third context it is used to contrast the result from the process: thrombus is the result, thrombosis is the process.
References
== External links == |
Olfactory reference syndrome | Olfactory reference syndrome (ORS) is a psychiatric condition in which there is a persistent false belief and preoccupation with the idea of emitting abnormal body odors which the patient thinks are foul and offensive to other individuals. People with this condition often misinterpret others behaviors, e.g. sniffing, touching their nose or opening a window, as being referential to an unpleasant body odor which in reality is non-existent and cannot be detected by other people.This disorder is often accompanied by shame, embarrassment, significant distress, avoidance behavior, social phobia and social isolation.
Signs and symptoms
The onset of ORS may be sudden, where it usually follows after a precipitating event, or gradual.
Odor complaint
The defining feature of ORS is excessive thoughts of having offensive body odor(s) which are detectable to others. The individual may report that the odor comes from: the nose and/or mouth, i.e. halitosis (bad breath); the anus; the genitals; the skin generally; or specifically the groin, armpits or feet. The source(s) of the supposed odor may also change over time. There are also some who are unsure of the exact origin of the odor. The odor is typically reported to be continuously present. The character of the odor may be reported as similar to bodily substances, e.g. feces, flatus, urine, sweat, vomitus, semen, vaginal secretions; or alternatively it may be an unnatural, non-human or chemical odor, e.g. ammonia, detergent, rotten onions, burnt rags, candles, garbage, burning fish, medicines, old cheese. Again, the reported character of the odor complaint may change over time. Halitosis appears to be the most common manifestation of ORS, with 75% complaining of bad breath, alone or in combination with other odors. The next most common complaint was sweat (60%).Although all individuals with ORS believe they have an odor, in some cases the individual reports they cannot perceive the odor themselves. In the latter cases, the belief arises via misinterpretation of the behavior of others or with the rationale that a disorder of smell which prevents self detection of the odor (i.e. anosmia) exists. In the cases where the non-existent odor can be detected, this is usually considered as phantosmia (olfactory hallucination). Olfactory hallucination can be considered the result of the belief in an odor delusion, or the belief a result of the olfactory hallucination. In one review, the individual with ORS was unreservedly convinced that he or she could detect the odor themselves in 22% of cases, whilst in 19% there was occasional or intermittent detection and in 59% lack of self-detection was present.Some distinguish delusional and non-delusional forms of ORS. In the delusional type, there is complete conviction that the odor is real. In the non-delusional type, the individual is capable of some insight into the condition, and can recognize that the odor might not be real, and that their level of concern is excessive. Others argue that reported cases of ORS present a spectrum of different levels of insight. Since sometimes the core belief of ORS is not of delusional intensity, it is argued that considering the condition as a form of delusional disorder, as seems to occur in the DSM, is inappropriate. In one review, in 57% of cases the beliefs were fixed, held with complete conviction, and the individual could not be reassured that the odor was non existent. In 43% of cases the individual held the beliefs with less than complete conviction, and was able to varying degrees to consider the possibility that the odor was not existent.Other symptoms may be reported and are claimed to be related to the cause of the odor, such as malfunction of the anal sphincter, a skin disease, "diseased womb", stomach problems or other unknown organic disease. Excessive washing in ORS has been reported to cause the development of eczema.
Referential ideas
People with ORS misinterpret the behavior of others to be related to the imagined odor (thoughts of reference). In one review, ideas of reference were present in 74% of cases. Usually, these involve misinterpretations of comments, gestures and actions of other people such that it is believed that an offensive smell from the individual is being referred to. These thoughts of reference are more pronounced in social situations which the individual with ORS may find stressful, such as public transport, crowded lift, workplace, classroom, etc. Example behaviors which are misinterpreted include coughing, sneezing, turning of the head, opening a window, facial expressions, sniffing, touching nose, scratching head, gestures, moving away, avoiding the person, whistling. Commonly, when being in proximity to others who are talking among themselves, persons with ORS will be convinced that the conversation is about his or her odor. Even the actions of animals (e.g. barking of dogs) can be interpreted as referential to an odor. Persons with ORS may have trouble concentrating at a given task or in particular situations due to obsessive thoughts concerning body odor.
Repetitive behavior
95% of persons with ORS engage in at least one excessive hygiene, grooming or other related repetitive practice in an attempt to alleviate, mask and monitor the perceived odor. This has been described as a contrite reaction, and repetitive, counterphobic, "safety", ritual or compulsive behaviors. Despite these measures, the odor symptom is reported to still offend other people. Example ORS behaviors include: repetitive showering and other grooming behaviors, excessive tooth brushing, or tongue scraping (a treatment for halitosis), repeated smelling of oneself to check for any odor, over-frequent bathroom use, attempts to mask the odor, with excessive use of deodorants, perfumes, mouthwash, mint, chewing gum, scented candles, and soap; changing clothes (e.g. underwear), multiple times per day, frequent washing of clothes, wearing several layers of clothing, wrapping feet in plastic, wearing garments marketed as odor-reducing, eating special diets, dietary supplements (e.g. intended to reduce flatulence odor), repeatedly seeking reassurance from others that there is no odor, although the negative response is usually interpreted instead as politeness rather than truth, and avoidance behaviors such as habitually sitting at a distance from others, minimizing movement in an attempt "not to spread the odor", keeping the mouth closed and avoiding talking or talking with a hand in front of the mouth.
Functional impairment
Persons with ORS tend to develop a behavior pattern of avoidance of social activities and progressive social withdrawal. They often avoid travel, dating, relationships, break off engagements and avoid family activities. Due to shame and embarrassment, they may avoid school or work, or repeatedly change jobs and move to another town. Significant developments may occur such as loss of employment, divorce, becoming housebound, psychiatric hospitalization, and suicide attempts. According to some reports, 74% of persons with ORS avoid social situations, 47% avoid work, academic or other important activities, 40% had been housebound for at least one week because of ORS, and 31.6% had experienced psychiatric hospitalization. With regards to suicide, reports range from 43 to 68% with suicidal ideation, and 32% with a history of at least one suicide attempt. 5.6% died by suicide.
Psychiatric co-morbidity
Psychiatric co-morbidity in ORS is reported. Depression, which is often severe, may be a result of ORS, or may be pre-existing. Personality disorders, especially cluster C, and predominantly the avoidant type, may exist with ORS. Bipolar disorder, schizophrenia, hypochondriasis, alcohol or drug abuse and obsessive compulsive disorder may also be co-morbid with ORS.
Causes
The causes of ORS are unknown. It is thought that significant negative experiences may trigger the development of ORS. These have been considered as two types: key traumatic experiences related to smell, and life stressors present when the condition developed but which were unrelated to smell. In one review, 85% of reported cases had traumatic, smell-related experiences, and 17% of cases had stress factors unrelated to smell. Reported smell-related experiences usually revolve around family members, friends, co-workers, peers or other people making comments about an odor from the person, which causes embarrassment and shame. Examples include accusation of flatulence during a religious ceremony, or being bullied for flatulence such at school, accidental urination in class, announcements about a passenger needing to use deodorant over speaker by a driver on public transport, sinusitis which caused a bad taste in the mouth, mockery about a fish odor from a finger which had been inserted into the persons vagina in the context of a sexual assault, and revulsion about menarche and brothers sexual intimacy. It has been suggested that a proportion of such reported experiences may not have been real, but rather early symptom of ORS (i.e. referential thoughts). Examples of non smell-related stressful periods include guilt due to a romantic affair, being left by a partner, violence in school, family illness when growing up (e.g. cancer), and bullying.The importance of a family history of mental illness or other conditions in ORS is unclear, because most reported cases have lacked this information. In some cases, there has been reported psychiatric and medical conditions in first degree relatives such as schizophrenia, psychosis, alcoholism, suicide, affective disorders, obsessive compulsive disorder, anxiety, paranoia, neurosis, sociopathy, and epilepsy. Sometimes more than one family member had a noteworthy condition.Neuroimaging has been used to investigate ORS. Hexamethylpropyleneamine oxime single-photon emission computed tomography (HMPAO SPECT) demonstrated hypoperfusion of the frontotemporal lobe in one case. That is to say, part of the brain was receiving insufficient blood flow. In another, functional magnetic resonance imaging was carried out while the person with ORS listened to both neutral words and emotive words. Compared to an age and sex matched healthy control subject under the same conditions, the individual with ORS showed more activation areas in the brain when listening to emotionally loaded words. This difference was described as abnormal, but less pronounced as would be observed in the brain of a person with a psychotic disorder.
Diagnosis
Classification
Although the existence of ORS is generally accepted, there is some controversy as to whether it is a distinct condition or merely a part or manifestation of other psychiatric conditions, mainly due to the overlapping similarities. Similarly, there is controversy with regards how the disorder should be classified. As ORS has obsessive and compulsive features, some consider it as a type of obsessive–compulsive spectrum disorder, while others consider it an anxiety disorder due to the strong anxiety component. It is also suggested to be a type of body dysmorphic disorder or, as it involves a single delusional belief, some suggest that ORS is a monosymptomatic hypochondriacal psychosis (hypochondriacal type of delusional disorder, see monothematic delusion).The World Health Organizations 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) does not have a specific entry for ORS, or use the term, but in the "persistent delusional disorders" section, states delusions can "express a conviction that others think that they smell."ORS has also never been allocated a dedicated entry in any edition of the American Psychiatric Associations Diagnostic and Statistical Manual of Mental Disorders. In the third edition (DSM-III), ORS was mentioned under "atypical somatoform disorders". The revised third edition (DSM-III-R) mentions ORS in the text, stating that "convictions that the person emits a foul odor are one of the most common types of delusion disorder, somatic type." The fourth edition (DSM-IV), does not use the term ORS but again mentions such a condition under "delusional disorder, somatic type", stating "somatic delusions can occur in several forms. Most common are the persons conviction that he or she emits a foul odor from the skin, mouth, rectum or vagina." In the fifth edition (DSM-5), ORS again does not appear as a distinct diagnosis, but it is mentioned in relation to taijin kyōfushō (対人恐怖症, "disorder of fear of personal interaction"). The variants of taijin kyōfushō (shubo-kyofu "the phobia of a deformed body" and jikoshu-kyofu "fear of foul body odor") are listed under 300.3 (F42) "other specified obsessive compulsive and related disorders", and is about someones fear that his or her body, or its functions, is offensive to other people. There are four subtypes of taijin kyōfushō. 17% of these individuals have "the phobia of having foul body odor", the subtype termed jikoshu-kyofu. Although taijin kyōfushō has been described as a culture-bound syndrome confined to east Asia (e.g. Japan and Korea), it has been suggested that the jikoshu-kyofu variant of taijin kyōfushō is closely related or identical to ORS, and that such a condition occurs in other cultures. However, some Western sources state that jikoshu-kyofu and ORS are distinguishable because of cultural differences, i.e. Western culture being primarily concerned with individual needs, and Japanese culture primarily with the needs of the many. Hence, it is claimed that ORS mainly focuses on the affected individuals embarrassment, and jikoshu-kyofu is focused on the fear of creating embarrassment in others. In this article, jikoshu-kyofu and ORS are considered as one condition.
Synonyms for ORS, many historical, include bromidrosiphobia, olfactory phobic syndrome, chronic olfactory paranoid syndrome, autodysomophobia, delusions of bromosis, hallucinations of smell and olfactory delusional syndrome. By definition, the many terms which have been suggested in the dental literature to refer to subjective halitosis complaints (i.e. when a person complains of halitosis yet no odor is detectable clinically) can also be considered under the umbrella of ORS. Examples include halitophobia, non-genuine halitosis, delusional halitosis, pseudo-halitosis, imaginary halitosis, psychosomatic halitosis, and self halitosis.
Diagnostic criteria
Diagnostic criteria have been proposed for ORS:
Persistent (more than six months), false belief that one emits an offensive odor, which is not perceived by others. There may be degrees of insight (i.e. the belief may or may not be of delusional intensity).
This pre-occupation causes clinically significant distress (depression, anxiety, shame), social and occupational disability, or may be time-consuming (i.e. preoccupies the individual at least one hour per day).
The belief is not a symptom of schizophrenia or other psychotic disorder, and not due to the effects of medication or recreational drug abuse, or any other general medical condition.
Differential diagnosis
The differential diagnosis for ORS may be complicated as the disorder shares features with other conditions. Consequently, ORS may be misdiagnosed as another medical or psychiatric condition and vice versa.
The typical history of ORS involves a long delay while the person continues to believe there is a genuine odor. On average, a patient with ORS goes undiagnosed for about eight years. Repeated consultation with multiple different non-psychiatric medical specialists ("doctor shopping") in an attempt to have their non-existent body odor treated is frequently reported. Individuals with ORS may present to dermatologists, gastroentrologists, otolaryngologists, dentists, proctologists, and gynecologists. Despite the absence of any clinically detectable odor, physicians and surgeons may embark on unnecessary investigations (e.g. gastroscopy), and treatments, including surgery such as, among others, thoracic sympathectomy and tonsillectomy Such treatments generally have no long-term effect on the individuals belief in an odor symptom. If non-psychiatric clinicians refuse to carry out treatment on the basis that there is no real odor and offer to refer the patient to a psychologist or psychiatrist, persons with ORS typically refuse and instead seek "a better" doctor or dentist.Conversely, some have suggested that medical conditions which cause genuine odor may sometimes be misdiagnosed as ORS. There are a great many different medical conditions which are reported to potentially cause a genuine odor, and these are usually considered according to the origin of the odor, e.g. halitosis (bad breath), bromhidrosis (body odor), etc. These conditions are excluded before a diagnosis of ORS is made. Although there are many different publications on topics like halitosis, the symptom is still poorly understood and managed in practice. It is recognized that symptoms such as halitosis can be intermittent, and therefore may not be present at the time of the consultation, leading to misdiagnosis. Individuals with genuine odor symptoms may present with similar mindset and behavior to persons with ORS. For example, one otolaryngologist researcher noted "behavioral problems such as continuous occupation with oral hygiene issues, obsessive use of cosmetic breath freshening products such as mouthwashes, candies, chewing gums, and sprays, avoiding close contact with other people, and turning the head away during conversation" as part of what was termed "skunk syndrome" in patients with genuine halitosis secondary to chronic tonsillitis. Another author, writing about halitosis, noted that there are generally three types of persons that complain of halitosis: those with above-average odor, those with average or near-average odor who are oversensitive, and those with below-average or no odor who believe they have offensive breath. Therefore, in persons with genuine odor complaints, the distress and concern may typically be out of proportion to the reality of the problem. Genuine halitosis has been described as a social barrier between the individual and friends, relatives, partners and colleagues, and may negatively alter self-esteem and quality of life. Similar psychosocial problems are reported in other conditions which cause genuine odor symptoms. In the literature on halitosis, emphasis is frequently placed on multiple consultations to reduce the risk of misdiagnosis, and also asking the individual to have a reliable confidant accompany them to the consultation who can confirm the reality of the reported symptom. ORS patients are unable to provide such confidants as they have no objective odor.Various organic diseases may cause parosmias (distortion of the sense of smell). Also, since smell and taste are intimately linked senses, disorders of gustation (e.g. dysgeusia—taste dysfunction) can present as a complaint related to smell, and vice versa. These conditions, collectively termed chemosensory dysfunctions, are many and varied, and they may trigger a person to complain of an odor than is not present; however, the diagnostic criteria for ORS require the exclusion of any such causes. They include pathology of the right hemisphere of the brain, substance abuse, arteriovenous malformations in the brain, and temporal lobe epilepsy.Social anxiety disorder (SAD) and ORS have some demographic and clinical similarities. Where the social anxiety and avoidance behavior is primarily focussed on concern about body odors, ORS is a more appropriate diagnosis than avoidant personality disorder or SAD. Body dismorphic disorder (BDD) has been described as the closest diagnosis in DSM-IV to ORS as both primarily focus on bodily symptoms. The defining difference between the two is that in BDD the preoccupation is with physical appearance, not body odors. Similarly, where obsessive behaviors are directly and consistently related to body odors rather than anything else, ORS is a more appropriate diagnosis than obsessive–compulsive disorder, in which obsessions are different and multiple over time.ORS may be misdiagnosed as schizophrenia. About 13% of people with schizophrenia have olfactory hallucinations. Generally, schizophrenic hallucinations are perceived as having an imposed, external origin, while in ORS they are recognized as originating from the individual. The suggested diagnostic criteria mean that the possibility of ORS is negated by a diagnosis of schizophrenia in which persistent delusions of an offensive body odor and olfactory hallucinations are contributing features for criterion A. However, some reported ORS cases were presented as co-morbid. Indeed, some have suggested that ORS may in time transform into schizophrenia, but others state there is little evidence for this. Persons with ORS have none of the other criteria to qualify for a diagnosis of schizophrenia.It has been suggested that various special investigations may be indicated to help rule out some of the above conditions. Depending upon the case, this might include neuroimaging, thyroid and adrenal hormone tests, and analysis of body fluids (e.g. blood) with gas chromatography.
Treatment
There is no agreed treatment protocol. In most reported cases of ORS the attempted treatment was antidepressants, followed by antipsychotics and various psychotherapies. Little data are available regarding the efficacy of these treatments in ORS, but some suggest that psychotherapy yields the highest rate of response to treatment, and that antidepressants are more efficacious than antipsychotics (response rates 78%, 55% and 33% respectively). According to one review, 43% of cases which showed overall improvement required more than one treatment approach, and in only 31% did the first administered treatment lead to some improvement.Pharmacotherapies that have been used for ORS include antidepressants, (e.g. selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors), antipsychotics, (e.g. blonanserin, lithium, chlorpromazine), and benzodiazepines. The most common treatment used for ORS is SSRIs. Specific antidepressants that have been used include clomipramine.Psychotherapies that have been used for ORS include cognitive behavioral therapy, eye movement desensitization and reprocessing. Dunne (2015) reported a Case Study treatment of ORS using EMDR which was successful using a trauma model formulation rather than an OCD approach.
Prognosis
When untreated, the prognosis for ORS is generally poor. It is chronic, lasting many years or even decades with worsening of symptoms rather than spontaneous remission. Transformation to another psychiatric condition is unlikely, although very rarely what appears to be ORS may later manifest into schizophrenia, psychosis, mania, or major depressive disorder. The most significant risk is suicide.
When treated, the prognosis is better. In one review, the proportion of treated ORS cases which reported various outcomes were assessed. On average, the patients were followed for 21 months (range: two weeks to ten years). With treatment, 30% recovered (i.e. no longer experienced ORS odor beliefs and thoughts of reference), 37% improved and in 33% there was a deterioration in the condition (including suicide) or no change from the pre-treatment status.
Epidemiology
Cases have been reported from many different countries around the world. It is difficult to estimate the prevalence of ORS in the general population because data are limited and unreliable, and due to the delusional nature of the condition and the characteristic secrecy and shame.For unknown reasons, males appear to be affected twice as commonly as females. High proportions of ORS patients are unemployed, single, and not socially active. The average age reported is around 20–21 years, with almost 60% of cases occurring in subjects under 20 in one report, although another review reported an older average age for both males (29) and females (40).
History
The term olfactory reference syndrome was first proposed in 1971 by William Pryse-Phillips. Prior to this, published descriptions of what is now thought to be ORS appear from the late 1800s, with the first being Potts 1891. Often the condition was incorrectly described as other conditions, e.g. schizophrenia.
Society
In modern times, commercial advertising pressures have altered the publics attitude towards problems such as halitosis, which have taken on greater negative psychosocial sequelae as a result. For example, in the United States, a poll reported that 55–75 million citizens consider bad breath a "principal concern" during social encounters.
Etymology
The term olfactory reference syndrome comes from:
Olfactory, pertaining to the sense of smell.
Reference, because of the belief that the behavior of others is referential to a supposed odor.
Syndrome, because it is a recognizable set of features that occur together.
See also
Fish Odor syndrome
Bad breath
Schizophrenia
Delusional disorder
Bipolar disorder
References
Dunne, T.P. (2015). "EMDR: An Effective and Less Stigmatising Treatment for Olfactory Reference Syndrome", EMDR Now, Vol. 7, No.1, Jan, pp 6–7. |
Noonan syndrome with multiple lentigines | Noonan syndrome with multiple lentigines (NSML) which is part of a group called Ras/MAPK pathway syndromes, is a rare autosomal dominant, multisystem disease caused by a mutation in the protein tyrosine phosphatase, non-receptor type 11 gene (PTPN11). The disease is a complex of features, mostly involving the skin, skeletal and cardiovascular systems, which may or may not be present in all patients. The nature of how the mutation causes each of the conditions symptoms is not well known; however, research is ongoing. It is a RASopathy.
Noonan syndrome with multiple lentigines is caused by a different missense mutation of the same gene. Noonan syndrome is fairly common (1:1,000 to 1:2,500 live births), and neurofibromatosis 1 (which was once thought to be related to NSML) is also common (1:3500); however, no epidemiological data exists for NSML.
Signs and symptoms
An alternative name of the condition, LEOPARD syndrome, is a mnemonic, originally coined in 1969, as the condition is characterized by some of the following seven conditions, the first letters of which spell LEOPARD, along with the characteristic "freckling" of the skin, caused by the lentigines that is reminiscent of the large cat.
Lentigines — Reddish-brown to dark brown macules (surface skin lesion) generally occurring in a high number (10,000+) over a large portion of the skin, at times higher than 80% coverage. These can even appear inside the mouth (buccal), or on the surface of the eye (scleral). These have irregular borders and range in size from 1 mm in diameter to café-au-lait spots, several centimeters in diameter. Also, some areas of vitiligo-like hypopigmentation may be observed.
Electrocardiographic conduction abnormalities: Generally observed on an electrocardiograph as a bundle branch block.
Ocular hypertelorism: Wideset eyes, which lead to a similar facial resemblance between patients. Facial abnormalities are the second highest occurring symptom after the lentigines. Abnormalities also include: broad nasal root, prognathism (protruding lower jaw), or low-set, possibly rotated, ears.
Pulmonary stenosis: Narrowing of the pulmonary artery as it exits the heart. Other cardiac abnormalities may be present, including aortic stenosis, or mitral valve prolapse.
Abnormal genitalia: usually cryptorchidism (retention of testicles in body) or monorchism (single testicle). In female patients, this presents as missing or single ovaries, much harder by nature to detect. Ultrasound imaging is performed at regular intervals, from the age of 1 year, to determine if ovaries are present.
Retarded growth: Slow, or stunted growth. Most newborns with this syndrome are of normal birth weight and length, but will often slow within the first year.
Deafness: Sensorineural (nerve deafness).The presence of all of these hallmarks is not needed for a diagnosis. A clinical diagnosis is considered made when, with lentigines present there are 2 other symptoms observed, such as ECG abnormalities and ocular hypertelorism, or without lentigines, 3 of the above conditions are present, with a first-degree relative (i.e. parent, child, sibling) with a clinical diagnosis.
Additional dermatologic abnormalities (axillary freckling, localized hypopigmentation, interdigital webbing, hyperelastic skin)
Mild mental retardation is observed in about 30% of those affected by the syndrome
Nystagmus (involuntary eye movements), seizures, or hyposmia (reduced ability to smell) has been documented in a few patients
In 2004, a patient was reported with recurrent upper extremity aneurysms that required surgical repairs.
In 2006, a NSML patient was reported with acute myelogenous leukemia.Due to the rarity of the syndrome itself, it is hard to determine whether certain additional diseases are actually part of the syndrome. With a base population of possibly less than one thousand individuals, one or two outlying cases can skew the statistical population very quickly.
Pathophysiology
In the two predominant mutations of NSML (Y279C and T468M) the mutations cause a loss of catalytic activity of the SHP2 protein (the gene product of the PTPN11 gene), which is a previously unrecognized behavior for this class of mutations. This interferes with growth factor and related signalling. While further research confirms this mechanism, additional research is needed to determine how this relates to all of the observed effects of NSML.
Diagnosis
The presence of the disease can be confirmed with a genetic test. In a study of 10 infants with clinical indications of NSML prior to their first birthday, 8 (80%) patients were confirmed to have the suspected mutation. An additional patient with the suspected mutation was subsequently found to have NF1, following evaluation of the mother.There are 5 identified allelic variants responsible for NSML. Y279C, T468M, A461T, G464A, and Q510P which seems to be a unique familial mutation, in that all other variants are caused by transition errors, rather than transversion.
Treatment
It is suggested that, once diagnosed, individuals be routinely followed by a cardiologist, endocrinologist, dermatologist, and other appropriate specialties as symptoms present.
It is recommended that those with the syndrome who are capable of having children seek genetic counseling before deciding to have children. As the syndrome presents frequently as a forme fruste (incomplete, or unusual form) variant, an examination of all family members must be undertaken. As an autosomal dominant trait there is a fifty percent chance with each child that they will also be born with the syndrome. Although fully penetrant, since the syndrome has variable expressivity, one generation may have a mild expression of the syndrome, while the next may be profoundly affected.
Once a decision to have children is made, and the couple conceives, the fetus is monitored during the pregnancy for cardiac evaluation. If a gross cardiac malformation is found, parents receive counseling on continuing with the pregnancy.
Other management is routine care as symptoms present:
For those with endocrine issues (low levels of thyrotopin [a pituitary hormone responsible for regulating thyroid hormones], follicle stimulating hormone) drug therapy is recommended.
For those who are disturbed by the appearance of lentigines, cryosurgery may be beneficial. Due to the large number of lentigines this may prove time-consuming. An alternative treatment with tretinoin or hydroquinone creams may help.
Drug therapies for those with cardiac abnormalities, as those abnormalities become severe enough to warrant the use of these therapies. ECGs are mandatory prior to any surgical interventions, due to possible arrythmia.
Prognosis
In itself, NSML is not a life-threatening diagnosis, most people diagnosed with the condition live normal lives. Obstructive cardiomyopathy and other pathologic findings involving the cardiovascular system may be a cause of death in those whose cardiac deformities are profound.
Epidemiology
Various literature describes the syndrome as being "rare" or "extremely rare". There is no epidemiologic data available regarding how many individuals have the syndrome worldwide; however, there are approximately 200 cases described in medical literature.
History
Zeisler and Becker first described a syndrome with multiple lentigines, hypertelorism, pectus carinatum (protruding breastbone) and prognathism (protrusion of lower jaw) in 1936. Sporadic descriptions were added through the years. In 1962, cardiac abnormalities and short stature were first associated with the condition. In 1966, three familial cases were added, a mother, her son and daughter. Another case of mother to two separate children, with different paternity of the two children, was added in 1968.It was believed as late as 2002 that Noonan Syndrome with Multiple Lentigines (NSML) was related to neurofibromatosis type I (von Recklinghausen syndrome). In fact, since both ICD9 and ICD10 lack a specific diagnosis code for NSML, the diagnosis code for NF1 is still sometimes used for diagnostic purposes, although it has been shown that the gene is not linked to the NF1 locus.
See also
Neurofibromatosis
Noonan syndrome
References
External links
NSML at NIH/UW GeneTests
Gorlins syndrome II at Who Named It?
DermAtlas 981603547
Dermnetnz
DermIS |
Pelvis justo major | Pelvis justo major (also called "Giant Pelvis") is a rare condition of the adult female pelvis where the pelvis flairs above the Iliopectineal line. It is 1.5 or more times larger than an average pelvis in every direction and is at least 42 cm (16.5 inches) biiliac width. Even though this condition is classified as a congenital abnormality, it is not a medical disease or abnormality of the pelvis (as the pelvis is a true gynecoid shape, only larger).
Women with this condition, at the time of delivery, may have a precipitous birth. There is virtually no resistance of the huge pelvic opening to the size of a newborn so only the soft parts resist the birth. With a huge Justo Major Pelvis, there is no pelvic bone "molding" of the fetal head. With the average pelvic size (2/3 or less Justo Major size) the usual pelvic molding process slows the birth, resulting in a slow and gradual stretching of the vaginal opening for primiparous women. When a huge Justo Major Pelvis allows such an extremely rapid vaginal birth, there can be tears of the perineal soft tissues. At the time of delivery the strong uterine contractions and maternal bearing down almost instantly overwhelm the integrity of a tightened and previously unstretched vaginal orifice. This is often the case if such women have not previously practiced vaginal stretching to the degree that allows such an instant birthing, especially so for a primiparous woman. This "instant delivery" problem causes many OBGYN doctors to stress the importance of women with a huge pelvis practicing pre-delivery vaginal stretching to avoid perineal injury.
Such a large size for the female pelvis is present in less than one in a thousand adult women. When women reach their maximum pelvis size, often by 21 years of age, if they have a huge pelvis the resulting big hips will not go away—no matter how much they diet, as bone will not shrink. It is not unusual for such women, whose pear shape is due to a huge pelvis, to give up watching calories for smaller hips... leading to obesity. However, such pear shaped obese women do not necessarily have a huge pelvis and a measurement scan or anthropometry by calipers is required to diagnose the Justo Major condition. The incidence of Justo Major Pelvis is not found to be a strictly standard deviation type variation as it follows a tail skewed deviation to the right. Incidence varies with geographic regions of the world (e.g. Poland has a high incidence). Justo Major Pelvis is classified as congenital and thought to be partially inherited, especially from the maternal side.
== References == |
Measles | Measles is a highly contagious infectious disease caused by measles virus. Symptoms usually develop 10–12 days after exposure to an infected person and last 7–10 days. Initial symptoms typically include fever, often greater than 40 °C (104 °F), cough, runny nose, and inflamed eyes. Small white spots known as Kopliks spots may form inside the mouth two or three days after the start of symptoms. A red, flat rash which usually starts on the face and then spreads to the rest of the body typically begins three to five days after the start of symptoms. Common complications include diarrhea (in 8% of cases), middle ear infection (7%), and pneumonia (6%). These occur in part due to measles-induced immunosuppression. Less commonly seizures, blindness, or inflammation of the brain may occur. Other names include morbilli, rubeola, red measles, and English measles. Both rubella, also known as German measles, and roseola are different diseases caused by unrelated viruses.Measles is an airborne disease which spreads easily from one person to the next through the coughs and sneezes of infected people. It may also be spread through direct contact with mouth or nasal secretions. It is extremely contagious: nine out of ten people who are not immune and share living space with an infected person will be infected. Furthermore, measless reproductive number estimates vary beyond the frequently cited range of 12 to 18. The NIH quote this 2017 paper saying: "[a] review in 2017 identified feasible measles R0 values of 3.7–203.3". People are infectious to others from four days before to four days after the start of the rash. While often regarded as a childhood illness, it can affect people of any age. Most people do not get the disease more than once. Testing for the measles virus in suspected cases is important for public health efforts. Measles is not known to occur in other animals.Once a person has become infected, no specific treatment is available, although supportive care may improve outcomes. Such care may include oral rehydration solution (slightly sweet and salty fluids), healthy food, and medications to control the fever. Antibiotics should be prescribed if secondary bacterial infections such as ear infections or pneumonia occur. Vitamin A supplementation is also recommended for children. Among cases reported in the U.S. between 1985 and 1992, death occurred in only 0.2% of cases, but may be up to 10% in people with malnutrition. Most of those who die from the infection are less than five years old.The measles vaccine is effective at preventing the disease, is exceptionally safe, and is often delivered in combination with other vaccines. Vaccination resulted in an 80% decrease in deaths from measles between 2000 and 2017, with about 85% of children worldwide having received their first dose as of 2017.
Measles affects about 20 million people a year, primarily in the developing areas of Africa and Asia. It is one of the leading vaccine-preventable disease causes of death. In 1980, 2.6 million people died from measles, and in 1990, 545,000 died due to the disease; by 2014, global vaccination programs had reduced the number of deaths from measles to 73,000. Despite these trends, rates of disease and deaths increased from 2017 to 2019 due to a decrease in immunization.
Signs and symptoms
Symptoms typically begin 10–14 days after exposure. The classic symptoms include a four-day fever (the 4 Ds) and the three Cs—cough, coryza (head cold, fever, sneezing), and conjunctivitis (red eyes)—along with a maculopapular rash. Fever is common and typically lasts for about one week; the fever seen with measles is often as high as 40 °C (104 °F).Kopliks spots seen inside the mouth are diagnostic for measles, but are temporary and therefore rarely seen. Koplik spots are small white spots that are commonly seen on the inside of the cheeks opposite the molars. They appear as "grains of salt on a reddish background." Recognizing these spots before a person reaches their maximum infectiousness can help reduce the spread of the disease.The characteristic measles rash is classically described as a generalized red maculopapular rash that begins several days after the fever starts. It starts on the back of the ears and, after a few hours, spreads to the head and neck before spreading to cover most of the body, often causing itching. The measles rash appears two to four days after the initial symptoms and lasts for up to eight days. The rash is said to "stain", changing color from red to dark brown, before disappearing. Overall, measles usually resolves after about three weeks.People who have been vaccinated against measles but have incomplete protective immunity may experience a form of modified measles. Modified measles is characterized by a prolonged incubation period, milder, and less characteristic symptoms (sparse and discrete rash of short duration).
Complications
Complications of measles are relatively common, ranging from mild ones such as diarrhea to serious ones such as pneumonia (either direct viral pneumonia or secondary bacterial pneumonia), laryngotracheobronchitis (croup) (either direct viral laryngotracheobronchitis or secondary bacterial bronchitis), otitis media, acute brain inflammation (and very rarely subacute sclerosing panencephalitis), and corneal ulceration (leading to corneal scarring).In addition, measles can suppress the immune system for weeks to months, and this can contribute to bacterial superinfections such as otitis media and bacterial pneumonia. Two months after recovery there is a 11–73% decrease in the number of antibodies against other bacteria and viruses.The death rate in the 1920s was around 30% for measles pneumonia. People who are at high risk for complications are infants and children aged less than 5 years; adults aged over 20 years; pregnant women; people with compromised immune systems, such as from leukemia, HIV infection or innate immunodeficiency; and those who are malnourished or have vitamin A deficiency. Complications are usually more severe in adults. Between 1987 and 2000, the case fatality rate across the United States was three deaths per 1,000 cases attributable to measles, or 0.3%. In underdeveloped nations with high rates of malnutrition and poor healthcare, fatality rates have been as high as 28%. In immunocompromised persons (e.g., people with AIDS) the fatality rate is approximately 30%.Even in previously healthy children, measles can cause serious illness requiring hospitalization. One out of every 1,000 measles cases progresses to acute encephalitis, which often results in permanent brain damage. One to three out of every 1,000 children who become infected with measles will die from respiratory and neurological complications.
Cause
Measles is caused by the measles virus, a single-stranded, negative-sense, enveloped RNA virus of the genus Morbillivirus within the family Paramyxoviridae.The virus is highly contagious and is spread by coughing and sneezing via close personal contact or direct contact with secretions. Measles is the most contagious transmissible virus known. It remains infective for up to two hours in that airspace or nearby surfaces. Measles is so contagious that if one person has it, 90% of non-immune people who have close contact with them (e.g., household members) will also become infected. Humans are the only natural hosts of the virus, and no other animal reservoirs are known to exist, although mountain gorillas are believed to be susceptible to the disease.
Risk factors for measles virus infection include immunodeficiency caused by HIV or AIDS, immunosuppression following receipt of an organ or a stem cell transplant, alkylating agents, or corticosteroid therapy, regardless of immunization status; travel to areas where measles commonly occurs or contact with travelers from such an area; and the loss of passive, inherited antibodies before the age of routine immunization.
Pathophysiology
Once the measles virus gets onto the mucosa, it infects the epithelial cells in the trachea or bronchi. Measles virus uses a protein on its surface called hemagglutinin (H protein), to bind to a target receptor on the host cell, which could be CD46, which is expressed on all nucleated human cells, CD150, aka signaling lymphocyte activation molecule or SLAM, which is found on immune cells like B or T cells, and antigen-presenting cells, or nectin-4, a cellular adhesion molecule. Once bound, the fusion, or F protein helps the virus fuse with the membrane and ultimately get inside the cell.As the virus is a single-stranded negative-sense RNA virus, it includes the enzyme RNA-dependent RNA polymerase (RdRp) which is used to transcribe its genome into a positive-sense mRNA strand.After entering a cell, it is ready to be translated into viral proteins, wrapped in the cells lipid envelope, and sent out of the cell as a newly made virus. Within days, the measles virus spreads through local tissue and is picked up by dendritic cells and alveolar macrophages, and carried from that local tissue in the lungs to the local lymph nodes. From there it continues to spread, eventually getting into the blood and spreading to more lung tissue, as well as other organs like the intestines and the brain. Functional impairment of the infected dendritic cells by the measles virus is thought to contribute to measles-induced immunosuppression.
Diagnosis
Typically, clinical diagnosis begins with the onset of fever and malaise about 10 days after exposure to the measles virus, followed by the emergence of cough, coryza, and conjunctivitis that worsen in severity over 4 days of appearing. Observation of Kopliks spots is also diagnostic. Other possible condition that can result in these symptoms include parvovirus, dengue fever, Kawasaki disease, and scarlet fever. Laboratory confirmation is however strongly recommended.
Laboratory testing
Laboratory diagnosis of measles can be done with confirmation of positive measles IgM antibodies or detection of measles virus RNA from throat, nasal or urine specimen by using the reverse transcription polymerase chain reaction assay. This method is particularly useful to confirm cases when the IgM antibodies results are inconclusive. For people unable to have their blood drawn, saliva can be collected for salivary measles-specific IgA testing. Salivary tests used to diagnose measles involve collecting a saliva sample and testing for the presence of measles antibodies. This method is not ideal, as saliva contains many other fluids and proteins which may make it difficult to collect samples and detect measles antibodies. Saliva also contains 800 times fewer antibodies than blood samples do, which makes salivary testing additionally difficult. Positive contact with other people known to have measles adds evidence to the diagnosis.
Prevention
Mothers who are immune to measles pass antibodies to their children while they are still in the womb, especially if the mother acquired immunity through infection rather than vaccination. Such antibodies will usually give newborn infants some immunity against measles, but these antibodies are gradually lost over the course of the first nine months of life. Infants under one year of age whose maternal anti-measles antibodies have disappeared become susceptible to infection with the measles virus.In developed countries, it is recommended that children be immunized against measles at 12 months, generally as part of a three-part MMR vaccine (measles, mumps, and rubella). The vaccine is generally not given before this age because such infants respond inadequately to the vaccine due to an immature immune system. A second dose of the vaccine is usually given to children between the ages of four and five, to increase rates of immunity. Measles vaccines have been given to over a billion people. Vaccination rates have been high enough to make measles relatively uncommon. Adverse reactions to vaccination are rare, with fever and pain at the injection site being the most common. Life-threatening adverse reactions occur in less than one per million vaccinations (<0.0001%).In developing countries where measles is common, the World Health Organization (WHO) recommends two doses of vaccine be given, at six and nine months of age. The vaccine should be given whether the child is HIV-infected or not. The vaccine is less effective in HIV-infected infants than in the general population, but early treatment with antiretroviral drugs can increase its effectiveness. Measles vaccination programs are often used to deliver other child health interventions as well, such as bed nets to protect against malaria, antiparasite medicine and vitamin A supplements, and so contribute to the reduction of child deaths from other causes.The Advisory Committee on Immunization Practices (ACIP) recommends that all adult international travelers who do not have positive evidence of previous measles immunity receive two doses of MMR vaccine before traveling, although birth before 1957 is presumptive evidence of immunity. Those born in the United States before 1957 are likely to have been naturally infected with measles virus and generally need not be considered susceptible.There have been false claims of an association between the measles vaccine and autism; this incorrect concern has reduced the rate of vaccination and increased the number of cases of measles where immunization rates became too low to maintain herd immunity. Additionally, there have been false claims that measles infection protects against cancer.Administration of the MMR vaccine may prevent measles after exposure to the virus (post-exposure prophylaxis). Post-exposure prophylaxis guidelines are specific to jurisdiction and population. Passive immunization against measles by an intramuscular injection of antibodies could be effective up to the seventh day after exposure. Compared to no treatment, the risk of measles infection is reduced by 83%, and the risk of death by measles is reduced by 76%. However, the effectiveness of passive immunization in comparison to active measles vaccine is not clear.The MMR vaccine is 95% effective for preventing measles after one dose if the vaccine is given to a child who is 12 months or older; if a second dose of the MMR vaccine is given, it will provide immunity in 99% of children.There is no evidence that the measles vaccine virus can be transmitted to other persons.
Treatment
There is no specific antiviral treatment if measles develops. Instead the medications are generally aimed at treating superinfections, maintaining good hydration with adequate fluids, and pain relief. Some groups, like young children and the severely malnourished, are also given vitamin A, which acts as an immunomodulator that boosts the antibody responses to measles and decreases the risk of serious complications.
Medications
Treatment is supportive, with ibuprofen or paracetamol (acetaminophen) to reduce fever and pain and, if required, a fast-acting medication to dilate the airways for cough. As for aspirin, some research has suggested a correlation between children who take aspirin and the development of Reye syndrome.The use of vitamin A during treatment is recommended to decrease the risk of blindness; however, it does not prevent or cure the disease. A systematic review of trials into its use found no reduction in overall mortality, but two doses (200 000 IU) of vitamin A was shown to reduce mortality for measles in children younger than two years of age. It is unclear if zinc supplementation in children with measles affects outcomes as it has not been sufficiently studied. There are no adequate studies on whether Chinese medicinal herbs are effective.
Prognosis
Most people survive measles, though in some cases, complications may occur. About 1 in 4 individuals will be hospitalized and 1–2 in 1000 will die. Complications are more likely in children under age 5 and adults over age 20. Pneumonia is the most common fatal complication of measles infection and accounts for 56-86% of measles-related deaths.Possible consequences of measles virus infection include laryngotracheobronchitis, sensorineural hearing loss, and—in about 1 in 10,000 to 1 in 300,000 cases—panencephalitis, which is usually fatal. Acute measles encephalitis is another serious risk of measles virus infection. It typically occurs two days to one week after the measles rash breaks out and begins with very high fever, severe headache, convulsions and altered mentation. A person with measles encephalitis may become comatose, and death or brain injury may occur.For people having had measles, it is rare to ever have a symptomatic reinfection.The measles virus can deplete previously acquired immune memory by killing cells that make antibodies, and thus weakens the immune system which can cause deaths from other diseases. Suppression of the immune system by measles lasts about two years and has been epidemiologically implicated in up to 90% of childhood deaths in third world countries, and historically may have caused rather more deaths in the United States, the UK and Denmark than were directly caused by measles. Although the measles vaccine contains an attenuated strain, it does not deplete immune memory.
Epidemiology
Measles is extremely infectious and its continued circulation in a community depends on the generation of susceptible hosts by birth of children. In communities that generate insufficient new hosts the disease will die out. This concept was first recognized in measles by Bartlett in 1957, who referred to the minimum number supporting measles as the critical community size (CCS). Analysis of outbreaks in island communities suggested that the CCS for measles is around 250,000. To achieve herd immunity, more than 95% of the community must be vaccinated due to the ease with which measles is transmitted from person to person.In 2011, the WHO estimated that 158,000 deaths were caused by measles. This is down from 630,000 deaths in 1990. As of 2018, measles remains a leading cause of vaccine-preventable deaths in the world. In developed countries the mortality rate is lower, for example in England and Wales from 2007 to 2017 death occurred between two and three cases out of 10,000. In children one to three cases out of every 1,000 die in the United States (0.1–0.2%). In populations with high levels of malnutrition and a lack of adequate healthcare, mortality can be as high as 10%. In cases with complications, the rate may rise to 20–30%. In 2012, the number of deaths due to measles was 78% lower than in 2000 due to increased rates of immunization among UN member states.
Even in countries where vaccination has been introduced, rates may remain high. Measles is a leading cause of vaccine-preventable childhood mortality. Worldwide, the fatality rate has been significantly reduced by a vaccination campaign led by partners in the Measles Initiative: the American Red Cross, the United States CDC, the United Nations Foundation, UNICEF and the WHO. Globally, measles fell 60% from an estimated 873,000 deaths in 1999 to 345,000 in 2005. Estimates for 2008 indicate deaths fell further to 164,000 globally, with 77% of the remaining measles deaths in 2008 occurring within the Southeast Asian region. There were 142,300 measles related deaths globally in 2018, of which most cases were reported from African and eastern Mediterranean regions. These estimates were slightly higher than that of 2017, when 124,000 deaths were reported due to measles infection globally.In 2000, the WHO established the Global Measles and Rubella Laboratory Network (GMRLN) to provide laboratory surveillance for measles, rubella, and congenital rubella syndrome. Data from 2016 to 2018 show that the most frequently detected measles virus genotypes are decreasing, suggesting that increasing global population immunity has decreased the number of chains of transmission.Cases reported in the first three months of 2019, were 300% higher than in the first three months of 2018, with outbreaks in every region of the world, even in countries with high overall vaccination coverage where it spread among clusters of unvaccinated people. The numbers of reported cases as of mid-November is over 413,000 globally, with an additional 250,000 cases in DRC (as reported through their national system), similar to the increasing trends of infection reported in the earlier months of 2019, compared to 2018. In 2019, the total number of cases worldwide climbed to 869,770. The number of cases reported for 2020 is lower compare to 2019. According to the WHO, the COVID-19 pandemic hindered vaccination campaigns in at least 68 countries, including in countries that were experiencing outbreaks, which caused increased risk of additional cases.
Europe
In England and Wales, though deaths from measles were uncommon, they averaged about 500 per year in the 1940s. Deaths diminished with the improvement of medical care in the 1950s but the incidence of the disease did not retreat until vaccination was introduced in the late 1960s. Wider coverage was achieved in the 1980s with the measles, mumps and rubella, MMR vaccine.In 2013–14, there were almost 10,000 cases in 30 European countries. Most cases occurred in unvaccinated individuals and over 90% of cases occurred in Germany, Italy, Netherlands, Romania, and United Kingdom. Between October 2014 and March 2015, a measles outbreak in the German capital of Berlin resulted in at least 782 cases. In 2017, numbers continued to increase in Europe to 21,315 cases, with 35 deaths. In preliminary figures for 2018, reported cases in the region increased 3-fold to 82,596 in 47 countries, with 72 deaths; Ukraine had the most cases (53,218), with the highest incidence rates being in Ukraine (1209 cases per million), Serbia (579), Georgia (564) and Albania (500). The previous year (2017) saw an estimated measles vaccine coverage of 95% for the first dose and 90% for the second dose in the region, the latter figure being the highest-ever estimated second-dose coverage.In 2019, the United Kingdom, Albania, the Czech Republic, and Greece lost their measles-free status due to ongoing and prolonged spread of the disease in these countries. In the first 6 months of 2019, 90,000 cases occurred in Europe.
Americas
As a result of widespread vaccination, the disease was declared eliminated from the Americas in 2016. However, there were cases again in 2017, 2018, 2019, and 2020 in this region.
United States
In the United States, measles affected approximately 3,000 people per million in the 1960s before the vaccine was available. With consistent widespread childhood vaccination, this figure fell to 13 cases per million by the 1980s, and to about 1 case per million by 2000.In 1991, an outbreak of measles in Philadelphia was centered at the Faith Tabernacle Congregation, a faith healing church that actively discouraged parishioners from vaccinating their children. Over 1400 people were infected with measles and nine children died.Before immunization in the United States, between three and four million cases occurred each year. The United States was declared free of circulating measles in 2000, with 911 cases from 2001 to 2011. In 2014 the CDC said endemic measles, rubella, and congenital rubella syndrome had not returned to the United States. Occasional measles outbreaks persist, however, because of cases imported from abroad, of which more than half are the result of unvaccinated U.S. residents who are infected abroad and infect others upon return to the United States. The CDC continues to recommend measles vaccination throughout the population to prevent outbreaks like these.In 2014, an outbreak was initiated in Ohio when two unvaccinated Amish men harboring asymptomatic measles returned to the United States from missionary work in the Philippines. Their return to a community with low vaccination rates led to an outbreak that rose to include a total of 383 cases across nine counties. Of the 383 cases, 340 (89%) occurred in unvaccinated individuals.From 4 January, to 2 April 2015, there were 159 cases of measles reported to the CDC. Of those 159 cases, 111 (70%) were determined to have come from an earlier exposure in late December 2014. This outbreak was believed to have originated from the Disneyland theme park in California. The Disneyland outbreak was held responsible for the infection of 147 people in seven U.S. states as well as Mexico and Canada, the majority of which were either unvaccinated or had unknown vaccination status. Of the cases 48% were unvaccinated and 38% were unsure of their vaccination status. The initial exposure to the virus was never identified.In 2015, a U.S. woman in Washington state died of pneumonia, as a result of measles. She was the first fatality in the U.S. from measles since 2003. The woman had been vaccinated for measles and was taking immunosuppressive drugs for another condition. The drugs suppressed the womans immunity to measles, and the woman became infected with measles; she did not develop a rash, but contracted pneumonia, which caused her death.In June 2017, the Maine Health and Environmental Testing Laboratory confirmed a case of measles in Franklin County. This instance marks the first case of measles in 20 years for the state of Maine. In 2018 one case occurred in Portland, Oregon, with 500 people exposed; 40 of them lacked immunity to the virus and were being monitored by county health officials as of 2 July 2018. There were 273 cases of measles reported throughout the United States in 2018, including an outbreak in Brooklyn with more than 200 reported cases from October 2018 to February 2019. The outbreak was tied with population density of the Orthodox Jewish community, with the initial exposure from an unvaccinated child that caught measles while visiting Israel.A resurgence of measles occurred during 2019, which has been generally tied to parents choosing not to have their children vaccinated as most of the reported cases have occurred in people 19 years old or younger. Cases were first reported in Washington state in January, with an outbreak of at least 58 confirmed cases most within Clark County, which has a higher rate of vaccination exemptions compared to the rest of the state; nearly one in four kindergartners in Clark did not receive vaccinations, according to state data. This led Washington state governor Jay Inslee to declare a state of emergency, and the states congress to introduce legislation to disallow vaccination exemption for personal or philosophical reasons. In April 2019, New York Mayor Bill de Blasio declared a public health emergency because of "a huge spike" in cases of measles where there were 285 cases centred on the Orthodox Jewish areas of Brooklyn in 2018, while there were only two cases in 2017. There were 168 more in neighboring Rockland County. Other outbreaks have included Santa Cruz County and Butte County in California, and the states of New Jersey and Michigan. As of April 2019, there have been 695 cases of measles reported in 22 states. This is the highest number of measles cases since it was declared eradicated in 2000. From 1 January, to 31 December 2019, 1,282 individual cases of measles were confirmed in 31 states. This is the greatest number of cases reported in the U.S. since 1992. Of the 1,282 cases, 128 of the people who got measles were hospitalized, and 61 reported having complications, including pneumonia and encephalitis.
Brazil
The spread of measles had been interrupted in Brazil in 2016, with the last known case twelve months earlier. This last case was in the state of Ceará.Brazil won a measles elimination certificate by the Pan American Health Organization in 2016, but the Ministry of Health has proclaimed that the country has struggled to keep this certificate, since two outbreaks had already been identified in 2018, one in the state of Amazonas and another one in Roraima, in addition to cases in other states (Rio de Janeiro, Rio Grande do Sul, Pará, São Paulo and Rondônia), totaling 1053 confirmed cases until 1 August 2018. In these outbreaks, and in most other cases, the contagion was related to the importation of the virus, especially from Venezuela. This was confirmed by the genotype of the virus (D8) that was identified, which is the same that circulates in Venezuela.
Sou |
Measles | theast Asia
In the Vietnamese measles epidemic in spring of 2014, an estimated 8,500 measles cases were reported as of 19 April, with 114 fatalities; as of 30 May, 21,639 suspected measles cases had been reported, with 142 measles-related fatalities. In the Naga Self-Administered Zone in a remote northern region of Myanmar, at least 40 children died during a measles outbreak in August 2016 that was probably caused by lack of vaccination in an area of poor health infrastructure. Following the 2019 Philippines measles outbreak, 23,563 measles cases have been reported in the country with 338 fatalities. A measles outbreak also happened among the Malaysian Orang Asli sub-group of Batek people in the state of Kelantan from May 2019, causing the deaths of 15 from the tribe.
South Pacific
A measles outbreak in New Zealand has 2193 confirmed cases and two deaths. A measles outbreak in Tonga has 612 cases of measles.
Samoa
A measles outbreak in Samoa in late 2019 has over 5,700 cases of measles and 83 deaths, out of a Samoan population of 200,000. Over three percent of the population were infected, and a state of emergency was declared from 17 November to 7 December. A vaccination campaign brought the measles vaccination rate from 31 to 34% in 2018 to an estimated 94% of the eligible population in December 2019.
Africa
The Democratic Republic of the Congo and Madagascar have reported the highest numbers of cases in 2019. However, cases have decreased in Madagascar as a result of nationwide emergency measles vaccine campaigns. As of August 2019 outbreaks were occurring in Angola, Cameroon, Chad, Nigeria, South Sudan and Sudan.
Madagascar
An outbreak of measles in 2018 has resulted in 118,000 cases and 1,688 deaths. This followed outbreaks of bubonic and pneumonic plague in 2017 (2575 cases, 221 deaths) and 2014 (263 confirmed cases, 71 deaths).
Democratic Republic of Congo
An outbreak of measles with nearly 5,000 deaths and 250,000 infections occurred in 2019, after the disease spread to all the provinces in the country. Most deaths were among children under five years of age. The World Health Organization (WHO) has reported this as the worlds largest and fastest-moving epidemic.
History
Measles is of zoonotic origin, having evolved from rinderpest, which infects cattle. A precursor of the measles began causing infections in humans as early as the 4th century BC or as late as after AD 500. The Antonine Plague of AD 165–180 has been speculated to have been measles, but the actual cause of this plague is unknown and smallpox is a more likely cause. The first systematic description of measles, and its distinction from smallpox and chickenpox, is credited to the Persian physician Muhammad ibn Zakariya al-Razi (860–932), who published The Book of Smallpox and Measles. At the time of Razis book, it is believed that outbreaks were still limited and that the virus was not fully adapted to humans. Sometime between AD 1100 and 1200, the measles virus fully diverged from rinderpest, becoming a distinct virus that infects humans. This agrees with the observation that measles requires a susceptible population of >500,000 to sustain an epidemic, a situation that occurred in historic times following the growth of medieval European cities.
Measles is an endemic disease, meaning it has been continually present in a community and many people develop resistance. In populations not exposed to measles, exposure to the new disease can be devastating. In 1529, a measles outbreak in Cuba killed two-thirds of those indigenous people who had previously survived smallpox. Two years later, measles was responsible for the deaths of half the population of Honduras, and it has ravaged Mexico, Central America, and the Inca civilization.Between roughly 1855 and 2005, measles is estimated to have killed about 200 million people worldwide.The 1846 measles outbreak in the Faroe Islands was unusual for being well-studied. Measles had not been seen on the islands for 60 years, so almost no residents had any acquired immunity. Three-quarters of the residents got sick, and more than 100 (1–2%) died from it before the epidemic burned itself out. Peter Ludvig Panum observed the outbreak and determined that measles was spread through direct contact of contagious people with people who had never had measles.Measles killed 20 percent of Hawaiis population in the 1850s. In 1875, measles killed over 40,000 Fijians, approximately one-third of the population. In the 19th century, the disease killed more than half of the Great Andamanese population. Seven to eight million children are thought to have died from measles each year before the vaccine was introduced.In 1914, a statistician for the Prudential Insurance Company estimated from a survey of 22 countries that 1% of all deaths in the temperate zone were caused by measles. He observed also that 1–6% of cases of measles ended fatally, the difference depending on age (0–3 being the worst), social conditions (e.g. overcrowded tenements) and pre-existing health conditions.In 1954, the virus causing the disease was isolated from a 13-year-old boy from the United States, David Edmonston, and adapted and propagated on chick embryo tissue culture. The World Health Organization recognizes eight clades, named A, B, C, D, E, F, G, and H. Twenty-three strains of the measles virus have been identified and designated within these clades. While at Merck, Maurice Hilleman developed the first successful vaccine. Licensed vaccines to prevent the disease became available in 1963. An improved measles vaccine became available in 1968. Measles as an endemic disease was eliminated from the United States in 2000, but continues to be reintroduced by international travelers. In 2019 there were at least 1,241 cases of measles in the United States distributed across 31 states, with over three quarters in New York.
Society and culture
German anti-vaccination campaigner and HIV/AIDS denialist Stefan Lanka posed a challenge on his website in 2011, offering a sum of €100,000 for anyone who could scientifically prove that measles is caused by a virus and determine the diameter of the virus. He posited that the illness is psychosomatic and that the measles virus does not exist. When provided with overwhelming scientific evidence from various medical studies by German physician David Bardens, Lanka did not accept the findings, forcing Bardens to appeal in court. The initial legal case ended with the ruling that Lanka was to pay the prize. However, on appeal, Lanka was ultimately not required to pay the award because the submitted evidence did not meet his exact requirements. The case received wide international coverage that prompted many to comment on it, including neurologist, well-known skeptic and science-based medicine advocate Steven Novella, who called Lanka "a crank".As outbreaks easily occur in under-vaccinated populations, the disease is seen as a test of sufficient vaccination within a population. Measles outbreaks have been on the rise in the United States, especially in communities with lower rates of vaccination. A different vaccine distribution within a single territory by age or social class may define different general perceptions of vaccination efficacy. It is often introduced to a region by travelers from other countries and it typically spreads to those who have not received the measles vaccination.
Alternative names
Other names include morbilli, rubeola, red measles, and English measles.
Research
In May 2015, the journal Science published a report in which researchers found that the measles infection can leave a population at increased risk for mortality from other diseases for two to three years. Results from additional studies that show the measles virus can kill cells that make antibodies were published in November 2019.A specific drug treatment for measles, ERDRP-0519, has shown promising results in animal studies, but has not yet been tested in humans.
References
External links
Initiative for Vaccine Research (IVR): Measles, World Health Organization (WHO)
Measles FAQ U.S. Centers for Disease Control and Prevention (CDC)
Case of an adult male with measles (facial photo)
Pictures of measles
Virus Pathogen Database and Analysis Resource (ViPR): Paramyxoviridae |
Hypothenar hammer syndrome | Hypothenar hammer syndrome (HHS) is a vascular occlusion in humans in the region of the ulna. It is caused by repetitive trauma to the hand or wrist (such as that caused by the use of a hammer) by the vulnerable portion of the ulnar artery as it passes over the hamate bone, which may result in thrombosis, irregularity or aneurysm formation. HHS is a potentially curable cause of Raynauds syndrome, distinct from hand–arm vibration syndrome.
Cause
Diagnosis
A physical examination of the hand may show discoloration (blanching, mottling, and/ or cyanosis; gangrene may be present in advanced cases), unusual tenderness/ a callous over the hypothenar eminence, and fingertip ulcerations and splinter hemorrhages over ulnar digits; if an aneurysm is present, there may also be a pulsatile mass. Allens test will be positive if an occlusion is present and negative if an aneurysm is present. An angiogram may show a "corkscrew" ulnar artery or an occlusion or aneurysm at the hook of the hamate.
Treatment
Noninvasive treatments have an 80% success rate; Example: switch jobs, stop smoking, regular finger exercise, surgical options exist for other instances.
Epidemiology
HHS, though rare, occurs much more frequently in men than in women (9:1) and principally affects those in their 40s and 50s.
== References == |
Keratoacanthoma | Keratoacanthoma (KA) is a common low-grade (unlikely to metastasize or invade) rapidly-growing skin tumour that is believed to originate from the hair follicle (pilosebaceous unit) and can resemble squamous cell carcinoma.The defining characteristic of a keratoacanthoma is that it is dome-shaped, symmetrical, surrounded by a smooth wall of inflamed skin, and capped with keratin scales and debris. It grows rapidly, reaching a large size within days or weeks, and if untreated for months will almost always starve itself of nourishment, necrose (die), slough, and heal with scarring. Keratoacanthoma is commonly found on sun-exposed skin, often face, forearms and hands. It is rarely found at a mucocutaneous junction or on mucous membranes.Keratoacanthoma may be difficult to distinguish visually from a skin cancer. Under the microscope, keratoacanthoma very closely resembles squamous cell carcinoma. In order to differentiate between the two, almost the entire structure needs to be removed and examined. While some pathologists classify keratoacanthoma as a distinct entity and not a malignancy, about 6% of clinical and histological keratoacanthomas do progress to invasive and aggressive squamous cell cancers; some pathologists may label KA as "well-differentiated squamous cell carcinoma, keratoacanthoma variant", and prompt definitive surgery may be recommended.
Classification
Frequently reported and reclassified over the last century, keratoacanthoma can be divided into various subtypes and despite being considered benign, their unpredictable behaviour has warranted the same attention as with squamous cell carcinoma.Keratoacanthomas may be divided into the following types:: 763–764 : 643–646
Giant keratoacanthomas are a variant of keratoacanthoma, which may reach dimensions of several centimeters.: 763
Keratoacanthoma centrifugum marginatum is a cutaneous condition, a variant of keratoacanthomas, which is characterized by multiple tumors growing in a localized area.: 763 : 645
Multiple keratoacanthomas (also known as "Ferguson–Smith syndrome," "Ferguson-Smith type of multiple self-healing keratoacanthomas,") is a cutaneous condition, a variant of keratoacanthomas, which is characterized by the appearance of multiple, sometimes hundreds of keratoacanthomas.: 763 : 644
A solitary keratoacanthoma (also known as "Subungual keratoacanthoma") is a benign, but rapidly growing, locally aggressive tumor which sometimes occur in the nail apparatus.: 667, 764 : 644
Generalized eruptive keratoacanthoma (also known as "Generalized eruptive keratoacanthoma of Grzybowski") is a cutaneous condition, a variant of keratoacanthomas, characterized by hundreds to thousands of tiny follicular keratotic papules over the entire body.: 763 : 645 Treatments are not successful for many people with generalized eruptive keratoacanthoma. Use of emollients and anti-itch medications can ease some symptoms. Improvement or complete resolutions of the condition has occurred with the application of the following medications: acitretin, isotretinoin, fluorouracil, methotrexate, cyclophosphamide.
Cause
Keratoacanthomas usually occurs in older individuals. A number of causes have been suggested including ultraviolet light, chemical carcinogens, recent injury to the skin, immunosuppression and genetic predisposition. As with squamous cell cancer, sporadic cases have been found co-infected with the human papilloma virus (HPV). Although HPV has been suggested as a causal factor, it is unproven.Many new treatments for melanoma are also known to increase the rate of keratoacanthoma, such as the BRAF inhibitor medications vemurafenib and dabrafenib.
Diagnosis
Keratoacanthomas presents as a fleshy, elevated and nodular lesion with an irregular crater shape and a characteristic central hyperkeratotic core. Usually the people will notice a rapidly growing dome-shaped tumor on sun-exposed skin.If the entire lesion is removed, the pathologist will probably be able to differentiate between keratoacanthoma and squamous cell carcinoma. Follow-up would be required to monitor for recurrence of disease.
Treatment
Excision of the entire lesion, with adequate margin, will remove the lesion, allow full tissue diagnosis, and leave a planned surgical wound which can usually be repaired with a good cosmetic result. However, removing the entire lesion (especially on the face) may present difficult problems of plastic reconstruction. (On the nose and face, Mohs surgery may allow for good margin control with minimal tissue removal, but many insurance companies require the definitive diagnosis of a malignancy before they are prepared to pay the extra costs of Mohs surgery.) Especially in more cosmetically-sensitive areas, and where the clinical diagnosis is reasonably certain, alternatives to surgery may include no treatment (awaiting spontaneous resolution).On the trunk, arms, and legs, electrodesiccation and curettage often suffice to control keratoacanthomas until they regress. Other modalities of treatment include cryosurgery and radiotherapy; intralesional injection of methotrexate or 5-fluorouracil have also been used.Recurrence after electrodesiccation and curettage can occur; it can usually be identified and treated promptly with either further curettage or surgical excision.
History
In 1889, Sir Jonathan Hutchinson described a crateriform ulcer on the face”. In 1936, the same condition was renamed "molluscum sebaceum" by MacCormac and Scarf. Later, the term “keratoacanthoma” was coined by Walter Freudenthal and the term became established by Arthur Rook and pathologist Ian Whimster in 1950.
See also
List of cutaneous conditions
Marian Grzybowski
References
== External links == |
Achilles bursitis | Achilles bursitis is bursitis (inflammation of synovial sac) of bursa situated above the insertion of tendon to calcaneus. It results from overuse and wearing of tight shoes.
References
== External links == |
Spondylo-ocular syndrome | Spondylo-ocular syndrome is a rare genetic disorder characterised by lesions in the eye and the spine.
Presentation
These can be divided into those affecting the eyes, spine and other areas:
Genetics
This syndrome is caused by inactivating mutations in the xylosyltransferase (XYLT2) gene. It is inherited in an autosomal recessive manner.
Diagnosis
Treatment
History
This syndrome was first described by Schmidt et al in consanginous Iraqi family in 2001.
References
== External links == |
Acatalasia | Acatalasia is an autosomal recessive peroxisomal disorder caused by absent or very low levels of the enzyme catalase. Catalase breaks down hydrogen peroxide in cells into water and oxygen. Low levels of catalase can cause hydrogen peroxide to build up, causing damage to cells.
Presentation
The disorder is relatively benign, although it causes an increased incidence of oral ulcers, and can under rare circumstances lead to gangrene. Symptoms primarily affect children.
Genetic
Acatalasia is often the result of mutations in both copies of the CAT gene which codes for the enzyme catalase. There are multiple types of mutation that can cause this condition. Inheriting a single CAT mutation results in hypocatalasia, in which catalase levels are reduced, but still at functional levels.
Diagnosis
This disorder is commonly diagnosed pouring hydrogen peroxide on the patients blood sample. Instead of a very bubbling reaction, blood turns brown-colored, which means the patient suffers from acatalasia.
Management
Epidemiology
In parts of Japan, this condition has been found in approximately 1.4% of people. Researchers estimate that the condition occurs in 1 in 20,000 people in Hungary and Switzerland.
History
In 1948, Dr. Shigeo Takahara (1908–1994), a Japanese otolaryngologist first reported this new disease. He had examined a patient with an oral ulcer. He had spread hydrogen peroxide on the diseased part, but oxygen was not generated due to the lack of catalase.
See also
List of cutaneous conditions
References
== External links == |
Nasodigitoacoustic syndrome | Nasodigitoacoustic syndrome, also called Keipert syndrome, is a rare congenital syndrome first described by J.A. Keipert and colleagues in 1973. The syndrome is characterized by a misshaped nose, broad thumbs and halluces (the big toes), brachydactyly, sensorineural hearing loss, facial features such as hypertelorism (unusually wide-set eyes), and developmental delay.
It is believed to be inherited in an X-linked recessive manner, which means a genetic mutation causing the disorder is located on the X chromosome, and while two copies of the mutated gene must be inherited for a female to be born with the disorder, just one copy is sufficient to cause a male to be born with the disorder. Nasodigitoacoustic syndrome is likely caused by a mutated gene located on the X chromosome between positions Xq22.2–q28.
The incidence of the syndrome has not been determined, but it is considered to affect less than 200,000 people in the United States, and no greater than 1 per 2,000 in Europe. It is similar to Keutel, Muenke, Rubinstein and Teunissen–Cremers syndrome.
Characteristics
Nasodigitoacoustic syndrome is congenital and is characterized by a number of nasal, facial and cranial features. These include a broad and high, sometimes depressed nasal bridge (top of the nose, between the eyes) and a flattened nasal tip. This can give the nose a shortened, arch-like appearance. Hypertelorism (unusually wide-set eyes), prominent frontal bones and supraorbital ridge (the eyebrow ridge), bilateral epicanthic folds (an extra flap of skin over the eyelids), a broad forehead and an overall enlarged head circumference have also been observed. A bulging of the upper lip with an exaggerated cupids bow shape, and maxillary hypoplasia (underdevelopment of the upper jaw) with retraction have also been reported.Several anomalies affecting the digits (fingers and toes) have been observed with the syndrome. A broadening of the thumbs and big toes (halluces) was reported in two brothers. The broadening was apparent in all distal phalanges of the fingers, although the pinkies were unaffected yet appeared to be clinodactylic (warped, or bent toward the other fingers). Additional reports described this broadness of the thumbs and big toes, with brachydactyly (shortness) in the distal phalanges of the other digits except the pinkies in affected individuals. On X-rays of a two-year-old boy with the disorder, the brachydactyly was shown to be caused by shortening of epiphyses (joint-ends) of the distal phalanges. The broadness and brachydactyly of the big toes in particular may give them a stunted, rounded and stub-like appearance.The auditory, or "acoustic" abnormalities observed with the syndrome include sensorineural hearing loss and hoarseness. Two affected Turkish brothers with a mild form of this hearing loss, and a hoarse voice were reported. A laryngoscopic examination of both brothers revealed swelling of the vocal cords, and a malformed epiglottis. Sensorineural-associated hearing impairment and hoarseness was also observed in a 10-year-old girl and her father, and in a number of other cases.Other characteristics seen with the syndrome include developmental delay, growth retardation, pulmonary stenosis (an obstruction of blood-flow from the right ventricle of the heart to the pulmonary artery) with associated dyspnea (shortness of breath), and renal agenesis (failure of the kidneys to develop during the fetal period). Undescended testes, hyperactivity and aggressive behavior have also been noted.
Genetics
Nasodigitoacoustic syndrome is thought to be caused by a mutation in a gene on the X chromosome. A 2007 study concluded, based on analysis of microsatellite markers (small gene sequences found in common among individuals having the same ethnicity, ancestry or genetic disease) of the family described by Keipert, that this gene was likely located on the long arm of the X chromosome between positions Xq22.2–q28. This is not definitive, however, and no specific gene has been named.The syndrome is strongly believed to be inherited in an X-linked recessive manner. When a female carries a mutated gene on one of her two copies of the X chromosome, there is a 50% chance of passing the mutation on to her children. Much like her, a daughter inheriting this mutation will be a carrier, but will not herself have the associated disease. However, a son who inherits the mutation will have the disease; this is because males have only one copy of the X chromosome and therefore could only express the disease mutation.
This form of inheritance for Nasodigitoacoustic syndrome is not yet absolute, though, as a girl has been reported with the disorder. It is suggested that further analysis is needed for the inheritance to be formally established.The mutations causing this syndrome have been mapped to the glypican 4 (GPC4) gene. This gene is located on the long arm of chromosome X (Xq26.2).
Diagnosis
The constellation of anomalies seen with nasodigitoacoustic syndrome result in a distinct diagnosis. The diagnostic criteria for the disorder are broad distal phalanges of the thumbs and big toes, accompanied by a broad and shortened nose, sensorineural hearing loss and developmental delay, with predominant occurrence in males.
Classification
Nasodigitoacoustic syndrome is similar to several syndromes that share its features. Brachydactyly of the distal phalanges, sensorineural deafness and pulmonary stenosis are common with Keutel syndrome. In Muenke syndrome, developmental delay, distal brachydactyly and sensorineural hearing loss are reported; features of Teunissen-Cremers syndrome include nasal aberrations and broadness of the thumbs and big toes, also with brachydactyly. Broad thumbs and big toes are primary characteristics of Rubinstein syndrome.
Management
A number of features found with nasodigitoacoustic syndrome can be managed or treated. Sensorineural hearing loss in humans may be caused by a loss of hair cells (sensory receptors in the inner ear that are associated with hearing). This can be hereditary and/or within a syndrome, as is the case with nasodigitoacoustic syndrome, or attributed to infections such as viruses. For the management of sensorineural hearing loss, hearing aids have been used. Treatments, depending upon the cause and severity, may include a pharmacological approach (i.e., the use of certain steroids), or surgical intervention, like a cochlear implant.Pulmonary, or pulmonic stenosis is an often congenital narrowing of the pulmonary valve; it can be present in nasodigitoacoustic-affected infants. Treatment of this cardiac abnormality can require surgery, or non-surgical procedures like balloon valvuloplasty (widening the valve with a balloon catheter).
History and epidemiology
The syndrome was initially described in 1973 by James A. Keipert and associates. They reported of two brothers with broad distal phalanges, sensorineural hearing loss, and facial features consistent with what would become known as Keipert or "nasodigitoacoustic" syndrome. Although no specific rate of incidence has been determined, the syndrome is considered a rare disease by both the Office of Rare Diseases (ORDR) at the National Institutes of Health, and Orphanet. This suggests, respectively, that nasodigitoacoustic syndrome affects less than 200,000 people in the U.S., or affects no greater than 1 per 2,000 people in Europe.
References
Publications
Gorlin, R. J.; Toriello, H. V.; Cohen, M. M. (1995). Hereditary hearing loss and its syndromes. U. S.: Oxford University Press. pp. 208–209. ISBN 9780195065527. Retrieved April 21, 2011.
External links
Nasodigitoacoustic syndrome listing at the Office of Rare Diseases website
Keipert syndrome - Orphanet |
Lethal arthrogryposis with anterior horn cell disease | Lethal arthrogryposis with anterior horn cell disease (LAAHD) is an autosomal recessive genetic disorder characterized by reduced mobility of the foetus and early death.
Presentation
LAAHD resembles LCCS1 disease but the phenotype is milder, with survival beyond 32nd gestational week. However, the foetuses are often stillborn or survive only few minutes. The movements of the foetus during pregnancy are scanty and stiff, often only in upper limbs. The malpositions are distal. The inwards spiral and especially the elbow contractures are less severe than in LCCS1 disease. Some patients have intrauterine long bone fractures. Skeletal muscles are affected and show neurogenic atrophy. The size and shape of spinal cord at different levels are normal but anterior horn motoneurons are diminished in number and degenerated.
Molecular genetics
LAAHD disease results from compound heterozygosity of GLE1FinMajor and a missense point mutation in exon 13 (6 cases in 3 families) or a missense mutation in exon 16 ( seven cases in 3 families). One of the latter cases survived 12 weeks, mostly under artificial respiration.
Diagnosis
Treatment
Epidemiology
LAAHD is one of approximately 40 Finnish heritage diseases. Families affected by these diseases come from different parts of Finland, and birthplaces of the ancestors of affected individuals do not show geographic clustering.
References
== External links == |
Persistent fetal circulation | Persistent fetal circulation is a condition caused by a failure in the systemic circulation and pulmonary circulation to convert from the antenatal circulation pattern to the "normal" pattern. Infants experience a high mean arterial pulmonary artery pressure and a high afterload at the right ventricle. This means that the heart is working against higher pressures, which makes it more difficult for the heart to pump blood.In a fetus, there is high pulmonary vascular resistance (PVR) and low pulmonary blood flow as the fetus does not use the lungs for oxygen transfer, but instead relies on the placenta for oxygen. When the baby is born, the lungs are needed for oxygen transfer and need high blood flow which is encouraged by low PVR. The failure of the circulatory system of the newborn to adapt to these changes by lowering PVR leads to persistent fetal circulation. The newborn is therefore born with elevated PVR, which leads to pulmonary hypertension. Because of this, the condition is also widely known as persistent pulmonary hypertension of the newborn (PPHN). This condition can be either acute or chronic, and is associated with significant morbidity and mortality.
Presentation
Complications
PPHN can range from mild to severe disease. In the most severe form, infants experience severe hypoxemia resulting in cardiac and pulmonary complications. As a result of low oxygen levels, infants with PPHN are at an increased risk of developing complications, such as asphyxia, chronic lung disease, neurodevelopment issues, and death.Nosocomial infections are another type of complication that may contribute to mortality in someone with PPHN. If the newborn acquires an infection while hospitalized, this could result in deterioration of the condition even after days of improvement.
Pathophysiology
Typically, a fetus experiences pulmonary hypertension in utero since it is relying on the placenta for oxygen rather than its lungs. When the fetus is born, it is no longer attached to the placenta and must use the lungs to receive oxygen. To facilitate this change from fetus to newborn, the baby must change from a state of high PVR to low PVR, allowing for increased blood flow to circulate throughout the body. This inability of the newborn to adapt to these changes is caused by various processes, such as:
Normal vascular anatomy with functional vasoconstriction: This has a good prognosis, as it is reversible. Causes include hypoxia, meconium aspiration, and respiratory distress syndrome. Left untreated, this can lead to hypoxic respiratory failure (HRF).
Decreased diameter of pulmonary vessels with hypertrophy of vessel walls: This has a poor prognosis, as it is a fixed abnormality. Causes include post-term pregnancy, placental insufficiency, and NSAID use by the mother.
Decreased size of pulmonary vascular bed: This has a poor prognosis, as it is a fixed abnormality. It is caused by space occupying lesions such as pleural effusions and diaphragmatic hernias.
Functional obstruction of pulmonary blood flow: This has a good prognosis if it is reversible. Causes include polycythemia and hyperfibrinogenemia.
Diagnosis
To help with diagnosis, the clinician can watch out for predisposing factors, such as: birth asphyxia, meconium aspiration, use of NSAIDs (non steroidal anti-inflammatory drugs) and SSRIs (selective serotonin reuptake inhibitors) by the mother, and early onset sepsis or pneumonia. To diagnose a fetus with pulmonary hypertension, PVR must be higher than systemic vascular resistance, resulting in high afterload and decreased systemic blood flow. This causes a significant decrease in oxygen concentration, which clinically manifests as insufficient blood flow to the lower body, while there is adequate circulation to the head and right side of the body. Other echocardiographic findings in PPHN include right ventricular hypertrophy, deviation of the ventricular septum, tricuspid regurgitation, and shunting at the patent foramen ovale.Other clinical signs that may signify PPHN are respiratory distress, partial pressure of oxygen greater than 100 mg and elevated partial pressure of carbon dioxide. A gradient of 10% or more in oxygenation saturation between simultaneous preductal and postductal arterial blood gas values in absence of structural heart disease documents persistent fetal circulation. Since this may be a sign of other conditions, persistent fetal circulation must also be characterized by enlargement of right and left ventricles often confirmed through a definitive ECG.Persistent fetal circulation in neonates can be reversible or irreversible depending on the classified etiology listed above. If related to pulmonary disorders, the amount of lung damage dictates whether or not treatment is efficacious in reversing newborn lung insufficiency. Other causes for acute pulmonary hypertension include: infection, endocrine disorders, and drug injury.Examples of cases with newborns who with sustained fetal circulation are pulmonary hypoplasia and genetic abnormalities.
Treatment
Treatment aims to increase the amount of oxygen in the blood and reverse any causes of hypoxia as well as gain adequate perfusion.Common treatments include:
Oxygen therapy
Mechanical ventilation
Pulmonary vasodilators
Nitrous Oxide Inhalation (iNO)
Sildenafil
Milrinone
GlucocorticoidsThe therapies available to manage PPHN include high frequency ventilation, surfactant instillation, pulmonary vasodilators, and extracorporeal membrane oxygenation.iNO is the preferred medication for PPHN due to its ability to more selectively cause pulmonary vasodilation in comparison to intravenous vasodilators. While this medication decreases the need for extracorporeal membrane oxygenation or extracorporeal life support, it has not been shown to reduce mortality. Intravenous sildenafil has been shown to have similar efficacy and is becoming more commonly used as treatment for PPHN.Assessment of the efficacy of these treatments includes chest radiographs and arterial blood gases. Signs of inefficacious treatments include prolonged capillary filling time, low pulse volume, low blood pressure, and sustained metabolic acidosis.In addition to treating the direct effects of this condition, other management strategies are implemented concurrently to stabilize the newborn.These include, but are not limited to nutritional support, reduction of stressful environment, gentle sedation, monitoring/treating acidosis and establishing normal systemic blood pressure.Challenges in developing countries:
PPHN has been seen more frequently in developing countries or resource-poor areas, though it occurs across the globe. Treating this condition often involves large interdisciplinary teams, which is not always possible in developing countries. In low-resource environments, it is recommended to focus on five main bundles of management:
Increasing oxygen supply
Decreasing oxygen demand
Facilitating gas exchange
Inducing pulmonary vasodilation
Fixing metabolic disturbances
Epidemiology
It occurs in 1–2 infants per 1000 live births. It is more common in males and in areas with higher altitudes. Additionally, two percent of infants with respiratory distress syndrome develop PPHN.
References
Further reading
Dunn PM (March 1994). "Professor Charles D Meigs (1792-1869) of Philadelphia and persistent fetal circulation". Archives of Disease in Childhood. Fetal and Neonatal Edition. 70 (2): F155-6. doi:10.1136/fn.70.2.f155. PMC 1061019. PMID 8154909.
== External links == |
Eosinophilic pustular folliculitis of infancy | Eosinophilic pustular folliculitis of infancy is a cutaneous condition characterized by recurrent pruritic crops of follicular vesiculopustular lesions.
See also
Eosinophilic pustular folliculitis
List of cutaneous conditions
== References == |
Hyperglycinemia | Hyperglycinemia may refer to one of two related inborn amino acid disorders that are characterized by elevated levels of glycine in the blood.
Propionic acidemia, also known as "ketotic glycinemia"
Glycine encephalopathy, also known as "non-ketotic hyperglycinemia" |
Olivopontocerebellar atrophy | Olivopontocerebellar atrophy (OPCA) is the degeneration of neurons in specific areas of the brain – the cerebellum, pons, and inferior olivary nucleus. OPCA is present in several neurodegenerative syndromes, including inherited and non-inherited forms of ataxia (such as the hereditary spinocerebellar ataxia known as Machado–Joseph disease) and multiple system atrophy (MSA), with which it is primarily associated.OPCA may also be found in the brains of individuals with prion disorders and inherited metabolic diseases. The characteristic areas of brain damage that indicate OPCA can be seen by imaging the brain using CT scans or MRI studies.The term was originally coined by Joseph Jules Dejerine and André Thomas.
Signs and symptoms
OPCA is characterized by progressive cerebellar ataxia, leading to clumsiness in body movements, veering from midline when walking, wide-based stance, and falls without signs of paralysis or weakness. Clinical presentation can vary greatly between patients, but mostly affects speech, balance and walking. Other possible neurological problems include spasmodic dysphonia, hypertonia, hyperreflexia, rigidity, dysarthria, dysphagia and neck dystonic posture.
Cause
Olivopontocerebellar atrophy is hereditary, but has an unknown genetic basis. There are two forms:
A few non-hereditary diseases formerly categorized as olivopontocerebellar atrophy have been reclassified as forms of multiple system atrophy as well as to four hereditary types, that have been currently reclassified as four different forms of spinocerebellar ataxia:
Diagnosis
A diagnosis of olivopontocerebellar atrophy (OPCA) may be based on a thorough medical exam; the presence of signs and symptoms; imaging studies; various laboratory tests; and an evaluation of the family history.MRI of the brain may show characteristics of OPCA, such as specific changes in the size of affected parts of the brain. This is more likely as the disease progresses; it is possible to have OPCA and have a normal brain MRI (especially within the first year of symptom onset).Hereditary OPCA may be suspected based on having a family history, and may be diagnosed by genetic testing (when available) for the condition suspected or known to be present in the family. Sporadic OPCA may be diagnosed if hereditary forms of OPCA, and other conditions associated with OPCA, have been ruled out.
Treatment
Physiotherapy intervention aims to improve balance and gait of OPCA patients, by stimulating neuroplastic changes in the atrophied neural structure. A challenge-oriented treatment program has previously been shown to be beneficial for individuals with ataxia from OPCA. The treatment program was composed of repetitive training with task challenges (e.g. obstacle course) and/or novel motor skills acquisition over a 12-week period under the supervision of a physiotherapist. Task challenges were progressed only when the patient showed mastery of a task.Overground harness systems may be used to allow OPCA patients to challenge their balance without chance of falling. Furthermore, home exercise programs and/or aquatic exercises are used to allow more repetitions to facilitate balance learning. Treatment programs should be frequently monitored and adjusted based on a patients progress. Outcome measures such as the Berg Balance Scale, Dynamic Gait Index and activities-specific balance confidence scales are useful to assess patients progress over time.
See also
Olivopontocerebellar atrophy-deafness syndrome
References
External links
Olivopontocerebellar atrophy at NINDS |
Adenoma | An adenoma is a benign tumor of epithelial tissue with glandular origin, glandular characteristics, or both. Adenomas can grow from many glandular organs, including the adrenal glands, pituitary gland, thyroid, prostate, and others. Some adenomas grow from epithelial tissue in nonglandular areas but express glandular tissue structure (as can happen in familial polyposis coli). Although adenomas are benign, they should be treated as pre-cancerous. Over time adenomas may transform to become malignant, at which point they are called adenocarcinomas. Most adenomas do not transform. However, even though benign, they have the potential to cause serious health complications by compressing other structures (mass effect) and by producing large amounts of hormones in an unregulated, non-feedback-dependent manner (causing paraneoplastic syndromes). Some adenomas are too small to be seen macroscopically but can still cause clinical symptoms.
Histopathology
Adenoma is a benign tumor of glandular tissue, such as the mucosa of stomach, small intestine, and colon, in which tumor cells form glands or gland like structures.
In hollow organs (digestive tract), the adenoma grows into the lumen - adenomatous polyp or polypoid adenoma. Depending on the type of the insertion base, adenoma may be pedunculated (lobular head with a long slender stalk) or sessile (broad base).
The adenomatous proliferation is characterized by different degrees of cell dysplasia (atypia or loss of normal differentiation of epithelium) irregular cells with hyperchromatic nuclei, stratified or pseudostratified nuclei, nucleolus, decreased mucosecretion, and mitosis. The architecture may be tubular, villous, or tubulo-villous. Basement membrane and muscularis mucosae are intact.
Locations
Colon
Adenomas of the colon, also called adenomatous polyps, are quite prevalent. They are found commonly at colonoscopy. They are removed because of their tendency to become malignant and to lead to colon cancer.
Ashkenazi Jews have a 6% higher risk rate of getting adenomas, and then colon cancer, than do the general population, so it is important that they have regular actual colonoscopies, and specifically none of the less invasive diagnostic methods.
Renal
This is a tumor that is most often small and asymptomatic, and is derived from renal tubules. It may be a precursor lesion to renal carcinoma.
Adrenal
Adrenal adenomas are common, and are often found on the abdomen, usually not as the focus of investigation; they are usually incidental findings. About one in 10,000 is malignant. Thus, a biopsy is rarely called for, especially if the lesion is homogeneous and smaller than 3 centimeters. Follow-up images in three to six months can confirm the stability of the growth.
While some adrenal adenomas do not secrete hormones at all, often some secrete cortisol, causing Cushings syndrome, aldosterone causing Conns syndrome, or androgens causing hyperandrogenism.
Thyroid
About one in 10 people is found to have solitary thyroid nodules. Investigation is required because a small percentage of these is malignant. Biopsy usually confirms the growth to be an adenoma, but, sometimes, excision at surgery is required, especially when the cells found at biopsy are of the follicular type.
Pituitary
Pituitary adenomas are seen in 10% of neurological patients. A lot of them remain undiagnosed. Treatment is usually surgical, to which patients generally respond well. The most common subtype, prolactinoma, is seen more often in women, and is frequently diagnosed during pregnancy as the hormone progesterone increases its growth. Medical therapy with cabergoline or bromocriptine generally suppresses prolactinomas; progesterone antagonist therapy has not proven to be successful.
Parathyroid
An adenoma of a parathyroid gland may secrete inappropriately high amounts of parathyroid hormone and thereby cause primary hyperparathyroidism.
Liver
Hepatic adenomas are a rare benign tumour of the liver, which may present with hepatomegaly or other symptoms.
Breast
Breast adenomas are called fibroadenomas. They are often very small and difficult to detect. Often there are no symptoms. Treatments can include a needle biopsy, and/or removal.
Appendix
Adenomas can also appear in the appendix. The condition is extremely rare. The most common version is called cystadenoma. They are usually discovered in the course of examination of the tissue following an appendectomy. If the appendix has ruptured and a tumor is present, this presents challenges, especially if malignant cells have formed and thus spread to the abdomen.
Bronchial
Bronchial adenomas are adenomas in the bronchi. They may cause carcinoid syndrome, a type of paraneoplastic syndrome.
Sebaceous
A sebaceous adenoma is a cutaneous condition characterized by a slow-growing tumour usually presenting as a pink, flesh-coloured, or yellow papule or nodule.
Salivary glands
Most salivary gland tumors are benign – that is, they are not cancer and will not spread to other parts of the body. These tumors are almost never life-threatening.
There are many types of benign salivary gland tumors, with names such as adenomas, oncocytomas, Warthin tumors, and benign mixed tumors (also known as pleomorphic adenomas).
Benign tumors are almost always cured by surgery. Very rarely, they may become cancer if left untreated for a long time or if they are not completely removed and grow back. Its not clear exactly how benign tumors become cancers. There are many types of salivary gland cancers. Normal salivary glands are made up of several different types of cells, and tumors can start in any of these cell types. Salivary gland cancers are named according to which of these cell types they most look like when seen under a microscope. The main types of cancers are described below.
Doctors usually give salivary cancers a grade (from 1 to 3, or from low to high), based on how abnormal the cancers look under a microscope. The grade gives a rough idea of how quickly it is likely to grow and spread.
Grade 1 cancers (also called low grade or well differentiated) look very much like normal salivary gland cells. They tend to grow slowly and have a good outcome (prognosis).
Grade 2 cancers (also called intermediate grade or moderately differentiated) have an appearance and outlook that is between grade 1 and grade 3 cancers.
Grade 3 cancers (also called high grade or poorly differentiated) look very different from normal cells and often grow and/or spread quickly. The outlook for these cancers is usually not as good as for lower grade cancers.
Prostate
Prostate adenoma develops from the periurethral glands at the site of the median or lateral lobes.
Treatment
A physicians response to detecting an adenoma in a patient will vary according to the type and location of the adenoma among other factors. Different adenomas will grow at different rates, but typically physicians can anticipate the rates of growth because some types of common adenomas progress similarly in most patients. Two common responses are removing the adenoma with surgery and then monitoring the patient according to established guidelines.One common example of treatment is the response recommended by specialty professional organizations upon removing adenomatous polyps from a patient. In the common case of removing one or two of these polyps from the colon from a patient with no particular risk factors for cancer, thereafter the best practice is to resume surveillance colonoscopy after 5–10 years rather than repeating it more frequently than the standard recommendation.
References
External links
Adrenal adenoma description at 00007 at CHORUSPhotos (colon adenoma) at Atlas of Pathology |
Macular hole | A macular hole is a small break in the macula, located in the center of the eyes light-sensitive tissue called the retina.
Symptoms
If the vitreous is firmly attached to the retina when it pulls away, it can tear the retina and create a macular hole. Also, once the vitreous has pulled away from the surface of the retina, some of the fibers can remain on the retinal surface and can contract. This increases tension on the retina and can lead to a macular hole. In either case, the fluid that has replaced the shrunken vitreous can then seep through the hole onto the macula, blurring and distorting central vision.
Causes
The eye contains a jelly-like substance called the vitreous. Shrinking of the vitreous usually causes the hole. As a person ages, the vitreous becomes watery and begins to pull away from the retina. If the vitreous is firmly attached to the retina when it pulls away, a hole can result.
Diagnosis
Macular degeneration is a condition affecting the tissues lying under the retina, while a macular hole involves damage from within the eye, at the junction between the vitreous and the retina itself. There is no relationship between the two diseases. Depending upon the degree of attachment or traction between the vitreous and the retina, there may be risk of developing a macular hole in the other eye. In those cases where the vitreous has already become separated from the retinal surface, there is very little chance of developing a macular hole in the other eye. On the other hand, when the vitreous remains adherent and pulling on the macular region in both eyes, then there may be a greater risk of developing a hole in the second eye. In very rare instances, trauma or other conditions lead to the development of a macular hole. In the vast majority of cases, however, macular holes develop spontaneously. As a result, there is no known way to prevent their development through any nutritional or chemical means, nor is there any way to know who is at risk for developing a hole prior to its appearance in one or both eyes.
Management
Vitrectomy is the common way to treat a macular hole. It is done by placing a gas bubble in the vitreous of the eye which helps flatten the macular hole and holds it in place as the eye heals. The gas bubble slowly shrinks on its own. Treatment is also done using ocriplasmin.
References
5. Saurabh K, Roy R, Mishra S, Garg B, Goel S. Multicolor imaging features of dissociated optic nerve fiber layer after internal limiting membrane peeling. Indian journal of ophthalmology. 2018 Dec 1;66(12):1853.
External links
Macular Hole Resource Guide from the National Eye Institute (NEI). |
Huntingtons disease | Huntingtons disease (HD), also known as Huntingtons chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unsteady gait often follow. It is also a basal ganglia disease causing a hyperkinetic movement disorder known as chorea. As the disease advances, uncoordinated, involuntary body movements of chorea become more apparent. Physical abilities gradually worsen until coordinated movement becomes difficult and the person is unable to talk. Mental abilities generally decline into dementia. The specific symptoms vary somewhat between people. Symptoms usually begin between 30 and 50 years of age but can start at any age. The disease may develop earlier in each successive generation. About eight percent of cases start before the age of 20 years, and are known as juvenile HD, which typically present with the slow movement symptoms of Parkinsons disease rather than those of chorea.HD is typically inherited from an affected parent, who carries a mutation in the huntingtin gene (HTT). However, up to 10% of cases are due to a new mutation. The huntingtin gene provides the genetic information for huntingtin protein (Htt). Expansion of CAG repeats of cytosine-adenine-guanine (known as a trinucleotide repeat expansion) in the gene coding for the huntingtin protein results in an abnormal mutant protein (mHtt), which gradually damages brain cells through a number of possible mechanisms. Diagnosis is by genetic testing, which can be carried out at any time, regardless of whether or not symptoms are present. This fact raises several ethical debates: the age at which an individual is considered mature enough to choose testing; whether parents have the right to have their children tested; and managing confidentiality and disclosure of test results.No cure for HD is known, and full-time care is required in the later stages. Treatments can relieve some symptoms, and in some, improve quality of life. The best evidence for treatment of the movement problems is with tetrabenazine. HD affects about 4 to 15 in 100,000 people of European descent. It is rare among Japanese, while the occurrence rate in Africa is unknown. The disease affects men and women equally. Complications such as pneumonia, heart disease, and physical injury from falls reduce life expectancy. Suicide is the cause of death in about 9% of cases. Death typically occurs 15–20 years from when the disease was first detected.The earliest known description of the disease was in 1841 by American physician Charles Oscar Waters. The condition was described in further detail in 1872 by American physician George Huntington. The genetic basis was discovered in 1993 by an international collaborative effort led by the Hereditary Disease Foundation. Research and support organizations began forming in the late 1960s to increase public awareness, provide support for individuals and their families and promote research. Research directions include determining the exact mechanism of the disease, improving animal models to aid with research, testing of medications and their delivery to treat symptoms or slow the progression of the disease, and studying procedures such as stem-cell therapy with the goal of replacing damaged or lost neurons.
Signs and symptoms
Signs and symptoms of Huntingtons disease most commonly become noticeable between the ages of 30 and 50 years, but they can begin at any age, and present as a triad of motor, cognitive, and psychiatric symptoms. In 50% of cases, the psychiatric symptoms appear first. Their progression is often described in early stages, middle stages, and late stages with an earlier prodromal phase. In the early stages, subtle personality changes, problems in cognition, and physical skills, irritability, and mood swings occur, all of which may go unnoticed, and these usually precede the motor symptoms. Almost everyone with HD eventually exhibits similar physical symptoms, but the onset, progression, and extent of cognitive and behavioral symptoms vary significantly between individuals.The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called chorea. Many people are not aware of their involuntary movements, or impeded by them. Chorea may be initially exhibited as general restlessness, small unintentionally initiated or uncompleted motions, lack of coordination, or slowed saccadic eye movements. These minor motor abnormalities usually precede more obvious signs of motor dysfunction by at least three years. The clear appearance of symptoms such as rigidity, writhing motions, or abnormal posturing appear as the disorder progresses. These are signs that the system in the brain that is responsible for movement has been affected. Psychomotor functions become increasingly impaired, such that any action that requires muscle control is affected. Common consequences are physical instability, abnormal facial expression, and difficulties chewing, swallowing, and speaking. Sleep disturbances and weight loss are also associated symptoms. Eating difficulties commonly cause weight loss and may lead to malnutrition. Juvenile HD generally progresses at a faster rate with greater cognitive decline, and chorea is exhibited briefly, if at all; the Westphal variant of slowness of movement, rigidity, and tremors is more typical in juvenile HD, as are seizures.Cognitive abilities are progressively impaired and tend to generally decline into dementia. Especially affected are executive functions, which include planning, cognitive flexibility, abstract thinking, rule acquisition, initiation of appropriate actions, and inhibition of inappropriate actions. As the disease progresses, memory deficits tend to appear. Reported impairments range from short-term memory deficits to long-term memory difficulties, including deficits in episodic (memory of ones life), procedural (memory of the body of how to perform an activity), and working memory.Reported neuropsychiatric signs are anxiety, depression, a reduced display of emotions, egocentrism, aggression, and compulsive behavior, the latter of which can cause or worsen addictions, including alcoholism, gambling, and hypersexuality. Difficulties in recognizing other peoples negative expressions have also been observed. The prevalence of these symptoms is highly variable between studies, with estimated rates for lifetime prevalence of psychiatric disorders between 33 and 76%. For many with the disease and their families, these symptoms are among the most distressing aspects of the disease, often affecting daily functioning and constituting reason for institutionalization. Early behavioral changes in HD result in an increased risk of suicide. Often, individuals have reduced awareness of chorea, cognitive, and emotional impairments.Mutant huntingtin is expressed throughout the body and associated with abnormalities in peripheral tissues that are directly caused by such expression outside the brain. These abnormalities include muscle atrophy, cardiac failure, impaired glucose tolerance, weight loss, osteoporosis, and testicular atrophy.
Genetics
Everyone has two copies of the huntingtin gene (HTT), which codes for the huntingtin protein (Htt). HTT is also called the HD gene, and the IT15 gene, (interesting transcript 15). Part of this gene is a repeated section called a trinucleotide repeat expansion – a short repeat, which varies in length between individuals, and may change length between generations. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant huntingtin protein (mHtt). The differing functions of these proteins are the cause of pathological changes, which in turn cause the disease symptoms. The Huntingtons disease mutation is genetically dominant and almost fully penetrant; mutation of either of a persons HTT alleles causes the disease. It is not inherited according to sex, but by the length of the repeated section of the gene, hence its severity can be influenced by the sex of the affected parent.
Genetic mutation
HD is one of several trinucleotide repeat disorders that are caused by the length of a repeated section of a gene exceeding a normal range. The HTT gene is located on the short arm of chromosome 4 at 4p16.3. HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e.... CAGCAGCAG...), known as a trinucleotide repeat. CAG is the three-letter genetic code (codon) for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the polyQ region.
Generally, people have fewer than 36 repeated glutamines in the polyQ region, which results in the production of the cytoplasmic protein huntingtin. However, a sequence of 36 or more glutamines results in the production of a protein with different characteristics. This altered form, called mutant huntingtin (mHtt), increases the decay rate of certain types of neurons. Regions of the brain have differing amounts and reliance on these types of neurons and are affected accordingly. Generally, the number of CAG repeats is related to how much this process is affected, and accounts for about 60% of the variation of the age of the onset of symptoms. The remaining variation is attributed to the environment and other genes that modify the mechanism of HD. About 36 to 39 repeats result in a reduced-penetrance form of the disease, with a much later onset and slower progression of symptoms. In some cases, the onset may be so late that symptoms are never noticed. With very large repeat counts (more than 60), HD onset can occur below the age of 20, known as juvenile HD. Juvenile HD is typically of the Westphal variant that is characterised by slowness of movement, rigidity, and tremors. This accounts for about 7% of HD carriers.
Inheritance
Huntingtons disease has autosomal dominant inheritance, meaning that an affected individual typically inherits one copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected parent. Since the penetrance of the mutation is very high, those who have a mutated copy of the gene will have the disease. In this type of inheritance pattern, each offspring of an affected individual has a 50% risk of inheriting the mutant allele, so are affected with the disorder (see figure). This probability is sex-independent.Trinucleotide CAG repeats numbering over 28 are unstable during replication, and this instability increases with the number of repeats present. This usually leads to new expansions as generations pass (dynamic mutations) instead of reproducing an exact copy of the trinucleotide repeat. This causes the number of repeats to change in successive generations, such that an unaffected parent with an "intermediate" number of repeats (28–35), or "reduced penetrance" (36–40), may pass on a copy of the gene with an increase in the number of repeats that produces fully penetrant HD. The earlier age of onset and greater severity of disease in successive generations due to increases in the number of repeats is known as genetic anticipation. Instability is greater in spermatogenesis than oogenesis; maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length. Rarely is Huntingtons disease caused by a new mutation, where neither parent has over 36 CAG repeats.In the rare situations where both parents have an expanded HD gene, the risk increases to 75%, and when either parent has two expanded copies, the risk is 100% (all children will be affected). Individuals with both genes affected are rare. For some time, HD was thought to be the only disease for which possession of a second mutated gene did not affect symptoms and progression, but it has since been found that it can affect the phenotype and the rate of progression.
Mechanisms
Huntingtin protein interacts with over 100 other proteins, and appears to have multiple functions. The behavior of the mutated protein (mHtt) is not completely understood, but it is toxic to certain cell types, particularly brain cells. Early damage is most evident in the subcortical basal ganglia, initially in the striatum, but as the disease progresses, other areas of the brain are also affected, including regions of the cerebral cortex. Early symptoms are attributable to functions of the striatum and its cortical connections—namely control over movement, mood, and higher cognitive function. DNA methylation also appears to be changed in HD.
Huntingtin function
Htt is expressed in all cells, with the highest concentrations found in the brain and testes, and moderate amounts in the liver, heart, and lungs. Its functions are unclear, but it does interact with proteins involved in transcription, cell signaling, and intracellular transporting. In animals genetically modified to exhibit HD, several functions of Htt have been identified. In these animals, Htt is important for embryonic development, as its absence is related to embryonic death. Caspase, an enzyme which plays a role in catalyzing apoptosis, is thought to be activated by the mutated gene through damaging the ubiquitin-protease system. It also acts as an antiapoptotic agent preventing programmed cell death and controls the production of brain-derived neurotrophic factor, a protein that protects neurons and regulates their creation during neurogenesis. Htt also facilitates synaptic vesicular transport and synaptic transmission, and controls neuronal gene transcription. If the expression of Htt is increased, brain cell survival is improved and the effects of mHtt are reduced, whereas when the expression of Htt is reduced, the resulting characteristics are more as seen in the presence of mHtt. Accordingly, the disease is thought not to be caused by inadequate production of Htt, but by a toxic gain-of-function of mHtt in the body.
Cellular changes
The toxic action of mHtt may manifest and produce the HD pathology through multiple cellular changes. In its mutant (polyglutamine expanded) form, the protein is more prone to cleavage that creates shorter fragments containing the polyglutamine expansion. These protein fragments have a propensity to undergo misfolding and aggregation, yielding fibrillar aggregates in which non-native polyglutamine β-strands from multiple proteins are bonded together by hydrogen bonds. These aggregates share the same fundamental cross-beta amyloid architecture seen in other protein deposition diseases. Over time, the aggregates accumulate to form inclusion bodies within cells, ultimately interfering with neuronal function. Inclusion bodies have been found in both the cell nucleus and cytoplasm. Inclusion bodies in cells of the brain are one of the earliest pathological changes, and some experiments have found that they can be toxic for the cell, but other experiments have shown that they may form as part of the bodys defense mechanism and help protect cells.Several pathways by which mHtt may cause cell death have been identified. These include effects on chaperone proteins, which help fold proteins and remove misfolded ones; interactions with caspases, which play a role in the process of removing cells; the toxic effects of glutamine on nerve cells; impairment of energy production within cells; and effects on the expression of genes.Mutant huntingtin protein has been found to play a key role in mitochondrial dysfunction. The impairment of mitochondrial electron transport can result in higher levels of oxidative stress and release of reactive oxygen species.Glutamine is known to be excitotoxic when present in large amounts, that can cause damage to numerous cellular structures. Excessive glutamine is not found in HD, but the interactions of the altered huntingtin protein with numerous proteins in neurons lead to an increased vulnerability to glutamine. The increased vulnerability is thought to result in excitotoxic effects from normal glutamine levels.
Macroscopic changes
Initially, damage to the brain is regionally specific with the dorsal striatum in the subcortical basal ganglia being primarily affected, followed later by cortical involvement in all areas. Other areas of the basal ganglia affected include the substantia nigra; cortical involvement includes cortical layers 3, 5, and 6; also evident is involvement of the hippocampus, Purkinje cells in the cerebellum, lateral tuberal nuclei of the hypothalamus and parts of the thalamus. These areas are affected according to their structure and the types of neurons they contain, reducing in size as they lose cells. Striatal medium spiny neurons are the most vulnerable, particularly ones with projections towards the external globus pallidus, with interneurons and spiny cells projecting to the internal globus pallidus being less affected. HD also causes an abnormal increase in astrocytes and activation of the brains immune cells, microglia.The basal ganglia play a key role in movement and behavior control. Their functions are not fully understood, but theories propose that they are part of the cognitive executive system and the motor circuit. The basal ganglia ordinarily inhibit a large number of circuits that generate specific movements. To initiate a particular movement, the cerebral cortex sends a signal to the basal ganglia that causes the inhibition to be released. Damage to the basal ganglia can cause the release or reinstatement of the inhibitions to be erratic and uncontrolled, which results in an awkward start to motion or motions to be unintentionally initiated, or a motion to be halted before, or beyond, its intended completion. The accumulating damage to this area causes the characteristic erratic movements associated with HD known as chorea, a dyskinesia. Because of the basal ganglias inability to inhibit movements, individuals affected by it inevitably experience a reduced ability to produce speech and swallow foods and liquids (dysphagia).
Transcriptional dysregulation
CREB-binding protein (CBP), a transcriptional coregulator, is essential for cell function because as a coactivator at a significant number of promoters, it activates the transcription of genes for survival pathways. Furthermore, the amino acids that form CBP include a strip of 18 glutamines. Thus, the glutamines on CBP interact directly with the increased numbers of glutamine on the HTT chain and CBP gets pulled away from its typical location next to the nucleus. Specifically, CBP contains an acetyltransferase domain to which HTT binds through its polyglutamine-containing domain. Autopsied brains of those who had Huntingtons disease also have been found to have incredibly reduced amounts of CBP. In addition, when CBP is overexpressed, polyglutamine-induced death is diminished, further demonstrating that CBP plays an important role in Huntingtons disease and neurons in general.
Diagnosis
Diagnosis of the onset of HD can be made following the appearance of physical symptoms specific to the disease. Genetic testing can be used to confirm a physical diagnosis if no family history of HD exists. Even before the onset of symptoms, genetic testing can confirm if an individual or embryo carries an expanded copy of the trinucleotide repeat (CAG) in the HTT gene that causes the disease. Genetic counseling is available to provide advice and guidance throughout the testing procedure and on the implications of a confirmed diagnosis. These implications include the impact on an individuals psychology, career, family-planning decisions, relatives, and relationships. Despite the availability of presymptomatic testing, only 5% of those at risk of inheriting HD choose to do so.
Clinical
A physical examination, sometimes combined with a psychological examination, can determine whether the onset of the disease has begun. Excessive unintentional movements of any part of the body are often the reason for seeking medical consultation. If these are abrupt and have random timing and distribution, they suggest a diagnosis of HD. Cognitive or behavioral symptoms are rarely the first symptoms diagnosed; they are usually only recognized in hindsight or when they develop further. How far the disease has progressed can be measured using the unified Huntingtons disease rating scale, which provides an overall rating system based on motor, behavioral, cognitive, and functional assessments. Medical imaging, such as a CT scan or MRI scan, can show atrophy of the caudate nuclei early in the disease, as seen in the illustration to the right, but these changes are not, by themselves, diagnostic of HD. Cerebral atrophy can be seen in the advanced stages of the disease. Functional neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), can show changes in brain activity before the onset of physical symptoms, but they are experimental tools and are not used clinically.
Predictive genetic testing
Because HD follows an autosomal dominant pattern of inheritance, a strong motivation exists for individuals who are at risk of inheriting it to seek a diagnosis. The genetic test for HD consists of a blood test, which counts the numbers of CAG repeats in each of the HTT alleles. Cutoffs are given as follows:
At 40 or more CAG repeats, full penetrance allele (FPA) exists. A "positive test" or "positive result" generally refers to this case. A positive result is not considered a diagnosis, since it may be obtained decades before the symptoms begin. However, a negative test means that the individual does not carry the expanded copy of the gene and will not develop HD. The test will tell a person who originally had a 50% chance of inheriting the disease if their risk goes up to 100% or is eliminated. Persons who test positive for the disease will develop HD sometime within their lifetimes, provided they live long enough for the disease to appear.
At 36 to 39 repeats, incomplete or reduced penetrance allele (RPA) may cause symptoms, usually later in the adult life. The maximum risk is 60% that a person with an RPA will be symptomatic at age 65, and 70% at 75.
At 27 to 35 repeats, intermediate allele (IA), or large normal allele, is not associated with symptomatic disease in the tested individual, but may expand upon further inheritance to give symptoms in offspring.
With 26 or fewer repeats, the result is not associated with HD.Testing before the onset of symptoms is a life-changing event and a very personal decision. The main reason given for choosing to test for HD is to aid in career and family decisions. Predictive testing for Huntingtons disease has been available via linkage analysis (which requires testing multiple family members) since 1986 and via direct mutation analysis since 1993. At that time, surveys indicated that 50–70% of at-risk individuals would have been interested in receiving testing, but since predictive testing has been offered far fewer choose to be tested. Over 95% of individuals at risk of inheriting HD do not proceed with testing, mostly because it has no treatment. A key issue is the anxiety an individual experiences about not knowing whether they will eventually develop HD, compared to the impact of a positive result. Irrespective of the result, stress levels are lower two years after being tested, but the risk of suicide is increased after a positive test result. Individuals found to have not inherited the disorder may experience survivor guilt about family members who are affected. Other factors taken into account when considering testing include the possibility of discrimination and the implications of a positive result, which usually means a parent has an affected gene and that the individuals siblings will be at risk of inheriting it. In one study, genetic discrimination was found in 46% of individuals at risk for Huntingtons disease. It occurred at higher rates within personal relationships than health insurance or employment relations. Genetic counseling in HD can provide information, advice and support for initial decision-making, and then, if chosen, throughout all stages of the testing process. Because of the implications of this test, patients who wish to undergo testing must complete three counseling sessions which provide information about Huntingtons.Counseling and guidelines on the use of genetic testing for HD have become models for other genetic disorders, such as autosomal dominant cerebellar ataxia. Presymptomatic testing for HD has also influenced testing for other illnesses with genetic variants such as polycystic kidney disease, familial Alzheimers disease and breast cancer. The European Molecular Genetics Quality Network have published yearly external quality assessment scheme for molecular genetic testing for this disease and have developed best practice guidelines for genetic testing for HD to assist in testing and reporting of results.
Preimplantation genetic diagnosis
Embryos produced using in vitro fertilization may be genetically tested for HD using preimplantation genetic diagnosis. This technique, where one or two cells are extracted from a typically 4- to 8-cell embryo and then tested for the genetic abnormality, can then be used to ensure embryos affected with HD genes are not implanted, so any offspring will not inherit the disease. Some forms of preimplantation genetic diagnosis—non-disclosure or exclusion testing—allow at-risk people to have HD-free offspring without revealing their own parental genotype, giving no information about whether they themselves are destined to develop HD. In exclusion testing, the embryos DNA is compared with that of the parents and grandparents to avoid inheritance of the chromosomal region containing the HD gene from the affected grandparent. In nondisclosure testing, only disease-free embryos are replaced in the uterus while the parental genotype and hence parental risk for HD are never disclosed.
Prenatal testing
Obtaining a prenatal diagnosis for an embryo or fetus in the womb is also possible, using fetal genetic material acquired through chorionic villus sampling. An amniocentesis can be performed if the pregnancy is further along, within 14–18 weeks. This procedure looks at the amniotic fluid surrounding the baby for indicators of the HD mutation. This, too, can be paired with exclusion testing to avoid disclosure of parental genotype. Prenatal testing can be done when parents have been diagnosed with HD, when they have had genetic testing showing the expansion of the HTTgene, or when they have a 50% chance of inheriting the disease. The parents can be counseled on their options, which include termination of pregnancy, and on the difficulties of a child with the identified gene.In addition, in at-risk pregnancies due to an affected male partner, noninvasive prenatal diagnosis can be performed by analyzing cell-free fetal DNA in a blood sample taken from the mother (via venipuncture) between six and 12 weeks of pregnancy. It has no procedure-related risk of miscarriage.
Differential diagnosis
About 99% of HD diagnoses based on the typical symptoms and a family history of the disease are confirmed by genetic testing to have the expanded trinucleotide repeat that causes HD. Most of the remaining are called HD-like (HDL) syndromes. The cause of most HDL diseases is unknown, but those with known causes are due to mutations in the prion protein gene (HDL1), the junctophilin 3 gene (HDL2), a recessively inherited unknown gene (HDL3—only found in two families and poorly understood), and the gene encoding the TATA box-binding protein (SCA17, sometimes called HDL4). Other autosomal dominant diseases that can be misdiagnosed as HD are dentatorubral-pallidoluysian atrophy and neuroferritinopathy. Also, some autosomal recessive disorders resemble sporadic cases of HD. These include chorea acanthocytosis and pantothenate kinase-associated neurodegeneration. One X-linked disorder of this type is McLeod syndrome.
Management
Treatments are available to reduce the severity of some of HD symptoms. For many of these treatments, evidence to confirm their effectiveness in treating symptoms of HD specifically are incomplete. As the disease progresses, the ability to care for oneself declines, and carefully managed multidisciplinary caregiving becomes increasingly necessary. Although relatively few studies of exercises and therapies have shown to be helpful to rehabilitate cognitive symptoms of HD, some evidence shows the usefulness of physical therapy, occupational therapy, and speech therapy.
Therapy
Weight loss and problems in eating due to dysphagia and other muscle discoordination are common, making nutrition management increasingly important as the disease advances. Thickening agents can be added to liquids, as thicker fluids are easier and safer to swallow. Reminding the affected person to eat slowly and to take smaller pieces of food into the mouth may also be of use to prevent choking. If eating becomes too hazardous or uncomfortable, the option of using a percutaneous endoscopic gastrostomy is available. This feeding tube, permanently attached through the abdomen into the stomach, reduces the risk of aspirating food and provides better nutritional management. Assessment and management by speech-language pathologists with experience in Huntingtons disease is recommended.People with Huntingtons disease may see a physical therapist for noninvasive and nonmedication-based ways of managing the physical symptoms. Physical therapists may implement fall risk assessment and prevention, as well as strengthening, stretching, and cardiovascular exercises. Walking aids may be prescribed as appropriate. Physical therapists also prescribe breathing exercises and airway clearance techniques with the development of respiratory problems. Consensus guidelines on physiotherapy in Huntingtons disease have been produced by the European HD Network. Goals of early rehabilitation interventions are prevention of loss of function. Participation in rehabilitation programs during the early to middle stage of the disease may be beneficial as |
Huntingtons disease | it translates into long-term maintenance of motor and functional performance. Rehabilitation during the late stage aims to compensate for motor and functional losses. For long-term independent management, the therapist may develop home exercise programs for appropriate people.Additionally, an increasing number of people with HD are turning to palliative care, which aims to improve quality of life through the treatment of the symptoms and stress of serious illness, in addition to their other treatments.
Medications
Tetrabenazine was approved in 2000 for treatment of chorea in Huntingtons disease in the EU, and in 2008 in the US. Although other drugs had been used "off label," tetrabenazine was the first approved treatment for Huntingtons disease in the U.S. The compound has been known since the 1950s. An alternative to tetrabenazine is amantadine but there is limited evidence for its safety and efficacy.Other drugs that help to reduce chorea include antipsychotics and benzodiazepines. Hypokinesia and rigidity, especially in juvenile cases, can be treated with antiparkinsonian drugs, and myoclonic hyperkinesia can be treated with valproic acid. Tentative evidence has found ethyl eicosapentaenoic acid to improve motor symptoms at one year. In 2017 Deutetrabenazine a heavier form of tetrabenazine medication for the treatment of chorea in HD was approved by the FDA. This is marketed as Austedo, and is the first small-molecule drug to receive U.S. FDA approval.Psychiatric symptoms can be treated with medications similar to those used in the general population. Selective serotonin reuptake inhibitors and mirtazapine have been recommended for depression, while atypical antipsychotics are recommended for psychosis and behavioral problems. Specialist neuropsychiatric input is recommended as people may require long-term treatment with multiple medications in combination.
Education
The families of individuals, and society at large, who have inherited or are at risk of inheriting HD have generations of experience of HD but may be unaware of recent breakthroughs in understanding the disease, and of the availability of genetic testing. Genetic counseling benefits these individuals by updating their knowledge, seeking to dispel any unfounded beliefs that they may have, and helping them consider their future options and plans. The Patient Education Program for Huntingtons Disease has been created to help educate family members, caretakers, and those diagnosed with Huntingtons disease. Also covered is information concerning family planning choices, care management, and other considerations.
Prognosis
The length of the trinucleotide repeat accounts for 60% of the variation of the age of symptoms onset and their rate of progress. A longer repeat results in an earlier age of onset and a faster progression of symptoms. Individuals with more than sixty repeats often develop the disease before age 20, while those with fewer than 40 repeats may remain asymptomatic. The remaining variation is due to environmental factors and other genes that influence the mechanism of the disease.Life expectancy in HD is generally around 20 years following the onset of visible symptoms. Most life-threatening complications result from muscle coordination, and to a lesser extent, behavioral changes induced by declining cognitive function. The largest risk is pneumonia, which causes death in one third of those with HD. As the ability to synchronize movements deteriorates, difficulty clearing the lungs, and an increased risk of aspirating food or drink both increase the risk of contracting pneumonia. The second-greatest risk is heart disease, which causes almost a quarter of fatalities of those with HD. Suicide is the third greatest cause of fatalities, with 7.3% of those with HD taking their own lives and up to 27% attempting to do so. To what extent suicidal thoughts are influenced by behavioral symptoms is unclear, as they signify a desire to avoid the later stages of the disease. Other associated risks include choking, physical injury from falls, and malnutrition.
Epidemiology
The late onset of Huntingtons disease means it does not usually affect reproduction. The worldwide prevalence of HD is 5–10 cases per 100,000 persons, but varies greatly geographically as a result of ethnicity, local migration and past immigration patterns. Prevalence is similar for men and women. The rate of occurrence is highest in peoples of Western European descent, averaging around seven per 100,000 people, and is lower in the rest of the world; e.g., one per million people of Asian and African descent. A 2013 epidemiological study of the prevalence of Huntingtons disease in the UK between 1990 and 2010 found that the average prevalence for the UK was 12.3 per 100,000. Additionally, some localized areas have a much higher prevalence than their regional average. One of the highest incidences is in the isolated populations of the Lake Maracaibo region of Venezuela, where HD affects up to 700 per 100,000 persons. Other areas of high localization have been found in Tasmania and specific regions of Scotland, Wales and Sweden. Increased prevalence in some cases occurs due to a local founder effect, a historical migration of carriers into an area of geographic isolation. Some of these carriers have been traced back hundreds of years using genealogical studies. Genetic haplotypes can also give clues for the geographic variations of prevalence. Iceland, on the contrary, has a rather low prevalence of 1 per 100,000, despite the fact that Icelanders as a people are descended of the early Germanic tribes of Scandinavia which also gave rise to the Swedes; all cases with the exception of one going back nearly two centuries having derived from the offspring of a couple living early in the 19th century. Finland, as well, has a low incidence of only 2.2 per 100,000 people.Until the discovery of a genetic test, statistics could only include clinical diagnosis based on physical symptoms and a family history of HD, excluding those who died of other causes before diagnosis. These cases can now be included in statistics; and, as the test becomes more widely available, estimates of the prevalence and incidence of the disorder are likely to increase.
History
The first definite mention of HD was in a letter by Charles Oscar Waters (1816–1892), published in the first edition of Robley Dunglisons Practice of Medicine in 1842. Waters described "a form of chorea, vulgarly called magrums", including accurate descriptions of the chorea, its progression, and the strong heredity of the disease. In 1846 Charles Rollin Gorman (1817–1879) observed how higher prevalence seemed to occur in localized regions. Independently of Gorman and Waters, both students of Dunglison at Jefferson Medical College in Philadelphia, Johan Christian Lund (1830–1906) also produced an early description in 1860. He specifically noted that in Setesdalen, a secluded mountain valley in Norway, the high prevalence of dementia was associated with a pattern of jerking movement disorders that ran in families.The first thorough description of the disease was by George Huntington in 1872. Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked; he presented his detailed and accurate definition of the disease as his first paper. Huntington described the exact pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.
Of its hereditary nature. When either or both the parents have shown manifestations of the disease... one or more of the offspring almost invariably suffer from the disease... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease.
Sir William Osler was interested in the disorder and chorea in general, and was impressed with Huntingtons paper, stating, "In the history of medicine, there are few instances in which a disease has been more accurately, more graphically or more briefly described." Oslers continued interest in HD, combined with his influence in the field of medicine, helped to rapidly spread awareness and knowledge of the disorder throughout the medical community. Great interest was shown by scientists in Europe, including Louis Théophile Joseph Landouzy, Désiré-Magloire Bourneville, Camillo Golgi, and Joseph Jules Dejerine, and until the end of the century, much of the research into HD was European in origin. By the end of the 19th century, research and reports on HD had been published in many countries and the disease was recognized as a worldwide condition.During the rediscovery of Mendelian inheritance at the turn of the 20th century, HD was used tentatively as an example of autosomal dominant inheritance. English biologist William Bateson used the pedigrees of affected families to establish that HD had an autosomal dominant inheritance pattern. The strong inheritance pattern prompted several researchers, including Smith Ely Jelliffe, to attempt to trace and connect family members of previous studies. Jelliffe collected information from across New York and published several articles regarding the genealogy of HD in New England. Jelliffes research roused the interest of his college friend, Charles Davenport, who commissioned Elizabeth Muncey to produce the first field study on the East Coast of the United States of families with HD and to construct their pedigrees. Davenport used this information to document the variable age of onset and range of symptoms of HD; he claimed that most cases of HD in the US could be traced back to a handful of individuals. This research was further embellished in 1932 by P. R. Vessie, who popularized the idea that three brothers who left England in 1630 bound for Boston were the progenitors of HD in the US. The claim that the earliest progenitors had been established and eugenic bias of Munceys, Davenports, and Vessies work contributed to misunderstandings and prejudice about HD. Muncey and Davenport also popularized the idea that in the past, some with HD may have been thought to be possessed by spirits or victims of witchcraft, and were sometimes shunned or exiled by society. This idea has not been proven. Researchers have found contrary evidence; for instance, the community of the family studied by George Huntington openly accommodated those who exhibited symptoms of HD.The search for the cause of this condition was enhanced considerably in 1968, when the Hereditary Disease Foundation (HDF) was created by Milton Wexler, a psychoanalyst based in Los Angeles, California, whose wife Leonore Sabin had been diagnosed earlier that year with Huntingtons disease. The three brothers of Wexlers wife also had this disease.
The foundation was involved in the recruitment of more than 100 scientists in the US-Venezuela Huntingtons Disease Collaborative Project, which over a 10-year period from 1979, worked to locate the genetic cause. This was achieved in 1983 when a causal gene was approximately located, and in 1993, the gene was precisely located at chromosome 4 (4p16.3). The study had focused on the populations of two isolated Venezuelan villages, Barranquitas and Lagunetas, where there was an unusually high prevalence of HD, and involved over 18,000 people, mostly from a single extended family, and resulted in making HD the first autosomal disease locus found using genetic linkage analysis. Among other innovations, the project developed DNA-marking methods which were an important step in making the Human Genome Project possible.In the same time, key discoveries concerning the mechanisms of the disorder were being made, including the findings by Anita Hardings research group on the effects of the genes length.Modelling the disease in various types of animals, such as the transgenic mouse developed in 1996, enabled larger-scale experiments. As these animals have faster metabolisms and much shorter lifespans than humans results from experiments are received sooner, speeding research. The 1997 discovery that mHtt fragments misfold led to the discovery of the nuclear inclusions they cause. These advances have led to increasingly extensive research into the proteins involved with the disease, potential drug treatments, care methods, and the gene itself.The condition was formerly called Huntingtons chorea, but this term has been replaced by Huntingtons disease because not all patients develop chorea and due to the importance of cognitive and behavioral problems.
Society and culture
Ethics
Genetic testing for Huntingtons disease has raised several ethical issues. The issues for genetic testing include defining how mature an individual should be before being considered eligible for testing, ensuring the confidentiality of results, and whether companies should be allowed to use test results for decisions on employment, life insurance or other financial matters. There was controversy when Charles Davenport proposed in 1910 that compulsory sterilization and immigration control be used for people with certain diseases, including HD, as part of the eugenics movement. In vitro fertilization has some issues regarding its use of embryos. Some HD research has ethical issues due to its use of animal testing and embryonic stem cells.The development of an accurate diagnostic test for Huntingtons disease has caused social, legal, and ethical concerns over access to and use of a persons results.
Many guidelines and testing procedures have strict procedures for disclosure and confidentiality to allow individuals to decide when and how to receive their results and also to whom the results are made available. Insurance companies and businesses are faced with the question of whether to use genetic test results when assessing an individual, such as for life insurance or employment. The United Kingdoms insurance companies agreed with the Department of Health and Social Care that until 2017 customers would not need to disclose predictive genetics tests to them, but this agreement explicitly excluded the government-approved test for Huntingtons when writing policies with a value over £500,000. As with other untreatable genetic conditions with a later onset, it is ethically questionable to perform pre-symptomatic testing on a child or adolescent, as there would be no medical benefit for that individual. There is consensus for testing only individuals who are considered cognitively mature, although there is a counter-argument that parents have a right to make the decision on their childs behalf. With the lack of an effective treatment, testing a person under legal age who is not judged to be competent is considered unethical in most cases.There are ethical concerns related to prenatal genetic testing or preimplantation genetic diagnosis to ensure a child is not born with a given disease. For example, prenatal testing raises the issue of selective abortion, a choice considered unacceptable by some. As it is a dominant disease, there are difficulties in situations in which a parent does not want to know his or her own diagnosis. This would require parts of the process to be kept secret from the parent.
Support organizations
In 1968, after experiencing HD in his wifes family, Dr. Milton Wexler was inspired to start the Hereditary Disease Foundation (HDF), with the aim of curing genetic illnesses by coordinating and supporting research. The foundation and Wexlers daughter, Nancy Wexler, were key parts of the research team in Venezuela which discovered the HD gene.At roughly the same time as the HDF formed, Marjorie Guthrie helped to found the committee to Combat Huntingtons Disease (now the Huntingtons Disease Society of America), after her husband, folk singer-songwriter Woody Guthrie died from complications of HD.Since then, support and research organizations have formed in many countries around the world and have helped to increase public awareness of HD. A number of these collaborate in umbrella organizations, like the International Huntington Association and the European HD network. Many support organizations hold an annual HD awareness event, some of which have been endorsed by their respective governments. For example, 6 June is designated "National Huntingtons Disease Awareness Day" by the US Senate. Many organizations exist to support and inform those affected by HD, including the Huntingtons Disease Association in the UK. The largest funder of research is provided by the Cure Huntingtons Disease Initiative Foundation (CHDI).
Research directions
Research into the mechanism of HD is focused on identifying the functioning of Htt, how mHtt differs or interferes with it, and the brain pathology that the disease produces. Research is conducted using in vitro methods, genetically modified animals, (also called transgenic animal models), and human volunteers. Animal models are critical for understanding the fundamental mechanisms causing the disease, and for supporting the early stages of drug development. The identification of the causative gene has enabled the development of many genetically modified organisms including nematodes (roundworms), Drosophila fruit flies, and genetically modified mammals including mice, rats, sheep, pigs and monkeys that express mutant huntingtin and develop progressive neurodegeneration and HD-like symptoms.Research is being conducted using many approaches to either prevent Huntingtons disease or slow its progression. Disease-modifying strategies can be broadly grouped into three categories: reducing the level of the mutant huntingtin protein (including gene splicing and gene silencing); approaches aimed at improving neuronal survival by reducing the harm caused by the protein to specific cellular pathways and mechanisms (including protein homeostasis and histone deacetylase inhibition); and strategies to replace lost neurons. In addition, novel therapies to improve brain functioning are under development; these seek to produce symptomatic rather than disease-modifying therapies, and include phosphodiesterase inhibitors.The CHDI Foundation funds a great many research initiatives providing many publications. The CHDI foundation is the largest funder of Huntingtons disease research globally and aims to find and develop drugs that will slow the progression of HD. CHDI was formerly known as the High Q Foundation. In 2006, it spent $50 million on Huntingtons disease research. CHDI collaborates with many academic and commercial laboratories globally and engages in oversight and management of research projects as well as funding.
Reducing huntingtin production
Gene silencing aims to reduce the production of the mutant protein, since HD is caused by a single dominant gene encoding a toxic protein. Gene silencing experiments in mouse models have shown that when the expression of mHtt is reduced, symptoms improve. The safety of RNA interference, and allele-specific oligonucleotide (ASO) methods of gene silencing has been demonstrated in mice and the larger primate macaque brain. Allele-specific silencing attempts to silence mutant htt while leaving wild-type Htt untouched. One way of accomplishing this is to identify polymorphisms present on only one allele and produce gene silencing drugs that target polymorphisms in only the mutant allele. The first gene silencing trial involving humans with HD began in 2015, testing the safety of IONIS-HTTRx, produced by Ionis Pharmaceuticals and led by UCL Institute of Neurology. Mutant huntingtin was detected and quantified for the first time in cerebrospinal fluid from Huntingtons disease mutation-carriers in 2015 using a novel "single-molecule counting" immunoassay, providing a direct way to assess whether huntingtin-lowering treatments are achieving the desired effect. A phase 3 trial of this compound, renamed tominersen and sponsored by Roche Pharmaceuticals, began in 2019 but was halted in 2021 after the safety monitoring board concluded that the risk-benefit balance was unfavourable. A huntingtin-lowering gene therapy trial run by Uniqure began in 2019, and several trials of orally administered huntingtin-lowering splicing modulator compounds have been announced. Gene splicing techniques are being looked at to try to repair a genome with the erroneous gene that causes HD, using tools such as CRISPR/Cas9.
Increasing huntingtin clearance
Another strategy to reduce the level of mutant huntingtin is to increase the rate at which cells are able to clear it. As mHtt (and many other protein aggregates) are degraded by autophagy, increasing the rate of autophagy has the potential to reduce levels of mHtt and thereby ameliorate disease. Pharmacological and genetic inducers of autophagy have been tested in a variety of Huntingtons disease models; many have been shown to reduce mHtt levels and decrease toxicity.
Improving cell survival
Among the approaches aimed at improving cell survival in the presence of mutant huntingtin are correction of transcriptional regulation using histone deacetylase inhibitors, modulating aggregation of huntingtin, improving metabolism and mitochondrial function and restoring function of synapses.
Neuronal replacement
Stem-cell therapy is used to replace damaged neurons by transplantation of stem cells into affected regions of the brain. Experiments in animal models (rats and mice only) have yielded positive results.Whatever their future therapeutic potential, stem cells are already a valuable tool for studying Huntingtons disease in the laboratory.
Clinical trials
In 2020 there were 197 clinical trials related to varied therapies and biomarkers for Huntingtons disease listed as either underway, recruiting or newly completed. Compounds trialled, that have failed to prevent or slow the progression of Huntingtons disease include remacemide, coenzyme Q10, riluzole, creatine, minocycline, ethyl-EPA, phenylbutyrate and dimebon.
See also
Medicine portal
References
External links
Huntingtons disease at Curlie
HOPES project – Stanford Universitys HD information project
HDBuzz – HD research news written by scientists in plain language
HD Drug Works – news about current treatments and planned trials |
Leukemia | Leukemia (also spelled leukaemia and pronounced loo-KEE-mee-ə) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called blasts or leukemia cells. Symptoms may include bleeding and bruising, bone pain, fatigue, fever, and an increased risk of infections. These symptoms occur due to a lack of normal blood cells. Diagnosis is typically made by blood tests or bone marrow biopsy.The exact cause of leukemia is unknown. A combination of genetic factors and environmental (non-inherited) factors are believed to play a role. Risk factors include smoking, ionizing radiation, some chemicals (such as benzene), prior chemotherapy, and Down syndrome. People with a family history of leukemia are also at higher risk. There are four main types of leukemia—acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML)—as well as a number of less common types. Leukemias and lymphomas both belong to a broader group of tumors that affect the blood, bone marrow, and lymphoid system, known as tumors of the hematopoietic and lymphoid tissues.Treatment may involve some combination of chemotherapy, radiation therapy, targeted therapy, and bone marrow transplant, in addition to supportive care and palliative care as needed. Certain types of leukemia may be managed with watchful waiting. The success of treatment depends on the type of leukemia and the age of the person. Outcomes have improved in the developed world. Five-year survival rate is 65% in the United States. In children under 15 in first-world countries, the five-year survival rate is greater than 60% or even 90%, depending on the type of leukemia. In children with acute leukemia who are cancer-free after five years, the cancer is unlikely to return.In 2015, leukemia was present in 2.3 million people worldwide and caused 353,500 deaths. In 2012 it newly developed in 352,000 people. It is the most common type of cancer in children, with three-quarters of leukemia cases in children being the acute lymphoblastic type. However, over 90% of all leukemias are diagnosed in adults, with CLL and AML being most common in adults. It occurs more commonly in the developed world.
Classification
General classification
Clinically and pathologically, leukemia is subdivided into a variety of large groups. The first division is between its acute and chronic forms:
Acute leukemia is characterized by a rapid increase in the number of immature blood cells. The crowding that results from such cells makes the bone marrow unable to produce healthy blood cells resulting in low hemoglobin and low platelets. Immediate treatment is required in acute leukemia because of the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. Acute forms of leukemia are the most common forms of leukemia in children.
Chronic leukemia is characterized by the excessive buildup of relatively mature, but still abnormal, white blood cells. Typically taking months or years to progress, the cells are produced at a much higher rate than normal, resulting in many abnormal white blood cells. Whereas acute leukemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy. Chronic leukemia mostly occurs in older people but can occur in any age group.Additionally, the diseases are subdivided according to which kind of blood cell is affected. This divides leukemias into lymphoblastic or lymphocytic leukemias and myeloid or myelogenous leukemias:
In lymphoblastic or lymphocytic leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form lymphocytes, which are infection-fighting immune system cells. Most lymphocytic leukemias involve a specific subtype of lymphocyte, the B cell.
In myeloid or myelogenous leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form red blood cells, some other types of white cells, and platelets.Combining these two classifications provides a total of four main categories. Within each of these main categories, there are typically several subcategories. Finally, some rarer types are usually considered to be outside of this classification scheme.
Specific types
Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in young children. It also affects adults, especially those 65 and older. Standard treatments involve chemotherapy and radiotherapy. Subtypes include precursor B acute lymphoblastic leukemia, precursor T acute lymphoblastic leukemia, Burkitts leukemia, and acute biphenotypic leukemia. While most cases of ALL occur in children, 80% of deaths from ALL occur in adults.
Chronic lymphocytic leukemia (CLL) most often affects adults over the age of 55. It sometimes occurs in younger adults, but it almost never affects children. Two-thirds of affected people are men. The five-year survival rate is 85%. It is incurable, but there are many effective treatments. One subtype is B-cell prolymphocytic leukemia, a more aggressive disease.
Acute myelogenous leukemia (AML) occurs far more commonly in adults than in children, and more commonly in men than women. It is treated with chemotherapy. The five-year survival rate is 20%. Subtypes of AML include acute promyelocytic leukemia, acute myeloblastic leukemia, and acute megakaryoblastic leukemia.
Chronic myelogenous leukemia (CML) occurs mainly in adults; a very small number of children also develop this disease. It is treated with imatinib (Gleevec in United States, Glivec in Europe) or other drugs. The five-year survival rate is 90%. One subtype is chronic myelomonocytic leukemia.
Hairy cell leukemia (HCL) is sometimes considered a subset of chronic lymphocytic leukemia, but does not fit neatly into this category. About 80% of affected people are adult men. No cases in children have been reported. HCL is incurable but easily treatable. Survival is 96% to 100% at ten years.
T-cell prolymphocytic leukemia (T-PLL) is a very rare and aggressive leukemia affecting adults; somewhat more men than women are diagnosed with this disease. Despite its overall rarity, it is the most common type of mature T cell leukemia; nearly all other leukemias involve B cells. It is difficult to treat, and the median survival is measured in months.
Large granular lymphocytic leukemia may involve either T-cells or NK cells; like hairy cell leukemia, which involves solely B cells, it is a rare and indolent (not aggressive) leukemia.
Adult T-cell leukemia is caused by human T-lymphotropic virus (HTLV), a virus similar to HIV. Like HIV, HTLV infects CD4+ T-cells and replicates within them; however, unlike HIV, it does not destroy them. Instead, HTLV "immortalizes" the infected T-cells, giving them the ability to proliferate abnormally. Human T-cell lymphotropic virus types I and II (HTLV-I/II) are endemic in certain areas of the world.
Clonal eosinophilias (also called clonal hypereosinophilias) are a group of blood disorders characterized by the growth of eosinophils in the bone marrow, blood, and/or other tissues. They may be pre-cancerous or cancerous. Clonal eosinophilias involve a "clone" of eosinophils, i.e., a group of genetically identical eosinophils that all grew from the same mutated ancestor cell. These disorders may evolve into chronic eosinophilic leukemia or may be associated with various forms of myeloid neoplasms, lymphoid neoplasms, myelofibrosis, or the myelodysplastic syndrome.
Pre-leukemia
Transient myeloproliferative disease, also termed transient leukemia, involves the abnormal proliferation of a clone of non-cancerous megakaryoblasts. The disease is restricted to individuals with Down syndrome or genetic changes similar to those in Down syndrome, develops in a baby during pregnancy or shortly after birth, and resolves within 3 months or, in ~10% of cases, progresses to acute megakaryoblastic leukemia. Transient myeloid leukemia is a pre-leukemic condition.
Signs and symptoms
The most common symptoms in children are easy bruising, pale skin, fever, and an enlarged spleen or liver.Damage to the bone marrow, by way of displacing the normal bone marrow cells with higher numbers of immature white blood cells, results in a lack of blood platelets, which are important in the blood clotting process. This means people with leukemia may easily become bruised, bleed excessively, or develop pinprick bleeds (petechiae).White blood cells, which are involved in fighting pathogens, may be suppressed or dysfunctional. This could cause the persons immune system to be unable to fight off a simple infection or to start attacking other body cells. Because leukemia prevents the immune system from working normally, some people experience frequent infection, ranging from infected tonsils, sores in the mouth, or diarrhea to life-threatening pneumonia or opportunistic infections.Finally, the red blood cell deficiency leads to anemia, which may cause dyspnea and pallor.Some people experience other symptoms, such as fevers, chills, night sweats, weakness in the limbs, feeling fatigued and other common flu-like symptoms. Some people experience nausea or a feeling of fullness due to an enlarged liver and spleen; this can result in unintentional weight loss. Blasts affected by the disease may come together and become swollen in the liver or in the lymph nodes causing pain and leading to nausea.If the leukemic cells invade the central nervous system, then neurological symptoms (notably headaches) can occur. Uncommon neurological symptoms like migraines, seizures, or coma can occur as a result of brain stem pressure. All symptoms associated with leukemia can be attributed to other diseases. Consequently, leukemia is always diagnosed through medical tests.
The word leukemia, which means white blood, is derived from the characteristic high white blood cell count that presents in most affected people before treatment. The high number of white blood cells is apparent when a blood sample is viewed under a microscope, with the extra white blood cells frequently being immature or dysfunctional. The excessive number of cells can also interfere with the level of other cells, causing further harmful imbalance in the blood count.Some people diagnosed with leukemia do not have high white blood cell counts visible during a regular blood count. This less-common condition is called aleukemia. The bone marrow still contains cancerous white blood cells that disrupt the normal production of blood cells, but they remain in the marrow instead of entering the bloodstream, where they would be visible in a blood test. For a person with aleukemia, the white blood cell counts in the bloodstream can be normal or low. Aleukemia can occur in any of the four major types of leukemia, and is particularly common in hairy cell leukemia.
Causes
There is no single known cause for any of the different types of leukemias. The few known causes, which are not generally factors within the control of the average person, account for relatively few cases. The cause for most cases of leukemia is unknown. The different leukemias likely have different causes.Leukemia, like other cancers, results from mutations in the DNA. Certain mutations can trigger leukemia by activating oncogenes or deactivating tumor suppressor genes, and thereby disrupting the regulation of cell death, differentiation or division. These mutations may occur spontaneously or as a result of exposure to radiation or carcinogenic substances.Among adults, the known causes are natural and artificial ionizing radiation and some chemicals, notably benzene and alkylating chemotherapy agents for previous malignancies. Use of tobacco is associated with a small increase in the risk of developing acute myeloid leukemia in adults. Cohort and case-control studies have linked exposure to some petrochemicals and hair dyes to the development of some forms of leukemia. Diet has very limited or no effect, although eating more vegetables may confer a small protective benefit.Viruses have also been linked to some forms of leukemia. For example, human T-lymphotropic virus (HTLV-1) causes adult T-cell leukemia.A few cases of maternal-fetal transmission (a baby acquires leukemia because its mother had leukemia during the pregnancy) have been reported. Children born to mothers who use fertility drugs to induce ovulation are more than twice as likely to develop leukemia during their childhoods than other children.
Radiation
Large doses of Sr-90 emission from nuclear reactor accidents, nicknamed bone seeker increases the risk of bone cancer and leukemia in animals and is presumed to do so in people.
Genetic conditions
Some people have a genetic predisposition towards developing leukemia. This predisposition is demonstrated by family histories and twin studies. The affected people may have a single gene or multiple genes in common. In some cases, families tend to develop the same kinds of leukemia as other members; in other families, affected people may develop different forms of leukemia or related blood cancers.In addition to these genetic issues, people with chromosomal abnormalities or certain other genetic conditions have a greater risk of leukemia. For example, people with Down syndrome have a significantly increased risk of developing forms of acute leukemia (especially acute myeloid leukemia), and Fanconi anemia is a risk factor for developing acute myeloid leukemia. Mutation in SPRED1 gene has been associated with a predisposition to childhood leukemia.Chronic myelogenous leukemia is associated with a genetic abnormality called the Philadelphia translocation; 95% of people with CML carry the Philadelphia mutation, although this is not exclusive to CML and can be observed in people with other types of leukemia.
Non-ionizing radiation
Whether or not non-ionizing radiation causes leukemia has been studied for several decades. The International Agency for Research on Cancer expert working group undertook a detailed review of all data on static and extremely low frequency electromagnetic energy, which occurs naturally and in association with the generation, transmission, and use of electrical power. They concluded that there is limited evidence that high levels of ELF magnetic (but not electric) fields might cause some cases of childhood leukemia. No evidence for a relationship to leukemia or another form of malignancy in adults has been demonstrated. Since exposure to such levels of ELFs is relatively uncommon, the World Health Organization concludes that ELF exposure, if later proven to be causative, would account for just 100 to 2400 cases worldwide each year, representing 0.2 to 4.9% of the total incidence of childhood leukemia for that year (about 0.03 to 0.9% of all leukemias).
Diagnosis
Diagnosis is usually based on repeated complete blood counts and a bone marrow examination following observations of the symptoms. Sometimes, blood tests may not show that a person has leukemia, especially in the early stages of the disease or during remission. A lymph node biopsy can be performed to diagnose certain types of leukemia in certain situations.Following diagnosis, blood chemistry tests can be used to determine the degree of liver and kidney damage or the effects of chemotherapy on the person. When concerns arise about other damages due to leukemia, doctors may use an X-ray, MRI, or ultrasound. These can potentially show leukemias effects on such body parts as bones (X-ray), the brain (MRI), or the kidneys, spleen, and liver (ultrasound). CT scans can be used to check lymph nodes in the chest, though this is uncommon.Despite the use of these methods to diagnose whether or not a person has leukemia, many people have not been diagnosed because many of the symptoms are vague, non-specific, and can refer to other diseases. For this reason, the American Cancer Society estimates that at least one-fifth of the people with leukemia have not yet been diagnosed.
Treatment
Most forms of leukemia are treated with pharmaceutical medication, typically combined into a multi-drug chemotherapy regimen. Some are also treated with radiation therapy. In some cases, a bone marrow transplant is effective.
Acute lymphoblastic
Management of ALL is directed towards control of bone marrow and systemic (whole-body) disease. Additionally, treatment must prevent leukemic cells from spreading to other sites, particularly the central nervous system (CNS) e.g. monthly lumbar punctures. In general, ALL treatment is divided into several phases:
Induction chemotherapy to bring about bone marrow remission. For adults, standard induction plans include prednisone, vincristine, and an anthracycline drug; other drug plans may include L-asparaginase or cyclophosphamide. For children with low-risk ALL, standard therapy usually consists of three drugs (prednisone, L-asparaginase, and vincristine) for the first month of treatment.
Consolidation therapy or intensification therapy to eliminate any remaining leukemia cells. There are many different approaches to consolidation, but it is typically a high-dose, multi-drug treatment that is undertaken for a few months. People with low- to average-risk ALL receive therapy with antimetabolite drugs such as methotrexate and 6-mercaptopurine (6-MP). People who are high-risk receive higher drug doses of these drugs, plus additional drugs.
CNS prophylaxis (preventive therapy) to stop cancer from spreading to the brain and nervous system in high-risk people. Standard prophylaxis may include radiation of the head and/or drugs delivered directly into the spine.
Maintenance treatments with chemotherapeutic drugs to prevent disease recurrence once remission has been achieved. Maintenance therapy usually involves lower drug doses and may continue for up to three years.
Alternatively, allogeneic bone marrow transplantation may be appropriate for high-risk or relapsed people.
Chronic lymphocytic
Decision to treat
Hematologists base CLL treatment on both the stage and symptoms of the individual person. A large group of people with CLL have low-grade disease, which does not benefit from treatment. Individuals with CLL-related complications or more advanced disease often benefit from treatment. In general, the indications for treatment are:
Falling hemoglobin or platelet count
Progression to a later stage of disease
Painful, disease-related overgrowth of lymph nodes or spleen
An increase in the rate of lymphocyte production
Treatment approach
Most CLL cases are incurable by present treatments, so treatment is directed towards suppressing the disease for many years, rather than curing it. The primary chemotherapeutic plan is combination chemotherapy with chlorambucil or cyclophosphamide, plus a corticosteroid such as prednisone or prednisolone. The use of a corticosteroid has the additional benefit of suppressing some related autoimmune diseases, such as immunohemolytic anemia or immune-mediated thrombocytopenia. In resistant cases, single-agent treatments with nucleoside drugs such as fludarabine, pentostatin, or cladribine may be successful. Younger and healthier people may choose allogeneic or autologous bone marrow transplantation in the hope of a permanent cure.
Acute myelogenous
Many different anti-cancer drugs are effective for the treatment of AML. Treatments vary somewhat according to the age of the person and according to the specific subtype of AML. Overall, the strategy is to control bone marrow and systemic (whole-body) disease, while offering specific treatment for the central nervous system (CNS), if involved.In general, most oncologists rely on combinations of drugs for the initial, induction phase of chemotherapy. Such combination chemotherapy usually offers the benefits of early remission and a lower risk of disease resistance. Consolidation and maintenance treatments are intended to prevent disease recurrence. Consolidation treatment often entails a repetition of induction chemotherapy or the intensification of chemotherapy with additional drugs. By contrast, maintenance treatment involves drug doses that are lower than those administered during the induction phase.
Chronic myelogenous
There are many possible treatments for CML, but the standard of care for newly diagnosed people is imatinib (Gleevec) therapy. Compared to most anti-cancer drugs, it has relatively few side effects and can be taken orally at home. With this drug, more than 90% of people will be able to keep the disease in check for at least five years, so that CML becomes a chronic, manageable condition.
In a more advanced, uncontrolled state, when the person cannot tolerate imatinib, or if the person wishes to attempt a permanent cure, then an allogeneic bone marrow transplantation may be performed. This procedure involves high-dose chemotherapy and radiation followed by infusion of bone marrow from a compatible donor. Approximately 30% of people die from this procedure.
Hairy cell
Decision to treat
People with hairy cell leukemia who are symptom-free typically do not receive immediate treatment. Treatment is generally considered necessary when the person shows signs and symptoms such as low blood cell counts (e.g., infection-fighting neutrophil count below 1.0 K/µL), frequent infections, unexplained bruises, anemia, or fatigue that is significant enough to disrupt the persons everyday life.Typical treatment approach
People who need treatment usually receive either one week of cladribine, given daily by intravenous infusion or a simple injection under the skin, or six months of pentostatin, given every four weeks by intravenous infusion. In most cases, one round of treatment will produce a prolonged remission.Other treatments include rituximab infusion or self-injection with Interferon-alpha. In limited cases, the person may benefit from splenectomy (removal of the spleen). These treatments are not typically given as the first treatment because their success rates are lower than cladribine or pentostatin.
T-cell prolymphocytic
Most people with T-cell prolymphocytic leukemia, a rare and aggressive leukemia with a median survival of less than one year, require immediate treatment.T-cell prolymphocytic leukemia is difficult to treat, and it does not respond to most available chemotherapeutic drugs. Many different treatments have been attempted, with limited success in certain people: purine analogues (pentostatin, fludarabine, cladribine), chlorambucil, and various forms of combination chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone CHOP, cyclophosphamide, vincristine, prednisone [COP], vincristine, doxorubicin, prednisone, etoposide, cyclophosphamide, bleomycin VAPEC-B). Alemtuzumab (Campath), a monoclonal antibody that attacks white blood cells, has been used in treatment with greater success than previous options.Some people who successfully respond to treatment also undergo stem cell transplantation to consolidate the response.
Juvenile myelomonocytic
Treatment for juvenile myelomonocytic leukemia can include splenectomy, chemotherapy, and bone marrow transplantation.
Teeth
Before dental work it is recommended that the persons physician be consulted. Dental work is recommended before chemotherapy or radiation therapy. Those in remission can be treated per normal.
Prognosis
The success of treatment depends on the type of leukemia and the age of the person. Outcomes have improved in the developed world. The average five-year survival rate is 65% in the United States. In children under 15, the five-year survival rate is greater (60 to 85%), depending on the type of leukemia. In children with acute leukemia who are cancer-free after five years, the cancer is unlikely to return.Outcomes depend on whether it is acute or chronic, the specific abnormal white blood cell type, the presence and severity of anemia or thrombocytopenia, the degree of tissue abnormality, the presence of metastasis and lymph node and bone marrow infiltration, the availability of therapies and the skills of the health care team. Treatment outcomes may be better when people are treated at larger centers with greater experience.
Epidemiology
In 2010, globally, approximately 281,500 people died of leukemia. In 2000, approximately 256,000 children and adults around the world developed a form of leukemia, and 209,000 died from it. This represents about 3% of the almost seven million deaths due to cancer that year, and about 0.35% of all deaths from any cause. Of the sixteen separate sites the body compared, leukemia was the 12th most common class of neoplastic disease and the 11th most common cause of cancer-related death. Leukemia occurs more commonly in the developed world.
United States
About 245,000 people in the United States are affected with some form of leukemia, including those that have achieved remission or cure. Rates from 1975 to 2011 have increased by 0.7% per year among children. Approximately 44,270 new cases of leukemia were diagnosed in the year 2008 in the US. This represents 2.9% of all cancers (excluding simple basal cell and squamous cell skin cancers) in the United States, and 30.4% of all blood cancers.Among children with some form of cancer, about a third have a type of leukemia, most commonly acute lymphoblastic leukemia. A type of leukemia is the second most common form of cancer in infants (under the age of 12 months) and the most common form of cancer in older children. Boys are somewhat more likely to develop leukemia than girls, and white American children are almost twice as likely to develop leukemia than black American children. Only about 3% cancer diagnoses among adults are for leukemias, but because cancer is much more common among adults, more than 90% of all leukemias are diagnosed in adults.Race is a risk factor in the United States. Hispanics, especially those under the age of 20, are at the highest risk for leukemia, while whites, Native Americans, Asian Americans, and Alaska Natives are at higher risk than African Americans.More men than women are diagnosed with leukemia and die from the disease. Around 30 percent more men than women have leukemia.
UK
Overall, leukemia is the eleventh most common cancer in the UK (around 8,600 people were diagnosed with the disease in 2011), and it is the ninth most common cause of cancer death (around 4,800 people died in 2012).
History
Leukemia was first described by anatomist and surgeon Alfred-Armand-Louis-Marie Velpeau in 1827. A more complete description was given by pathologist Rudolf Virchow in 1845. Around ten years after Virchows findings, pathologist Franz Ernst Christian Neumann found that the bone marrow of a deceased person with leukemia was colored "dirty green-yellow" as opposed to the normal red. This finding allowed Neumann to conclude that a bone marrow problem was responsible for the abnormal blood of people with leukemia.By 1900, leukemia was viewed as a family of diseases as opposed to a single disease. By 1947, Boston pathologist Sidney Farber believed from past experiments that aminopterin, a folic acid mimic, could potentially cure leukemia in children. The majority of the children with ALL who were tested showed signs of improvement in their bone marrow, but none of them was actually cured. This, however, led to further experiments.In 1962, researchers Emil J. Freireich, Jr. and Emil Frei III used combination chemotherapy to attempt to cure leukemia. The tests were successful with some people surviving long after the tests.
Etymology
Observing an abnormally large number of white blood cells in a blood sample from a person, Virchow called the condition Leukämie in German, which he formed from the two Greek words leukos (λευκός), meaning "white", and haima (αἷμα), meaning "blood".
Society and culture
According to Susan Sontag, leukemia was often romanticized in 20th-century fiction, portrayed as a joy-ending, clean disease whose fair, innocent and gentle victims die young or at the wrong time. As such, it was the cultural successor to tuberculosis, which held this cultural position until it was discovered to be an infectious disease. The 1970 romance novel Love Story is an example of this romanticization of leukemia.In the United States, around $5.4 billion is spent on treatment a year.
Research directions
Significant research into the causes, prevalence, diagnosis, treatment, and prognosis of leukemia is being performed. Hundreds of clinical trials are being planned or conducted at any given time. Studies may focus on effective means of treatment, better ways of treating the disease, improving the quality of life for people, or appropriate care in remission |
Leukemia | or after cures.In general, there are two types of leukemia research: clinical or translational research and basic research. Clinical/translational research focuses on studying the disease in a defined and generally immediately applicable way, such as testing a new drug in people. By contrast, basic science research studies the disease process at a distance, such as seeing whether a suspected carcinogen can cause leukemic changes in isolated cells in the laboratory or how the DNA changes inside leukemia cells as the disease progresses. The results from basic research studies are generally less immediately useful to people with the disease.Treatment through gene therapy is currently being pursued. One such approach used genetically modified T cells, known as chimeric antigen receptor T cells (CAR-T cells), to attack cancer cells. In 2011, a year after treatment, two of the three people with advanced chronic lymphocytic leukemia were reported to be cancer-free and in 2013, three of five subjects who had acute lymphocytic leukemia were reported to be in remission for five months to two years. Subsequent studies with a variety of CAR-T types continue to be promising. As of 2018, two CAR-T therapies have been approved by the Food and Drug Administration. CAR-T treatment has significant side effects, and loss of the antigen targeted by the CAR-T cells is a common mechanism for relapse. The stem cells that cause different types of leukemia are also being researched.
Pregnancy
Leukemia is rarely associated with pregnancy, affecting only about 1 in 10,000 pregnant women. How it is handled depends primarily on the type of leukemia. Nearly all leukemias appearing in pregnant women are acute leukemias. Acute leukemias normally require prompt, aggressive treatment, despite significant risks of pregnancy loss and birth defects, especially if chemotherapy is given during the developmentally sensitive first trimester. Chronic myelogenous leukemia can be treated with relative safety at any time during pregnancy with Interferon-alpha hormones. Treatment for chronic lymphocytic leukemias, which are rare in pregnant women, can often be postponed until after the end of the pregnancy.
See also
Acute erythroid leukemia
Antileukemic drugs, medications used to kill leukemia cells
Cancer-related fatigue
Hematologic diseases, the large class of blood-related disorders, including leukemia
Multiple myeloma
References
External links
Leukemia at Curlie
Leukaemia information from Cancer Research UK |
Amyloid | Amyloids are aggregates of proteins characterised by a fibrillar morphology of 7–13 nm in diameter, a beta sheet (β-sheet) secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the human body, amyloids have been linked to the development of various diseases. Pathogenic amyloids form when previously healthy proteins lose their normal structure and physiological functions (misfolding) and form fibrous deposits in amyloid plaques around cells which can disrupt the healthy function of tissues and organs.
Such amyloids have been associated with (but not necessarily as the cause of) more than 50 human diseases, known as amyloidosis, and may play a role in some neurodegenerative diseases. Some of these diseases are mainly sporadic and only a few cases are familial. Others are only familial. Some are iatrogenic as they result from medical treatment. Prions are an infectious form of amyloids that can act as a template to convert other non-infectious forms. Amyloids may also have normal biological functions; for example, in the formation of fimbriae in some genera of bacteria, transmission of epigenetic traits in fungi, as well as pigment deposition and hormone release in humans.Amyloids have been known to arise from many different proteins. These polypeptide chains generally form β-sheet structures that aggregate into long fibers; however, identical polypeptides can fold into multiple distinct amyloid conformations. The diversity of the conformations may have led to different forms of the prion diseases.An unusual secondary structure named alpha sheet has been proposed as the toxic constituent of amyloid precursor proteins. This idea is not widely accepted at present, but a fair amount of evidence has accumulated, especially recently, in its favor.
Definition
The name amyloid comes from the early mistaken identification by Rudolf Virchow of the substance as starch (amylumcode: lat promoted to code: la in Latin, from Ancient Greek: ἄμυλον, romanized: amylon), based on crude iodine-staining techniques. For a period, the scientific community debated whether or not amyloid deposits are fatty deposits or carbohydrate deposits until it was finally found (in 1859) that they are, in fact, deposits of albumoid proteinaceous material.
The classical, histopathological definition of amyloid is an extracellular, proteinaceous fibrillar deposit exhibiting β-sheet secondary structure and identified by apple-green birefringence when stained with congo red under polarized light. These deposits often recruit various sugars and other components such as serum amyloid P component, resulting in complex, and sometimes inhomogeneous structures. Recently this definition has come into question as some classic, amyloid species have been observed in distinctly intracellular locations.
A more recent, biophysical definition is broader, including any polypeptide that polymerizes to form a cross-β structure, in vivo or in vitro, inside or outside cells. Microbiologists, biochemists, biophysicists, chemists and physicists have largely adopted this definition, leading to some conflict in the biological community over an issue of language.
Proteins forming amyloids in diseases
To date, 37 human proteins have been found to form amyloid in pathology and be associated with well-defined diseases. The International Society of Amyloidosis classifies amyloid fibrils and their associated diseases based upon associated proteins (for example ATTR is the group of diseases and associated fibrils formed by TTR). A table is included below.
Non-disease and functional amyloids
Many examples of non-pathological amyloid with a well-defined physiological role have been identified in various organisms, including human. These may be termed as functional or physiological or native amyloid.
Functional amyloid in Homo sapiens:
Intralumenal domain of melanocyte protein PMEL
Peptide/protein hormones stored as amyloids within endocrine secretory granules
Receptor-interacting serine/threonine-protein kinase 1/3 (RIP1/RIP3)
Fragments of prostatic acid phosphatase and semenogelinsFunctional amyloid in other organisms:
Curli fibrils produced by E. coli, Salmonella, and a few other members of the Enterobacteriales (Csg). The genetic elements (operons) encoding the curli system are phylogenetic widespread and can be found in at least four bacterial phyla. This suggest that many more bacteria may express curli fibrils.
GvpA, forming the walls of particular Gas vesicles, i.e. the buoyancy organelles of aquatic archaea and eubacteria
Fap fibrils in various species of Pseudomonas
Chaplins from Streptomyces coelicolor
Spidroin from Trichonephila edulis (spider) (Spider silk)
Hydrophobins from Neurospora crassa and other fungi
Fungal cell adhesion proteins forming cell surface amyloid regions with greatly increased binding strength
Environmental biofilms according to staining with amyloid specific dyes and antibodies.
Tubular sheaths encasing Methanosaeta thermophila filamentsFunctional amyloid acting as prions
Several yeast prions are based on an infectious amyloid, e.g. [PSI+] (Sup35p); [URE3] (Ure2p); [PIN+] or [RNQ+] (Rnq1p); [SWI1+] (Swi1p) and [OCT8+] (Cyc8p)
Prion HET-s from Podospora anserina
Neuron-specific isoform of CPEB from Aplysia californica (marine snail)
Structure
Amyloids are formed of long unbranched fibers that are characterized by an extended beta-sheet secondary structure in which individual beta strands (β-strands) (coloured arrows in the adjacent figure) are arranged in an orientation perpendicular to the long axis of the fiber. Such a structure is known as cross-β structure. Each individual fiber may be 7–13 nanometres in width and a few micrometres in length. The main hallmarks recognised by different disciplines to classify protein aggregates as amyloid is the presence of a fibrillar morphology with the expected diameter, detected using transmission electron microscopy (TEM) or atomic force microscopy (AFM), the presence of a cross-β secondary structure, determined with circular dichroism, FTIR, solid-state nuclear magnetic resonance (ssNMR), X-ray crystallography, or X-ray fiber diffraction (often considered the "gold-standard" test to see whether a structure contains cross-β fibres), and an ability to stain with specific dyes, such as Congo red, thioflavin T or thioflavin S.The term "cross-β" was based on the observation of two sets of diffraction lines, one longitudinal and one transverse, that form a characteristic "cross" pattern. There are two characteristic scattering diffraction signals produced at 4.7 and 10 Ångstroms (0.47 nm and 1.0 nm), corresponding to the interstrand and stacking distances in beta sheets. The "stacks" of beta sheet are short and traverse the breadth of the amyloid fibril; the length of the amyloid fibril is built by aligned β-strands. The cross-β pattern is considered a diagnostic hallmark of amyloid structure.Amyloid fibrils are generally composed of 1–8 protofilaments (one protofilament also corresponding to a fibril is shown in the figure), each 2–7 nm in diameter, that interact laterally as flat ribbons that maintain the height of 2–7 nm (that of a single protofilament) and are up to 30 nm wide; more often protofilaments twist around each other to form the typically 7–13 nm wide fibrils. Each protofilament possesses the typical cross-β structure and may be formed by 1–6 β-sheets (six are shown in the figure) stacked on each other. Each individual protein molecule can contribute one to several β-strands in each protofilament and the strands can be arranged in antiparallel β-sheets, but more often in parallel β-sheets. Only a fraction of the polypeptide chain is in a β-strand conformation in the fibrils, the remainder forms structured or unstructured loops or tails.
For a long time our knowledge of the atomic-level structure of amyloid fibrils was limited by the fact that they are unsuitable for the most traditional methods for studying protein structures. Recent years have seen progress in experimental methods, including solid-state NMR spectroscopy and Cryo-Electron Microscopy. Combined, these methods have provided 3D atomic structures of amyloid fibrils formed by amyloid β peptides, α-synuclein, tau, and the FUS protein, associated with various neurodegenerative diseases.X-ray diffraction studies of microcrystals revealed atomistic details of core region of amyloid, although only for simplified peptides having a length remarkably shorter than that of peptides or proteins involved in disease. The crystallographic structures show that short stretches from amyloid-prone regions of amyloidogenic proteins run perpendicular to the filament axis, consistent with the "cross-β" feature of amyloid structure. They also reveal a number of characteristics of amyloid structures – neighboring β-sheets are tightly packed together via an interface devoid of water (therefore referred to as dry interface), with the opposing β-strands slightly offset from each other such that their side-chains interdigitate. This compact dehydrated interface created was termed a steric-zipper interface. There are eight theoretical classes of steric-zipper interfaces, dictated by the directionality of the β-sheets (parallel and anti-parallel) and symmetry between adjacent β-sheets. A limitation of X-ray crystallography for solving amyloid structure is represented by the need to form microcrystals, which can be achieved only with peptides shorter than those associated with disease.
Although bona fide amyloid structures always are based on intermolecular β-sheets, different types of "higher order" tertiary folds have been observed or proposed. The β-sheets may form a β-sandwich, or a β-solenoid which may be either β-helix or β-roll. Native-like amyloid fibrils in which native β-sheet containing proteins maintain their native-like structure in the fibrils have also been proposed.One complicating factor in studies of amyloidogenic polypeptides is that identical polypeptides can fold into multiple distinct amyloid conformations. This phenomenon is typically described as amyloid polymorphism. It has notable biological consequences given that it is thought to explain the prion strain phenomenon.
Formation
Amyloid is formed through the polymerization of hundreds to thousands of monomeric peptides or proteins into long fibers. Amyloid formation involves a lag phase (also called nucleation phase), an exponential phase (also called growth phase) and a plateau phase (also called saturation phase), as shown in the figure. Indeed, when the quantity of fibrils is plotted versus time, a sigmoidal time course is observed reflecting the three distinct phases.
In the simplest model of nucleated polymerization (marked by red arrows in the figure below), individual unfolded or partially unfolded polypeptide chains (monomers) convert into a nucleus (monomer or oligomer) via a thermodynamically unfavourable process that occurs early in the lag phase. Fibrils grow subsequently from these nuclei through the addition of monomers in the exponential phase.A different model, called nucleated conformational conversion and marked by blue arrows in the figure below, was introduced later on to fit some experimental observations: monomers have often been found to convert rapidly into misfolded and highly disorganized oligomers distinct from nuclei. Only later on, will these aggregates reorganise structurally into nuclei, on which other disorganised oligomers will add and reorganise through a templating or induced-fit mechanism (this nucleated conformational conversion model), eventually forming fibrils.Normally folded proteins have to unfold partially before aggregation can take place through one of these mechanisms. In some cases, however, folded proteins can aggregate without crossing the major energy barrier for unfolding, by populating native-like conformations as a consequence of thermal fluctuations, ligand release or local unfolding occurring in particular circumstances. In these native-like conformations, segments that are normally buried or structured in the fully folded and possessing a high propensity to aggregate become exposed to the solvent or flexible, allowing the formation of native-like aggregates, which convert subsequently into nuclei and fibrils. This process is called native-like aggregation (green arrows in the figure) and is similar to the nucleated conformational conversion model.
A more recent, modern and thorough model of amyloid fibril formation involves the intervention of secondary events, such as fragmentation, in which a fibril breaks into two or more shorter fibrils, and secondary nucleation, in which fibril surfaces (not fibril ends) catalyze the formation of new nuclei. Both secondary events increase the number of fibril ends able to recruit new monomers or oligomers, therefore accelerating fibril formation through a positive feedback mechanism. These events add to the well recognised steps of primary nucleation (formation of the nucleus from the monomers through one of models described above), fibril elongation (addition of monomers or oligomers to growing fibril ends) and dissociation (opposite process).
Such a new model is described in the figure on the right and involves the utilization of a master equation that includes all steps of amyloid fibril formation, i.e. primary nucleation, fibril elongation, secondary nucleation and fibril fragmentation. The rate constants of the various steps can be determined from a global fit of a number of time courses of aggregation (for example ThT fluorescence emission versus time) recorded at different protein concentrations. The general master equation approach to amyloid fibril formation with secondary pathways has been developed by Knowles, Vendruscolo, Cohen, Michaels and coworkers and considers the time evolution of the concentration
f
(
t
,
j
)
{\displaystyle f(t,j)}
of fibrils of length
j
{\displaystyle j}
(here
j
{\displaystyle j}
represents the number of monomers in an aggregate). where
δ
i
,
j
{\displaystyle \delta _{i,j}}
denotes the Kronecker delta. The physical interpretation of the various terms in the above master equation is straight forward: the terms on the first line describe the growth of fibrils via monomer addition with rate constant
k
+
{\displaystyle k_{+}}
(elongation). The terms on the second line describe monomer dissociation, i.e. the inverse process of elongation.
k
o
f
f
{\displaystyle k_{\rm {off}}}
is the rate constant of monomer dissociation. The terms on the third line describe the effect of fragmentation, which is assumed to occur homogeneously along fibrils with rate constant
k
−
{\displaystyle k_{-}}
. Finally, the terms on the last line describe primary and secondary nucleation respectively. Note that the rate of secondary nucleation is proportional to the mass of aggregates, defined as
M
(
t
)
=
∑
j
=
n
1
∞
j
f
(
t
,
j
)
{\displaystyle M(t)=\sum _{j=n_{1}}^{\infty }jf(t,j)}
.
Following this analytical approach, it has become apparent that the lag phase does not correspond necessarily to only nucleus formation, but rather results from a combination of various steps. Similarly, the exponential phase is not only fibril elongation, but results from a combination of various steps, involving primary nucleation, fibril elongation, but also secondary events. A significant quantity of fibrils resulting from primary nucleation and fibril elongation may be formed during the lag phase and secondary steps, rather than only fibril elongation, can be the dominant processes contributing to fibril growth during the exponential phase. With this new model, any perturbing agents of amyloid fibril formation, such as putative drugs, metabolites, mutations, chaperones, etc., can be assigned to a specific step of fibril formation.
Amino acid sequence and amyloid formation
In general, amyloid polymerization (aggregation or non-covalent polymerization) is sequence-sensitive, that is mutations in the sequence can induce or prevent self-assembly. For example, humans produce amylin, an amyloidogenic peptide associated with type II diabetes, but in rats and mice prolines are substituted in critical locations and amyloidogenesis does not occur. Studies comparing synthetic to recombinant β amyloid peptide in assays measuring rate of fibrillation, fibril homogeneity, and cellular toxicity showed that recombinant β amyloid peptide has a faster fibrillation rate and greater toxicity than synthetic β amyloid peptide.There are multiple classes of amyloid-forming polypeptide sequences. Glutamine-rich polypeptides are important in the amyloidogenesis of Yeast and mammalian prions, as well as trinucleotide repeat disorders including Huntingtons disease. When glutamine-rich polypeptides are in a β-sheet conformation, glutamines can brace the structure by forming inter-strand hydrogen bonding between its amide carbonyls and nitrogens of both the backbone and side chains. The onset age for Huntingtons disease shows an inverse correlation with the length of the polyglutamine sequence, with analogous findings in a C. elegans model system with engineered polyglutamine peptides.Other polypeptides and proteins such as amylin and the β amyloid peptide do not have a simple consensus sequence and are thought to aggregate through the sequence segments enriched with hydrophobic residues, or residues with high propensity to form β-sheet structure. Among the hydrophobic residues, aromatic amino-acids are found to have the highest amyloidogenic propensity.Cross-polymerization (fibrils of one polypeptide sequence causing other fibrils of another sequence to form) is observed in vitro and possibly in vivo. This phenomenon is important, since it would explain interspecies prion propagation and differential rates of prion propagation, as well as a statistical link between Alzheimers and type 2 diabetes. In general, the more similar the peptide sequence the more efficient cross-polymerization is, though entirely dissimilar sequences can cross-polymerize and highly similar sequences can even be "blockers" that prevent polymerization.
Amyloid toxicity
The reasons why amyloid cause diseases are unclear. In some cases, the deposits physically disrupt tissue architecture, suggesting disruption of function by some bulk process. An emerging consensus implicates prefibrillar intermediates, rather than mature amyloid fibers, in causing cell death, particularly in neurodegenerative diseases. The fibrils are, however, far from innocuous, as they keep the protein homeostasis network engaged, release oligomers, cause the formation of toxic oligomers via secondary nucleation, grow indefinitely spreading from district to district and, in some cases, may be toxic themselves.Calcium dysregulation has been observed to occur early in cells exposed to protein oligomers. These small aggregates can form ion channels through lipid bilayer membranes and activate NMDA and AMPA receptors. Channel formation has been hypothesized to account for calcium dysregulation and mitochondrial dysfunction by allowing indiscriminate leakage of ions across cell membranes. Studies have shown that amyloid deposition is associated with mitochondrial dysfunction and a resulting generation of reactive oxygen species (ROS), which can initiate a signalling pathway leading to apoptosis. There are reports that indicate amyloid polymers (such as those of huntingtin, associated with Huntingtons disease) can induce the polymerization of essential amyloidogenic proteins, which should be deleterious to cells. Also, interaction partners of these essential proteins can also be sequestered.All these mechanisms of toxicity are likely to play a role. In fact, the aggregation of a protein generates a variety of aggregates, all of which are likely to be toxic to some degree. A wide variety of biochemical, physiological and cytological perturbations has been identified following the exposure of cells and animals to such species, independently of their identity. The oligomers have also been reported to interact with a variety of molecular targets. Hence, it is unlikely that there is a unique mechanism of toxicity or a unique cascade of cellular events. The misfolded nature of protein aggregates causes a multitude of aberrant interactions with a multitude of cellular components, including membranes, protein receptors, soluble proteins, RNAs, small metabolites, etc.
Histological staining
In the clinical setting, amyloid diseases are typically identified by a change in the spectroscopic properties of planar aromatic dyes such as thioflavin T, congo red or NIAD-4. In general, this is attributed to the environmental change, as these dyes intercalate between beta-strands to confine their structure.Congo Red positivity remains the gold standard for diagnosis of amyloidosis. In general, binding of Congo Red to amyloid plaques produces a typical apple-green birefringence when viewed under cross-polarized light. Recently, significant enhancement of fluorescence quantum yield of NIAD-4 was exploited to super-resolution fluorescence imaging of amyloid fibrils and oligomers. To avoid nonspecific staining, other histology stains, such as the hematoxylin and eosin stain, are used to quench the dyes activity in other places such as the nucleus, where the dye might bind. Modern antibody technology and immunohistochemistry has made specific staining easier, but often this can cause trouble because epitopes can be concealed in the amyloid fold; in general, an amyloid protein structure is a different conformation from the one that the antibody recognizes.
See also
JUNQ and IPOD
Proteopathy
Protein aggregation predictors
References
External links
Bacterial Inclusion Bodies Contain Amyloid-Like Structure at SciVee
Amyloid Cascade Hypothesis
Amyloid: Journal of Protein Folding Disorders web page
Role of anesthetics in Alzheimers disease: Molecular details revealed |
Familial encephalopathy with neuroserpin inclusion bodies | Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a progressive disorder of the nervous system that is characterized by a loss of intellectual functioning (dementia) and seizures. At first, affected individuals may have difficulty sustaining attention and concentrating. Their judgment, insight, and memory become impaired as the condition progresses. Over time, they lose the ability to perform the activities of daily living, and most people with this condition eventually require comprehensive care.The signs and symptoms of familial encephalopathy with neuroserpin inclusion bodies vary in their severity and age of onset. In severe cases, the condition causes seizures and episodes of sudden, involuntary muscle jerking or twitching (myoclonus) in addition to dementia. These signs can appear as early as a persons teens. Less severe cases are characterized by a progressive decline in intellectual functioning beginning in a persons forties or fifties.Mutations in the SERPINI1 gene cause familial encephalopathy with neuroserpin inclusion bodies. The SERPINI1 gene provides instructions for making a protein called neuroserpin. This protein is found in nerve cells, where it plays a role in the development and function of the nervous system. Neuroserpin helps control the growth of nerve cells and their connections with one another, which suggests that this protein may be important for learning and memory. Mutations in the gene result in the production of an abnormally shaped, unstable version of neuroserpin. Abnormal neuroserpin proteins can attach to one another and form neuroserpin inclusion bodies or Collins bodies within nerve cells. Collins bodies form in cortical and subcortical neurons where they disrupt the cells normal functioning and ultimately lead to cell death. Progressive dementia results from this gradual loss of nerve cells in certain parts of the brain. Researchers believe that a buildup of related, potentially toxic substances in nerve cells may also contribute to the signs and symptoms of this condition.This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In many cases, an affected person has a parent with the condition.
References
National Library of Medicine. Genetics Home Reference - Familial encephalopathy with neuroserpin inclusion bodies
== External links == |
Cooks syndrome | Cooks syndrome is a hereditary disorder which is characterized in the hands by bilateral nail hypoplasia on the thumb, index finger, and middle finger, absence of fingernails (anonychia) on the ring finger and little finger, lengthening of the thumbs, and bulbousness of the fingers. In the feet, it is characterized by absence of toenails and absence/hypoplasia of the distal phalanges. In the second study of this disorder, it was found that the intermediate phalanges, proximal phalanges, and metacarpals were unaffected.The disorder was first described by Cooks et al. in 1985 after being discovered in two generations of one family. It was proposed that the inheritance of the disorder is autosomal dominant. A second family, this with three affected generations, confirmed that the inheritance of the disorder is autosomal dominant. Although several genetic disorders exist which can cause anonychia and onychodystrophy, such disorders often cause other anomalies such as deafness, mental retardation, and defects of the hair, eyes, and teeth. Cooks syndrome is not known to cause any such anomalies.In 1999, a pair of siblings was found with brachydactyly type B. Because the disorder primarily affected the nails and distal phalanges, the research group concluded that brachydactyly type B and Cooks syndrome are the same disorder. However, in 2007, a 2-year-old girl was found with symptoms consistent with both brachydactyly type B and Cooks syndrome. It was found that the two syndromes were distinct clinically, radiologically, and genetically.
Notes
== External links == |
Aspirin exacerbated respiratory disease | Aspirin exacerbated respiratory disease (AERD), also termed aspirin-induced asthma, is a medical condition initially defined as consisting of three key features: asthma, respiratory symptoms exacerbated by aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and nasal polyps. The symptoms of respiratory reactions in this syndrome are hypersensitivity reactions to NSAIDs rather than the typically described true allergic reactions that trigger other common allergen-induced asthma, rhinitis, or hives. The NSAID-induced reactions do not appear to involve the common mediators of true allergic reactions, immunoglobulin E or T cells. Rather, AERD is a type of NSAID-induced hypersensitivity syndrome. EAACI/WHO classifies the syndrome as one of five types of NSAID hypersensitivity or NSAID hypersensitivity reactions.
Signs and symptoms
The various non-allergic NSAID hypersensitivity syndromes affect 0.5–1.9% of the general population, with AERD affecting about 7% of all asthmatics and about 14% of adults with severe asthma. AERD, which is slightly more prevalent in women, usually begins in young adulthood (twenties and thirties are the most common onset times, although children are affected by it and present a diagnostic problem in pediatrics) and may not include any other allergies. Most commonly the first symptom is rhinitis (inflammation or irritation of the nasal mucosa), which may manifest as sneezing, runny nose, or congestion. The disorder typically progresses to asthma, then nasal polyposis, with aspirin sensitivity coming last. Anosmia (lack of smell) also is common, as inflammation within the nose and sinuses likely reaches the olfactory receptors.The respiratory reactions to NSAIDs vary in severity, ranging from mild nasal congestion and eye watering to lower respiratory symptoms including wheezing, coughing, an asthma attack, and in rare cases, anaphylaxis. In addition to the typical respiratory reactions, about 10% of patients with AERD manifest skin symptoms such as urticaria and/or gastrointestinal symptoms such as abdominal pain or vomiting during their reactions to aspirin.In addition to aspirin, patients also react to other NSAIDs such as ibuprofen, and to any medication that inhibits the cyclooxygenase-1 (COX-1) enzyme, although paracetamol (acetaminophen) in low doses is generally considered safe. NSAIDs that are highly selective in blocking COX-2 and do not block its closely related paralog, COX-1, such as the COX-2 inhibitors celecoxib and rofecoxib, also are regarded as safe. Nonetheless, recent studies do find that these types of drugs, e.g. acetaminophen and celecoxib, may trigger adverse reactions in these patients; caution is recommended in using any COX inhibitors. In addition to aspirin and NSAIDs, consumption of even small amounts of alcohol also produces uncomfortable respiratory reactions in many patients.
Cause
The disorder is thought to be caused by an anomaly in the arachidonic acid metabolizing cascade that leads to increased production of pro-inflammatory cysteinyl leukotrienes, a series of chemicals involved in the bodys inflammatory response. When medications such as NSAIDs or aspirin block the COX-1 enzyme, production of thromboxane and some anti-inflammatory prostaglandins is decreased, and in patients with aspirin-induced asthma, this results in the overproduction of pro-inflammatory leukotrienes, which can cause severe exacerbations of asthma and allergy-like symptoms. The underlying cause of the disorder is not fully understood, but there have been several important findings:
Abnormally low levels of prostaglandin E2 (PGE2), which is protective for the lungs, has been found in patients with aspirin-induced asthma and may worsen their lung inflammation.
In addition to the overproduction of cystinyl leukotrienes, overproduction of 15-lipoxygenase-derived arachidonic acid metabolites viz., 15-hydroxyicosatetraenoic acid and eoxins by the eosinophils isolated from the blood of individuals with AERD; certain of these products may help promote the inflammatory response.
Overexpression of both the cysteinyl leukotriene receptor 1 and the leukotriene C4 synthase enzyme has been shown in respiratory tissue from patients with aspirin-induced asthma, which likely relates to the increased response to leukotrienes and increased production of leukotrienes seen in the disorder.
The attachment of platelets to certain leukocytes in the blood of patients with aspirin-sensitive asthma also has been shown to contribute to the overproduction of leukotrienes.
There may be a relationship between aspirin-induced asthma and TBX21, PTGER2, and LTC4S.
Eosinophils isolated from the blood of aspirin-induced asthma subjects (as well as severe asthmatic patients) greatly overproduce 15-hydroxyicosatetraenoic acid and eoxin C4 when challenged with arachidonic acid or calcium ionophore A23187, compared to the eosinophils taken from normal or mildly asthmatic subjects; aspirin treatment of eosinophils from aspirin intolerant subjects causes the cells to mount a further increase in eoxin production. These results suggest that 15-lipoxygenase and certain of its metabolites, perhaps eoxin C4, is contributing to aspirin-induced asthma in a fashion similar to 5-lipoxygenase and its leukotriene metabolites.
Treatment
Medication
Avoidance of NSAID medications will not stop the progression of the disease. The preferred treatment for many patients is desensitization to aspirin, undertaken at a clinic or hospital specializing in such treatment. Patients who are desensitized then take a maintenance dose of aspirin daily to maintain their desensitization. The recommended maintenance dose for symptom control is 650 mg to 1300 mg aspirin daily. While on daily aspirin, most patients have reduced need for supporting medications, fewer asthma and sinusitis symptoms than previously, and an improved sense of smell. Desensitization to aspirin reduces the chance of nasal polyp recurrence and may slow the regrowth of nasal polyps. Once desensitized to aspirin, most patients can safely take other NSAID medications again.Even patients desensitized to aspirin may continue to need other medications including nasal steroids, inhaled steroids, and leukotriene antagonists. Leukotriene antagonists and inhibitors (montelukast, zafirlukast, and zileuton) often are helpful in treating the symptoms of AERD. In a large survey of AERD patients, it was reported that Zyflo (zileuton) was significantly more effective at controlling the symptoms of the disease than Singulair (montelukast).Biologic medications such as dupilumab, mepolizumab, and omalizumab may also be of benefit. In a 2021 survey of biologics, dupilumab was found to be most effective in treating symptoms of AERD.Despite optimal medical management, many patients continue to require oral steroid medications to alleviate asthma and chronic nasal congestion.
Surgery
Often surgery is required to remove nasal polyps, although they typically recur, particularly if aspirin desensitization is not undertaken. 90% of patients have been shown to have recurrence of nasal polyps within five years after surgery, with 47% requiring revision surgery in the same time period. A complete endoscopic sinus surgery followed by aspirin desensitization has been shown to reduce the need for revision surgeries. Exact cause of nasal polyp formation is unknown. However, Differential gene expression analysis of AERD nasal polyp epithelial cells versus AERD non polyp nasal mucosa revealed DMRT3 could be potentially involved in nasal polyp development in AERD patients. Furthermore, several genes are downregulated, hinting at the dedifferentiation phenomenon in AERD polyps.
Diet
The majority of those with aspirin exacerbated respiratory disease experience respiratory reactions to alcohol. One study found that 83% reported such reactions. Of those who had reactions, 75% had a sinus reaction (runny nose, nasal congestion) and 51% had a lower respiratory reaction (wheezing, shortness of breath). The current theory on the cause of these reactions is that they may be related to polyphenols found in alcoholic beverages. A 2017 study found that alcohol sensitive patients reacted to catechins in red wine, but not to resveratrol. It has been suggested that steel fermented white wines and clear liquors may cause less of a reaction than other alcoholic beverages. Desensitization to aspirin has been found to reduce reactions to alcohol.Some people have reported relief of symptoms by following a low-salicylate diet such as the Feingold diet. Aspirin is quickly converted in the body to salicylic acid, also known as 2-Hydroxybenzoic acid. A prospective randomized trial with 30 patients following a low-salicylate diet for six weeks demonstrated a clinically significant decrease in both subjective and objective scoring of severity of disease, but made note of the challenge for patients in following what is a fairly stringent diet. Despite these findings, experts on the disease do not believe that dietary salicylates contribute to AERD symptoms. Dietary salicylates do not significantly inhibit the COX-1 enzyme, which is the cause of AERD reactions. One confounding factor in the study that showed a benefit from avoidance of dietary salicylates is that a low salicylate diet involves eliminating wine and beer. The majority of AERD patients react to wine and beer for reasons that do not involve their salicylate content. There is also a strong placebo effect involved with any dietary intervention. In contrast to aspirin, dietary salicylates are not acetylated and therefore do not block cyclooxygenases and hence, there is no rationale why a low salicylate diet would be beneficial for AERD patients.A diet low in omega-6 oils (precursors of arachidonic acid), and high in omega-3 oils may also be of benefit. In a small study, aspirin-sensitive asthma patients taking 10 grams of fish oil daily reported relief of most symptoms after six weeks, however, symptoms returned if the supplement was stopped. In another study, a diet low in omega 6 fatty acids and high in omega 3 fatty acids significantly reduced sinus symptoms in AERD patients.
Alternate and related names
Aspirin-induced asthma
Leukotriene associated hypersensitivity
Samters triad
Acetylsalicylic acid triad
Widals triad
Francis triad
Aspirin triad
Aspirin-exacerbated respiratory disease (AERD).
NSAID-exacerbated respiratory disease (NERD)
Aspirin-induced asthma and rhinitis (AIAR) A person who has not yet experienced asthma or aspirin sensitivity might be diagnosed as having:
Non-allergic rhinitis
Non-allergic rhinitis with eosinophilia syndrome (NARES)
History
The syndrome is named for Max Samter.Initial reports on a linkage among asthma, aspirin, and nasal polyposis were made by Widal in 1922. Further studies were conducted by Samter and Beers in reports published in 1968.
See also
Salicylate sensitivity
Drug intolerance
Alcohol-induced respiratory reactions
References
== External links == |
Barodontalgia | Barodontalgia, commonly known as tooth squeeze, is a pain in a tooth caused by a change in ambient pressure. The pain usually ceases at ground level. Dental barotrauma is a condition in which such changes in barometric pressure changes cause damage to the dentition.
Description
The most common victims are underwater divers because in deep dives pressures can increase by several atmospheres, and military pilots because of rapid changes.
In pilots, barodontalgia may be severe enough to cause premature cessation of flights.Most of the available data regarding barodontalgia is derived from high-altitude chamber simulations rather than actual flights. Barodontalgia prevalence was between 0.7% and 2% in the 1940s, and 0.3% in the 1960s.Similarly, cases of barodontalgia were reported in 0.3% of high altitude-chamber simulations in the Luftwaffe.The rate of barodontalgia was about 1 case per 100 flight-years in the Israeli Air Force. During World War II, about one-tenth of American aircrews had one or more episodes of barodontalgia. In a recent study, 8.2% of 331 Israeli Air Force aircrews, reported at least one episode of barodontalgia.In addition, a large epidemiologic study suggested that changes in barometric pressure were the reason for the initiation and/or exacerbation of various oral pains observed in dental emergency departments.Barodontalgia is a symptom of dental disease, for example inflammatory cyst in the mandible.
Indeed, most of the common oral pathologies have been reported as possible sources of barodontalgia: dental caries, defective tooth restoration, pulpitis, pulp necrosis, apical periodontitis, periodontal pockets, impacted teeth, and mucous retention cysts. One exception is barodontalgia manifested as referred pain from barosinusitis or barotitis-media. The latter two conditions are generated from pressure changes rather than pressure-related flare-up of pre-existing conditions. A meta-analysis of studies conducted between 2001 and 2010 revealed a rate of 5 episodes/1,000 flight-years. Maxillary and mandibular dentitions were affected equally in flight, but in diving, maxillary dentition was affected more than the mandibular dentition, which can indicate a greater role for maxillary sinus pathology in diving barodontalgia. Surprisingly, despite cabin pressurization, the current in-flight barodontalgia incidence is similar to the incidence in the first half of the 20th century. Also, despite the greater fluctuation in divers pressures, the weighted incidence of barodontalgia among aircrews is similar to the weighted incidence among divers. Furthermore, contrary to common belief, and in contrast to diving conditions, the role of facial barotrauma in the cause of in-flight barodontalgia is only minor (about one-tenth of cases).
Classification
The Fédération dentaire internationale describes 4 classes of barodontalgia. The classes are based on signs and symptoms. They also provide specific and valuable recommendations for therapeutic intervention.
Barotrauma
Sometimes, pressure changes damage teeth (rather than just causing pain). When the external pressure rises or falls and the trapped air within the void cannot expand or contract to balance the external pressure, the pressure difference on the rigid structure of the tooth can occasionally induce stresses sufficient to fracture the tooth or dislodge a filling. Typically this is seen in underwater divers or aviators who experience pressure changes in the course of their activity. Identifying the pain during a pressure change is a diagnostic indicator for the clinician. Treatment involves removing the void space by carefully replacing the offending restoration, repeating the endodontic treatment or removing the tooth.
See also
Barotrauma – Injury caused by pressure
Dental trauma
List of diving hazards and precautions – Hazards associated with underwater diving
Toothache – Medical condition of the teeth
References
== External links == |
Symblepharon | A symblepharon is a partial or complete adhesion of the palpebral conjunctiva of the eyelid to the bulbar conjunctiva of the eyeball. It results either from disease (conjunctival sequelae of trachoma) or trauma. Cicatricial pemphigoid and, in severe cases, rosacea may cause symblepharon. It is rarely congenital. Its treatment is symblepharectomy.
See also
Ankyloblepharon
References
Further reading
Brazier, DJ; Hardman-Lea, SJ; Collin, JR (1986). "Cryptophthalmos: surgical treatment of the congenital symblepharon variant". The British Journal of Ophthalmology. 70 (5): 391–5. doi:10.1136/bjo.70.5.391. PMC 1041021. PMID 3008809. |
Hypoalphalipoproteinemia | Hypoalphalipoproteinemia is a high-density lipoprotein deficiency, inherited in an autosomal dominant manner.It can be associated with LDL receptor.Associated regions and genes include:
niacin is sometimes prescribed to raise HDL levels.
References
== External links == |
Calcinosis cutis | Calcinosis cutis is a type of calcinosis wherein calcium deposits form in the skin. A variety of factors can result in this condition. The most common source is dystrophic calcification, which occurs in soft tissue as a response to injury. In addition, calcinosis is seen in Limited Cutaneous Systemic Sclerosis, also known as CREST syndrome (the "C" in CREST). In dogs, calcinosis cutis is found in young, large breed dogs and is thought to occur after a traumatic injury.
Causes
Calcinosis may result from a variety of causes such as:
Trauma to the region
Inflammation (bug bites, acne)
Varicose veins
Infections
Tumors (malignant or benign)
Diseases of connective tissue
Hypercalcemia
HyperphosphatemiaCalcinosis cutis is associated with systemic sclerosis.
Diagnosis
Types
Calcinosis cutis may be divided into the following types:: 527–530
Dystrophic calcinosis cutis
Metastatic calcinosis cutis
Iatrogenic calcinosis cutis
Traumatic calcinosis cutis
Idiopathic calcinosis cutis
Idiopathic scrotal calcinosis
Subepidermal calcified nodule
Tumoral calcinosis
Osteoma cutis
Treatment
Intralesional corticosteroids may be beneficial. Colchicine has been shown to be effective in certain populations. The efficacy of other treatments, such as magnesium or aluminum antacids, sodium etidronate, diphosphonates and diltiazem is unclear, but they have been reported to be serviceable in refractory calcinosis. Surgical options may be considered, particularly if there is associated ulceration.
Gallery
See also
Calcinosis
List of cutaneous conditions
References
== External links == |
Autosomal recessive polycystic kidney disease | Autosomal recessive polycystic kidney disease (ARPKD) is the recessive form of polycystic kidney disease. It is associated with a group of congenital fibrocystic syndromes. Mutations in the PKHD1 (chromosomal locus 6p12.2) cause ARPKD.
Signs and symptoms
Symptoms and signs include abdominal discomfort, polyuria, polydipsia, incidental discovery of hypertension, and abdominal mass. The classic presentation for ARPKD is systemic hypertension with progression to end-stage kidney disease (ESKD) by the age of 15. In a typical presentation, a small number of individuals with ARPKD live to adulthood with some kidney function; but with significant deterioration in liver function. This outcome is postulated to result from expression of the polycystic kidney and hepatic disease gene PKHD1, which is located on chromosome 6p. In severe cases, a fetus will present with oligohydramnios and as a result, may present with Potter sequence.
Genetics
The cause of ARPKD is linked to mutations in the PKHD1 gene. PKHD1 gene codes forfibrocystin. Fibrocystin is found in the epithelial cells of both the renal tubule and the bile ducts; deficiency leads to the characteristic polycystic dilation of both structures
ARPKD is a significant hereditary renal disease in that appears in childhood. The prevalence is estimated to be of 1 in 20,000 live births, with a reported carrier frequency of up to 1:70. The single gene mutation called PKHD1 is fully responsible for the disease presentation of ARPKD. This PKHD1 is located on the human chromosome region 6p21.1–6p12.2. It is also one of the largest genes in the genome as it occupies approximately 450 kb of DNA, and contains at least 86 exons.It is capable of producing multiple alternatively spliced transcripts. The largest known transcript encodes fibrocystin /polyductin (FPC), which is a large receptor-like integral membrane protein of 4074 amino acids. The structure of the FPC consist of a single transmembrane, a large N-terminal extracellular region, and a short intracellular cytoplasmic domain. The FPC protein is found on the primary cilia of epithelia cells of cortical and medullary collecting ducts and cholangiocytes of bile ducts, and show similarity to polycystins and several other ciliopathy proteins. FPC is also found to be expressed on the basal body and plasma membrane. It is presumed that the large extracellular domain of FPC binds to a ligand(s) that is yet unknown and that is also involved in cell-cell and cell-matrix interactions.It is known that FPC interacts with ADPKD protein PC2 and may also participate in this regulation pathway of the mechanosensory function of the primary cilia, calcium signaling, and PCP. This is suggesting a common mechanism underlying cystogenesis between ADPKD and ARPKD. The FPC protein is also found on the centrosomes and mitotic spindle and may regulate centrosome duplication and mitotic spindle assembly during cell division. There have been a large number of various single-gene mutations found throughout PKHD1 and are unique to individual families. Most of the patients are compound heterozygotes for PKHD1 mutations. Patients with two nonsense mutations appear to have an earlier onset of the disease.
Diagnosis
Ultrasonography is the primary method to evaluate autosomal recessive polycystic kidney disease, particularly in the perinatal and neonatal stages.
Differential diagnosis
The differential diagnoses of this condition include:
Glomerulocystic kidney disease
Autosomal dominant polycystic kidney disease
Diffuse cystic dysplasia
Treatment
The treatment options for autosomal recessive polycystic kidney disease, given there is no current cure, are:
Medications for hypertension
Medications and/or surgery for pain
Antibiotics for infection
Dialysis (if kidney failure is present)
Kidney transplantation(in serious cases)
References
Further reading
Lonergan, Gael J.; Rice, Roy R.; Suarez, Eric S. (2000-05-01). "Autosomal Recessive Polycystic Kidney Disease: Radiologic-Pathologic Correlation". RadioGraphics. 20 (3): 837–855. doi:10.1148/radiographics.20.3.g00ma20837. ISSN 0271-5333. PMID 10835131.
Rajanna, Dayananda Kumar; Reddy, Anjani; Srinivas, Naren Satya; Aneja, Ankur (2013-03-29). "Autosomal Recessive Polycystic Kidney Disease: Antenatal Diagnosis and Histopathological Correlation". Journal of Clinical Imaging Science. 3: 13. doi:10.4103/2156-7514.109733. ISSN 2156-7514. PMC 3690676. PMID 23814685.
== External links == |
Rheumatoid nodulosis | Rheumatoid nodulosis is a cutaneous condition associated with rheumatoid arthritis, characterized by the appearance of multiple nodules, most often on the hands.
See also
Rheumatoid neutrophilic dermatitis
Rheumatoid nodule
List of cutaneous conditions
== References == |
Parathyroidectomy | Parathyroidectomy is the surgical removal of one or more of the (usually) four parathyroid glands. This procedure is used to remove an adenoma or hyperplasia of these glands when they are producing excessive parathyroid hormone (PTH): hyperparathyroidism. The glands are usually four in number and located adjacent to the posterior surface of the thyroid gland, but their exact location is variable. When an elevated PTH level is found, a sestamibi scan or an ultrasound may be performed in order to confirm the presence and location of abnormal parathyroid tissue.
Indications
The main indication for parathyroidectomy is primary hyperparathyroidism, a condition in which one or more of the parathyroid glands produce excessive parathyroid hormone. Not all cases of primary hyperparathyroidism require surgery, but it is recommended if the condition causes significant symptoms or if it affects the kidneys (nephrocalcinosis) or bone health (osteoporosis), and also in people under 50 even if they do not have symptoms. It is not always possible to anticipate if a parathyroid tumor is malignant (i.e. capable of invading other tissues or spreading elsewhere). Any suspicion of parathyroid carcinoma is therefore also an indication for surgery.Parathyroidectomy may also be required in secondary hyperparathyroidism. This situation arises mainly in people with severe chronic kidney disease in which the parathyroid glands are overactive to compensate for the low calcium and vitamin D levels often present in CKD. In many cases, the parathyroid hormone production improves when these abnormalities are treated with medication. A small proportion, however, have persistently raised hormone levels six months after treatment has started, thought to be autonomous production of hormone by the glands and loss of feedback mechanisms. In this situation surgical parathyroidectomy may be required, especially if calcium and phosphate levels remain elevated, there is calcium deposition in the wall of blood vessels (calciphylaxis in severe cases) or there is worsening bone disease. In people on dialysis, parathyroidectomy can improve their survival. It does appear that the procedure may be underused.
Procedure
The operation requires a general anesthetic (unconscious and pain free) or a local anesthetic (pain free). The surgeon makes an incision around an inch long in the neck just under the larynx (Adams apple), and locates the offending parathyroid glands. Preoperative testing using sestamibi scanning can help identify the location of glands. It can also be used to limit the extent of surgical exploration when used in conjunction with intraoperative PTH hormone monitoring. The particular problem or disease process will determine how many of the parathyroid glands are removed. Some parathyroid tissue must be left in place to help prevent hypoparathyroidism.
Recovery after the operation tends to be swift. The PTH level is back to normal within 10–15 minutes, and can be confirmed by intraoperative rapid assessment during the operation. However, the remaining parathyroid glands may take hours to several weeks to return to their normal functioning levels (as they may have become dormant). Calcium supplements are therefore often required to prevent symptoms of hypocalcemia and to restore lost bone mass.The patient is placed in a semi-Fowler position and the neck is extended. An abbreviated Kocher incision is made and the platysma muscle is dissected horizontally. The strap muscles are released off of the thyroid gland. Then the thyroid gland is mobilized and the parathyroid arterial blood supply is suture ligated. The entire parathyroid adenoma is identified and dissected out. Intraoperative PTH monitoring can begin at this time and will show falling PTH levels if the entire adenoma has been resected.
Complications
While mild hypocalcemia is common after partial parathyroidectomy, some people experience persistently prolonged low calcium levels. This is called hungry bone syndrome. Despite the reactivation of unresected parathyroid glands producing normal to elevated levels of PTH, serum calcium continues to be low. The balance between calcium influx and efflux within the bone continues to be disrupted, favoring the former. The bone is said to be "hungry" as it consumes minerals without regard to PTH; calcium, magnesium, and phosphate continue to be deposited into the bones, resulting in hypocalcemia, hypomagnesemia, and hypophosphatemia. Prolonged calcium supplementation may be required. Hungry bone syndrome is particularly common in people who are on long-term regular dialysis.
See also
List of surgeries by type
References
External links
"How is parathyroid surgery performed?". American Association of Endocrine Surgeons. Retrieved 11 May 2019.
"Parathyroid gland removal". Medical Encyclopedia. Medline Plus. 3 December 2018. Retrieved 8 December 2018. |
Arginine:glycine amidinotransferase deficiency | Arginine:glycine amidinotransferase deficiency or AGAT deficiency is an autosomal recessive cerebral creatine deficiency caused by a deficiency of the enzyme arginine:glycine amidinotransferase. This enzyme deficiency results in decreased creatine synthesis, and is caused by biallelic pathogenic variants in GATM. Individuals with AGAT deficiency are intellectually disabled and have muscle weakness. The symptoms of AGAT deficiency are caused by the lack of creatine in specific tissues, most notably muscle and brain. Oral creatine supplementation can be used to treat AGAT deficiency, with early intervention providing the best results. All creatine deficiencies are rare, and there have been fewer than 20 individuals reported in medical literature with AGAT deficiency. This disorder was first described in 2000.
Signs and symptoms
As with other cerebral creatine deficiency syndromes, individuals affected with AGAT deficiency are intellectually disabled and can have seizures. They can often have muscle weakness. These symptoms are caused by the lack of creatine in skeletal muscles and in the brain. AGAT deficiency was first identified in 2000, in a pair of sisters aged 4 and 6. Both sisters had severe intellectual disability.
Genetics
AGAT deficiency is caused by deficient activity of arginine:glycine amidinotransferase, which is coded for by GATM, located on the long arm of chromosome 15. AGAT deficiency is inherited in an autosomal recessive manner, which means pathogenic variants must be inherited from each parent. This enzyme catalyzes the first step in creatine biosynthesis, the combination of arginine and glycine to form guanidinoacetate, which also results in the formation or ornithine as a by product. These reactions take place primarily in the kidney and pancreas. The clinical manifestations of AGAT deficiency are caused by the decreased amounts of creatine produced.
Diagnosis
AGAT deficiency can be suspected from clinical findings, although there is significant phenotypic overlap with the most common presenting symptoms of intellectual disability and muscle weakness. Laboratory testing of plasma and urine will show decreased levels of creatine and guanidinoacetate. Non-specific elevations of metabolites on urine testing that are normalized to creatinine may appear falsely elevated. Magnetic resonance spectroscopy (MRS) of the brain will also show an absence of creatine, which is normally present. This finding is not specific to AGAT deficiency, it can be observed in all three cerebral creatine deficiencies. The combination of biochemical testing and MRS findings can be strongly suggestive of AGAT deficiency. Confirmation would most often be done with molecular testing of GATM. Identification of biallelic pathogenic variants in GATM would be confirmation of a diagnosis of AGAT deficiency. Uncertain findings on molecular testing may be able to be confirmed by enzyme assays, or by measuring creatine uptake in fibroblasts. Prenatal testing for AGAT deficiency can be performed on chorionic villi samples if the causative pathogenic variants in the family are known.
Treatment
The main focus of treatment for AGAT deficiency is supplementation of creatine, with the goal of replenishing cerebral creatine to normal levels. This is done with oral creatine supplementation. Treatment is most effective if it is started early in life, before symptoms are apparent. Treatment in affected individuals does not reverse intellectual disability or improve cognitive function. For treatment at any age, even if intellectual disability was present, all individuals showed improvement in muscle weakness. In an asymptomatic sibling, who was started on treatment due to the earlier diagnosis of an affected sibling, early intervention with creatine supplementation resulted in improved outcomes when compared to their untreated siblings at the same age. In addition to clinical findings, the effectiveness of treatment can be monitored by following creatine levels in blood and urine as well as the creatine signal by MRS. As creatine is rapidly converted and excreted as creatinine, treatment must be life long to continue to benefit the patient. Treatment during the early years of brain development is most important for preserving brain function.
References
== External links == |
Adenosine deaminase deficiency | Adenosine deaminase deficiency (ADA deficiency) is a metabolic disorder that causes immunodeficiency. It is caused by mutations in the ADA gene. It accounts for about 10–15% of all cases of autosomal recessive forms of severe combined immunodeficiency (SCID) among non-inbred populations.ADA deficiency can present in infancy, childhood, adolescence, or adulthood. Age of onset and severity is related to some 29 known genotypes associated with the disorder. It occurs in fewer than one in 100,000 live births worldwide.
Signs and symptoms
The main symptoms of ADA deficiency are pneumonia, chronic diarrhea, and widespread skin rashes. Affected children also grow much more slowly than healthy children and some have developmental delay. Most individuals with ADA deficiency are diagnosed with SCID in the first 6 months of life.An association with polyarteritis nodosa has been reported.
Genetics
The enzyme adenosine deaminase is encoded by the ADA gene on chromosome 20. ADA deficiency is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an autosome (chromosome 20 is 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.Age of onset and severity is related to some 29 known genotypes associated with the disorder.
Pathophysiology
ADA deficiency is due to a lack of the enzyme adenosine deaminase. This deficiency results in an accumulation of deoxyadenosine, which, in turn, leads to:
a buildup of dATP in all cells, which inhibits ribonucleotide reductase and prevents DNA synthesis, so cells are unable to divide. Since developing T cells and B cells are some of the most mitotically active cells, they are highly susceptible to this condition.
an increase in S-adenosylhomocysteine since the enzyme adenosine deaminase is important in the purine salvage pathway; both substances are toxic to immature lymphocytes, which thus fail to mature.Because T cells undergo proliferation and development in the thymus, affected individuals typically have a small, underdeveloped thymus. As a result, the immune system is severely compromised or completely lacking.
Diagnosis
The diagnosis is based on clinical features, with a concomitant decreased blood adenosine deaminase level supporting the diagnosis.
Treatment
Treatments include:
bone marrow transplant
ADA enzyme in PEG vehicle
Gene therapy
In September 1990, the first gene therapy to combat this disease was performed by Dr. William French Anderson on a four-year-old girl, Ashanti DeSilva, at the National Institutes of Health, Bethesda, Maryland, U.S.A.
In April 2016 the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed and recommended for approval a stem cell gene therapy called Strimvelis, for children with ADA-SCID for whom no matching bone marrow donor is available.
History
ADA deficiency was discovered in 1972 by Eloise Giblett, a professor at the University of Washington. The ADA gene was used as a marker for bone marrow transplants. A lack of ADA activity was discovered by Giblett in an immunocompromised transplant candidate. After discovering a second case of ADA deficiency in an immunocompromised patient, ADA deficiency was recognized as the first immunodeficiency disorder.
References
Further reading
Adenosine deaminase deficiency - Genetics Home Reference
== External links == |
Fryns syndrome | Fryns syndrome is an autosomal recessive multiple congenital anomaly syndrome that is usually lethal in the neonatal period. Fryns (1987) reviewed the syndrome.
Presentation
Usually associated with diaphragmatic hernia,
pulmonary hypoplasia,
imperforate anus,
micropenis,
bilateral cryptorchidism,
cerebral ventricular dilation,
camptodactyly,
agenesis of sacrum,
low-set ear.
Cytogenetics
In a newborn boy thought to have Fryns syndrome, Clark and Fenner-Gonzales (1989) found mosaicism for a tandem duplication of 1q24-q31.2. They suggested that the gene for this disorder is located in that region. However, de Jong et al. (1989), Krassikoff and Sekhon (1990), and Dean et al. (1991) found possible Fryns syndrome associated with anomalies of chromosome 15, chromosome 6, chromosome 8 and chromosome 22, respectively. Thus, these cases may all represent mimics of the mendelian syndrome and have no significance as to the location of the gene for the recessive disorder.By array CGH, Slavotinek et al. (2005) screened patients with DIH and additional phenotypic anomalies consistent with Fryns syndrome for cryptic chromosomal aberrations. They identified submicroscopic chromosome deletions in 3 probands who had previously been diagnosed with Fryns syndrome and had normal karyotyping with G-banded chromosome analysis. Two female infants were found to have microdeletions involving 15q26.2 (see 142340), and 1 male infant had a deletion in band 8p23.1 (see 222400).
Diagnosis
Prenatal Diagnosis:
Aymé, et al. (1989) reported prenatal diagnosis of Fryns syndrome by sonography between 24 and 27 weeks.
Manouvrier-Hanu et al. (1996) described the prenatal diagnosis of Fryns syndrome by ultrasonographic detection of diaphragmatic hernia and cystic hygroma. The diagnosis was confirmed after termination of the pregnancy. The fetus also had 2 erupted incisors; natal teeth had not been mentioned in other cases of Fryns syndrome.Differential Diagnosis:
McPherson et al. (1993) noted the phenotypic overlap between Fryns syndrome and the Pallister–Killian syndrome (601803), which is a dysmorphic syndrome with tissue-specific mosaicism of tetrasomy 12p.
Veldman et al. (2002) discussed the differentiation between Fryns syndrome and Pallister–Killian syndrome, noting that differentiation is important to genetic counseling because Fryns syndrome is an autosomal recessive disorder and Pallister–Killian syndrome is usually a sporadic chromosomal aberration. However, discrimination may be difficult due to the phenotypic similarity. In fact, in some infants with coarse face, acral hypoplasia, and internal anomalies, the initial diagnosis of Fryns syndrome had to be changed because mosaicism of isochromosome 12p was detected in fibroblast cultures or kidney tissue. Although congenital diaphragmatic hernia is a common finding in both syndromes, bilateral congenital diaphragmatic hernia had been reported only in patients with Fryns syndrome until the report of the patient with Pallister–Killian syndrome by Veldman et al. (2002).
Slavotinek (2004) reviewed the phenotypes of 52 reported cases of Fryns syndrome and reevaluated the diagnostic guidelines. She concluded that congenital diaphragmatic hernia and distal limb hypoplasia are strongly suggestive of Fryns syndrome, with other diagnostically relevant findings including pulmonary hypoplasia, craniofacial dysmorphism, polyhydramnios, and orofacial clefting. Slavotinek (2004) stated that other distinctive anomalies not mentioned in previous guidelines include ventricular dilatation or hydrocephalus, agenesis of the corpus callosum, abnormalities of the aorta, dilatation of the ureters, proximal thumbs, and broad clavicles.
Epidemiology
In France, Aymé, et al. (1989) estimated the prevalence of Fryns syndrome to be 0.7 per 10,000 births based on the diagnosis of 6 cases in a series of 112,276 consecutive births (live births and perinatal deaths).
Cases
Fryns et al. (1979) reported 2 stillborn sisters with a multiple congenital anomaly syndrome characterized by coarse facies with cloudy corneae, diaphragmatic defects, absence of lung lobulation, and distal limb deformities. A sporadic case was reported by Goddeeris et al. (1980). Fitch (1988) claimed that she and her colleagues were the first to describe this disorder. In 1978 they reported a single infant, born of second-cousin parents, who had absent left hemidiaphragm, hydrocephalus, arhinencephaly, and cardiovascular anomalies.
Lubinsky et al. (1983) reported a brother and sister with Fryns syndrome who both died in the neonatal period. Facial anomalies included broad nasal bridge, microretrognathia, abnormal helices, and cleft palate. Other features included distal digital hypoplasia, lung hypoplasia, and urogenital abnormalities, including shawl scrotum, uterus bicornis, and renal cysts. They were discordant for diaphragmatic hernia, cleft lip, and Dandy–Walker anomaly.
Meinecke and Fryns (1985) reported an affected child; consanguinity of the parents supported recessive inheritance. They noted that a diaphragmatic defect had been described in 4 of the 5 reported cases and lung hypoplasia in all. Young et al. (1986) reported a sixth case. The male infant survived for 12 days. These authors listed corneal clouding, camptodactyly with hypoplastic nails, and abnormalities of the diaphragm as cardinal features.
Samueloff et al. (1987) described a family in which all 4 children had Fryns syndrome and neonatal mortality. Features included hypoplastic lungs, cleft palate, retrognathia, micrognathism, small thorax, diaphragmatic hernia, distal limb hypoplasia, and early onset of polyhydramnios with premature delivery. Schwyzer et al. (1987) described an affected infant whose parents were second cousins.
Moerman et al. (1988) described infant brother and sister with the syndrome of diaphragmatic hernia, abnormal face, and distal limb anomalies. Both died shortly after birth with severe respiratory distress. Ultrasonography demonstrated fetal hydrops, diaphragmatic hernia, and striking dilatation of the cerebral ventricles in both infants. Post-mortem examination showed Dandy–Walker malformation, ventricular septal defect, and renal cystic dysplasia.
Cunniff et al. (1990) described affected brothers and 3 other cases, bringing the total reported cases of Fryns syndrome to 25. One of the affected brothers was still alive at the age of 24 months. Bilateral diaphragmatic hernias had been repaired on the first day of life. He required extracorporeal membrane oxygenation therapy for 5 days and oscillatory therapy for 3 months. Ventriculoperitoneal shunt was required because of slowly progressive hydrocephalus. Scoliosis was associated with extranumerary vertebral bodies and 13 ribs. Because of delayed gastric emptying, a gastrostomy tube was inserted. In addition, because of persistent chylothorax, he underwent decortication of the right lung and oversewing of the thoracic duct.
Kershisnik et al. (1991) suggested that osteochondrodysplasia is a feature of Fryns syndrome.
Willems et al. (1991) suggested that a diaphragmatic hernia is not a necessary feature of Fryns syndrome. They described a child with all the usual features except for diaphragmatic hernia; the diaphragm was reduced to a fibrous web with little muscular component. Bartsch et al. (1995) presented 2 unrelated cases with a typical picture of Fryns syndrome but without diaphragmatic hernia. One of these patients was alive at the age of 14 months, but had severe intellectual disability. Bamforth et al. (1987) and Hanssen et al. (1992) also described patients with this syndrome who survived the neonatal period. In the report of Hanssen et al. (1992), 2 older siblings had died in utero. The reports suggested that survival beyond the neonatal period is possible when the diaphragmatic defect and lung hypoplasia are not present. Nevertheless, intellectual disability has been present in all surviving patients.
Vargas et al. (2000) reported a pair of monozygotic twins with Fryns syndrome discordant for severity of diaphragmatic defect. Both twins had macrocephaly, coarse facial appearance, hypoplasia of distal phalanges, and an extra pair of ribs. Twin A lacked an apparent diaphragmatic defect, and at 1 year of age had mild developmental delay. Twin B had a left congenital diaphragmatic hernia and died neonatally. The authors suggested that absence of diaphragmatic defect in Fryns syndrome may represent a subpopulation of more mildly affected patients.
Aymé, et al. (1989) described 8 cases of Fryns syndrome in France. The most frequent anomalies were diaphragmatic defects, lung hypoplasia, cleft lip and palate, cardiac defects, including septal defects and aortic arch anomalies, renal cysts, urinary tract malformations, and distal limb hypoplasia. Most patients also had hypoplastic external genitalia and anomalies of internal genitalia, including bifid or hypoplastic uterus or immature testes. The digestive tract was also often abnormal; duodenal atresia, pyloric hyperplasia, malrotation and common mesentery were present in about half of the patients. When the brain was examined, more than half were found to have Dandy–Walker anomaly and/or agenesis of the corpus callosum. A few patients demonstrated cloudy cornea. Histologically, 2 of 3 patients showed retinal dysplasia with rosettes and gliosis of the retina, thickness of the posterior capsule of the lens, and irregularities of Bowman membrane.
Alessandri et al. (2005) reported a newborn from the Comores Islands with clinical features of Fryns syndrome without diaphragmatic hernia. They noted that diaphragmatic hernia is found in more than 80% of cases and that at least 13 other cases had been reported with an intact diaphragm.
In a postneonatal survivor of Fryns syndrome, Riela et al. (1995) described myoclonus appearing shortly after birth, which was well controlled on valproate. Progressive cerebral and brainstem atrophy was noted on serial MRIs made at 3 months and after 6 months of age.
Van Hove et al. (1995) described a boy with Fryns syndrome who survived to age 3 years and reviewed the outcome of other reported survivors (approximately 14% of reported cases). Survivors tended to have less frequent diaphragmatic hernia, milder lung hypoplasia, absence of complex cardiac malformation, and severe neurologic impairment. Their patient had malformations of gyration and sulcation, particularly around the central sulcus, and hypoplastic optic tracts beyond the optic chiasm associated with profound intellectual disability.
Fryns and Moerman (1998) reported a second-trimester male fetus with Fryns syndrome and midline scalp defects. The authors stated that the finding of a scalp defect in Fryns syndrome confirms that it is a true malformation syndrome with major involvement of the midline structures.
Ramsing et al. (2000) described 2 sibships with 4 fetuses and 1 preterm baby of 31 weeks gestation affected by a multiple congenital disorder suggestive of Fryns syndrome. In addition to the diaphragmatic defects and distal limb anomalies, they presented with fetal hydrops, cystic hygroma, and multiple pterygias. Two affected fetuses in 1 family showed severe craniofacial abnormalities with bilateral cleft lip and palate and cardiovascular malformation.
Arnold et al. (2003) reported a male fetus with Fryns syndrome and additional abnormalities, in particular, multiple midline developmental defects including gastroschisis, central nervous system defects with left arrhinencephaly and cerebellar hypoplasia, midline cleft of the upper lip, alveolar ridge, and maxillary bone, and cleft nose with bilateral choanal atresia.
Pierson et al. (2004) reviewed 77 reported patients with Fryns syndrome and summarized the abnormal eye findings identified in 12 of them. They also described 3 new patients with Fryns syndrome, 1 of whom demonstrated unilateral microphthalmia and cloudy cornea.
Slavotinek et al. (2005) noted that Fryns syndrome may be the most common autosomal recessive syndrome in which congenital diaphragmatic hernia (see DIH2, 222400) is a cardinal feature. The autosomal recessive inheritance in Fryns syndrome contrasts with the sporadic inheritance for most patients with DIH.
References
== External links == |
Persistent Müllerian duct syndrome | Persistent Müllerian duct syndrome (PMDS) is the presence of Müllerian duct derivatives (fallopian tubes, uterus, and/or the upper part of the vagina) in what would be considered a genetically and otherwise physically normal male animal by typical human based standards. In humans, PMDS typically is due to an autosomal recessive congenital disorder and is considered by some to be a form of pseudohermaphroditism due to the presence of Müllerian derivatives.Typical features include undescended testes (cryptorchidism) and the presence of a small, underdeveloped uterus in an XY infant or adult. This condition is usually caused by deficiency of fetal anti-Müllerian hormone (AMH) effect due to mutations of the gene for AMH or the anti-Müllerian hormone receptor, but may also be as a result of insensitivity to AMH of the target organ.PMDS can also present in non-human animals.
Presentation
The first visible signs of PMDS after birth is cryptorchidism (undescended testes) either unilaterally or bilaterally. Along with cryptorchidism, is also inguinal hernias which may be presented unilaterally (affects one testicle) or bilaterally (affects both testicles). Adults who have been oblivious to this condition may be presented with haematuria, which is when blood appears in urine because of hormonal imbalances. PMDS Type I, is also referred to as hernia uteri inguinalis, which exhibits one descended testis that has also pulled the fallopian tube and sometimes uterus, through the inguinal canal. The descended testes, fallopian tube and uterus all fall in the same inguinal canal, causing an inguinal hernia. Altogether when the aforementioned conditions occur, it is called transverse testicular ectopia.Under the microscope, some samples taken for biopsies displayed results where testicular tissue was at a stage of immaturity, and showed dysplasia.
Genetics
Mutation in AMH gene (PMDS Type 1) or AMHR2 gene (PMDS Type 2) are the primary causes of PMDS. AMH, or sometimes referred to as Müllerian inhibiting substance (MIS), is secreted by Sertoli cells during an individuals whole life. It is essential during the foetal period as it functions to regress the Müllerian ducts. However, AMH also functions in the last trimester of pregnancy, after birth, and even during adulthood in minimal amounts. The Sertoli cells in males secrete AMH, through the presence of a Y chromosome.The role of the AMH gene in reproductive development, is the production of a protein that contributes to male sex differentiation. During development of male foetuses, the AMH protein is secreted by cells within the testes. AMHs bind to the AMH Type 2 Receptors, which are present on cells on the surface of the Müllerian duct. The binding of AMH to its receptors on the Müllerian duct induces the apoptosis of the Müllerian duct cells, thus the regression of the Müllerian duct within males. However, for females who originally do not produce AMH proteins during foetal development, the Müllerian duct eventually becomes the uterus and fallopian tubes as normal. With the AMH gene mutation (PMDS Type 1), the AMH is either not produced, produced in deficient amounts, defective, secreted at the wrong critical period for male differentiation or the Müllerian ducts manifested a resistance to AMH.AMHR2 contains the instructions for generating the receptors that AMH binds to. If there if a mutation in the AMHR2 gene, the response to AMH molecules binding to the receptor cannot be properly reciprocated. Other possibilities include an absence of the receptors, such that the AMH molecules cannot induce differentiation. Mutation in the AMHR2 is critical to proper male sex differentiation. The genetic mutational cause of PMDS, is a 27 base-pair deletion of the Anti-Müllerian Type 2 Receptor gene. The 27-base-pair deletion that occurs PMDS is in exon 10 on one allele.PMDS is inherited in an autosomal recessive manner. The male individuals inherit mutated copies of the X chromosomes from the maternal and paternal genes, implying the parents are carriers and do not show symptoms. Females inheriting two mutated genes do not display symptoms of PMDS, though remain as carriers. Males are affected genotypically with the karyotype (46, XY) and phenotypically.
Mechanism
AMH (anti Müllerian hormone) is produced by the primitive Sertoli cells as one of the earliest Sertoli cell products and induces regression of the Müllerian ducts. Fetal Müllerian ducts are only sensitive to AMH action around the 7th or 8th week of gestation, and Müllerian regression is completed by the end of the 9th week. The AMH induced regression of the Müllerian duct occurs in cranio-caudal direction via apoptosis. The AMH receptors are on the Müllerian duct mesenchyme and transfer the apoptotic signal to the Müllerian epithelial cell, presumably via paracrine actors. The Wolffian ducts differentiate into epididymides, vasa deferentia and seminal vesicles under the influence of testosterone, produced by the fetal Leydig cells.
Diagnosis
Persistent Müllerian duct syndrome (PMDS), also known as persistent oviduct syndrome, is a congenital disorder related to male sexual development. PMDS usually affects phenotypically normal male individuals with the karyotype (46, XY) and is a form of pseudohermaphroditism.The condition occurs in males and consists of normal-functioning reproductive organs and gonads, but also female reproductive organs such as the uterus and the fallopian tubes. The fetus has two sets of tubes which give rise to accessory reproductive organs - the (Wolffian) mesonephric ducts and the (Müllerian) paramesonephric ducts. Usually, the Wolffian duct gives rise to male reproductive organs (specifically the testicle, epididymis and vas deferens) while the Müllerian to female (the fallopian tubes, the uterus and the vagina), while the other duct regresses. In PMDS, an abnormality in the anti-Müllerian hormone signalling pathway causes the in-males-redundant Müllerian duct to persist and give rise to variously developed female reproductive organs.PMDS has various causes related to AMH or receptor abnormalities. For example, AMH has failed to synthesize, failed to release or was secreted at the wrong time. Normally, both the Müllerian and Wolffian ducts are present during the 7th week of gestation. At approximately the end of the 7th and the beginning of the 8th week of gestation, the Sertoli cells secretion of AMH occurs, causing male sex differentiation during fetal development. The AMH molecules bind to AMHRII (anti-Müllerian hormone receptor type II) regressing the Müllerian duct. The Leydig cells secrete testosterone to aid the male differentiation process by inducing structures such as the epididymis, vas deferens and seminal vesicles. However, with PMDS individuals, the Müllerian duct persists instead of regressing, either due to AMH secretion (PMDS Type I) or AMH receptors (PMDS Type II). PMDS is usually coincidentally found during surgery for inguinal hernia, or when searching for adult male infertility causes.
Other diagnostic tests
Genetic
Another method for the confirmation of PMDS is genetic testing. It is not usually preferred because of its processing period and cost. With image screenings such as ultrasound and MRI, the condition can be efficiently confirmed. Genetic tests can identify those who hold the mutated gene, identify the family members chances and risks, and advise those who are trying to get pregnant. Genetic counseling and further genetic testing is offered to confirm the chances and risks of an individuals offspring obtaining the pair of mutated genes. Further research into the family tree and inheritance is possible as well.
ELISA
An ELISA test is a form of immunoassay, a technique which uses an antibody or antigen to identify the presence of particular substances. For PMDS, ELISA tests can be used to determine the levels of AMH within the male individuals serum, but this is only effective before the individual reaches puberty as it normally increases during this period. PMDS patients display low levels of AMH within the serum, and low levels of testosterone.
Treatment
The main form of treatment is laparotomy, a modern and minimally invasive type of surgery. Laparotomy properly positions the testes within the scrotum (orchidopexy) and remove Müllerian structures, the uterus and fallopian tubes. Occasionally they are unsalvageable if located high in the retroperitoneum. During this surgery, the uterus is usually removed and attempts made to dissect away Müllerian tissue from the vas deferens and epididymis to improve the chance of fertility. If the person has male gender identity and the testes cannot be retrieved, testosterone replacement will be usually necessary at puberty should the affected individual choose to pursue medical attention. Recently, laparoscopic hysterectomy is offered to patients as a solution to both improve the chances of fertility and to prevent the occurrence of neoplastic tissue formation. The surgery is recommended to be performed when the individual is between one and two years old, but usually done when less than one year old. Having a target age for surgery reduces the risks of damaging the vas deferens. The vas deferens is in close proximity to the Müllerian structures, and is sometimes lodged in the uterine wall. Overall, the purpose of the treatment improves self-identification of an individual, reduces the increased risk of cancer and reduces the possibility of infertility, if not already present.
PMDS patients have a possibility of infertility in the future if not promptly operated on. When the affected males are adults, those who are not aware of the condition may find the presence of blood in their semen (hematospermia). The Müllerian structures and cryptorchidism can also develop into cancer if ignored, or if there are pieces of Müllerian structures left from past surgery. If PMDS is found during adulthood, or if Müllerian structures had to be left behind due to risks in surgery, biopsies of the remaining Müllerian structures can be performed. Upon pathohistological observation, the endometrial tissues appear atrophied, and the fallopian tubes have begun to congest showing signs of fibrosis.
Epidemiology
PMDS is a relatively rare congenital disease. From current data, approximately 45% of the known cases are caused by mutations in the AMH gene, being a mutation on chromosome 19 (Type I PMDS). Approximately, 40% are AMHR2 mutations, on the AMH receptor type 2 gene, which is on chromosome 12 (Type 2 PMDS). The remaining unknown 15% are referred to as idiopathic PMDS.
Case studies
Especially before the 21st century, these conditions were hard to diagnose due to the lack of modern imaging capabilities. For this reason, the older population, or those in poorer countries found out later. PMDS was usually overlooked because the external symptoms, such as the cryptorchidism and inguinal hernias, were assumed to be the only complication.
A case reported in 2013, involves a 50-year-old male with a history of low testosterone levels, high cholesterol and the congenital absence of his right testis. Imaging revealed that the patient had three cystic masses, with structures similar to the uterus and ovaries, thus PMDS. During the operation, the surgeons found malignant degeneration of the Müllerian remnants which occurs if PMDS is unnoticed for a long period of time. The cause of the complications presented in the male patient was due to the unidentified bilateral cryptorchidism since birth, as doctors at that time assumed the complication was just the "congenital absence of his right testis". Overlooking the symptoms of PDMS can cause permanent negative effects such as infertility and future malignancies, as shown by this male patient. The malignant degeneration of the Müllerian structures is supportive evidence for the cause of the male patients infertility.
See also
Intersex
Sexual differentiation
Cryptorchidism
Anti-Müllerian hormone
References
Further reading
== External links == |
Ellis–Van Creveld syndrome | Ellis–Van Creveld syndrome (also called mesoectodermal dysplasia but see Nomenclature section below) is a rare genetic disorder of the skeletal dysplasia type.
Signs and symptoms
It involves numerous anomalies including:
Post-axial polydactyly
Congenital heart defects (most commonly an atrial septal defect producing a common atrium, occurring in 60% of affected individuals)
Teeth present at birth (natal teeth)
Fingernail dysplasia
Short-limbed dwarfism, mesomelic pattern
Short ribs
Cleft palate
Malformation of the wrist bones (fusion of the hamate and capitate bones).
Genetics
Ellis–Van Creveld syndrome often is the result of founder effects in isolated human populations, such as the Amish and some small island inhabitants. Although relatively rare, this disorder does occur with higher incidence within founder-effect populations due to lack of genetic variability. Observation of the inheritance pattern has illustrated that the disease is autosomal recessive, meaning that both parents have to carry the gene in order for an individual to be affected by the disorder.Ellis–Van Creveld syndrome is caused by a mutation in the EVC gene, as well as by a mutation in a nonhomologous gene, EVC2, located close to the EVC gene in a head-to-head configuration. The gene was identified by positional cloning. The EVC gene maps to the chromosome 4 short arm (4p16). The function of a healthy EVC gene is not well understood at this time.
Relation to other rare disorders: genetic ciliopathy
Until recently, the medical literature did not indicate a connection among many genetic disorders, both genetic syndromes and genetic diseases, that are now being found to be related. As a result of new genetic research, some of these are, in fact, highly related in their root cause despite the widely varying set of medical symptoms that are clinically visible in the disorders. Ellis–Van Creveld syndrome is one such disease, part of an emerging class of diseases called ciliopathies. The underlying cause may be a dysfunctional molecular mechanism in the primary cilia structures of the cell, organelles which are present in many cellular types throughout the human body. The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development and thus offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases. Known ciliopathies include primary ciliary dyskinesia, Bardet–Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Alström syndrome, Meckel–Gruber syndrome and some forms of retinal degeneration.Weyers acrofacial dysostosis is due to another mutation in the EVC gene and hence is allelic with Ellis–Van Creveld syndrome.
Treatment
There is no causative / curative therapy. Symptomatic medical treatments are focussing on symptoms caused by orthopaedic, dental or cardiac problems. Regarding perioperative / anesthesiological management, recommendations for medical professionals are published at OrphanAnesthesia.
History
The disorder was described by Richard W. B. Ellis (1902–1966) of Edinburgh and Simon van Creveld (1895–1971) of Amsterdam. Each had a patient with this syndrome, as they had discovered when they met in the same train compartment on the way to a pediatrics conference in England in the late 1930s. A third patient had been referred to by L. Emmett Holt, Jr. and Rustin McIntosh in a textbook of pediatrics (Holt and McIntosh, 1933) and was included in full in the paper by Ellis and Van Creveld (1940).McCusick et al. (1964) followed up with a study of its incidence in the Amish population. He observed the largest pedigree so far, in an inbred religious isolate, the Old Order Amish, in Lancaster County, Pennsylvania. Almost as many persons were known in this one kindred as had been reported in all the medical literature up to that time.
Nomenclature
Six-fingered dwarfism (digital integer deficiency) was an alternative designation used for this condition when it was being studied in the Amish and may have served a useful function in defining this then little known condition for the medical profession, as well as the lay public. The term, however, has been found offensive by some because of the reference to the polydactyly, which is seen as a freakish label. For this reason, six-fingered dwarfism has been removed as an alternative name for this entry. This leaves Ellis–Van Creveld syndrome with its initialism, EVC, as the only satisfactory designation. Chondroectodermal dysplasia and mesoectodermal dysplasia do not well define the entity and are not satisfactory for general usage, either medical or otherwise.
References
External links
Media related to Ellis–van Creveld syndrome at Wikimedia Commons |
Akinetic mutism | Akinetic mutism is a medical term describing patients tending neither to move (akinesia) nor speak (mutism). Akinetic mutism was first described in 1941 as a mental state where patients lack the ability to move or speak. However, their eyes may follow their observer or be diverted by sound. Patients lack most motor functions such as speech, facial expressions, and gestures, but demonstrate apparent alertness. They exhibit reduced activity and slowness, and can speak in whispered monosyllables. Patients often show visual fixation on their examiner, move their eyes in response to an auditory stimulus, or move after often repeated commands. Patients with akinetic mutism are not paralyzed, but lack the will to move. Many patients describe that as soon as they "will" or attempt a movement, a "counter-will" or "resistance" rises up to meet them.
Types
Akinetic mutism varies across all patients. Its form, intensity, and clinical features correspond more closely to its functional anatomy rather than to its pathology. However, akinetic mutism most often appears in two different forms: frontal and mesencephalic.
Frontal akinetic mutism
Akinetic mutism can occur in the frontal region of the brain and occurs because of bilateral frontal lobe damage. Akinetic mutism as a result of frontal lobe damage is clinically characterized as hyperpathic. It occurs in patients with bilateral circulatory disturbances in the supply area of the anterior cerebral artery.
Mesencephalic akinetic mutism
Akinetic mutism can also occur as a result of damage to the mesencephalic region of the brain. Mesencephalic akinetic mutism is clinically categorized as somnolent or apathetic akinetic mutism. It is characterized by vertical gaze palsy and ophthalmoplegia. This state of akinetic mutism varies in intensity, but it is distinguished by drowsiness, lack of motivation, hyper-somnolence, and reduction in spontaneous verbal and motor actions.
Symptoms and signs
Lack of motor function (but not paralysis)
Lack of speech
Apathy
Slowness
Disinhibition
Causes
Akinetic mutism can be caused by a variety of things. It often occurs after brain injury or as a symptom of other diseases.
Frontal lobe damage
Akinetic mutism is often the result of severe frontal lobe injury in which the pattern of inhibitory control is one of increasing passivity and gradually decreasing speech and motion.
Thalamic stroke
Many cases of akinetic mutism occur after a thalamic stroke. The thalamus helps regulate consciousness and alertness.
Ablation of cingulate gyrus
Another cause of both akinesia and mutism is ablation of the cingulate gyrus. Destruction of the cingulate gyrus has been used in the treatment of psychosis. Such lesions result in akinesia, mutism, apathy, and indifference to painful stimuli. The anterior cingulate cortex is thought to supply a "global energizing factor" that stimulates decision making. When the anterior cingulate cortex is damaged, it can result in akinetic mutism.
Other
Akinetic mutism is a symptom during the final stages of Creutzfeldt–Jakob disease (a rare degenerative brain disease) and can help diagnose patients with this disease. It can also occur in a stroke that affects both anterior cerebral artery territories. Another cause is neurotoxicity due to exposure to certain drugs such as tacrolimus and cyclosporine.
Other causes of akinetic mutism are as follows:
Respiratory arrest and cerebral hypoxia
Acute cases of encephalitis lethargica
Meningitis
Hydrocephalus
Trauma
Tumors
Aneurysms
Olfactory groove meningioma
Cyst in third ventricle
Toxical lesions and infections of central nervous system
Delayed post-hypoxic leukoencephalopathy (DPHL)
Creutzfeldt–Jakob disease (mesencephalic form)
Diagnosis
Akinetic mutism can be misdiagnosed as depression, delirium, or locked-in syndrome, all of which are common following a stroke. Patients with depression can experience apathy, slurring of speech, and body movements similar to akinetic mutism. Similarly to akinetic mutism, patients with locked-in syndrome experience paralysis and can only communicate with their eyes. Correct diagnosis is important to ensure proper treatment. A variety of treatments for akinetic mutism have been documented, but treatments vary between patients and cases.
Treatment
Magnesium sulfate
Treatments using intravenous magnesium sulfate have shown to reduce the symptoms of akinetic mutism. In one case, a 59-year-old woman was administered intravenous magnesium sulfate in an attempt to resolve her akinetic mutism. The patient was given 500 mg of magnesium every eight hours, and improvement was seen after 24 hours. She became more verbal and attentive, and treatment was increased to 1000 mg every eight hours as conditions continued to improve.
Cyst puncture
As seen in the case of Elsie Nicks, the puncture or removal of a cyst causing akinetic mutism can relieve symptoms almost immediately. However, if the cyst fills up again, the symptoms can reappear.
Dopamine agonist therapy
Symptoms of akinetic mutism suggest a possible presynaptic deficit in the nigrostriatal pathway, which transmits dopamine. Some patients with akinetic mutism have shown to improve with levodopa or dopamine agonist therapy, or by repleting dopamine in the motivational circuit with stimulants, antidepressants, or agonists such as bromocriptine or amantadine.Other treatments include amantadine, carbidopa-levodopa, donepezil, memantine, and oral magnesium oxide.
History
Fourteen-year-old Elsie Nicks was the first patient to be diagnosed with akinetic mutism by Hugh Cairns in 1941. She suffered from severe headaches her entire life and was eventually given morphine to help with treatment. She began to enter a state of akinetic mutism, experiencing apathy and loss of speech and motor control. A cyst on her right lateral ventricle was tapped, and as soon as the needle advanced toward the cyst, she let out a loud noise and was able to state her name, age, and address. After her cyst was emptied, she regained her alertness and intelligence, and she had no recollection of her time spent in the hospital. The cyst was drained two more times over the next seven months and was eventually removed. After eight months of rehabilitation, Elsie no longer experienced headaches or akinetic mutism symptoms.
See also
Selective mutism
Locked-in syndrome
Athymhormic syndrome
Catatonia
Aboulia
References
== External links == |
Hypertensive retinopathy | Hypertensive retinopathy is damage to the retina and retinal circulation due to high blood pressure (i.e. hypertension).
Signs and symptoms
Most patients with hypertensive retinopathy have no symptoms. However, some may report decreased or blurred vision, and headaches.
Signs
Signs of damage to the retina caused by hypertension include:
Arteriolar changes, such as generalized arteriolar narrowing, focal arteriolar narrowing, arteriovenous nicking, changes in the arteriolar wall (arteriosclerosis) and abnormalities at points where arterioles and venules cross. Manifestations of these changes include Copper wire arterioles where the central light reflex occupies most of the width of the arteriole and Silver wire arterioles where the central light reflex occupies all of the width of the arteriole, and "arterio-venular (AV) nicking" or "AV nipping", due to venous constriction and banking.
advanced retinopathy lesions, such as microaneurysms, blot hemorrhages and/or flame hemorrhages, ischemic changes (e.g. "cotton wool spots"), hard exudates and in severe cases swelling of the optic disc (optic disc edema), a ring of exudates around the retina called a "macular star" and visual acuity loss, typically due to macular involvement.
Strongly modulated blood flow pulse in central and branch arteries can result from hypertension. Microangiography by laser Doppler imaging may reveal altered hemodynamics non-invasively.Mild signs of hypertensive retinopathy can be seen quite frequently in normal people (3–14% of adult individuals aged ≥40 years), even without hypertension. Hypertensive retinopathy is commonly considered a diagnostic feature of a hypertensive emergency although it is not invariably present.
Pathophysiology
The changes in hypertensive retinopathy result from damage and adaptive changes in the arterial and arteriolar circulation in response to the high blood pressure.
Diagnosis
Fundoscopy and patients history.
Differential Diagnoses
Several other diseases can result in retinopathy that can be confused with hypertensive retinopathy. These include diabetic retinopathy, retinopathy due to autoimmune disease, anemia, radiation retinopathy, and central retinal vein occlusion.
Keith Wagener Barker (KWB) Grades
Grade 1
Vascular Attenuation
Grade 2
As grade 1 + Irregularly located, tight constrictions – Known as "AV nicking" or "AV nipping" – Saluss sign
Grade 3
As grade 2 + Retinal edema, cotton wool spots and flame-hemorrhages "Copper Wiring" + Bonnets Sign + Gunns Sign
Grade 4
As grade 3 + optic disc edema + macular star "Silver Wiring"There is an association between the grade of retinopathy and mortality. In a classic study in 1939 Keith and colleagues described the prognosis of people with differing severity of retinopathy. They showed 70% of those with grade 1 retinopathy were alive after 3 years whereas only 6% of those with grade 4 survived. The most widely used modern classification system bears their name. The role of retinopathy grading in risk stratification is debated, but it has been proposed that individuals with signs of hypertensive retinopathy signs, especially retinal hemorrhages, microaneurysms and cotton-wool spots, should be assessed carefully.
Management
A major aim of treatment is to prevent, limit, or reverse target organ damage by lowering the persons high blood pressure to reduce the risk of cardiovascular disease and death. Treatment with antihypertensive medications may be required to control the high blood pressure.
See also
Hypertensive crisis
List of systemic diseases with ocular manifestations
Ophthalmology
Optometry
References
Further reading
The Wills Eye Manual: Office and Emergency Room Diagnosis and Treatment of Eye Disease, J.B. Lippincott, 1994.
Hypertensive retinopathy
== External links == |
Hypercholesterolemia | Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia (high levels of lipids in the blood), hyperlipoproteinemia (high levels of lipoproteins in the blood), and dyslipidemia (any abnormalities of lipid and lipoprotein levels in the blood).Elevated levels of non-HDL cholesterol and LDL in the blood may be a consequence of diet, obesity, inherited (genetic) diseases (such as LDL receptor mutations in familial hypercholesterolemia), or the presence of other diseases such as type 2 diabetes and an underactive thyroid.Cholesterol is one of three major classes of lipids produced and used by all animal cells to form membranes. Plant cells manufacture phytosterols (similar to cholesterol), but in rather small quantities. Cholesterol is the precursor of the steroid hormones and bile acids. Since cholesterol is insoluble in water, it is transported in the blood plasma within protein particles (lipoproteins). Lipoproteins are classified by their density: very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL). All the lipoproteins carry cholesterol, but elevated levels of the lipoproteins other than HDL (termed non-HDL cholesterol), particularly LDL-cholesterol, are associated with an increased risk of atherosclerosis and coronary heart disease. In contrast, higher levels of HDL cholesterol are protective.Avoiding trans fats and replacing saturated fats in adult diets with polyunsaturated fats are recommended dietary measures to reduce total blood cholesterol and LDL in adults. In people with very high cholesterol (e.g., familial hypercholesterolemia), diet is often not sufficient to achieve the desired lowering of LDL, and lipid-lowering medications are usually required. If necessary, other treatments such as LDL apheresis or even surgery (for particularly severe subtypes of familial hypercholesterolemia) are performed. About 34 million adults in the United States have high blood cholesterol.
Signs and symptoms
Although hypercholesterolemia itself is asymptomatic, longstanding elevation of serum cholesterol can lead to atherosclerosis (hardening of arteries). Over a period of decades, elevated serum cholesterol contributes to formation of atheromatous plaques in the arteries. This can lead to progressive narrowing of the involved arteries. Alternatively smaller plaques may rupture and cause a clot to form and obstruct blood flow. A sudden blockage of a coronary artery may result in a heart attack. A blockage of an artery supplying the brain can cause a stroke. If the development of the stenosis or occlusion is gradual, blood supply to the tissues and organs slowly diminishes until organ function becomes impaired. At this point tissue ischemia (restriction in blood supply) may manifest as specific symptoms. For example, temporary ischemia of the brain (commonly referred to as a transient ischemic attack) may manifest as temporary loss of vision, dizziness and impairment of balance, difficulty speaking, weakness or numbness or tingling, usually on one side of the body. Insufficient blood supply to the heart may cause chest pain, and ischemia of the eye may manifest as transient visual loss in one eye. Insufficient blood supply to the legs may manifest as calf pain when walking, while in the intestines it may present as abdominal pain after eating a meal.Some types of hypercholesterolemia lead to specific physical findings. For example, familial hypercholesterolemia (Type IIa hyperlipoproteinemia) may be associated with xanthelasma palpebrarum (yellowish patches underneath the skin around the eyelids), arcus senilis (white or gray discoloration of the peripheral cornea), and xanthomata (deposition of yellowish cholesterol-rich material) of the tendons, especially of the fingers. Type III hyperlipidemia may be associated with xanthomata of the palms, knees and elbows.
Causes
Hypercholesterolemia is typically due to a combination of environmental and genetic factors. Environmental factors include weight, diet, and stress. Loneliness is also a risk factor.
Diet
Diet has an effect on blood cholesterol, but the size of this effect varies between individuals.A diet high in sugar or saturated fats increases total cholesterol and LDL. Trans fats have been shown to reduce levels of HDL while increasing levels of LDL.A 2016 review found tentative evidence that dietary cholesterol is associated with higher blood cholesterol. As of 2018 there appears to be a modest positive, dose-related relationship between cholesterol intake and LDL cholesterol.
Medical conditions and treatments
A number of other conditions can also increase cholesterol levels including diabetes mellitus type 2, obesity, alcohol use, monoclonal gammopathy, dialysis therapy, nephrotic syndrome, hypothyroidism, Cushings syndrome and anorexia nervosa. Several medications and classes of medications may interfere with lipid metabolism: thiazide diuretics, ciclosporin, glucocorticoids, beta blockers, retinoic acid, antipsychotics), certain anticonvulsants and medications for HIV as well as interferons.
Genetics
Genetic contributions are usually due to the additive effects of multiple genes ("polygenic"), though occasionally may be due to a single gene defect such as in the case of familial hypercholesterolaemia. In familial hypercholesterolemia, mutations may be present in the APOB gene (autosomal dominant), the autosomal recessive LDLRAP1 gene, autosomal dominant familial hypercholesterolemia (HCHOLA3) variant of the PCSK9 gene, or the LDL receptor gene. Familial hypercholesterolemia affects about one in 250 individuals.
Diagnosis
Cholesterol is measured in milligrams per deciliter (mg/dL) of blood in the United States and some other countries. In the United Kingdom, most European countries and Canada, millimoles per liter of blood (mmol/L) is the measure.For healthy adults, the UK National Health Service recommends upper limits of total cholesterol of 5 mmol/L, and low-density lipoprotein cholesterol (LDL) of 3 mmol/L. For people at high risk of cardiovascular disease, the recommended limit for total cholesterol is 4 mmol/L, and 2 mmol/L for LDL.In the United States, the National Heart, Lung, and Blood Institute within the National Institutes of Health classifies total cholesterol of less than 200 mg/dL as "desirable", 200 to 239 mg/dL as "borderline high", and 240 mg/dL or more as "high".There is no absolute cutoff between normal and abnormal cholesterol levels, and values must be considered in relation to other health conditions and risk factors.Higher levels of total cholesterol increase the risk of cardiovascular disease, particularly coronary heart disease. Levels of LDL or non-HDL cholesterol both predict future coronary heart disease; which is the better predictor is disputed. High levels of small dense LDL may be particularly adverse, although measurement of small dense LDL is not advocated for risk prediction. In the past, LDL and VLDL levels were rarely measured directly due to cost. Levels of fasting triglycerides were taken as an indicator of VLDL levels (generally about 45% of fasting triglycerides is composed of VLDL), while LDL was usually estimated by the Friedewald formula:
LDL
≈
{\displaystyle \approx }
total cholesterol – HDL – (0.2 x fasting triglycerides).However, this equation is not valid on nonfasting blood samples or if fasting triglycerides are elevated (>4.5 mmol/L or >∼400 mg/dL). Recent guidelines have, therefore, advocated the use of direct methods for measurement of LDL wherever possible. It may be useful to measure all lipoprotein subfractions (VLDL, IDL, LDL, and HDL) when assessing hypercholesterolemia and measurement of apolipoproteins and lipoprotein (a) can also be of value. Genetic screening is now advised if a form of familial hypercholesterolemia is suspected.
Classification
Classically, hypercholesterolemia was categorized by lipoprotein electrophoresis and the Fredrickson classification. Newer methods, such as "lipoprotein subclass analysis", have offered significant improvements in understanding the connection with atherosclerosis progression and clinical consequences. If the hypercholesterolemia is hereditary (familial hypercholesterolemia), more often a family history of premature, earlier onset atherosclerosis is found.
Screening method
The U.S. Preventive Services Task Force in 2008 strongly recommends routine screening for men 35 years and older and women 45 years and older for lipid disorders and the treatment of abnormal lipids in people who are at increased risk of coronary heart disease. They also recommend routinely screening men aged 20 to 35 years and women aged 20 to 45 years if they have other risk factors for coronary heart disease. In 2016 they concluded that testing the general population under the age of 40 without symptoms is of unclear benefit.In Canada, screening is recommended for men 40 and older and women 50 and older. In those with normal cholesterol levels, screening is recommended once every five years. Once people are on a statin further testing provides little benefit except possibly to determine compliance with treatment.
Treatment
Treatment recommendations have been based on four risk levels for heart disease. For each risk level, LDL cholesterol levels representing goals and thresholds for treatment and other action are made. The higher the risk category, the lower the cholesterol thresholds.
For those at high risk, a combination of lifestyle modification and statins has been shown to decrease mortality.
Lifestyle
Lifestyle changes recommended for those with high cholesterol include: smoking cessation, limiting alcohol consumption, increasing physical activity, and maintaining a healthy weight.Overweight or obese individuals can lower blood cholesterol by losing weight – on average a kilogram of weight loss can reduce LDL cholesterol by 0.8 mg/dl.
Diet
Eating a diet with a high proportion of vegetables, fruit, dietary fibre, and low in fats results in a modest decrease in total cholesterol.Eating dietary cholesterol causes a small rise in serum cholesterol, the magnitude of which can be predicted using the Keys and Hegsted equations. Dietary limits for cholesterol were proposed in United States, but not in Canada, United Kingdom, and Australia. However, in 2015 the Dietary Guidelines Advisory Committee in the United States removed its recommendation of limiting cholesterol intake.A 2020 Cochrane review found replacing saturated fat with polyunsaturated fat resulted in a small decrease in cardiovascular disease by decreasing blood cholesterol. Other reviews have not found an effect from saturated fats on cardiovascular disease. Trans fats are recognized as a potential risk factor for cholesterol-related cardiovascular disease, and avoiding them in an adult diet is recommended.The National Lipid Association recommends that people with familial hypercholesterolemia restrict intakes of total fat to 25–35% of energy intake, saturated fat to less than 7% of energy intake, and cholesterol to less than 200 mg per day. Changes in total fat intake in low calorie diets do not appear to affect blood cholesterol.Increasing soluble fiber consumption has been shown to reduce levels of LDL cholesterol, with each additional gram of soluble fiber reducing LDL by an average of 2.2 mg/dL (0.057 mmol/L). Increasing consumption of whole grains also reduces LDL cholesterol, with whole grain oats being particularly effective. Inclusion of 2 g per day of phytosterols and phytostanols and 10 to 20 g per day of soluble fiber decreases dietary cholesterol absorption. A diet high in fructose can raise LDL cholesterol levels in the blood.
Medication
Statins are the typically used medications, in addition to healthy lifestyle interventions. Statins can reduce total cholesterol by about 50% in the majority of people, and are effective in reducing the risk of cardiovascular disease in both people with and without pre-existing cardiovascular disease. In people without cardiovascular disease, statins have been shown to reduce all-cause mortality, fatal and non-fatal coronary heart disease, and strokes. Greater benefit is observed with the use of high-intensity statin therapy. Statins may improve quality of life when used in people without existing cardiovascular disease (i.e. for primary prevention). Statins decrease cholesterol in children with hypercholesterolemia, but no studies as of 2010 show improved outcomes and diet is the mainstay of therapy in childhood.Other agents that may be used include fibrates, nicotinic acid, and cholestyramine. These, however, are only recommended if statins are not tolerated or in pregnant women. Injectable antibodies against the protein PCSK9 (evolocumab, bococizumab, alirocumab) can reduce LDL cholesterol and have been shown to reduce mortality.
Guidelines
In the US, guidelines exist from the National Cholesterol Education Program (2004) and a joint body of professional societies led by the American Heart Association.In the UK, the National Institute for Health and Clinical Excellence has made recommendations for the treatment of elevated cholesterol levels, published in 2008, and a new guideline appeared in 2014 that covers the prevention of cardiovascular disease in general.The Task Force for the management of dyslipidaemias of the European Society of Cardiology and the European Atherosclerosis Society published guidelines for the management of dyslipidaemias in 2011.
Specific populations
Among people whose life expectancy is relatively short, hypercholesterolemia is not a risk factor for death by any cause including coronary heart disease. Among people older than 70, hypercholesterolemia is not a risk factor for being hospitalized with myocardial infarction or angina. There are also increased risks in people older than 85 in the use of statin drugs. Because of this, medications which lower lipid levels should not be routinely used among people with limited life expectancy.The American College of Physicians recommends for hypercholesterolemia in people with diabetes:
Lipid-lowering therapy should be used for secondary prevention of cardiovascular mortality and morbidity for all adults with known coronary artery disease and type 2 diabetes.
Statins should be used for primary prevention against macrovascular complications in adults with type 2 diabetes and other cardiovascular risk factors.
Once lipid-lowering therapy is initiated, people with type 2 diabetes mellitus should be taking at least moderate doses of a statin.
For those people with type 2 diabetes who are taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circumstances.
Alternative medicine
According to a survey in 2002, alternative medicine was used in an attempt to treat cholesterol by 1.1% of U.S. adults. Consistent with previous surveys, this one found the majority of individuals (55%) used it in conjunction with conventional medicine. A systematic review of the effectiveness of herbal medicines utilized in traditional Chinese medicine had inconclusive results due to the poor methodological quality of the included studies.
A review of trials of phytosterols and/or phytostanols, average dose 2.15 g/day, reported an average of 9% lowering of LDL-cholesterol. In 2000, the Food and Drug Administration approved the labeling of foods containing specified amounts of phytosterol esters or phytostanol esters as cholesterol-lowering; in 2003, an FDA Interim Health Claim Rule extended that label claim to foods or dietary supplements delivering more than 0.8 g/day of phytosterols or phytostanols. Some researchers, however, are concerned about diet supplementation with plant sterol esters and draw attention to lack of long-term safety data.
Epidemiology
Rates of high total cholesterol in the United States in 2010 are just over 13%, down from 17% in 2000.Average total cholesterol in the United Kingdom is 5.9 mmol/L, while in rural China and Japan, average total cholesterol is 4 mmol/L. Rates of coronary artery disease are high in Great Britain, but low in rural China and Japan.
Research directions
Gene therapy is being studied as a potential treatment.
References
== External links == |
Ocular tilt reaction | The ocular tilt reaction (OTR) comprises skew deviation, head tilt and ocular torsion involving structures of the inner ear responsible for maintenance of balance of the body i.e. the semi-circular canals (SCC), utricle and saccule.
Each anterior semi-circular canals has excitatory projections to the ipsilateral superior rectus muscle and its yoke i.e., the contralateral inferior oblique while simultaneously inhibiting the ipsilateral inferior rectus muscle and its yoke i.e. the contralateral superior oblique. Also, each posterior semi-circular canals has excitatory projections to the ipsilateral superior oblique and its yoke i.e. the contralateral inferior rectus, while simultaneously inhibiting the ipsilateral inferior oblique and its yoke i.e. the contralateral superior rectus. A head tilt causes stimulation of both anterior semi-circular canals and the posterior semi-circular canals resulting in excitation of ipsilateral intorters (superior oblique and superior rectus) and contralateral extorters (inferior oblique and inferior rectus) while their antagonists are simultaneously inhibited. The otoliths (utricle and saccule) probably follow a similar pathway.
Normally, a body tilt (along with the initial head tilt) to the right causes a shift of the subjective visual vertical (SVV) to the left resulting in reflex, compensatory orientation of the head to left to realign the SVV to the true vertical.
The initial head tilt to right will cause stimulation of the right utricle resulting in excitory signals to pass to the SR and SO (right eye), and IO and IR (left eye). Simultaneously, inhibitory signals pass to their antagonists. The stimulated two intorters (right eye) and the two extorters (left eye) have opposite vertical actions i.e., one is an elevator and the other is a depressor. The opposite vertical actions nearly cancel each other and therefore only a small vertical deviation occurs, whereas their identical torsional actions are additive.
In case of any lesion from the utricle to the brainstem, diminished input from the affected vestibular pathway, for example the left vestibular is the same as stimulation of right vestibular pathway, resulting in the erroneous interpretation by the brain that the head is tilted to the right and consequently that the SVV is tilted to the left. This causes reflex rotation of the head to the left, thus realigning the eyes and head to a position that is actually tilted but which the brain interprets as vertical.
Published literature on ocular torsion in physiologic ocular counter-roll are usually not very clear on the type of head tilt inducing the torsion, i.e., initial head tilt causing a tilt in the SVV or the compensatory head tilt to realign SVV with the true vertical. It has been stated that the ocular torsion in physiologic ocular counter-roll appears in the opposite direction as that of the head tilt in contrast to the same direction of ocular torsion as the head tilt in pathologic ocular tilt reaction.
If instead of the actual head tilt (as compared to true vertical), the direction of the head tilt as interpreted by the brain (subjective head tilt) is given importance, then it is seen that the head tilt and ocular torsion are actually in the same direction in both the physiologic ocular counter-roll and the pathologic ocular tilt reaction. The subjective head tilt as interpreted by the brain in the presence of asymmetric signals from the inner ear neural afferents is the principal factor in determining the direction of ocular torsion in ocular tilt reaction.
== References == |
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