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Hallermann–Streiff syndrome | Hallermann–Streiff syndrome is a congenital disorder that affects growth, cranial development, hair-growth, and dental development. There are fewer than 200 people with the syndrome worldwide. One notable organization that is supporting people with Hallermann–Streiff syndrome is the Germany-based "Schattenkinder e.V".
Presentation
Patients with this syndrome are shorter than the average person and may not develop hair in many places, including in the facial, leg and pubic areas. Patients also have eye problems including reduced eye size, bilateral cataracts and glaucoma. The syndrome can be associated with sleep apnea. The physical characteristics of the syndrome can result in difficult intubation by medical professionals. Intelligence is usually normal.
Cause
The genetic cause of Hallermann–Streiff syndrome has not been conclusively determined. It is most likely due to a de novo mutation, and it may be associated with the GJA1 gene.
Diagnosis
Diagnosis is based on the physical characteristics and symptoms. There is no established clinical genetic testing for Hallermann–Streiff syndrome, however some laboratories offer research genetic testing for the condition.
Treatment
There is no cure for Hallermann–Streiff syndrome. Treatments center around the particular symptoms in each individual. Early measures are based around ensuring proper breathing and intake of nutrients and may include a tracheostomy. Early surgery for cataracts may be recommended, however some studies have suggested that spontaneous resolution of cataracts occurs in up to 50% of untreated patients. Regular visits to an ophthalmologist to monitor and deal with other eye problems, some of which may require surgery, are strongly recommended.Management of the condition may also include surgical reconstruction of certain craniofacial malformations (particularly in the mandibular and nasal region) at an appropriate age. Additionally, management for certain heart defects, such as medication or surgery, may be needed.
History
It is named after German ophthalmologist Wilhelm Hallermann (1909–2005) and Italian–Swiss ophthalmologist Enrico Bernardo Streiff (1908–1988), who first described the syndrome in 1948 and 1950 respectively.
References
12. Shandilya VK, Parmar LD, Shandilya AV. Functional ambulation with bent knee prostheses for an adult with bilateral 90 degrees knee flexion contractures—A case report. J Family Med Prim Care [serial online] 2020 [cited 2020 Jun 2];9:2492-5. Available from: http://www.jfmpc.com/text.asp?2020/9/5/2492/285055
External links
Jablonskis Syndrome Database |
Portal vein thrombosis | Portal vein thrombosis (PVT) is a vascular disease of the liver that occurs when a blood clot occurs in the hepatic portal vein, which can lead to increased pressure in the portal vein system and reduced blood supply to the liver. The mortality rate is approximately 1 in 10.An equivalent clot in the vasculature that exits the liver carrying deoxygenated blood to the right atrium via the inferior vena cava, is known as hepatic vein thrombosis or Budd-Chiari syndrome.
Signs and symptoms
Portal vein thrombosis causes upper abdominal pain, possibly accompanied by nausea and an enlarged liver and/or spleen; the abdomen may be filled with fluid (ascites). A persistent fever may result from the generalized inflammation. While abdominal pain may come and go if the thrombus forms suddenly, long-standing clot build-up can also develop without causing symptoms, leading to portal hypertension before it is diagnosed.Other symptoms can develop based on the cause. For example, if portal vein thrombosis develops due to liver cirrhosis, bleeding or other signs of liver disease may be present. If portal vein thrombosis develops due to pylephlebitis, signs of infection such as fever, chills, or night sweats may be present.
Causes
Slowed blood flow due to underlying cirrhosis or congestive heart failure is often implicated. The prevalence of PVT in patients with cirrhosis is unclear, with a wide variety of incidence claimed by various researchers (estimated to be 1 in 100 by some while others believe it affects nearly 1 in 4).Thrombophilia (including inherited conditions such as factor V Leiden deficiency, protein C or S deficiency, or antiphospholipid antibody syndrome) is another common cause. Nearly one-third of patients have a myeloproliferative disorder (e.g. polycythemia vera or primary thrombocytosis), most commonly due to a Janus kinase 2 (JAK2) gene mutation. Oral contraceptive use or pregnancy are other non-inherited tendencies for thrombosis.Alternatively, the portal vein may be injured as a result of pancreatitis, diverticulitis, cholangiocarcinoma, hepatocellular carcinoma (HCC), or abdominal surgery/trauma. Red flags for cancerous growth as a cause are elevated alpha fetoprotein levels, portal vein diameter greater than 2.3 cm, pulsatility on Doppler ultrasound imaging, or hyperintense hepatic arterial phase (HAP) on CT scan with contrast.PVT is also a known complication of surgical removal of the spleen. During the last several years, myeloproliferative neoplasms (MPNs) have emerged as a leading systemic cause of splanchnic vein thromboses (which include PVT).
Mechanism
The main portal vein is formed by the union of the splenic vein and superior mesenteric vein (SMV). It is responsible for approximately three-fourths of the liver’s blood flow, transported from much of the gastrointestinal system as well as the pancreas, gallbladder, and spleen. Cirrhosis alters bleeding pathways thus patients are simultaneously at risk of uncontrolled bleeding and forming clots. A long-standing hindrance in flow as in chronic PVT, also known as portal cavernoma, can cause an increase in the hepatic venous pressure gradient (portal hypertension) and increased blood flow through subsidiary veins. This may lead to ascites or bleeding from varices.An infected thrombus may become septic, known as pylephlebitis; if blood cultures are positive for growth at this time, the most common organism is Bacteroides.
Diagnosis
The diagnosis of portal vein thrombosis is usually made with imaging confirming a clot in the portal vein; ultrasound is the least invasive method and the addition of Doppler technique shows a filling defect in blood flow. PVT may be classified as either occlusive or nonocclusive based on evidence of blood flow around the clot. An alternative characterization based on site can be made: Type 1 is limited to the main portal vein, Type 2 involves only a portal vein branch (2a, or 2b if both branches are affected), and Type 3 if clot is found throughout both areas. Determination of condition severity may be derived via computed tomography (CT) with contrast, magnetic resonance imaging (MRI), or MR angiography (MRA). Those with chronic PVT may undergo upper endoscopy (esophagogastroduodenoscopy, EGD) to evaluate the presence of concurrent dilated veins (varices) in the stomach or esophagus. Other than perhaps slightly elevated transaminases, laboratory tests to evaluate liver function are typically normal. D-dimer levels in the blood may be elevated as a result of fibrin breakdown.On duplex ultrasound, demonstration of echogenic material within the portal vein, complete or partial absence of colour flow in the portal vein, presence of collateral vessels around the portal vein or gall bladder that bypass the portal vein.
Treatment
Treatment is aimed at opening the blocked veins to minimize complications; the duration of clot (acute versus chronic) affects treatment. Unless there are underlying reasons why it would be harmful, anticoagulation (low molecular weight heparin, followed by warfarin) is often initiated and maintained in patients who do not have cirrhosis. Anticoagulation for patients with cirrhosis who experience portal vein thrombosis is usually not advised unless they have chronic PVT 1) with thrombophilia, 2) with clot burden in the mesenteric veins, or 3) inadequate blood supply to the bowels. In more severe instances, shunts or a liver transplant may be considered. If blood flow to the gastrointestinal tract has been compromised chronically, surgery may be required to remove dead intestine.Different considerations are made in the management of PVT in pediatric patients or those who have already received a liver transplant.
See also
Pylephlebitis
Budd–Chiari syndrome
References
External links
Merck |
Coronary occlusion | A coronary occlusion is the partial or complete obstruction of blood flow in a coronary artery. This condition may cause a heart attack.In some patients coronary occlusion causes only mild pain, tightness or vague discomfort which may be ignored; however, the myocardium, the muscle tissue of the heart, may be damaged.
In history
According to Robert K. Massies Nicholas and Alexandra: The Fall of the Romanov Dynasty, Tsar Nicholas II may have suffered a coronary occlusion right before he was toppled from his throne during the Russian Revolution in 1917.
See also
Arterial embolism
== References == |
Visual agnosia | Visual agnosia is an impairment in recognition of visually presented objects. It is not due to a deficit in vision (acuity, visual field, and scanning), language, memory, or intellect. While cortical blindness results from lesions to primary visual cortex, visual agnosia is often due to damage to more anterior cortex such as the posterior occipital and/or temporal lobe(s) in the brain.[2] There are two types of visual agnosia: apperceptive agnosia and associative agnosia.
Recognition of visual objects occurs at two primary levels. At an apperceptive level, the features of the visual information from the retina are put together to form a perceptual representation of an object. At an associative level, the meaning of an object is attached to the perceptual representation and the object is identified. If a person is unable to recognize objects because they cannot perceive correct forms of the objects, although their knowledge of the objects is intact (i.e. they do not have anomia), they have apperceptive agnosia. If a person correctly perceives the forms and has knowledge of the objects, but cannot identify the objects, they have associative agnosia.
Symptoms and signs
While most cases of visual agnosia are seen in older adults who have experienced extensive brain damage, there are also cases of young children with less brain damage during developmental years acquiring the symptoms. Commonly, visual agnosia presents as an inability to recognize an object in the absence of other explanations, such as blindness or partial blindness, anomia, memory loss, etc.. Other common manifestations of visual agnosia that are generally tested for include difficulty identifying objects that look similar in shape, difficulty with identifying line drawings of objects, and recognizing objects that are shown from less common views, such as a horse from a top-down view.Within any given patient, a variety of symptoms can occur, and the impairment of ability is not only binary but can range in severity. For example, Patient SM is a prosopagnosic with a unilateral lesion to left extrastriate cortex due to an accident in his twenties who displays behavior similar to congenital prosopagnosia. Although he can recognize facial features and emotions – indeed he sometimes uses a standout feature to recognize a face – face recognition is almost impossible purely from visual stimuli, even for faces of friends, family, and himself. The disorder also affects his memory of faces, both in storing new memories of faces and recalling stored memories.Nevertheless, it is important to note the reach of symptoms to other domains. SMs object recognition is similarly impaired though not entirely; when given line drawings to identify, he was able to give names of objects with properties similar to the drawing, implying that he is able to see the features of the drawing. Similarly, copying a line drawing of a beach scene led to a simplified version of the drawing, though the main features were accounted for. For recognition of places, he is still impaired but familiar places are remembered and new places can be stored into memory.
Pathophysiology
Visual agnosia occurs after damage to visual association cortex or to parts of the ventral stream of vision, known as the "what pathway" of vision for its role in object recognition. This occurs even when no damage has been done to the eyes or optic tract that leads visual information into the brain; in fact, visual agnosia occurs when symptoms cannot be explained by such damage. Damage to specific areas of the ventral stream impair the ability to recognize certain categories of visual information, such as the case of prospagnosia. Patients with visual agnosia generally do not have damage to the dorsal stream of vision, known as the "where pathway" of vision because of its role determining objects position in space, allowing individuals with visual agnosia to show relatively normal visually guided behavior.For example, patient DF had lesions to the ventral surface that gave her apperceptive agnosia. One of the tasks she was tested on required her to place a card through a thin slot that could be rotated into all orientations. As an apperceptive agnosic, it would be expected that since she cannot recognize the slot, she should not be able to correctly place the card into the slot. Indeed, when she was asked to give the direction of the slot, her responses were no better than chance. Yet, when she was asked to place the card into the slot, her success was almost to the level of the controls. This implies that in the event of a ventral stream deficit, the dorsal stream can help with processing of special information to aid movement regardless of object recognition.More specifically, the lateral occipital complex appears to respond to many different types of objects. Prosopagnosia (inability to recognize faces) is due to damage of the fusiform face area (FFA). An area in the fusiform gyrus of the temporal lobe that has been strongly associated with a role in facial recognition. However, this area is not exclusive to faces; recognition of other objects of expertise are also processed in this area. The extrastriate body cortex (EBA) was found to be activated by photographs, silhouettes, or stick drawings of human bodies. The parahippocampal place area (PPA) of the limbic cortex has been found to be activated by the sight of scenes and backgrounds. Cerebral achromatopsia (the inability to discriminate between different hues) is caused by damage to the V8 area of the visual association cortex.The left hemisphere seems to play a critical role in recognizing the meaning of common objects.
Diagnosis
Classification
Broadly, visual agnosia is divided into apperceptive and associative visual agnosia.Apperceptive agnosia is failure of object recognition even when the basic visual functions (acuity, color, motion) and other mental processing, such as language and intelligence, are normal. The brain must correctly integrate features such as edges, light intensity, and color from sensory information to form a complete percept of an object. If a failure occurs during this process, a percept of an object is not fully formed and thus it cannot be recognized. Tasks requiring copying, matching, or drawing simple figures can distinguish the individuals with apperceptive agnosia because they cannot perform such tasks.Associative agnosia is an inability to identify objects even with apparent perception and knowledge of them. It involves a higher level of processing than apperceptive agnosia. Individuals with associative agnosia can copy or match simple figures, indicating that they can perceive objects correctly. They also display the knowledge of objects when tested with tactile or verbal information. However, when tested visually, they cannot name or describe common objects. This means that there is an impairment in associating the perception of objects with the stored knowledge of them.Although visual agnosia can be general, there exist many variants that impair recognition of specific types. These variants of visual agnosia include prosopagnosia (inability to recognize faces), pure word blindness (inability to recognize words, often called "agnosic alexia" or "pure alexia"), agnosias for colors (inability to differentiate colors), agnosias for the environment (inability to recognize landmarks or difficulty with spatial layout of an environment, i.e. topographagnosia) and simultanagnosia (inability to sort out multiple objects in a visual scene).
Categories and subtypes of visual agnosia
The two main categories of visual agnosia are:
Apperceptive visual agnosia, impaired object recognition. Individuals with apperceptive visual agnosia cannot form a whole percept of visual information.
Associative visual agnosia, impaired object identification. Individuals with associative agnosia cannot give a meaning to a formed percept. The percept is created, but it would have no meaning for individuals who have an associative agnosia.
Subtypes of associative visual agnosia
Achromatopsia, an inability to distinguish different colors.
Prosopagnosia, an inability to recognize human faces. Individuals with prosopagnosia know that they are looking at faces, but cannot recognize people by the sight of their face, even people whom they know well.
Simultagnosia, an inability to recognize multiple objects in a scene, including distinct objects within a spatial layout and distinguishing between "local" objects and "global" objects, such as being able to see a tree but not the forest or vice versa.
Topographagnosia, an inability to process the spatial layout of an environment, including landmark agnosia, difficulty recognizing buildings and places; difficulty building mental maps of a location or scene; and/or an inability to discern the orientation between objects in space.
Pure alexia, an inability to read.
Orientation agnosia: an inability to judge or determine orientation of objects.
Pantomime agnosia: an inability to understand pantomimes (gestures). It appears that the inferior cortical visual cortex is critical in recognizing pantomimes.
Patient CK
Background
Patient C.K. was born in 1961 in England and emigrated to Canada in 1980. In January 1988, C.K. sustained a head injury from a motor vehicle accident while out for a jog. Following the accident, C.K. experienced many cognitive issues, mood swings, poor memory, and temper outbursts. C.K. also had motor weakness on the left side and a left homonymous hemianopia. He recovered well, retaining normal intelligence and normal visual acuity. He was able to complete a masters degree in history, later working as a manager at a large corporation. Although his recovery was successful in other areas of cognition, C.K. still struggles to make sense of the visual world.
Associative visual agnosia
Magnetic resonance imaging (MRI) showed bilateral thinning of C.K.s occipital lobe which resulted in associative visual agnosia. Patients that have visual agnosia are unable to identify visually presented objects. They can identify these objects through other modalities such as touch but if presented visually, they are unable to. Associative agnosic patients cannot create a detailed representation of the visual world in their brains, they can only perceive elements of whole objects. They also cannot form associations between objects or assign meaning to objects.C.K. makes many mistakes when trying to identify objects. For example, he called an abacus "skewers on a kebab" and a badminton racquet a "fencers mask". A dart was a "feather duster" and a protractor was mistaken for a "cockpit". Despite this impairment in visual object recognition, C.K. retained many abilities such as drawing, visual imagery, and internal imagery. As a native of England, he was tasked with drawing England, marking London and where he was born. His accurate drawing of England is just one example of his excellent drawing abilities.As aforementioned, C.K. is able to identify parts of objects but cannot generate a whole representation. It should not be surprising then that his visual imagery for object size, shape, and color is intact. For example, when shown a picture of an animal, he can correctly answer questions such as "are the ears up or down?" and "is the tail long or short?" He can correctly identify colors, for example that the inside of a cantaloupe is orange. Finally, C.K. can generate internal images and perceive these generated objects. For example, Finke, Pinker, and Farah instructed C.K. to imagine a scenario where a B is rotated 90 degrees to the left, a triangle is put below, and the line in the middle is removed. C.K. can correctly identify this object as a heart by picturing this transformation in his head.
Evidence for double dissociation between face and object processing
Patient C.K. provided evidence for a double dissociation between face processing and visual object processing. Patients with prosopagnosia have damage to the Fusiform Face Area (FFA) and are unable to recognize upright faces. C.K. has no difficulty with face processing and matches the performance of controls when tasked with identifying upright famous faces. When shown inverted faces of famous people, C.K. performs significantly worse than controls. This is because processing inverted faces involves a piecemeal strategy. C.K.s performance is compared to patients with prosopagnosia who are impaired in face processing but perform well identifying inverted faces. This was the first evidence for a double dissociation between face and object processing suggesting a face-specific processing system.
In popular culture
A famous report on this condition is the title essay of Oliver Sacks book, The Man Who Mistook His Wife for a Hat.
The murder suspect in the Picket Fences episode "Strangers" supposedly had agnosia.
The patient in the House episode "Adverse Events" had agnosia.
In the graphic novel Preacher, the character Lorie has an extreme version of agnosia resulting from being born with a single eye. For example, she perceives Arseface, a man with severe facial deformities, as resembling a young James Dean.
Val Kilmers character has visual agnosia in the film At First Sight.
In "Folie à Deux", a fifth-season episode of The X-Files, Mulder succumbs to the same belief as telemarketer Gary Lambert, that his boss Greg Pincus is a monster who disguises his true appearance by means of hypnosis. Scully, although believing this notion preposterous, suggests that what Mulder describes is analogous to an induced visual agnosia.
The short story "Liking What You See: A Documentary" by Ted Chiang examines the cultural effects of a noninvasive medical procedure that induces a visual agnosia toward physical beauty.
In the manga and anime Odd Taxi, the main character Odokawa has agnosia, which causes him to see himself and everyone around him as an animal.
See also
References
Further reading
Cant JD, Goodale MA (March 2007). "Attention to form or surface properties modulates different regions of human occipitotemporal cortex". Cereb. Cortex. 17 (3): 713–31. doi:10.1093/cercor/bhk022. PMID 16648452.
Cavina-Pratesi C, Kentridge RW, Heywood CA, Milner AD (February 2010). "Separate processing of texture and form in the ventral stream: evidence from FMRI and visual agnosia". Cereb. Cortex. 20 (2): 433–46. doi:10.1093/cercor/bhp111. PMID 19478035.
Goodale MA; Milner AD (2004). Sight Unseen: An Exploration of Conscious and Unconscious Vision. Oxford UK: Oxford University Press. pp. 139. ISBN 978-0-19-856807-0. OCLC 54408420.
Farah M (2004). Visual Agnosia. 2nd Edition. Cambridge MA: MIT Press: Bradford Books. p. 192. ISBN 978-0-262-56203-4. OCLC 57182718. |
Immature teratoma | An immature teratoma is a teratoma that contains anaplastic immature elements, and is often synonymous with malignant teratoma. A teratoma is a tumor of germ cell origin, containing tissues from more than one germ cell line, It can be ovarian or testicular in its origin. and are almost always benign. An immature teratoma is thus a very rare tumor, representing 1% of all teratomas, 1% of all ovarian cancers, and 35.6% of malignant ovarian germ cell tumors. It displays a specific age of incidence, occurring most frequently in the first two decades of life and almost never after menopause. Unlike a mature cystic teratoma, an immature teratoma contains immature or embryonic structures. It can coexist with mature cystic teratomas and can constitute of a combination of both adult and embryonic tissue. The most common symptoms noted are abdominal distension and masses. Prognosis and treatment options vary and largely depend on grade, stage and karyotype of the tumor itself.
Diagnosis
At CT and MRI, an immature teratoma possesses characteristic appearance. It is typically large (12–25 cm) and has prominent solid components with cystic elements. It is usually filled with lipid constituents and therefore demonstrates fat density at CT and MRI. Ultrasound appearance of an immature teratoma is nonspecific. It is highly heterogeneous with partially solid lesions and scattered calcifications.
Stage
Traditionally, comprehensive surgical staging is performed via exploratory laparotomy with cytologic washings, peritoneal biopsies, an omental assessment (either biopsy or rarely a full omentectomy), and both pelvic and aortic lymph node dissection. Laproscopy is often suggested as an alternative to surgically stage patients with immature teratoma.Ovarian cancer is staged using the FIGO staging system and uses information obtained after surgery, which can include a total abdominal hysterectomy via midline laparotomy, unilateral (or bilateral) salpingo-oophorectomy, pelvic (peritoneal) washings, assessment of retroperitoneal lymph nodes and/or appendectomy. The AJCC staging system, identical to the FIGO staging system, describes the extent of tumor (T), the presence of absences of metastases to lymph nodes (N), the presence or absence of distant metastases (M).
Pathology
An immature teratoma contains varying compositions of adult and embryonic tissue. The most common embryonic component identified in immature teratomas is the neuroectoderm. Occasionally, tumors may present neuroepithelium that resemble neuroblasts. Tumors may also present embryonic components such as immature cartilage and skeletal muscle of mesodermal origin. Immature teratomas composed of embryonic endodermal derivatives are rare.Often a mature cystic teratoma is misdiagnosed as its immature counterpart due to the misinterpretation of mature neural tissue as immature. While mature neural cells have nuclei with uniformly dense chromatin and neither exhibit apoptotic or mitotic activity, immature neural cells have nuclei with vesicular chromatin and exhibit both apoptotic and mitotic activity. A recent study has identified the use of Oct-4 as a reliable biomarker for the diagnosis of highly malignant cases of immature teratomas.
Grade
Thurlbeck and Scully devised a grading system for “pure” immature teratomas on the basis of differentiation of the cellular elements of the tumor. The proportion of immature tissue elements defines the grade of immaturity. This was later modified by Norris et al. (1976), who added a quantitative aspect to the degree of immaturity.
Karyotype
An ovarian immature teratoma is karyotypically normal 46,XX or near-normal. Grade 1 or 2 tumors exhibit 46,XX normal karyotype, whereas grade 3 tumors show a variety of abnormal karyotypes. Though immature teratoma cells show a normal karyotype, there may still be detectable alterations in the gene level and that these aberrations may influence the stability of chromosome status.
Genetics
Ovarian immature teratomas have been classified as among the least mutated of all solid cancers. Immature teratomas originate from germ cells that undergo one of several meiotic failures, leading to a tumor genome with high levels of copy neutral loss of heterozygosity.
Prognosis
Though several studies have shown that size and stage of the primary tumor are related to survival, the grade of the tumor is the best determinant of prognosis prior to peritoneal spread. Once peritoneal spread has occurred, the grade of metastatic lesions or implants is the best determinant of prognosis. Multiple sections of the primary tumor and wide sampling of the implants are necessary to properly grade the tumor. In most cases, the implants are better differentiated than the primary tumors. Gliomatosis peritonei, a rare condition often associated with immature ovarian teratoma, is characterized by the presence of mature glial implants in the peritoneum. Yoon et al. (2012), reported that immature ovarian teratoma patients with Gliomatosis peritonei have larger tumors, more frequent recurrence and higher CA-125 levels than immature ovarian teratoma patients without gliomatosis peritonei.A high degree of immaturity in the primary tumor, one that corresponds with a grade 3 diagnosis is a sign of poor prognosis. Grade 3 tumors often display chromosomal abnormalities, also an indication of poor prognosis. Tumor grade is the most important factor for relapse in immature teratomas. Vicus et al. (2011), reported that grade 2 or 3 tumors are associated with a greater chance of relapse that can be fatal, predominantly within 2 years of diagnosis. Among grade 3 patients, the stage was significantly associated with relapse.In the past, survival rates were low for high-grade immature teratomas. Norris et al. (1976), reported a survival rate of 82% for patients with grade 1 tumors, 62% for grade 2 and 30% for grade 3 tumors. However, these results antedate the use of multi-agent chemotherapy. With the advent of multiagent chemotherapy after surgical resection, long-term remission and increased survival rates have been achieved. Pashankar et al. (2016), reported that the estimated 5-year overall survival rate for grade 3 Stage I and II disease was 91% compared with 88% for grade 3, Stage III and IV disease.
Treatment
Histologic grade and fertility desires of the patient are key considerations in determining treatment options. In adult women postoperative adjuvant chemotherapy is standard except for stage I /grade 1 disease. In pediatric patients, surgery alone is standard.
Surgery
Since the occurrence of immature teratoma is very rarely bilateral, current standard of care of unilateral salpingo-oophorectomy with wide sampling of peritoneal implants. Total abdominal hysterectomy with bilateral salpingo-oophorectomy are not indicated as they do not influence outcomes. Fertility-sparing surgery in the form of unilateral salpingo-oophorectomy is the primary treatment modality in young patients. Some physicians recommend ovarian cystectomy alone, rather than a unilateral salpingo-oophorectomy for patients with an early stage low grade disease. Zhao et al. (2017), reported no significant differences in survival rates or post-operative fertility outcomes between the two treatment options. However, others caution against such an approach.
Chemotherapy
Norris et al. (1976) observed an 18% recurrence rate in grade 2 tumors and 70% recurrence in grade 3 tumors. Gershenson et al. (1986), reported outcomes of 41 patients with Stage I-IV disease and observed recurrences in 94% of patients treated with surgery alone compared with 14% in patients treated with surgery and chemotherapy. Studies like these resulted in the recommendation to use chemotherapy for grade 2 and 3 tumors. Currently, the use of multi agent chemotherapy for adult patients with ovarian immature teratoma is standard of care except for grade 1, stage I tumors. There is considerable experience with a combination of vincristine, dactinomycin, and cyclophosphamide (VAC) given in an adjuvant setting; however, combinations containing cisplatin, etoposide, and bleomycin (BEP) are now preferred because of a lower relapse rate and shorter treatment time. While a prospective comparison of VAC versus BEP has not been performed, in well-staged patients with completely resected tumors, relapse is essentially unheard of following platinum-based chemotherapy. However, the disease will recur in about 25% of well-staged patients treated with 6 months of VAC.
See also
Teratoma
Ovarian Cancer
Germ Cell Tumor
References
External links
Immature teratoma entry in the public domain NCI Dictionary of Cancer Terms This article incorporates public domain material from Dictionary of Cancer Terms. U.S. National Cancer Institute. |
Oculofaciocardiodental syndrome | Oculofaciocardiodental syndrome is a rare X-linked dominant genetic disorder.
Presentation
The incidence of this condition is less than 1 per million. It is primarily only found in females. Its highly rare in males, but some males were born with it. Teeth with large roots (radiculomegaly), heart defects and small eyes (microphthalmia) are the characteristic triad found in this syndrome.
Typical features of the condition include:
Face
Deep set eyes
Broad nasal tip divided by a cleft
Eyes
Microphthalmia (small eyes)
Early cataracts
Glaucoma
Teeth
Radiculomegaly (teeth with very large roots)
Delayed loss of primary teeth
Missing (oligodontia) or abnormally small teeth
Misaligned teeth
Defective tooth enamel
Heart defects
Atrial and/or ventricular defects
Mitral valve prolapse
Mild intellectual disability and conductive or sensorineural hearing loss may occur.
Genetics
This condition is caused by lesions in the BCOR gene located on the short arm of the X chromosome (Xp11.4). This protein encodes the BCL6 corepressor, but little is currently known about its function. The inheritance is X-linked dominant.A genetically related disorder is Lenz microphthalmia syndrome.
Diagnosis
Diagnosis can be confirmed through DNA testing.
Treatment
History
The first features of this syndrome noted were the abnormal teeth, which were described by Hayward in 1980.
== References == |
Folliculitis nares perforans | Folliculitis nares perforans is characterized by small pustules near the tip of the inside of the nose, lesions that become crusted, and when the crust is removed it is found that the bulbous end of the affected vibrissa is embedded in the inspissated material.: 774
See also
Skin lesion
== References == |
Pseudopterygium | Pseudopterygium is the conjunctival adhesion to cornea caused by limbal or corneal inflammation or trauma. The pseudopterygium can be easily distinguished from pterygium by bowmans probe test. Because of the lack of adherence of pseudopterygium at every point, the probe can be passed beneath it at some point.
Causes
Chemical burn
Marginal corneal ulcer
Cicatrizing conjunctivitis
Trauma
Surgery
Differential diagnosis
Treatment
Pseudopterygium can be removed by surgical excision.
See also
Symblepharon
Pterygium
== Reference == |
Smokeless tobacco keratosis | Smokeless tobacco keratosis (STK) is a condition which develops on the oral mucosa (the lining of the mouth) in response to smokeless tobacco use. Generally it appears as a white patch, located at the point where the tobacco is held in the mouth. The condition usually disappears once the tobacco habit is stopped. It is associated with slightly increased risk of mouth cancer.
There are many types of smokeless tobacco. Chewing tobacco is shredded, air-cured tobacco with flavoring. Dipping tobacco ("moist snuff") is air or fire-cured, finely cut tobacco. Dry snuff is ground or pulverised tobacco leaves. In the Indian subcontinent, the Middle-East and South-East Asia, tobacco may be combined in a quid or paan with other ingredients such as betel leaf, Areca nut and slaked lime. Use of Areca nut is associated with oral submucous fibrosis. An appearance termed Betel chewers mucosa describes morsicatio buccarum with red-staining of mucosa due to betel quid ingredients. In Scandinavian countries, snus, a variant of dry snuff, is sometimes used. In the United States of America, the most common form of smokeless tobacco is dipping tobacco, although chewing tobacco is sometimes used by outdoor workers and dry snuff is common among females in the Southern states. The overall prevalence of smokeless tobacco use in the USA is about 4.5%, but this is higher in Mid-Western and Southern states.
Signs and symptoms
STK typically occurs in the buccal sulcus (inside the cheek) or the labial sulcus (between the lips and the teeth) and corresponds to the site where the tobacco is held in the mouth. It is painless.The appearance of the lesion is variable depending upon the type of tobacco used, and the frequency and duration of use. It takes about 1-5 years of smokeless tobacco use for the lesion to appear. Early lesions may appear as thin, translucent and granular or wrinkled mucosa. The later lesion may appear thicker, more opaquely white and hyperkeratotic with fissures and folds. Oral snuff causes more pronounced changes in the oral mucosa than tobacco chewing. Snuff dipping is associated more with verrucous keratosis.As well as the white changes of the oral mucosa, there may be gingival recession (receding gums) and staining of tooth roots in the area where the tobacco is held.
Diagnosis
Diagnosis is mainly clinical, based on the history and clinical appearance. The differential diagnosis includes other oral white lesions such as Leukoplakia, squamous cell carcinoma, oral candidiasis, lichen planus, white sponge nevus and contact stomatitis. In contrast to pseudomembraneous candidiasis, this white patch cannot be wiped off. Tissue biopsy is sometimes carried out to rule out other lesions, although biopsy is not routinely carried out for this condition.
Treatment
Apart from stopping the habit, no other treatment is indicated. Long term follow-up is usually carried out. Some recommend biopsy if the lesions persists more than 6 weeks after giving up smokeless tobacco use, or if the lesion undergoes a change in appearance (e.g. ulceration, thickening, color changes, especially to speckled white and red or entirely red). Surgical excision may be carried out if the lesion does not resolve.
Prognosis
Usually this lesion is reversible if the tobacco habit is stopped completely, even after many years of use. In one report, 98% of lesions disappeared within 2 weeks of stopping tobacco use. The risk of the lesion developing into oral cancer (generally squamous cell carcinoma and its variant verrucous carcinoma) is relatively low. Indeed, veruccous carcinoma is sometimes term "snuff dippers cancer". In most reported cases, malignant transformation has occurring in individuals with a very long history of chewing tobacco or who use dry snuff.Smokeless tobacco use is also accompanied by increased risk of other oral conditions such as dental caries (tooth decay), periodontitis (gum disease), attrition (tooth wear) and staining.
Epidemiology
STK is extremely common among smokeless tobacco users. Given the association with smokeless tobacco use, this condition tends to occur in adults. A national USA survey estimated an overall prevalence of 1.5% of all types of smokeless tobacco lesions, with males affected more commonly than females.
See also
Stomatitis nicotina
Smokers melanosis
References
== External links == |
Left posterior fascicular block | A left posterior fascicular block (LPFB), also known as left posterior hemiblock (LPH), is a condition where the left posterior fascicle, which travels to the inferior and posterior portion of the left ventricle, does not conduct the electrical impulses from the atrioventricular node. The wave-front instead moves more quickly through the left anterior fascicle and right bundle branch, leading to a right axis deviation seen on the ECG.
Definition
The American Heart Association has defined a LPFB as:
Frontal plane axis between 90° and 180° in adults
rS pattern in leads I and aVL
qR pattern in leads III and aVF
QRS duration less than 120 msThe broad nature of the posterior bundle as well as its dual blood supply makes isolated LPFB rare.
See also
Left bundle branch block
Left anterior fascicular block
References
Further reading
Ma FS, Ma J, Tang K, et al. (March 2006). "Left posterior fascicular block: a new endpoint of ablation for verapamil-sensitive idiopathic ventricular tachycardia". Chin. Med. J. 119 (5): 367–72. doi:10.1097/00029330-200603010-00003. PMID 16542578.
== External links == |
Laryngotracheitis | Laryngotracheitis may refer to:
the combination of the following two medical conditions: laryngitis and tracheitis
a disease of poultry caused by Gallid alphaherpesvirus 1 |
Hutchinsons sign | Hutchinsons sign is a clinical sign which may refer to:
Hutchinsons pupil, an unresponsive and enlarged pupil on the side of an intracranial mass
Vesicles on the tip of the nose, or vesicles on the side of the nose, precedes the development of ophthalmic herpes zoster. This occurs because the nasociliary branch of the trigeminal nerve innervates both the cornea and the lateral dorsum of the nose as well as the tip of the nose. This sign is named after Sir Jonathan Hutchinson.
Melanonychia with pigmentation of the proximal nail fold.: 671 This is an important sign of subungual melanoma although is not an infallible predictor. Periungual hyperpigmentation occurs in at least one nonmelanoma skin cancer, Bowens disease of the nail unit. This is a nail fold pigmentation which then widens progressively to produce a triangular pigmented macule with associated nail dystrophy. Hyperpigmentation of the nail bed and matrix may reflect through the "transparent" nailfolds simulating Hutchinsons sign.
Hutchinsons triad - pattern of presentation of congenital syphilis.
See also
Green nail sign
List of cutaneous conditions
== References == |
Adenocarcinoma of the lung | Adenocarcinoma of the lung is the most common type of lung cancer, and like other forms of lung cancer, it is characterized by distinct cellular and molecular features. It is classified as one of several non-small cell lung cancers (NSCLC), to distinguish it from small cell lung cancer which has a different behavior and prognosis. Lung adenocarcinoma is further classified into several subtypes and variants. The signs and symptoms of this specific type of lung cancer are similar to other forms of lung cancer, and patients most commonly complain of persistent cough and shortness of breath.
Adenocarcinoma is more common in patients with a history of cigarette smoking, and is the most common form of lung cancer in younger women and Asian populations. The pathophysiology of adenocarcinoma is complicated, but generally follows a histologic progression from cells found in healthy lungs to distinctly dysmorphic, or irregular cells. There are several distinct molecular and genetic pathways that contribute to this progression. Like many lung cancers, adenocarcinoma of the lung is often advanced by the time of diagnosis. Once a lesion or tumor is identified with various imaging modalities, such as computed tomography (CT) or X-ray, a biopsy is required to confirm the diagnosis.
Treatment of this lung cancer is based upon the specific subtype and the extent of spread from the primary tumor. Surgical resection, chemotherapy, radiotherapy, targeted therapy and immunotherapy are used in attempt to eradicate the cancerous cells based upon these factors.
Signs and symptoms
The majority of patients who are diagnosed with lung cancer usually present with locally advanced or metastatic disease. Only about one third of patients have stage I disease when diagnosed. The symptoms that the patient exhibits usually reflect the extent of the cancers spread. Lung cancers that are discovered early may cause symptoms localized to the respiratory system. However, lung cancer that is advanced will cause patients to experience additional signs and symptoms secondary to the cancer spreading to other organ systems. In order of highest frequency, the most common signs of lung cancer include:
cough that does not go away or gets worse
weight loss
dyspnea (shortness of breath or difficulty breathing)
chest pain, which may be aggravated by deep breathing, coughing, or laughing
hemoptysis (coughing up blood or rust-colored phlegm)
bone pain
clubbing
fever
generally feeling tired or weak
superior vena cava obstruction- facial, neck, upper torso swelling. This is caused by compression of vasculature by the lung tumor that restricts blood return from the upper body.
dysphagia (trouble swallowing or the sensation that something is caught in the throat) and hoarseness
new onset of wheezing without history of asthmaClinicians should have a high level of suspicion for lung cancer, especially in patients with a smoking history. Patients with recurring or unresolving lung infections (e.g. bronchitis and pneumonia) that are unresponsive to antibiotics should also be further evaluated for lung cancer. In nonsmokers, women and East Asians are more likely to present with symptoms of an underlying lung cancer at younger ages.
Importantly, many of these signs are commonly due to other causes that are not cancer. A detailed medical history should be obtained from each patient to determine the relevance of further diagnostic workup and management.
Extrapulmonary manifestations
Adenocarcinoma, like other forms of lung cancer, is usually advanced or metastatic at time of diagnosis. Patients may complain of signs or symptoms outside of the respiratory tract that represent a hematologic or metabolic complication of the malignancy without, however, resulting necessarily from obstruction or metastasis. These go under the name of paraneoplastic syndromes, which often indicate advanced disease and worse prognosis. The most common paraneoplastic syndromes associated with adenocarcinoma of the lung are described below:
Hypercalcemia of malignancy is more common in squamous cell carcinoma of the lung, but can occur in adenocarcinoma as well. Parathyroid hormone-related peptide (PTHrP) is produced by tumor cells and functions similarly to parathyroid hormone (PTH). The production of this hormonally active peptide by cancer cells causes increased bone resorption via upregulation of osteoclasts, one of the cells responsible for bone remodeling. When bone is broken down, calcium is released into the bloodstream, resulting in hypercalcemia. The signs and symptoms of elevated calcium in the blood include: thirst, fatigue, constipation, polyuria (increased urination), and nausea. It is important to rule out boney metastases in patients with NSCLC because they also present with hypercalcemia.
Hypertrophic pulmonary osteoarthropathy (HPO) is fairly rare in adenocarcinoma. Less than 1% of patients with adenocarcinoma of the lung will exhibit this finding, but when it does occur, it is a poor prognostic factor. The exact mechanism of HPO is unknown but it thought to be hormonal or neurogenic in etiology. The triad of HPO includes distal clubbing, arthritis, and bilateral symmetrical periosteal formation.
Causes
Risk factors
According to the Nurses Health Study, the risk of pulmonary adenocarcinoma increases substantially after a long duration of tobacco smoking: smokers with a previous smoking duration of 30–40 years are more than twice as likely to develop lung adenocarcinoma compared to never-smokers (relative risk of approximately 2.4); a duration of more than 40 years increases relative risk to 5.This cancer usually is seen peripherally in the lungs, as opposed to small cell lung cancer and squamous cell lung cancer, which both tend to be more centrally located, although it may also occur as central lesions. For unknown reasons, it often arises in relation to peripheral lung scars. The current theory is that the scar probably occurred secondary to the tumor, rather than causing the tumor. The adenocarcinoma has an increased incidence in smokers, and is the most common type of lung cancer seen in non-smokers and women. Deeper inhalation of cigarette smoke results in peripheral lesions that are often the case in adenocarcinomas of the lung. Generally, adenocarcinoma grows more slowly and forms smaller masses than the other subtypes. However, it tends to metastasize at an early stage.
Mechanism
Pathogenesis
Large scale studies such as The Cancer Genome Atlas (TCGA) have systematically characterized recurrent somatic alterations likely driving lung adenocarcinoma initiation and development.
Gene mutations and copy number alterations
Since smoking is a strong mutagenic factor, lung adenocarcinoma is one of the tumor types with the highest number of mutations. Common somatic mutations in lung adenocarcinoma affect many oncogenes and tumor suppressor genes, including TP53 (mutated in 46% of cases), EGFR (27%), KRAS (32%), KEAP1, STK11 and NF1. EGFR and KRAS mutations tend to appear in a mutually exclusive fashion. KRAS mutations are associated with smoking habits, whereas EGFR mutations occur more frequently in females, people of Asian ethnicity and never-smokers.Copy number amplifications in oncogenes such as TERT, MDM2, EGFR, MET, and MYC have been reported, as well as deletions of tumor suppressor genes such as CDKN2A.Frequent alterations occur in genes belonging to the receptor tyrosine kinase pathway, of which EGFR is the most prominent example. This pathway is involved in cell proliferation and survival and it is often deregulated in cancer. As a consequence, targeted therapies have been developed to inhibit mutant pathway components.
Chromosomal rearrangements
Three membrane associated tyrosine kinase receptors are recurrently involved in fusions or rearrangements in adenocarcinomas: ALK, ROS1, and RET, and more than eighty other translocations have also been reported in adenocarcinomas of the lung.In ALK rearrangements, the most common partner gene is EML4. EML4-ALK fusions tend to occur in tumors that do not carry EGFR or KRAS mutations and have also a lower frequency of TP53 mutations. ALK and ROS fusions offer opportunities for targeted therapies with tyrosine kinase inhibitors.
Pathophysiology
The respiratory tract can be divided into two main components: the conducting airways and the gas exchange airways. The gas exchange airways are made of alveoli, small microscopic air sacs that are responsible for the exchange of oxygen and carbon dioxide during normal breathing. Alveoli are composed of two cell types, type I and type II pneumocytes. Type I pneumocytes cover 95% of alveolar surfaces, and are not able to regenerate. Type II pneumocytes are more common, making up 60% of the cells within alveolar epithelium, but constitute only 3% of the alveolar surface.There are several factors that contribute to the transformation of normal alveolar epithelium into dysplastic, or pre-cancerous, lesions. Adenocarcinoma of the lung develops in a step-wise progression as type II pneumocytes undergo consecutive molecular changes that disrupt normal cell regulation and turnover. Atypical adenomatous hyperplasia (AAH) is considered a pre-cancerous lesion, and is thought to further progress to adenocarcinoma in situ and invasive adenocarcinoma of the lung. The lesions of AAH are <5 mm, can be single or multiple, and have a ground glass appearance on CT imaging. As more genetic mutations and dysregulation of normal cell signaling pathways accumulate, AAH can progress to adenocarcinoma in situ (AIS). AIS lesions are classified as small tumors <3 cm with abnormal type II pneumocyte cell growth that is limited to the alveolar spaces i.e. without invasion into the stroma, pleura, or vasculature. This type of growth is termed "lepidic" and is characteristic of adenocarcinoma of the lung in its earliest stages.
Diagnosis
A diagnosis of lung cancer may be suspected on the basis of typical symptoms, particularly in a person with smoking history. Symptoms such as coughing up blood and unintentional weight loss may prompt further investigation, such as medical imaging.
Classification
The majority of lung cancers can be characterized as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Lung adenocarcinoma is one of the three major subtypes of NSCLC, which also include squamous carcinoma and large cell carcinoma.Historically, there has been much debate in the most accurate method of describing adenocarcinoma of the lung and several revisions of classification systems have been published. Most recently, the International Multidisciplinary Classification of Lung Adenocarcinoma was published in 2011 and represents the consensus of several organizations to more accurately describe this specific type of lung cancer. The current classification system aims to more reliably predict prognosis and determination of therapeutic management.The tumor size, pattern of cell growth, and depth of cell invasion into normal lung tissue are considered in determining classification. The following names represent a step-wise pathologic progression in the natural course of adenocarcinoma development; Adenocarcinoma in situ (AIS), Minimally invasive adenocarcinoma (MIA), and Invasive adenocarcinoma. Invasive adenocarcinoma of the lung includes a heterogenous mixture of subtypes and variants.
The 2011 consensus describes five subtypes of invasive adenocarcinomas based on the cell pattern that is most predominant. These subtypes are described below:
lepidic predominant
acinar predominant
papillary predominant
micropapillary predominant
solid predominant with mucin production Cell patterns identifying subtypes are associated with prognosis, ranging from favorable (lepidic) to intermediate (acinar and papillary) to poor (micropapillary and solid).Four discrete variants of invasive adenocarcinomas not assignable to these five subtypes are also included in the current classification:
invasive mucinous adenocarcinoma
colloid adenocarcinoma
fetal adenocarcinoma
primary pulmonary enteric adenocarcinoma
Imaging
A chest x-ray (radiograph) is often the first imaging test performed when a person presents with cough or chest pain, particularly in the primary care setting. A chest radiograph may detect a lung nodule/mass that is suggestive of cancer, although sensitivity and specificity are limited.CT imaging provides better evaluation of the lungs, with higher sensitivity and specificity for lung cancer compared to chest radiograph (although still significant false positive rate). Computed tomography (CT) that is specifically aimed at evaluating lung cancer includes the chest and the upper abdomen. This allows for evaluation of other relevant anatomic structures such as nearby lymph nodes, adrenal glands, liver, and bones which may show evidence of metastatic spread of disease. Indeed, the US Preventative Services Task Force recommends annual screening with low-dose CT in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years, with certain caveats (see Lung cancer screening).Nuclear medicine imaging, such as PET/CT and bone scan, may also be helpful to diagnose and detect metastatic disease elsewhere in the body. PET/CT uses a metabolically active tracer that allows clinicians to identify areas of the body that are hypermetabolic. Increased uptake of the tracer occurs in malignant cells and areas of inflammation or infection. Integrating the imaging reflective of metabolic activity with normal CT imaging allows for higher sensitivity and specificity compared to PET alone.MRI is reserved for patients with advanced disease where intracranial, or brain, involvement is likely. It is also helpful for evaluating the extent of chest wall, diaphragmatic, brachial plexus (such as in the case of superior sulcus tumors), or spine involvement.
Histopathology
If possible, a biopsy of any suspected lung tumor is performed in order to make a microscopic evaluation of the cells involved and is ultimately required to confirm diagnosis. Biopsy should be attempted in distant lesions first to establish a histologic diagnosis and to simultaneously confirm metastatic staging. The biopsy material is also used to analyze whether the tumor express any specific mutations suitable for tageted therapy (e.g. EGFR mutation or ALK mutation). Biopsy can be accomplished via bronchoscopy, transthoracic needle biopsy, and video-assisted thorascopic surgery (VATS).While sputum cytology has been shown to have limited utility, thoracentesis, or aspiration of pleural fluid with an ultrasound-guided needle, should be performed when pleural effusion is present. When malignant cells are identified in the pleural aspirate of patients highly suspect for lung cancer, a definitive diagnosis and staging (stage IV adenocarcinoma of the lung) is established.Adenocarcinoma of the lung tends to stain mucin positive as it is derived from the mucus-producing glands of the lungs. Similar to other adenocarcinoma, if this tumor is well differentiated (low grade) it will resemble the normal glandular structure. Poorly differentiated adenocarcinoma will not resemble the normal glands (high grade) and will be detected by seeing that they stain positive for mucin (which the glands produce). Adenocarcinoma can also be distinguished by staining for TTF-1, a cell marker for adenocarcinoma.As discussed previously, the category of adenocarcinoma includes are range of subtypes, and any one tumor tends to be heterogeneous in composition. Several major subtypes are currently recognized by the World Health Organization (WHO) and the International Association for the Study of Lung Cancer (IASLC) / American Thoracic Society (ATS) / European Respiratory Society (ERS): lepidic predominant adenocarcinoma, acinar predominant adenocarcinoma, papillary predominant adenocarcinoma, micropapillary predominant adenocarcinoma, solid predominant adenocarcinoma, and solid predominant with mucin production. In as many as 80% of these tumors, components of more than one subtype will be recognized. Surgically resected tumors should be classified by comprehensive histological subtyping, describing patterns of involvement in increments of 5%. The predominant histologic subtype is then used to classify the tumor overall. The predominant subtype is prognostic for survival after complete resection.To reveal the adenocarcinomatous lineage of the solid variant, demonstration of intracellular mucin production may be performed. Foci of squamous metaplasia and dysplasia may be present in the epithelium proximal to adenocarcinomas, but these are not the precursor lesions for this tumor. Rather, the precursor of peripheral adenocarcinomas has been termed atypical adenomatous hyperplasia (AAH). Microscopically, AAH is a well-demarcated focus of epithelial proliferation, containing cuboidal to low-columnar cells resembling club cells or type II pneumocytes. These demonstrate various degrees of cytologic atypia, including hyperchromasia, pleomorphism, prominent nucleoli. However, the atypia is not to the extent as seen in frank adenocarcinomas. Lesions of AAH are monoclonal, and they share many of the molecular aberrations (like KRAS mutations) that are associated with adenocarcinomas.Signet ring and clear cell adenocarcinoma are no longer histological subtypes, but rather cytological features that can occur in tumour cells of multiple histological subtypes, most often solid adenocarcinoma.
Treatment
The treatment of adenocarcinoma of the lung depends on several factors including stage, resectability, performance status, histology and genomic alterations acquired by the individual tumor. As in most cancer types, treatment approaches can be broadly divided into 5 categories: surgery, chemotherapy, radiotherapy, targeted therapy and immunotherapy.
Surgery
Early stage (I, II and IIIA) lung adenocarcinomas are typically treated surgically to remove the tumor with pneumonectomy or lobectomy, if it is found to be resectable with imaging studies and biopsies and if the patient is considered able to tolerate surgery. Video-assisted thorascopic surgery (VATS) is often adopted, which consists in the insertion of a thorascope inside a small incision made in the chest; a lobe can be removed via the scope through this small incision.
Chemotherapy
For advanced (stage IV) and unresectable lung tumors, the first-line therapy is platinum-based doublet chemotherapy, combining cisplatin or carboplatin with another cytotoxic agent. Regimens strongly depend on each patient performance status and response, and when the risk of adverse events could worsen quality of life significantly, basic supportive care is more recommended. Chemotherapy is also used as an adjuvant therapy following surgery to kill remaining cancer cells in patients with stage IIA, IIB and IIIA NSCLC.
Radiotherapy
Adenocarcinoma is a non-small cell lung carcinoma, and it is not as responsive to radiation therapy compared to small cell lung carcinoma. However, radiotherapy may be used as an adjuvant therapy for patients who have undergone a resection surgery to reduce the risk of lung cancer relapse. It may also benefit inoperable tumors that are localized to the chest and be part of palliative care to improve quality of life in patients not responding to surgery or chemotherapy.
Targeted therapy
Targeted therapy is available for lung adenocarcinomas with certain molecular characteristics. Tyrosine kinase inhibitors (TKIs) have been developed to target mutant components of the receptor tyrosine kinase pathway such as EGFR, ALK and ROS1, which show frequent alterations in lung adenocarcinomas.
First-generation EGFR TKIs, including gefitinib and erlotinib, have been shown to be more effective in treating EGFR-mutated patients with respect to cytotoxic chemotherapy. Second-generation inhibitors such as afatinib and dacomitinib provided a broader scope of application as they are able to target not only the protein EGFR itself but also other members of the EGFR family, such as HER2 and HER4 (also known as ERBB2 and ERBB4), and they have shown improved progression-free survival compared to gefitinib. As the most common cause of acquired resistance to first-generation TKIs is a second EGFR mutation on codon 790, a third-generation EGFR TKI, osimertinib, has been developed to target this new mutation as well. MET amplification is another known mechanism of acquired resistance.ALK inhibitors such as crizotinib showed to be effective against tumors harboring ALK fusions. Most patients previously treated with crizotinib benefited from second-generation ALK inhibitors including ceritinib, alectinib and brigatinib. Resistance to ALK inhibitors can occur with novel acquired ALK mutations or amplifications.Also ROS1-positive tumors have shown high sensitivity to ALK inhibitors due to the high homology between the kinase domains of ROS1 and ALK.
Immunotherapy
Immune response can be prevented via activation of immune checkpoints, which consist in the binding of a ligand protein (e.g. PD-L1) to a receptor (e.g. PD-1) on the immune cell surface. As a consequence, cancer cells expressing PD-L1 can inactivate T cells thus fostering tumor growth. Immune checkpoint inhibitors have been developed to restore T cell-mediated antitumor immunity by blocking either the ligand or the receptor.Immune checkpoint inhibitors have been approved for NSCLC, including anti-PD-1 nivolumab and pembrolizumab. Anti-PD-1 agents are used for patients with advanced NSCLC whose tumors progress after first-line cytotoxic chemotherapy. Pembrolizumab was established as a new standard of care for patients with advanced or metastatic NSCLC with high PD-L1 expression levels, and responses are even more pronounced for tumor with a high mutational burden (i.e. having an elevated number of mutations).Therapeutic approaches combining multiple immune checkpoint inhibitors or one immune checkpoint inhibitors and a cytotoxic agent are undergoing clinical trials as of 2018. Howerver, the KEYNOTE-598 phase III trial has reported in 2021 that adding ipilimumab to pembrolizumab for NSCLC patients with PD-L1 tumor proportion score ≥50% does not confer any efficacy benefit, but may introduce greater toxicity. The potential role of anti-PD-1 agents as neoadjuvant therapy in resectable NSCLCs is also being investigated.
Epidemiology
As for other lung cancer subtypes, lung adenocarcinoma incidence is strongly associated with smoking.
Incidence of pulmonary adenocarcinoma has been increasing in many developed Western nations in the past few decades, with a share reaching 43.3% of all lung cancers in the US as of 2012, thus replacing squamous cell lung carcinoma as the most common type of lung cancer. This can be largely attributed to the decreasing smoking rates, which favors the adenocarcinoma histology. Indeed, although smoking is still its strongest risk factor, lung adenocarcinoma is by far the most common among lifelong non-smokers (<100 cigarettes in a lifetime).
== References == |
Gangliocytic paraganglioma | A gangliocytic paraganglioma is a rare tumour that is typically found in the duodenum and consists of three components: (1) ganglion cells, (2) epithelioid cells (paraganglioma-like) and, (3) spindle cells (schwannoma-like).
Symptoms and signs
The most common presentation is gastrointestinal bleed (~45% of cases), followed by abdominal pain (~43% of cases) and anemia (~15% of cases).
Pathology
GP consist of three components (1) ganglion cells, (2) epithelioid cells (neuroendocrine-like), and (3) spindle cells (schwannoma-like). The microscopic differential diagnosis includes poorly differentiated carcinoma, neuroendocrine tumour and paraganglioma.GPs may be sporadic or arise in the context neurofibromatosis type 1.
See also
Schwannoma
Paraganglioma
== References == |
Idiopathic giant-cell myocarditis | Idiopathic giant-cell myocarditis (IGCM) is a cardiovascular disease of the muscle of the heart (myocardium).
The condition is rare; however, it is often fatal and there is no proven cure because of the unknown nature of the disorder.
IGCM frequently leads to death with a high rate of about 70% in first year. A patient with IGCM typically presents with symptoms of heart failure, although some may present initially with ventricular arrhythmia or heart block. Median age from the time the disease is diagnosed to the time of death is approximately 6 months. 90% of patients are either deceased by the end of 1 year or have received a heart transplant. Diagnosis is made by endomyocardial biopsy during heart catheterization. Biopsy shows multinucleated giant cells and thus the name. While previously cases universally required heart transplantation, recent studies show that two-thirds of patients can survive past one year with high doses of immunosuppressants such as prednisone and cyclosporine. The transplanted heart has a high chance of disease recurrence. Compared to lymphocytic (presumed viral) myocarditis, giant cell myocarditis is much more severe with much more rapid progression.
It is suggested to be caused by T-lymphocytes.
See also
Idiopathic
Giant cell
Myocarditis
References
== External links == |
Heberdens node | Heberdens nodes are hard or bony swellings that can develop in the distal interphalangeal joints (DIP) (the joints closest to the end of the fingers and toes). They are a sign of osteoarthritis and are caused by formation of osteophytes (calcific spurs) of the articular (joint) cartilage in response to repeated trauma at the joint.Heberdens nodes typically develop in middle age, beginning either with a chronic swelling of the affected joints or the sudden painful onset of redness, numbness, and loss of manual dexterity. This initial inflammation and pain eventually subsides, and the patient is left with a permanent bony outgrowth that often skews the fingertip sideways. Bouchards nodes may also be present; these are similar bony growths in the proximal interphalangeal (PIP) joints (middle joints of the fingers), and are also associated with osteoarthritis.
Heberdens nodes are more common in women than in men, and there seems to be a genetic component involved in predisposition to the condition.
They are named after William Heberden (1710–1801).
See also
Bouchards nodes Also present in martial artists, in particular judoka and Brazilian jiu-jitsu practitioners.
References
== External links == |
Nicotine poisoning | Nicotine poisoning describes the symptoms of the toxic effects of nicotine following ingestion, inhalation, or skin contact. Nicotine poisoning can potentially be deadly, though serious or fatal overdoses are rare. Historically, most cases of nicotine poisoning have been the result of use of nicotine as an insecticide. More recent cases of poisoning typically appear to be in the form of Green Tobacco Sickness, or due to unintended ingestion of tobacco or tobacco products or consumption of nicotine-containing plants.Standard textbooks, databases, and safety sheets consistently state that the lethal dose of nicotine for adults is 60 mg or less (30–60 mg), but there is overwhelming data indicating that more than 0.5 g of oral nicotine is required to kill an adult.Children may become ill following ingestion of one cigarette; ingestion of more than this may cause a child to become severely ill. The nicotine in the e-liquid of an electronic cigarette can be hazardous to infants and children, through accidental ingestion or skin contact. In some cases children have become poisoned by topical medicinal creams which contain nicotine.People who harvest or cultivate tobacco may experience Green Tobacco Sickness (GTS), a type of nicotine poisoning caused by skin contact with wet tobacco leaves. This occurs most commonly in young, inexperienced tobacco harvesters who do not consume tobacco.
Signs and symptoms
Nicotine poisoning tends to produce symptoms that follow a biphasic pattern. The initial symptoms are mainly due to stimulatory effects and include nausea and vomiting, excessive salivation, abdominal pain, pallor, sweating, hypertension, tachycardia, ataxia, tremor, headache, dizziness, muscle fasciculations, and seizures. After the initial stimulatory phase, a later period of depressor effects can occur and may include symptoms of hypotension and bradycardia, central nervous system depression, coma, muscular weakness and/or paralysis, with difficulty breathing or respiratory failure.From September 1, 2010 to December 31, 2014, there were at least 21,106 traditional cigarette calls to US poison control centers. During the same period, the ten most frequent adverse effects to traditional cigarettes reported to US poison control centers were vomiting (80.0%), nausea (9.2%), drowsiness (7.8%), cough (7.2%), agitation (6.6%), pallor (3.0%), tachycardia (2.5%), diaphoresis (1.5%), dizziness (1.5%), and diarrhea (1.4%). 95% of traditional cigarette calls were related to children 5 years old or less. Most of the traditional cigarette calls were a minor effect.Calls to US poison control centers related to e-cigarette exposures involved inhalations, eye exposures, skin exposures, and ingestion, in both adults and young children. Minor, moderate, and serious adverse effects involved adults and young children. Minor effects correlated with e-cigarette liquid poisoning were tachycardia, tremor, chest pain and hypertension. More serious effects were bradycardia, hypotension, nausea, respiratory paralysis, atrial fibrillation and dyspnea. The exact correlation is not fully known between these effects and e-cigarettes. 58% of e-cigarette calls to US poison control centers were related to children 5 years old or less. E-cigarette calls had a greater chance to report an adverse effect and a greater chance to report a moderate or major adverse effect than traditional cigarette calls. Most of the e-cigarette calls were a minor effect.From September 1, 2010 to December 31, 2014, there were at least 5,970 e-cigarette calls to US poison control centers. During the same period, the ten most frequent adverse effects to e-cigarettes and e-liquid reported to US poison control centers were vomiting (40.4%), eye irritation or pain (20.3%), nausea (16.8%), red eye or conjunctivitis (10.5%), dizziness (7.5%), tachycardia (7.1%), drowsiness (7.1%), agitation (6.3%), headache (4.8%), and cough (4.5%).E-cigarette exposure cases in the US National Poison Data System increased greatly between 2010 and 2014, peaking at 3,742 in 2014, fell in 2015 though 2017, and then between 2017 and 2018 e-cigarette exposure cases increased from 2,320 to 2,901. The majority of cases (65%) were in children under age five and 15% were in ages 5-24. Approximately 0.1% of cases developed life-threatening symptoms.
Toxicology
The LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 0.5–1.0 mg/kg can be a lethal dosage for adult humans, and 0.1 mg/kg for children. However the widely used human LD50 estimate of 0.5–1.0 mg/kg was questioned in a 2013 review, in light of several documented cases of humans surviving much higher doses; the 2013 review suggests that the lower limit causing fatal outcomes is 500–1000 mg of ingested nicotine, corresponding to 6.5–13 mg/kg orally. An accidental ingestion of only 6 mg may be lethal to children.It is unlikely that a person would overdose on nicotine through smoking alone. The US Food and Drug Administration (FDA) stated in 2013: "There are no significant safety concerns associated with using more than one [over the counter] OTC [nicotine replacement therapy] NRT at the same time, or using an OTC NRT at the same time as another nicotine-containing product—including a cigarette." Ingestion of nicotine pharmaceuticals, tobacco products, or nicotine containing plants may also lead to poisoning. Smoking excessive amounts of tobacco has also led to poisoning; a case was reported where two brothers smoked 17 and 18 pipes of tobacco in succession and were both fatally poisoned. Spilling an extremely high concentration of nicotine onto the skin can result in intoxication or even death since nicotine readily passes into the bloodstream following skin contact.The recent rise in the use of electronic cigarettes, many forms of which are designed to be refilled with nicotine-containing "e-liquid" supplied in small plastic bottles, has renewed interest in nicotine overdoses, especially the possibility of young children ingesting the liquids. A 2015 Public Health England report noted an "unconfirmed newspaper report of a fatal poisoning of a two-year old child" and two published case reports of children of similar age who had recovered after ingesting e-liquid and vomiting. They also noted case reports of suicides by nicotine, where adults drank liquid containing up to 1,500 mg of nicotine. They recovered (helped by vomiting), but an ingestion apparently of about 10,000 mg was fatal, as was an injection. They commented that "Serious nicotine poisoning seems normally prevented by the fact that relatively low doses of nicotine cause nausea and vomiting, which stops users from further intake." Four adults died in the US and Europe, after intentionally ingesting liquid. Two children, one in the US in 2014 and another in Israel in 2013, died after ingesting liquid nicotine.The discrepancy between the historically stated 60-mg dose and published cases of nicotine intoxication has been noted previously (Matsushima et al. 1995; Metzler et al. 2005). Nonetheless, this value is still widely accepted over the 500mg figure as the basis for safety regulations of tobacco and other nicotine-containing products (such as the EU wide TPD, set at a maximum of 20mg.
Pathophysiology
The symptoms of nicotine poisoning are caused by effects at nicotinic cholinergic receptors. Nicotine is an agonist at nicotinic acetylcholine receptor which are present in the central and autonomic nervous systems, and the neuromuscular junction. At low doses nicotine causes stimulatory effects on these receptors, however, higher doses or more sustained exposures can cause inhibitory effects leading to neuromuscular blockade.It is sometimes reported that people poisoned by organophosphate insecticides experience the same symptoms as nicotine poisoning. Organophosphates inhibit an enzyme called acetylcholinesterase, causing a buildup of acetylcholine, excessive stimulation of all types of cholinergic neurons, and a wide range of symptoms. Nicotine is specific for nicotinic cholinergic receptors only and has some, but not all of the symptoms of organophosphate poisoning.
Diagnosis
Increased nicotine or cotinine (the nicotine metabolite) is detected in urine or blood, or serum nicotine concentrations increase.
Treatment
The initial treatment of nicotine poisoning may include the administration of activated charcoal to try to reduce gastrointestinal absorption. Treatment is mainly supportive and further care can include control of seizures with the administration of a benzodiazepine, intravenous fluids for hypotension, and administration of atropine for bradycardia. Respiratory failure may necessitate respiratory support with rapid sequence induction and mechanical ventilation. Hemodialysis, hemoperfusion or other extracorporeal techniques do not remove nicotine from the blood and are therefore not useful in enhancing elimination. Acidifying the urine could theoretically enhance nicotine excretion, although this is not recommended as it may cause complications of metabolic acidosis.
Prognosis
The prognosis is typically good when medical care is provided and patients adequately treated are unlikely to have any long-term sequelae. However, severely affected patients with prolonged seizures or respiratory failure may have ongoing impairments secondary to the hypoxia. It has been stated that if a patient survives nicotine poisoning during the first 4 hours, they usually recover completely. At least at "normal" levels, as nicotine in the human body is broken down, it has an approximate biological half-life of 1–2 hours. Cotinine is an active metabolite of nicotine that remains in the blood for 18–20 hours, making it easier to analyze due to its longer half-life.
See also
Nicotine dependence
Nicotine withdrawal
References
== External links == |
Amino acid transport disorder | Amino acid transport disorders are medical conditions associated with a failure of amino acids to be absorbed from the kidney or intestine.
An example is Hartnup disease.
Reference
External links
Milne MD (1971). "Disorders of intestinal amino-acid transport". J Clin Pathol. 5 (Suppl): 41–4. doi:10.1136/jcp.s3-5.1.41. PMC 1176258. |
Midline cervical cleft | Midline cervical clefts are a rare congenital anomaly resulting from incomplete fusion during embryogenesis of the first and second branchial arches in the ventral midline of the neck. The condition presents as a midline cutaneous defect of the anterior neck with a skin projection or sinus, or as a subcutaneous erythematous fibrous cord. Surgical excision is the preferred treatment.
See also
Accessory tragus
List of cutaneous conditions
== References == |
Antibiotic-associated diarrhea | Antibiotic-associated diarrhea (AAD) results from an imbalance in the colonic microbiota caused by antibiotics. Microbiotal alteration changes carbohydrate metabolism with decreased short-chain fatty acid absorption and an osmotic diarrhea as a result. Another consequence of antibiotic therapy leading to diarrhea is overgrowth of potentially pathogenic organisms such as Clostridium difficile. It is defined as frequent loose and watery stools with no other complications.
Cause
Clostridium difficile, also known more commonly as C. diff, accounts for 10 to 20% of antibiotic-associated diarrhea cases, because the antibiotics administered for the treatment of certain disease processes such as inflammatory colitis also inadvertently kill a large portion of the gut flora, the normal flora that is usually present within the bowel. With this lower level of "healthy" bacteria present, the overgrowth of C. diff is then responsible "for elaborating the enterotoxin".
Treatment
Meta-analyses have concluded that probiotics may protect against antibiotic-associated diarrhea in both children and adults. Evidence is insufficient, however, regarding an effect on rates of C. difficile colitis.Efficacy of probiotic AAD prevention is dependent on the probiotic strain(s) used and on the dosage. Up to a 50% reduction of AAD occurrences has been found. No side effects have been reported. Caution is advised when using probiotics in immunocompromised individuals or those who have a compromised intestinal barrier because of the risk of an infection caused by the probiotic supplements.
== References == |
Atypical hemolytic uremic syndrome | Atypical hemolytic uremic syndrome (aHUS) is an extremely rare, life-threatening, progressive disease that frequently has a genetic component. In most cases it can be effectively controlled by interruption of the complement cascade. Particular monoclonal antibodies, discussed later in the article, have proven efficacy in many cases.
AHUS is usually caused by chronic, uncontrolled activation of the complement system, a branch of the bodys immune system that destroys and removes foreign particles. The disease affects both children and adults and is characterized by systemic thrombotic microangiopathy (TMA), the formation of blood clots in small blood vessels throughout the body, which can lead to stroke, heart attack, kidney failure, and death. The complement system activation may be due to mutations in the complement regulatory proteins (factor H, factor I, or membrane cofactor protein), or is occasionally due to acquired neutralizing autoantibody inhibitors of these complement system components, for example anti–factor H antibodies.: 1933 Prior to availability of eculizumab (Soliris)and ravulizumab(Ultomiris), an estimated 33–40% of patients died or developed end-stage renal disease (ESRD) (despite the use of supportive care, e.g. plasmapheresis) with the first clinical bout of aHUS. Including subsequent relapses, a total of approximately two-thirds (65%) of patients died, required dialysis, or had permanent renal damage within the first year after diagnosis despite plasma exchange or plasma infusion (PE/PI).
Signs and symptoms
Clinical signs and symptoms of complement-mediated TMA can include abdominal pain, confusion, fatigue, edema (swelling), nausea/vomiting and diarrhea. aHUS often presents with malaise and fatigue, as well as microangiopathic anemia.: 1931 However, severe abdominal pain and bloody diarrhea are unusual.: 1931 Laboratory tests may also reveal low levels of platelets (cells in the blood that aid in clotting), elevated lactate dehydrogenase (LDH, a chemical released from damaged cells, and which is therefore a marker of cellular damage), decreased haptoglobin (indicative of the breakdown of red blood cells), anemia (low red blood cell count)/schistocytes (damaged red blood cells), elevated creatinine (indicative of kidney dysfunction), and proteinuria (indicative of kidney injury). Patients with aHUS often present with an abrupt onset of systemic signs and symptoms such as acute kidney failure, hypertension (high blood pressure), myocardial infarction (heart attack), stroke, lung complications, pancreatitis (inflammation of the pancreas), liver necrosis (death of liver cells or tissue), encephalopathy (brain dysfunction), seizure, or coma. Failure of neurologic, cardiac, kidney, and gastrointestinal (GI) organs, as well as death, can occur unpredictably at any time, either very quickly or following prolonged symptomatic or asymptomatic disease progression. For example, approximately 1 in 6 patients with aHUS initially will present with proteinuria or hematuria without acute kidney failure. Patients who survive the presenting signs and symptoms endure a chronic thrombotic and inflammatory state, which puts many of them at lifelong elevated risk of sudden blood clotting, kidney failure, other severe complications and premature death.
Comorbidities
Although many patients experience aHUS as a single disease, comorbidities are common. In one study, 25% (47/191) of patients with no known family history of aHUS were found to have a coexisting disease or condition. Comorbidities in this study included malignant hypertension (30%), TMA with a history of transplant (23%), TMA associated with pregnancy (21%), glomerulopathy (17%), systemic disease such as systemic lupus erythematosus (SLE) or progressive systemic sclerosis (PSS) (6%), and malignancy (1%). The presence of mutations in complement regulatory proteins, or of disease-associated variations in the genes encoding these proteins (i.e., in most patients with comorbid conditions as well as in patients with aHUS as a single disease), suggests that deviations from the normal genetic coding of these factors could result in a genetic predisposition to TMA. Individuals so predisposed could have aHUS episodes precipitated by one of the known disease triggers (e.g., infection, pregnancy, surgery, trauma) as well as by other systemic diseases (e.g., malignant hypertension, SLE, cancer).
Mechanisms
In healthy individuals, complement is used to attack foreign substances, and the complement system is highly regulated to prevent it from damaging healthy tissues and organs. However, in most patients with aHUS, it has been demonstrated that chronic, uncontrolled, and excessive activation of complement can result from production of anti-factor H autoantibodies or from genetic mutations in any of several complement regulatory proteins (e.g., factor H, factor HR1 or HR3, membrane cofactor protein, factor I, factor B, complement C3, and thrombomodulin). This results in platelet activation, damage to endothelial cells (cells that line the blood vessels), and white blood cell activation, leading to systemic TMA, which manifests as decreased platelet count, hemolysis (breakdown of red blood cells), damage to multiple organs, and often, death.
Diagnosis
aHUS is not the only condition that causes systemic TMA, a fact that makes differential diagnosis essential. Historically, the clinical diagnosis of TMA-causing diseases was grouped into a broad category that (in addition to aHUS) included thrombotic thrombocytopenic purpura (TTP) and Shiga-toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS). However, it is now understood that although aHUS, STEC-HUS, and TTP have similar clinical presentations, they have distinct causes and specific tests can be conducted to differentiate these diseases. In addition, there are other conditions that can cause TMA as a secondary manifestation; these entities include systemic lupus erythematosus (SLE), malignant hypertension, progressive systemic sclerosis (PSS, also known as scleroderma), the pregnancy-associated HELLP (hemolysis, liver dysfunction, and low platelets) syndrome, and toxic drug reaction (e.g., to cocaine, cyclosporine, or tacrolimus). Nevertheless, aHUS should be suspected in patients presenting with systemic TMA, and appropriate diagnostic work-up should be undertaken.The neurological and kidney-related signs and symptoms of aHUS overlap with those of TTP. However, unlike aHUS, TTP is primarily an autoimmune disorder in which the presence of an inhibitory autoantibody results in severe deficiency of ADAMTS13, an enzyme that cleaves von Willebrand factor (vWf), a large protein involved in blood clotting, into smaller pieces. (TTP also can be a genetic disorder characterized by mutations in the ADAMTS13 gene leading to severe ADAMTS13 deficiency. This congenital cause of ADAMTS13 deficiency is called Upshaw-Schülman syndrome.) A lab test showing ADAMTS13 activity levels of ≤5% is indicative of TTP.Similarly, the gastrointestinal (GI) signs and symptoms of aHUS overlap with those of STEC-HUS. Stool samples from patients with diarrhea or other GI symptoms should be tested for STEC and the presence of Shiga-toxin. However, a positive identification of Shiga-toxin, which is required to diagnose STEC-HUS, does not rule out aHUS. Nevertheless, in the appropriate clinical setting, a positive identification of Shiga-toxin makes aHUS very unlikely.aHUS patients report a mean timeline of 29 days for the overall diagnosis process from first noticing symptoms to receiving an aHUS diagnosis. During which time they report their overall health state drops from 88% of patients feeling good to excellent, to 99% feeling good to very poor and a more than halving of their health status index from 3.8 (on a scale of 1 to 5) pre-illness to 1.4 at diagnosis.
Treatment
Plasma exchange/infusion
Although plasma exchange/infusion (PE/PI) is frequently used, there are no controlled trials of its safety or efficacy in aHUS. Even though PE/PI often partially controls some of the hematological manifestations of aHUS in some patients, its effectiveness has not been demonstrated in terms of inducing total disease remission. PE/PI is associated with significant safety risks, including risk of infection, allergic reactions, thrombosis, loss of vascular access, and poor quality of life. Importantly, terminal complement activation has been shown to be chronically present on the surface of platelets in patients with aHUS who appear to be clinically well while receiving chronic PE/PI.Guidelines issued by the European Paediatric Study Group for HUS recommend rapid administration of plasma exchange or plasma infusion (PE/PI), intensively administered daily for 5 days and then with reducing frequency. However, the American Society for Apheresis offers a "weak" recommendation for plasma exchange to treat aHUS, due to the "low" or "very low" quality of evidence supporting its use. Although some patients experienced improvements in red blood cell and platelet counts, plasma therapies generally did not result in full remission.
Monoclonal antibody therapy
Eculizumab (Soliris) appears to be useful for atypical hemolytic uremic syndrome (aHUS). In September 2011 the U.S. Food and Drug Administration (FDA) approved it as an orphan drug to treat people with aHUS. This approval was based on two small prospective trials of 17 people and 20 people. In the UK, NICE issued guidance on the use of Eculizumab for treating aHUS, based on five evidence sources, including those used by the FDA No randomised controlled trials were identified. All prospective studies were phase 2, open‑label, non‑randomised, single‑arm studies that included patients with different clinical baseline characteristics. The prospective studies lasted 26 weeks; however, patients were allowed to continue treatment with eculizumab in a long‑term extension study.Ravulizumab-cwvz (Ultomiris) is a second generation monoclonal antibody for aHUS made by Alexion pharmaceuticals, Inc. The target of ravulizumab-cwvz is the same eculizumab (Soliris) with changes to the structure of the antibody resulting in a longer serum half life and therefore reduced dosing regimen.
Dialysis
Patients with aHUS who have ESRD are generally consigned to lifelong dialysis, which carries a 5-year survival rate of 34–38%, with infections accounting for 14% of deaths. These patients also remain at ongoing risk of non-kidney systemic complications of the disease.
Kidney transplantation
Despite its history of use in patients with aHUS, kidney transplantation does not address the continued and uncontrolled complement activation that leads to progressive, systemic TMA. As many as 90% of patients with aHUS and who are not treated with Soliris or Ultomiris, experience TMA in the transplanted organ, leading to transplant failure. Patients who have undergone kidney transplantation are still at continued risk of neurological, gastrointestinal, and cardiovascular complications and, importantly, premature mortality. Following kidney transplantation, the ongoing, uncontrolled, chronic complement activation associated with aHUS causes graft loss in 66% of children and 55% of adults, as well as continued inflammatory and TMA insult to other organs. Combined liver-kidney transplantation is only available to very few patients, due to the limited supply of solid organs. In addition, there is a substantial near-term risk of mortality, which many physicians and patients consider excessive. In recent years, some transplant centers have begun to administer eculizumab to patients with TMA who receive a kidney transplant. This strategy has been effective in preventing TMA recurrences in these patients.
Terminal complement inhibition
Patients using either eculizumab or ravulizumab for the treatment of aHUS showed improvements in kidney function even avoiding dialysis and minimizing death. Markers of disease activity in the blood also had a great improvement. However, the only available evidence has substantial bias and low quality and therefore there should be careful considerations for futures studies in treatment duration, adverse outcomes and risk of disease recurrence associated with this treatment.
Historical Prognosis
Prior to the use of monoclonal antibodies(e.g., Soliris, Ultomiris) patients with aHUS had an extremely poor prognosis. Among those with the most commonly identified aHUS genetic mutation, the proportion of patients experiencing negative outcomes (e.g., need for dialysis, permanent kidney damage, death) within the first year rose to 70%. However, sudden morbidity and mortality could occur regardless of mutational status. aHUS can arise at any age, with more than 40% of cases first reported after 18 years of age. The oldest presentation in one study was at age 83. As noted above, kidney transplantation for aHUS patients with ESRD was rarely considered because of a high incidence of graft loss due to TMA recurrence in the transplanted organ in up to 90% of patients. Consequently, most untreated aHUS patients develop ESRD and undergo chronic dialysis, which is associated with significant morbidities and worsened prognosis. Combined liver-kidney transplantation has been attempted in patients with aHUS, although this high-risk procedure has a mortality rate approaching 50%.Prior to availability and usage of the treatments, quality of life was very poor for patients with aHUS; burdened with fatigue, renal complications, hypertension, neurological impairment, gastrointestinal distress, clotting at the site of venous access, and in worst cases, death. PE/PI is also reported to be associated with significant safety risks and is highly disruptive to patients lives due to the requirements for extensive vascular access and frequent administration.Since the approval of eculizumab (Soliris) the prognosis for aHUS patients has improved greatly. Risk of relapse is present after discontinuation of eculizumab treatment and close monitoring is required.
Epidemiology
aHUS can be inherited or acquired, and does not appear to vary by race, gender, or geographic area. As expected with an ultra-rare disease, data on the prevalence of aHUS are extremely limited. A pediatric prevalence of 3.3 cases per million population is documented in one publication of a European hemolytic uremic syndrome (HUS) registry involving 167 pediatric patients.
Society and culture
Naming
Atypical hemolytic uremic syndrome (aHUS) has also been referred to as diarrhea-negative hemolytic-uremic syndrome (D− HUS).: 2170
Research directions
Patient advocacy groups have been helping to determine research priorities.
References
== External links == |
Scarlet fever | Scarlet fever is an infectious disease resulting from a group A streptococcus (group A strep) infection, also known as Streptococcus pyogenes. The signs and symptoms include a sore throat, fever, headaches, swollen lymph nodes, and a characteristic rash. The rash is red and feels like sandpaper and the tongue may be red and bumpy. It most commonly affects children between five and 15 years of age.Scarlet fever affects a small number of people who have strep throat or streptococcal skin infections. The bacteria are usually spread by people coughing or sneezing. It can also be spread when a person touches an object that has the bacteria on it and then touches their mouth or nose. The characteristic rash is due to the erythrogenic toxin, a substance produced by some types of the bacterium. The diagnosis is typically confirmed by culturing the throat.There is no vaccine for scarlet fever. Prevention is by frequent handwashing, not sharing personal items, and staying away from other people when sick. The disease is treatable with antibiotics, which prevent most complications. Outcomes with scarlet fever are typically good if treated. Long-term complications as a result of scarlet fever include kidney disease, rheumatic heart disease, and arthritis. In the early 20th century, before antibiotics were available, it was a leading cause of death in children. An antitoxin was produced before antibiotics; however, it was never made in sufficient quantities, and could not be used to treat any other disease as antibiotics can.There have been signs of antibiotic resistance, and there have been recent outbreaks in Hong Kong in 2011 and in the UK in 2014, with occurrence rising 68% in the UK in the four years up to 2018. Research published in October 2020 has shown that infection of the bacterium by three viruses has led to stronger strains of the bacterium.
Signs and symptoms
Rash which has a characteristic appearance, spreading pattern, and desquamating process e.g.
"Strawberry tongue":
The tongue initially has a white coating on it, while the papillae of the tongue are swollen and reddened. The protrusion of the red papillae through the white coating gives the tongue a "white strawberry" appearance.
A few days later (following the desquamating process, or the shedding of the tissue which created the white coating), the whiteness disappears, and the red and enlarged papillae give the tongue the "red strawberry" appearance. The symptomatic appearance of the tongue is part of the rash that is characteristic of scarlet fever.
Pastias lines
Lines of petechiae, which appear as pink/red areas located in arm pits and elbow pits
Vomiting and abdominal pain
Strep throat
Typical signs and symptoms of streptococcal pharyngitis (also known as strep throat):
Sore throat, painful swallowing
Fever – typically over 39 °C (102.2 °F)
Fatigue
Enlarged and reddened tonsils with yellow or white exudates present (this is typically an exudative pharyngitis)
Enlarged and tender lymph nodes usually located on the front of the neckThe following signs will usually be absent: cough, hoarseness, runny nose, diarrhea, and conjunctivitis. Such symptoms indicate what is more likely a viral infection.
Rash
The rash begins 1–2 days following the onset of symptoms caused by the strep pharyngitis (sore throat, fever, fatigue). This characteristic rash has been denoted as "scarlatiniform", and it appears as a diffuse redness of the skin with small papules, or bumps, which resemble goose bumps. These bumps are what give the characteristic sandpaper texture to the rash. The reddened skin will blanch when pressure is applied to it. The skin may feel itchy, but it will not be painful. The rash generally starts at the flexion of the elbow and other surfaces. It appears next on the trunk and gradually spreads out to the arms and legs. The palms, soles and face are usually left uninvolved by the rash. The face, however, is usually flushed, most prominently in the cheeks, with a ring of paleness around the mouth. After the rash spreads, it becomes more pronounced in creases in the skin, such as the skin folds in the inguinal and axillary regions of the body. Also in those areas, Pastias Lines may appear: petechiae arranged in a linear pattern. Within 1 week of onset, the rash begins to fade followed by a longer process of desquamation, or shedding of the outer layer of skin. This lasts several weeks. The desquamation process usually begins on the face and progresses downward on the body. After the desquamation, the skin will be left with a sunburned appearance.
Mouth
The streptococcal pharyngitis, which is the usual presentation of scarlet fever in combination with the characteristic rash, commonly involves the tonsils. The tonsils will appear swollen and reddened. The palate and uvula are also commonly affected by the infection. The involvement of the soft palate can be seen as tiny red and round spots known as Forchheimer spots.
Variable presentations
The features of scarlet fever can differ depending on the age and race of the person. Children less than 5 years old can have atypical presentations. Children less than 3 years old can present with nasal congestion and a lower grade fever. Infants may present with symptoms of increased irritability and decreased appetite.Children who have darker skin can have a different presentation, as the redness of the skin involved in the rash and the ring of paleness around the mouth can be less obvious. Suspicion based on accompanying symptoms and diagnostic studies are important in these cases.
Course
Following exposure to streptococcus, onset of symptoms occur 12 hours to 7 days later. These may include fever, fatigue, and sore throat. The characteristic scarlatiniform rash appears 12–48 hours later. During the first few days of the rash development and rapid generalization, the Pastias Lines and strawberry tongue are also present. The rash starts fading within 3–4 days, followed by the desquamation of the rash, which lasts several weeks to a month. If the case of scarlet fever is uncomplicated, recovery from the fever and clinical symptoms, other than the process of desquamation, occurs in 5–10 days.
Complications
The complications, which can arise from scarlet fever when left untreated or inadequately treated, can be divided into two categories: suppurative and nonsuppurative.Suppurative complications: These are rare complications that arise either from direct spread to structures that are close to the primary site of infection, or spread through the lymphatic system or blood. In the first case, scarlet fever may spread to the pharynx. Possible problems from this method of spread include peritonsillar or retropharyngeal abscesses, cellulitis, mastoiditis or sinusitis.In the second case, the streptococcal infection may spread through the lymphatic system or the blood to areas of the body further away from the pharynx. A few examples of the many complications that can arise from those methods of spread include endocarditis, pneumonia, or meningitis.Nonsuppurative complications: These complications arise from certain subtypes of group A streptococci that cause an autoimmune response in the body through what has been termed molecular mimicry. In these cases, the antibodies which the persons immune system developed to attack the group A streptococci are also able to attack the persons own tissues. The following complications result, depending on which tissues in the persons body are targeted by those antibodies.
Acute rheumatic fever: This is a complication that results 2–6 weeks after a group A streptococcal infection of the upper respiratory tract. It presents in developing countries, where antibiotic treatment of streptococcal infections is less common, as a febrile illness with several clinical manifestations, which are organized into what is called the Jones criteria. These criteria include arthritis, carditis, neurological issues, and skin findings. Diagnosis also depends on evidence of a prior group A streptococcal infection in the upper respiratory tract (as seen in streptococcal pharyngitis and scarlet fever). The carditis is the result of the immunologic response targeting the persons heart tissue, and it is the most serious sequelae that develops from acute rheumatic fever. When this involvement of the heart tissue occurs, it is called rheumatic heart disease. In most cases of rheumatic heart disease, the mitral valve is affected, ultimately leading to mitral stenosis. The link to rheumatic fever and heart disease is a particular concern in Australia, because of the high prevalence of these diseases in Aboriginal and Torres Strait Islander communities.
Poststreptococcal glomerulonephritis: This is inflammation of the kidney, which presents 1–2 weeks after a group A streptococcal pharyngitis. It can also develop after an episode of Impetigo or any group A streptococcal infection in the skin (this differs from acute rheumatic fever which only follows group A streptococcal pharyngitis). It is the result of the autoimmune response to the streptococcal infection affecting part of the kidney. Persons present with what is called acute nephritic syndrome, in which they have high blood pressure, swelling, and urinary abnormalities. Urinary abnormalities include blood and protein found in the urine, as well as less urine production overall.
Poststreptococcal reactive arthritis: The presentation of arthritis after a recent episode of group A streptococcal pharyngitis raises suspicion for acute rheumatic fever, since it is one of the Jones criteria for that separate complication. But, when the arthritis is an isolated symptom, it is referred to as poststreptococcal reactive arthritis. This arthritis can involve a variety of joints throughout the body, unlike the arthritis of acute rheumatic fever, which primarily affects larger joints such as the knee joints. It can present less than 10 days after the group A streptococcal pharyngitis.
Cause
Strep throat spreads by close contact among people, via respiratory droplets (for example, saliva or nasal discharge). A person in close contact with another person infected with group A streptococcal pharyngitis has a 35% chance of becoming infected. One in ten children who are infected with group A streptococcal pharyngitis will develop scarlet fever.
Pathophysiology
The rash of scarlet fever, which is what differentiates this disease from an isolated group A strep pharyngitis (or strep throat), is caused by specific strains of group A streptococcus which produce a pyrogenic exotoxin, mainly responsible for the skin manifestation of the infection. These toxin-producing strains cause scarlet fever in people who do not already have antitoxin antibodies. Streptococcal pyrogenic exotoxins A, B, and C (speA, speB, and speC) have been identified. The pyrogenic exotoxins are also called erythrogenic toxins and cause the erythematous rash of scarlet fever. The strains of group A streptococcus that cause scarlet fever need specific bacteriophages for there to be pyrogenic exotoxin production. Specifically, bacteriophage T12 is responsible for the production of speA. Streptococcal Pyrogenic Exotoxin A, speA, is the one which is most commonly associated with cases of scarlet fever which are complicated by the immune-mediated sequelae acute rheumatic fever and post-streptococcal glomerulonephritis.These toxins are also known as "superantigens" because they are able to cause an extensive immune response within the body through activation of some of the main cells responsible for the persons immune system. The body responds to these toxins by making antibodies to those specific toxins. However, those antibodies do not completely protect the person from future group A streptococcal infections, because there are 12 different pyrogenic exotoxins possible.
Microbiology
The disease is caused by secretion of pyrogenic exotoxins by the infecting Streptococcus bacteria. Streptococcal pyrogenic exotoxin A (speA) is probably the best studied of these toxins. It is carried by the bacteriophage T12 which integrates into the streptococcal genome from where the toxin is transcribed. The phage itself integrates into a serine tRNA gene on the chromosome.The T12 virus itself has not been placed into a taxon by the International Committee on Taxonomy of Viruses. It has a double-stranded DNA genome and on morphological grounds appears to be a member of the Siphoviridae.The speA gene was cloned and sequenced in 1986. It is 753 base pairs in length and encodes a 29.244 kiloDalton (kDa) protein. The protein contains a putative 30-
amino-acid signal peptide; removal of the signal sequence gives a predicted molecular weight of 25.787 kDa for the secreted protein. Both a promoter and a ribosome binding site (Shine-Dalgarno sequence) are present upstream of the gene. A transcriptional terminator is located 69 bases downstream from the translational termination codon. The carboxy terminal portion of the protein exhibits extensive homology with the carboxy terminus of Staphylococcus aureus enterotoxins B and C1.Streptococcal phages other than T12 may also carry the speA gene.
Diagnosis
Although the presentation of scarlet fever can be clinically diagnosed, further testing may be required to distinguish it from other illnesses. Also, history of a recent exposure to someone with strep throat can be useful in diagnosis. There are two methods used to confirm suspicion of scarlet fever; rapid antigen detection test and throat culture.The rapid antigen detection test is a very specific test but not very sensitive. This means that if the result is positive (indicating that the group A strep antigen was detected and therefore confirming that the person has a group A strep pharyngitis), then it is appropriate to treat the people with scarlet fever with antibiotics. But, if the rapid antigen detection test is negative (indicating that they do not have group A strep pharyngitis), then a throat culture is required to confirm, as the first test could have yielded a false negative result. In the early 21st century, the throat culture is the current "gold standard" for diagnosis.Serologic testing seeks evidence of the antibodies that the body produces against the streptococcal infection, including antistreptolysin-O and antideoxyribonuclease B. It takes the body 2–3 weeks to make these antibodies, so this type of testing is not useful for diagnosing a current infection. But, it is useful when assessing a person who may have one of the complications from a previous streptococcal infection.Throat cultures done after antibiotic therapy can show if the infection has been removed. These throat swabs, however, are not indicated, because up to 25% of properly treated individuals can continue to carry the streptococcal infection while being asymptomatic.
Differential diagnosis
Viral exanthem: Viral infections are often accompanied by a rash which can be described as morbilliform or maculopapular. This type of rash is accompanied by a prodromal period of cough and runny nose in addition to a fever, indicative of a viral process.
Allergic or contact dermatitis: The erythematous appearance of the skin will be in a more localized distribution rather than the diffuse and generalized rash seen in scarlet fever.
Drug eruption: These are potential side effects of taking certain drugs such as penicillin. The reddened maculopapular rash which results can be itchy and be accompanied by a fever.
Kawasaki disease: Children with this disease also present a strawberry tongue and undergo a desquamative process on their palms and soles. However, these children tend to be younger than 5 years old, their fever lasts longer (at least five days), and they have additional clinical criteria (including signs such as conjunctival redness and cracked lips), which can help distinguish this from scarlet fever.
Toxic shock syndrome: Both streptococcal and staphylococcal bacteria can cause this syndrome. Clinical manifestations include diffuse rash and desquamation of the palms and soles. It can be distinguished from scarlet fever by low blood pressure, lack of sandpaper texture for the rash, and multi-organ system involvement.
Staphylococcal scalded skin syndrome: This is a disease that occurs primarily in young children due to a toxin-producing strain of the bacteria Staphylococcus aureus. The abrupt start of the fever and diffused sunburned appearance of the rash can resemble scarlet fever. However, this rash is associated with tenderness and large blister formation. These blisters easily pop, followed by causing the skin to peel.
Staphylococcal scarlet fever: The rash is identical to the streptococcal scarlet fever in distribution and texture, but the skin affected by the rash will be tender.
Prevention
One method is long-term use of antibiotics to prevent future group A streptococcal infections. This method is only indicated for people who have had complications like recurrent attacks of acute rheumatic fever or rheumatic heart disease. Antibiotics are limited in their ability to prevent these infections since there are a variety of subtypes of group A streptococci that can cause the infection.The vaccine approach has a greater likelihood of effectively preventing group A streptococcal infections because vaccine formulations can target multiple subtypes of the bacteria. A vaccine developed by George and Gladys Dick in 1924 was discontinued due to poor efficacy and the introduction of antibiotics. Difficulties in vaccine development include the considerable strain variety of group A streptococci present in the environment and the amount of time and number of people needed for appropriate trials for safety and efficacy of any potential vaccine. There have been several attempts to create a vaccine in the past few decades. These vaccines, which are still in the development phase, expose the person to proteins present on the surface of the group A streptococci to activate an immune response that will prepare the person to fight and prevent future infections.There used to be a diphtheria scarlet fever vaccine. It was, however, found not to be effective. This product was discontinued by the end of World War II.
Treatment
Antibiotics to combat the streptococcal infection are the mainstay of treatment for scarlet fever. Prompt administration of appropriate antibiotics decreases the length of illness. Peeling of the outer layer of skin, however, will happen despite treatment. One of the main goals of treatment is to prevent the child from developing one of the suppurative or nonsuppurative complications, especially acute rheumatic fever. As long as antibiotics are started within nine days, it is very unlikely for the child to develop acute rheumatic fever. Antibiotic therapy has not been shown to prevent the development of post-streptococcal glomerulonephritis. Another important reason for prompt treatment with antibiotics is the ability to prevent transmission of the infection between children. An infected individual is most likely to pass on the infection to another person during the first 2 weeks. A child is no longer contagious (able to pass the infection to another child) after 24 hours of antibiotics.The antibiotic of choice is Penicillin V which is taken by mouth. In countries without a liquid Penicillin V product, children unable to take tablets can be given amoxicillin which comes in a liquid form and is equally effective. Duration of treatment is 10 days. Benzathine penicillin G can be given as a one time intramuscular injection as another alternative if swallowing pills is not possible. If the person is allergic to the family of antibiotics which both penicillin and amoxicillin are a part of (beta-lactam antibiotics), a first generation cephalosporin is used. Cephalosporin antibiotics, however, can still cause adverse reactions in people whose allergic reaction to penicillin is a Type 1 Hypersensitivity reaction. In those cases it is appropriate to choose clindamycin or erythromycin instead. Tonsillectomy, although once a reasonable treatment for recurrent streptococcal pharyngitis, is not indicated, as a person can still be infected with group A streptococcus without their tonsils.
Antibiotic resistance and resurgence
A drug-resistant strain of scarlet fever, resistant to macrolide antibiotics such as erythromycin, but retaining drug-sensitivity to beta-lactam antibiotics such as penicillin, emerged in Hong Kong in 2011, accounting for at least two deaths in that city—the first such in over a decade. About 60% of circulating strains of the group A streptococcus that cause scarlet fever in Hong Kong are resistant to macrolide antibiotics, says Professor Kwok-yung Yuen, head of Hong Kong Universitys microbiology department. Previously, observed resistance rates had been 10–30%; the increase is likely the result of overuse of macrolide antibiotics in recent years.There was also an outbreak in the UK in 2014, and the National Health Service reported a 68% increase in the number of S. pyogenes identified in laboratory reports between 2014 and 2018.New research published in October 2020 in the journal that the bacterium appears to be getting more robust after being infected with viruses, specifically the North-East Asian serotype M12 (emm12) (group A Streptococcus, GAS). They found three new genes, acquired from viruses, leading to the development of "superantigens" targeting white blood cells, leading to a more virulent strain of the bacterium.A vaccine that will protect against the 180 to 200 types of bacteria causing the disease has been worked on for over 20 years, but as of 2020 a safe one had not yet been developed.
Epidemiology
Scarlet fever occurs equally in both males and females. Children are most commonly infected, typically between 5–15 years old. Although streptococcal infections can happen at any time of year, infection rates peak in the winter and spring months, typically in colder climates.The morbidity and mortality of scarlet fever has declined since the 18th and 19th century when there were epidemics caused by this disease. Around 1900 the mortality rate in multiple places reached 25%. The improvement in prognosis can be attributed to the use of penicillin in the treatment of this disease. The frequency of scarlet fever cases has also been declining over the past century. There have been several reported outbreaks of the disease in various countries in the past decade. The reason for these recent increases remains unclear in the medical community. Between 2013 and 2016 population rates of scarlet fever in England increased from 8.2 to 33.2 per 100,000 and hospital admissions for scarlet fever increased by 97%.
History
It is unclear when a description of this disease was first recorded. Hippocrates, writing around 400 BC, described the condition of a person with a reddened skin and fever.The first unambiguous description of the disease in the medical literature appeared in the 1553 book De Tumoribus praeter Naturam by the Sicilian anatomist and physician Giovanni Filippo Ingrassia, where he referred to it as rossalia. He also made a point to distinguish that this presentation had different characteristics from measles. It was redescribed by Johann Weyer during an epidemic in lower Germany between 1564 and 1565; he referred to it as scarlatina anginosa. The first unequivocal description of scarlet fever appeared in a book by Joannes Coyttarus of Poitiers, De febre purpura epidemiale et contagiosa libri duo, which was published in 1578 in Paris. Daniel Sennert of Wittenberg described the classical scarlatinal desquamation in 1572 and was also the first to describe the early arthritis, scarlatinal dropsy, and ascites associated with the disease.In 1675 the term that has been commonly used to refer to scarlet fever, "scarlatina", was written by Thomas Sydenham, an English physician.
In 1827, Richard Bright was the first to recognize the involvement of the renal system in scarlet fever.The association between streptococci and disease was first described in 1874 by Theodor Billroth, discussing people with skin infections. Billroth also coined the genus name Streptococcus. In 1884 Friedrich Julius Rosenbach edited the name to its current one, Streptococcus pyogenes, after further looking at the bacteria in the skin lesions. The organism was first cultured in 1883 by the German surgeon Friedrich Fehleisen from erysipelas lesions.Also in 1884, the German physician Friedrich Loeffler was the first to show the presence of streptococci in the throats of people with scarlet fever. Because not all people with pharyngeal streptococci developed scarlet fever, these findings remained controversial for some time. The association between streptococci and scarlet fever was confirmed by Alphonse Dochez and George and Gladys Dick in the early 1900s.Also in 1884, the worlds first convalescent home for people with scarlet fever was opened at Brockley Hill, Stanmore, founded by Mary Wardell.Nil Filatov (in 1895) and Clement Dukes (in 1894) described an exanthematous disease which they thought was a form of rubella, but in 1900, Dukes described it as a separate illness which came to be known as Dukes disease, Filatovs disease, or fourth disease. However, in 1979, Keith Powell identified it as in fact the same illness as the form of scarlet fever which is caused by staphylococcal exotoxin and is known as staphylococcal scalded skin syndrome.Scarlet fever serum from horses blood was used in the treatment of children beginning in 1900 and reduced mortality rates significantly.In 1906, the Austrian pediatrician Clemens von Pirquet postulated that disease-causing immune complexes were responsible for the nephritis that followed scarlet fever.Bacteriophages were discovered in 1915 by Frederick Twort. His work was overlooked and bacteriophages were later rediscovered by Felix dHerelle in 1917. The specific association of scarlet fever with the group A streptococci had to await the development of Lancefields streptococcal grouping scheme in the 1920s. George and Gladys Dick showed that cell-free filtrates could induce the erythematous reaction characteristic of scarlet fever, proving that this reaction was due to a toxin. Karelitz and Stempien discovered that extracts from human serum globulin and placental globulin can be used as lightening agents for scarlet fever and this was used later as the basis for the Dick test. The association of scarlet fever and bacteriophages was described in 1926 by Cantacuzène (Ioan Cantacuzino) and Bonciu.An antitoxin for scarlet fever was developed in 1924.
The first toxin which causes this disease was cloned and sequenced in 1986 by Weeks and Ferretti. The discovery of penicillin and its subsequent widespread use has significantly reduced the mortality of this once feared disease. Reports of cases of scarlet fever have been on the rise in countries including England, Wales, South Korea, Vietnam, China, and Hong Kong in recent years. Researchers are unsure as to what has caused the spike in cases of the disease.
The Dick test
The Dick test, invented in 1924 by George F. Dick and Gladys Dick, was used to identify those susceptible to scarlet fever. The Dick test consisted of injecting a diluted strain of the streptococci known to cause scarlet fever into a persons skin. A local reaction in the skin at the site of injection appeared in people who were susceptible to developing scarlet fever. The reaction was most notable around |
Scarlet fever | 24 hours after the injection but could be seen as early as 4 hours. If no reaction was seen in the skin, then that person was assumed to have already developed immunity to the disease and was not at risk of developing it.
References
== External links == |
Hyphema | Hyphema is a condition that occurs when blood enters the front (anterior) chamber of the eye between the iris and the cornea. People usually first notice a loss of vision or decrease in vision. The eye may also appear to have a reddish tinge, or it may appear as a small pool of blood at the bottom of the iris or in the cornea. A traumatic hyphema is caused by a hit to the eye from a projected object or a blow to the eye. A hyphema can also occur spontaneously.
Presentation
A decrease in vision or a loss of vision is often the first sign of a hyphema. People with microhyphema may have slightly blurred or normal vision. A person with a full hyphema may not be able to see at all (complete loss of vision). The persons vision may improve over time as the blood moves by gravity lower in the anterior chamber of the eye, between the iris and the cornea. In many people, the vision will improve, however some people may have other injuries related to trauma to the eye or complications related to the hyphema. A microhyphema, where red blood cells are hanging in the anterior chamber of the eye, is less severe. A layered hyphema when fresh blood is seen lower in the anterior chamber is moderately severe. A full hyphema (total hyphema), when blood fills up the chamber completely, is the most severe.
Complications
While the vast majority of hyphemas resolve on their own without issue, sometimes complications occur. Traumatic hyphema may lead to increased intraocular pressure (IOP), peripheral anterior synechiae, atrophy of the optic nerve, staining of the cornea with blood, re-bleeding, and impaired accommodation.Secondary hemorrhage, or rebleeding of the hyphema, is thought to worsen outcomes in terms of visual function and lead to complications such as glaucoma, corneal staining, optic atrophy, or vision loss. Rebleeding occurs in 4–35% of hyphema cases and is a risk factor for glaucoma. Young children with traumatic hyphema are at an increased risk of developing amblyopia, an irreversible condition.
Causes
Hyphemas are frequently caused by injury, and may partially or completely block vision. The most common causes of hyphema are intraocular surgery, blunt trauma, and lacerating trauma. Hyphemas may also occur spontaneously, without any inciting trauma. Spontaneous hyphemas are usually caused by the abnormal growth of blood vessels (neovascularization), tumors of the eye (retinoblastoma or iris melanoma), uveitis, or vascular anomalies (juvenile xanthogranuloma). Additional causes of spontaneous hyphema include: rubeosis iridis, myotonic dystrophy, leukemia, hemophilia, and von Willebrand disease. Conditions or medications that cause thinning of the blood, such as aspirin, warfarin, or drinking alcohol may also cause hyphema. Source of bleeding in hyphema with blunt trauma to eye is circulus iridis major artery.
Treatment
The main goals of treatment are to decrease the risk of re-bleeding within the eye, corneal blood staining, and atrophy of the optic nerve. Small hyphemas can usually be treated on an outpatient basis. There is little evidence that most of the commonly used treatments for hyphema (antifibrinolytic agents [oral and systemic aminocaproic acid, tranexamic acid, and aminomethylbenzoic acid], corticosteroids [systemic and topical], cycloplegics, miotics, aspirin, conjugated estrogens, traditional Chinese medicine, monocular versus bilateral patching, elevation of the head, and bed rest) are effective at improving visual acuity after two weeks. Surgery may be necessary for non-resolving hyphemas, or hyphemas that are associated with high pressure that does not respond to medication. Surgery can be effective for cleaning out the anterior chamber and preventing corneal blood staining.If pain management is necessary, acetaminophen can be used. Aspirin and ibuprofen should be avoided, because they interfere with platelets ability to form a clot and consequently increase the risk of additional bleeding. Sedation is not usually necessary for patients with hyphema.
Aminocaproic or tranexamic acids are often prescribed for hyphema on the basis that they reduce the risk of rebleeding by inhibiting the conversion of plasminogen to plasmin, and thereby keeping clots stable. However, the evidence for their effectiveness is limited and aminocaproic acid may actually cause hyphemas to take longer to clear.
Prognosis
Hyphemas require urgent assessment by an optometrist or ophthalmologist as they may result in permanent visual impairment.A long-standing hyphema may result in hemosiderosis and heterochromia. Blood accumulation may also cause an elevation of the intraocular pressure. On average, the increased pressure in the eye remains for six days before dropping. Most uncomplicated hyphemas resolve within 5–6 days.
Epidemiology
As of 2012, the rate of hyphemas in the United States are about 20 cases per 100,000 people annually. The majority of people with a traumatic hyphema are children and young adults. 60% of traumatic hyphemas are sports-related, and there are more cases in males compared to females.
See also
Hypopyon
2-D from Gorillaz
Uveitis–Glaucoma–Hyphema syndrome
References
External links
Hyphema - Handbook of Ocular Disease Management |
Mild cognitive impairment | Mild cognitive impairment (MCI) is a neurocognitive disorder which involves cognitive impairments beyond those expected based on an individuals age and education but which are not significant enough to interfere with instrumental activities of daily living. MCI may occur as a transitional stage between normal aging and dementia, especially Alzheimers disease. It includes both memory and non-memory impairments. The cause of the disorder remains unclear, as well as both its prevention and treatment, with some 50 percent of people diagnosed with it going on to develop Alzheimers disease within five years. The diagnosis can also serve as an early indicator for other types of dementia, although MCI may remain stable or even remit.Mild cognitive impairment has been relisted as mild neurocognitive disorder in DSM-5, and in ICD-11, the latter effective on the 1st of January 2022.
Classification
MCI can present with a variety of symptoms, but is divided generally into two types.Amnestic MCI (aMCI) is mild cognitive impairment with memory loss as the predominant symptom; aMCI is frequently seen as a prodromal stage of Alzheimers disease. Studies suggest that these individuals tend to progress to probable Alzheimers disease at a rate of approximately 10% to 15% per year. It is possible that being diagnosed with cognitive decline may serve as an indicator of MCI.Nonamnestic MCI (naMCI) is mild cognitive impairment in which impairments in domains other than memory (for example, language, visuospatial, executive) are more prominent. It may be further divided as nonamnestic single- or multiple-domain MCI, and these individuals are believed to be more likely to convert to other dementias (for example, dementia with Lewy bodies).The International Classification of Diseases classifies MCI as a "mental and behavioural disorder."
Causes
Mild cognitive impairment (MCI) may be caused due to alteration in the brain triggered during early stages of Alzheimers disease or other forms of dementia. Exact causes of MCI are unknown. It is controversial whether MCI even should be identified as a disorder.Risk factors of both dementia and MCI are considered to be the same: these are aging, genetic (heredity) cause of Alzheimers or other dementia, and cardiovascular disease.Individuals with MCI have increased oxidative damage in their nuclear and mitochondrial brain DNA.
Diagnosis
The diagnosis of MCI requires considerable clinical judgement, and as such a comprehensive clinical assessment including clinical observation, neuroimaging, blood tests and neuropsychological testing are best in order to rule out an alternate diagnosis.
MCI is diagnosed when there is:
Evidence of memory impairment
Preservation of general cognitive and functional abilities
Absence of diagnosed dementia
Neuropathology
Although amnestic MCI patients may not meet criteria for Alzheimers disease, patients may be in a transitional stage of evolving Alzheimers disease.Magnetic resonance imaging can observe deterioration, including progressive loss of gray matter in the brain, from mild cognitive impairment to full-blown Alzheimer disease. A technique known as PiB PET imaging is used to show the sites and shapes of beta amyloid deposits in living subjects using a 11C tracer that binds selectively to such deposits.
Treatment
As of January 2018, there are no USFDA-approved medications for the treatment of mild cognitive impairment. Moreover, as of January 2018, there is no high-quality evidence that supports the efficacy of any pharmaceutical drugs or dietary supplements for improving cognitive symptoms in individuals with mild cognitive impairment. A moderate amount of high-quality evidence supports the efficacy of regular physical exercise for improving cognitive symptoms in individuals with MCI. The clinical trials that established the efficacy of exercise therapy for MCI involved twice weekly exercise over a period of six months. A small amount of high-quality evidence supports the efficacy of cognitive training for improving some measures of cognitive function in individuals with mild cognitive impairment. Due to the heterogeneity among studies which assessed the effect of cognitive training in individuals with MCI, there are no particular cognitive training interventions that have been found to provide greater symptomatic benefits for MCI relative to other forms of cognitive training.The American Academy of Neurologys (AAN) clinical practice guideline on mild cognitive impairment from January 2018 stated that clinicians should identify modifiable risk factors in individuals with MCI, assess functional impairments, provide treatment for any behavioral or neuropsychiatric symptoms, and monitor the individuals cognitive status over time. It also stated that medications which cause cognitive impairment should be discontinued or avoided if possible. Due to the lack of evidence supporting the efficacy of cholinesterase inhibitors in individuals with MCI, the AAN guideline stated that clinicians who choose to prescribe them for the treatment of MCI must inform patients about the lack of evidence supporting this therapy. The guideline also indicated that clinicians should recommend that individuals with MCI engage in regular physical exercise for cognitive symptomatic benefits; clinicians may also recommend cognitive training, which appears to provide some symptomatic benefit in certain cognitive measures.As MCI may represent a prodromal state to clinical Alzheimers disease, treatments proposed for Alzheimers disease, such as antioxidants and cholinesterase inhibitors, could potentially be useful; however, as of January 2018, there is no evidence to support the efficacy of cholinesterase inhibitors for the treatment of mild cognitive impairment. Two drugs used to treat Alzheimers disease have been assessed for their ability to treat MCI or prevent progression to full Alzheimers disease. Rivastigmine failed to stop or slow progression to Alzheimers disease or to improve cognitive function for individuals with mild cognitive impairment; donepezil showed only minor, short-term benefits and was associated with significant side effects.
Intervention
Current evidence suggests that cognition-based interventions do improve mental performance (i.e. memory, executive function, attention, and speed) in older adults and people with mild cognitive impairment. Especially, immediate and delayed verbal recall resulted in higher performance gains from memory training.
Nutrition
There is currently limited evidence to form a strong conclusion to recommend the use of any form of carbohydrate in preventing or reducing cognitive decline in older adults with normal cognition or mild cognitive impairment. So, more large and higher quality evidence is needed to evaluate memory improvement and find nutritional issues due to carbohydrates.
Outlook
MCI does not usually interfere with daily life, but around 50 percent of people diagnosed with it go on to develop Alzheimers disease within five years (mainly for people diagnosed with memory impairments). This diagnosis can also serve as an early indicator for other types of dementia, although MCI may remain stable or even remit.
Prevalence
The prevalence of MCI varies by age. The prevalence of MCI among different age groups is as follows: 6.7% for ages 60–64; 8.4% for ages 65–69, 10.1% for ages 70–74, 14.8% for ages 75–79, and 25.2% for ages 80–84. After a two-year follow-up, the cumulative incidence of dementia among individuals who are over 65 years old and were diagnosed with MCI was found to be 14.9%.Globally, approximately 16% of the population over the age of 70 experiences some type of mild cognitive impairment.
See also
Menopause-related cognitive impairment – similar symptoms, appears shortly after menopause, and can be treated with hormone replacement therapy
== References == |
Mood disorder | A mood disorder, also known as an affective disorder, is any of a group of conditions of mental and behavioral disorder where a disturbance in the persons mood is the main underlying feature. The classification is in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD).
Mood disorders fall into seven groups, including; abnormally elevated mood, such as mania or hypomania; depressed mood, of which the best-known and most researched is major depressive disorder (MDD) (alternatively known as clinical depression, unipolar depression, or major depression); and moods which cycle between mania and depression, known as bipolar disorder (BD) (formerly known as manic depression). There are several sub-types of depressive disorders or psychiatric syndromes featuring less severe symptoms such as dysthymic disorder (similar to MDD, but longer lasting and more persistent, though often milder) and cyclothymic disorder (similar to but milder than BD).In some cases, more than one mood disorder can be present in an individual, like bipolar disorder and depressive disorder. If a mood disorder and schizophrenia are both present in an individual, this is known as schizoaffective disorder. Mood disorders may also be substance induced, or occur in response to a medical condition.
English psychiatrist Henry Maudsley proposed an overarching category of affective disorder. The term was then replaced by mood disorder, as the latter term refers to the underlying or longitudinal emotional state, whereas the former refers to the external expression observed by others.
Classification
Depressive disorders
Major depressive disorder (MDD), commonly called major depression, unipolar depression, or clinical depression, wherein a person has one or more major depressive episodes. After a single episode, Major Depressive Disorder (single episode) would be diagnosed. After more than one episode, the diagnosis becomes Major Depressive Disorder (Recurrent). Depression without periods of mania is sometimes referred to as unipolar depression because the mood remains at the bottom "pole" and does not climb to the higher, manic "pole" as in bipolar disorder.Individuals with a major depressive episode or major depressive disorder are at increased risk for suicide. Seeking help and treatment from a health professional dramatically reduces the individuals risk for suicide. Studies have demonstrated that asking if a depressed friend or family member has thought of committing suicide is an effective way of identifying those at risk, and it does not "plant" the idea or increase an individuals risk for suicide in any way. Epidemiological studies carried out in Europe suggest that, at this moment, roughly 8.5 percent of the worlds population have a depressive disorder. No age group seems to be exempt from depression, and studies have found that depression appears in infants as young as 6 months old who have been separated from their mothers.Depressive disorder is frequent in primary care and general hospital practice but is often undetected. Unrecognized depressive disorder may slow recovery and worsen prognosis in physical illness, therefore it is important that all doctors be able to recognize the condition, treat the less severe cases, and identify those requiring specialist care.Diagnosticians recognize several subtypes or course specifiers:Atypical depression (AD) is characterized by mood reactivity (paradoxical anhedonia) and positivity, significant weight gain or increased appetite ("comfort eating"), excessive sleep or somnolence (hypersomnia), a sensation of heaviness in limbs known as leaden paralysis, and significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection. Difficulties in measuring this subtype have led to questions of its validity and prevalence.Melancholic depression is characterized by a loss of pleasure (anhedonia) in most or all activities, a failure of reactivity to pleasurable stimuli, a quality of depressed mood more pronounced than that of grief or loss, a worsening of symptoms in the morning hours, early-morning waking, psychomotor retardation, excessive weight loss (not to be confused with anorexia nervosa), or excessive guilt.Psychotic major depression (PMD), or simply psychotic depression, is the term for a major depressive episode, in particular of melancholic nature, wherein the patient experiences psychotic symptoms such as delusions or, less commonly, hallucinations. These are most commonly mood-congruent (content coincident with depressive themes).Catatonic depression is a rare and severe form of major depression involving disturbances of motor behavior and other symptoms. Here, the person is mute and almost stuporose, and either is immobile or exhibits purposeless or even bizarre movements. Catatonic symptoms can also occur in schizophrenia or a manic episode, or can be due to neuroleptic malignant syndrome.Postpartum depression (PPD) is listed as a course specifier in DSM-IV-TR; it refers to the intense, sustained and sometimes disabling depression experienced by women after giving birth. Postpartum depression, which affects 10–15% of women, typically sets in within three months of labor, and lasts as long as three months. It is quite common for women to experience a short-term feeling of tiredness and sadness in the first few weeks after giving birth; however, postpartum depression is different because it can cause significant hardship and impaired functioning at home, work, or school as well as, possibly, difficulty in relationships with family members, spouses, or friends, or even problems bonding with the newborn. In the treatment of postpartum major depressive disorders and other unipolar depressions in women who are breastfeeding, nortriptyline, paroxetine (Paxil), and sertraline (Zoloft) are in general considered to be the preferred medications. Women with personal or family histories of mood disorders are at particularly high risk of developing postpartum depression.Premenstrual dysphoric disorder (PMDD) is a severe and disabling form of premenstrual syndrome affecting 3–8% of menstruating women. The disorder consists of a "cluster of affective, behavioral and somatic symptoms" that recur monthly during the luteal phase of the menstrual cycle. PMDD was added to the list of depressive disorders in the Diagnostic and Statistical Manual of Mental Disorders in 2013. The exact pathogenesis of the disorder is still unclear and is an active research topic. Treatment of PMDD relies largely on antidepressants that modulate serotonin levels in the brain via serotonin reuptake inhibitors as well as ovulation suppression using contraception.Seasonal affective disorder (SAD), also known as "winter depression" or "winter blues", is a specifier. Some people have a seasonal pattern, with depressive episodes coming on in the autumn or winter, and resolving in spring. The diagnosis is made if at least two episodes have occurred in colder months with none at other times over a two-year period or longer. It is commonly hypothesised that people who live at higher latitudes tend to have less sunlight exposure in the winter and therefore experience higher rates of SAD, but the epidemiological support for this proposition is not strong (and latitude is not the only determinant of the amount of sunlight reaching the eyes in winter). It is said that this disorder can be treated by light therapy. SAD is also more prevalent in people who are younger and typically affects more females than males.Dysthymia is a condition related to unipolar depression, where the same physical and cognitive problems are evident, but they are not as severe and tend to last longer (usually at least 2 years). The treatment of dysthymia is largely the same as for major depression, including antidepressant medications and psychotherapy.Double depression can be defined as a fairly depressed mood (dysthymia) that lasts for at least two years and is punctuated by periods of major depression.Unspecified Depressive Disorder is designated by the code 311 for depressive disorders. In the DSM-5, Unspecified Depressive Disorder encompasses symptoms that are characteristic of depressive disorders and cause significant impairment in functioning, but do not meet the criteria for the diagnosis of any specified depressive disorders. In the DSM-IV, this was called Depressive Disorder Not Otherwise Specified.Depressive personality disorder (DPD) is a controversial psychiatric diagnosis that denotes a personality disorder with depressive features. Originally included in the DSM-II, depressive personality disorder was removed from the DSM-III and DSM-III-R. Recently, it has been reconsidered for reinstatement as a diagnosis. Depressive personality disorder is currently described in Appendix B in the DSM-IV-TR as worthy of further study.Recurrent brief depression (RBD), distinguished from major depressive disorder primarily by differences in duration. People with RBD have depressive episodes about once per month, with individual episodes lasting less than two weeks and typically less than 2–3 days. Diagnosis of RBD requires that the episodes occur over the span of at least one year and, in female patients, independently of the menstrual cycle. People with clinical depression can develop RBD, and vice versa, and both illnesses have similar risks.Minor depressive disorder, or simply minor depression, which refers to a depression that does not meet full criteria for major depression but in which at least two symptoms are present for two weeks.
Bipolar disorders
Bipolar disorder (BD) (also called "manic depression" or "manic-depressive disorder"), an unstable emotional condition characterized by cycles of abnormal, persistent high mood (mania) and low mood (depression), which was formerly known as "manic depression" (and in some cases rapid cycling, mixed states, and psychotic symptoms). Subtypes include:Bipolar I is distinguished by the presence or history of one or more manic episodes or mixed episodes with or without major depressive episodes. A depressive episode is not required for the diagnosis of Bipolar I Disorder, but depressive episodes are usually part of the course of the illness.
Bipolar II consisting of recurrent intermittent hypomanic and depressive episodes or mixed episodes.
Cyclothymia is a form of bipolar disorder, consisting of recurrent hypomanic and dysthymic episodes, but no full manic episodes or full major depressive episodes.
Bipolar disorder not otherwise specified (BD-NOS), sometimes called "sub-threshold" bipolar, indicates that the patient has some symptoms in the bipolar spectrum (e.g., manic and depressive symptoms) but does not fully qualify for any of the three formal bipolar DSM-IV diagnoses mentioned above.
It is estimated that roughly 1% of the adult population has bipolar I, a further 1% has bipolar II or cyclothymia, and somewhere between 2% and 5% percent have "sub-threshold" forms of bipolar disorder. Furthermore, the possibility of getting bipolar disorder when one parent is diagnosed with it is 15–30%. Risk, when both parents have it, is 50–75%. Also, while with bipolar siblings the risk is 15–25%, with identical twins it is about 70%.A minority of people with bipolar disorder have high creativity, artistry or a particular gifted talent. Before the mania phase becomes too extreme, its energy, ambition, enthusiasm and grandiosity often bring people with this type of mood disorder lifes masterpieces.
Substance-induced
A mood disorder can be classified as substance-induced if its etiology can be traced to the direct physiologic effects of a psychoactive drug or other chemical substance, or if the development of the mood disorder occurred contemporaneously with substance intoxication or withdrawal. Also, an individual may have a mood disorder coexisting with a substance abuse disorder. Substance-induced mood disorders can have features of a manic, hypomanic, mixed, or depressive episode. Most substances can induce a variety of mood disorders. For example, stimulants such as amphetamine, methamphetamine, and cocaine can cause manic, hypomanic, mixed, and depressive episodes.
Alcohol-induced
High rates of major depressive disorder occur in heavy drinkers and those with alcoholism. Controversy has previously surrounded whether those who abused alcohol and developed depression were self-medicating their pre-existing depression. Recent research has concluded that, while this may be true in some cases, alcohol misuse directly causes the development of depression in a significant number of heavy drinkers. Participants studied were also assessed during stressful events in their lives and measured on a Feeling Bad Scale. Likewise, they were also assessed on their affiliation with deviant peers, unemployment, and their partners substance use and criminal offending. High rates of suicide also occur in those who have alcohol-related problems. It is usually possible to differentiate between alcohol-related depression and depression that is not related to alcohol intake by taking a careful history of the patient. Depression and other mental health problems associated with alcohol misuse may be due to distortion of brain chemistry, as they tend to improve on their own after a period of abstinence.
Benzodiazepine-induced
Benzodiazepines, such as alprazolam, clonazepam, lorazepam and diazepam, can cause both depression and mania.Benzodiazepines are a class of medication commonly used to treat anxiety, panic attacks and insomnia, and are also commonly misused and abused. Those with anxiety, panic and sleep problems commonly have negative emotions and thoughts, depression, suicidal ideations, and often have comorbid depressive disorders. While the anxiolytic and hypnotic effects of benzodiazepines disappear as tolerance develops, depression and impulsivity with high suicidal risk commonly persist. These symptoms are "often interpreted as an exacerbation or as a natural evolution of previous disorders and the chronic use of sedatives is overlooked". Benzodiazepines do not prevent the development of depression, can exacerbate preexisting depression, can cause depression in those with no history of it, and can lead to suicide attempts. Risk factors for suicide and suicide attempts while using benzodiazepines include high dose prescriptions (even in those not misusing the medications), benzodiazepine intoxication, and underlying depression.The long-term use of benzodiazepines may have a similar effect on the brain as alcohol, and are also implicated in depression. As with alcohol, the effects of benzodiazepine on neurochemistry, such as decreased levels of serotonin and norepinephrine, are believed to be responsible for the increased depression. Additionally, benzodiazepines can indirectly worsen mood by worsening sleep (i.e., benzodiazepine-induced sleep disorder). Like alcohol, benzodiazepines can put people to sleep but, while asleep, they disrupt sleep architecture: decreasing sleep time, delaying time to REM sleep, and decreasing deep sleep (the most restorative part of sleep for both energy and mood). Just as some antidepressants can cause or worsen anxiety in some patients due to being activating, benzodiazepines can cause or worsen depression due to being a central nervous system depressant—worsening thinking, concentration and problem solving (i.e., benzodiazepine-induced neurocognitive disorder). However, unlike antidepressants, in which the activating effects usually improve with continued treatment, benzodiazepine-induced depression is unlikely to improve until after stopping the medication.In a long-term follow-up study of patients dependent on benzodiazepines, it was found that 10 people (20%) had taken drug overdoses while on chronic benzodiazepine medication despite only two people ever having had any pre-existing depressive disorder. A year after a gradual withdrawal program, no patients had taken any further overdoses.Just as with intoxication and chronic use, benzodiazepine withdrawal can also cause depression. While benzodiazepine-induced depressive disorder may be exacerbated immediately after discontinuation of benzodiazepines, evidence suggests that mood significantly improves after the acute withdrawal period to levels better than during use. Depression resulting from withdrawal from benzodiazepines usually subsides after a few months but in some cases may persist for 6–12 months.
Due to another medical condition
"Mood disorder due to a general medical condition" is used to describe manic or depressive episodes which occur secondary to a medical condition. There are many medical conditions that can trigger mood episodes, including neurological disorders (e.g. dementias), metabolic disorders (e.g. electrolyte disturbances), gastrointestinal diseases (e.g. cirrhosis), endocrine disease (e.g. thyroid abnormalities), cardiovascular disease (e.g. heart attack), pulmonary disease (e.g. chronic obstructive pulmonary disease), cancer, and autoimmune diseases (e.g. multiple sclerosis).
Not otherwise specified
Mood disorder not otherwise specified (MD-NOS) is a mood disorder that is impairing but does not fit in with any of the other officially specified diagnoses. In the DSM-IV MD-NOS is described as "any mood disorder that does not meet the criteria for a specific disorder." MD-NOS is not used as a clinical description but as a statistical concept for filing purposes. The diagnosis of MD-NOS does not exist in the DSM-5, however the diagnoses of unspecified depressive disorder and unspecified bipolar disorder are in the DSM-5.Most cases of MD-NOS represent hybrids between mood and anxiety disorders, such as mixed anxiety-depressive disorder or atypical depression. An example of an instance of MD-NOS is being in minor depression frequently during various intervals, such as once every month or once in three days. There is a risk for MD-NOS not to get noticed, and for that reason not to get treated.
Causes
Meta-analyses show that high scores on the personality domain neuroticism are a strong predictor for the development of mood disorders. A number of authors have also suggested that mood disorders are an evolutionary adaptation (see also evolutionary psychiatry). A low or depressed mood can increase an individuals ability to cope with situations in which the effort to pursue a major goal could result in danger, loss, or wasted effort. In such situations, low motivation may give an advantage by inhibiting certain actions. This theory helps to explain why negative life incidents precede depression in around 80 percent of cases, and why they so often strike people during their peak reproductive years. These characteristics would be difficult to understand if depression were a dysfunction.A depressed mood is a predictable response to certain types of life occurrences, such as loss of status, divorce, or death of a child or spouse. These are events that signal a loss of reproductive ability or potential, or that did so in humans ancestral environment. A depressed mood can be seen as an adaptive response, in the sense that it causes an individual to turn away from the earlier (and reproductively unsuccessful) modes of behavior.A depressed mood is common during illnesses, such as influenza. It has been argued that this is an evolved mechanism that assists the individual in recovering by limiting their physical activity. The occurrence of low-level depression during the winter months, or seasonal affective disorder, may have been adaptive in the past, by limiting physical activity at times when food was scarce. It is argued that humans have retained the instinct to experience low mood during the winter months, even if the availability of food is no longer determined by the weather.Much of what is known about the genetic influence of clinical depression is based upon research that has been done with identical twins. Identical twins have exactly the same genetic code. It has been found that when one identical twin becomes depressed the other will also develop clinical depression approximately 76% of the time. When identical twins are raised apart from each other, they will both become depressed about 67% of the time. Because both twins become depressed at such a high rate, the implication is that there is a strong genetic influence. If it happened that when one twin becomes clinically depressed the other always develops depression, then clinical depression would likely be entirely genetic.Bipolar disorder is also considered a mood disorder and it is hypothesized that it might be caused by mitochondrial dysfunction.
Sex differences
Mood disorders, specifically stress-related mood disorders such as anxiety and depression, have been shown to have differing rates of diagnosis based on sex. In the United States, women are two times more likely than men to be diagnosed with a stress-related mood disorder. Underlying these sex differences, studies have shown a dysregulation of stress-responsive neuroendocrine function causing an increase in the likelihood of developing these affective disorders. Overactivation of the hypothalamic-pituitary-adrenal (HPA) axis could provide potential insight into how these sex differences arise. Neuropeptide corticotropin-releasing factor (CRF) is released from the paraventricular nucleus (PVN) of the hypothalamus, stimulating adrenocorticotropic hormone (ACTH) release into the blood stream. From here ACTH triggers the release of glucocorticoids such as cortisol from the adrenal cortex. Cortisol, known as the main stress hormone, creates a negative feedback loop back to the hypothalamus to deactivate the stress response. When a constant stressor is present, the HPA axis remains overactivated and cortisol is constantly produced. This chronic stress is associated with sustained CRF release, resulting in the increased production of anxiety- and depressive-like behaviors and serving as a potential mechanism for differences in prevalence between men and women.
Diagnosis
DSM-5
The DSM-5, released in May 2013, separates the mood disorder chapter from the DSM-TR-IV into two sections: Depressive and related disorders and bipolar and related disorders. Bipolar disorders fall in between depressive disorders and schizophrenia spectrum and related disorders "in recognition of their place as a bridge between the two diagnostic classes in terms of symptomatology, family history and genetics" (Ref. 1, p 123). Bipolar disorders underwent a few changes in the DSM-5, most notably the addition of more specific symptomology related to hypomanic and mixed manic states. Depressive disorders underwent the most changes, the addition of three new disorders: disruptive mood dysregulation disorder, persistent depressive disorder (previously dysthymia), and premenstrual dysphoric disorder (previously in appendix B, the section for disorders needing further research). Disruptive mood dysregulation disorder is meant as a diagnosis for children and adolescents who would normally be diagnosed with bipolar disorder as a way to limit the bipolar diagnosis in this age cohort. Major depressive disorder (MDD) also underwent a notable change, in that the bereavement clause has been removed. Those previously exempt from a diagnosis of MDD due to bereavement are now candidates for the MDD diagnosis.
Treatment
There are different types of treatments available for mood disorders, such as therapy and medications. Behaviour therapy, cognitive behaviour therapy and interpersonal therapy have all shown to be potentially beneficial in depression. Major depressive disorder medications usually include antidepressants; a combination of antidepressants and cognitive behavioral therapy has shown to be more effective than one treatment alone. Bipolar disorder medications can consist of antipsychotics, mood stabilizers, anticonvulsants and/or lithium. Lithium specifically has been proven to reduce suicide and all causes of mortality in people with mood disorders. If mitochondrial dysfunction or mitochondrial diseases are the cause of mood disorders like bipolar disorder, then it has been hypothesized that N-acetyl-cysteine (NAC), acetyl-L-carnitine (ALCAR), S-adenosylmethionine (SAMe), coenzyme Q10 (CoQ10), alpha-lipoic acid (ALA), creatine monohydrate (CM), and melatonin could be potential treatment options. In determining treatment, there are many types of depression scales that are used. One of the depression scales is a self-report scale called Beck Depression Inventory (BDI). Another scale is the Hamilton Depression Rating Scale (HAMD). HAMD is a clinical rating scale in which the patient is rated based on clinician observation. The Center for Epidemiologic Studies Depression Scale (CES-D) is a scale for depression symptoms that applies to the general population. This scale is typically used in research and not for self-reports. The PHQ-9 which stands for Patient-Health Questionnaire-9 questions, is a self-report as well. Finally, the Mood Disorder Questionnaire (MDQ) evaluates bipolar disorder.
Epidemiology
According to a substantial number of epidemiology studies conducted, women are twice as likely to develop certain mood disorders, such as major depression. Although there is an equal number of men and women diagnosed with bipolar II disorder, women have a slightly higher frequency of the disorder.The prevalence of depressive symptoms has increased over the years with recent generations reporting a 6% increase in symptoms of depression compared to individuals from older generations.In 2011, mood disorders were the most common reason for hospitalization among children aged 1–17 years in the United States, with approximately 112,000 stays. Mood disorders were top principal diagnosis for Medicaid super-utilizers in the United States in 2012. Further, a study of 18 States found that mood disorders accounted for the highest number of hospital readmissions among Medicaid patients and the uninsured, with 41,600 Medicaid patients and 12,200 uninsured patients being readmitted within 30 days of their index stay—a readmission rate of 19.8 per 100 admissions and 12.7 per 100 admissions, respectively. In 2012, mood and other behavioral health disorders were the most common diagnoses for Medicaid-covered and uninsured hospital stays in the United States (6.1% of Medicaid stays and 5.2% of uninsured stays).A study conducted in 1988 to 1994 amongst young American adults involved a selection of demographic and health characteristics. A population-based sample of 8,602 men and women ages 17–39 years participated. Lifetime prevalence were estimated based on six mood measures:
major depressive episode (MDE) 8.6%,
major depressive disorder with severity (MDE-s) 7.7%,
dysthymia 6.2%,
MDE-s with dysthymia 3.4%,
any bipolar disorder 1.6%, and
any mood disorder 11.5%.
Research
Kay Redfield Jamison and others have explored the possible links between mood disorders – especially bipolar disorder – and creativity. It has been proposed that a "ruminating personality type may contribute to both [mood disorders] and art."Jane Collingwood notes an Oregon State University study that
"looked at the occupational status of a large group of typical patients and found that those with bipolar illness appear to be disproportionately concentrated in the most creative occupational category. They also found that the likelihood of engaging in creative activities on the job is significantly higher for bipolar than nonbipolar workers".In Liz Patereks article "Bipolar Disorder and the Creative Mind" she wrote
"Memory and creativity are related to mania. Clinical studies have shown that those in a manic state will rhyme, find synonyms, and use alliteration more than controls. This mental fluidity could contribute to an increase in creativity. Moreover, mania creates increases in productivity and energy. Those in a manic state are more emotionally sensitive and show less inhibition about attitudes, which could create greater expression. Studies performed at Harvard looked into the amount of original thinking in solving creative tasks. Bipolar individuals, whose disorder was not severe, tended to show greater degrees of creativity".The relationship between depression and creativity appears to be especially strong among poets.
See also
Personality disorder
References
Cited textsAmerican Psychiatric Association (2000). Diagnostic and statistical manual of mental disorders, Fourth Edition, Text Revision: DSM-IV-TR. Washington, DC: American Psychiatric Publishing, Inc. ISBN 978-0-89042-025-6.
American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders, Fifth Edition, Text Revision: DSM-5. Washington, DC: American Psychiatric Association, Inc. ISBN 978-0-89042-554-1.
Carlson, Neil R.; Heth, C. Donald (2007). Psychology the science of behaviour (4th ed.). Pearson Education Inc. ISBN 978-0-205-64524-4.
Collier, Judith; Longmore, Murray (2003). "4". In Scally, Peter (ed.). Oxford Handbook of Clinical Specialties (6th ed.). Oxford University Press. ISBN 978-0-19-852518-9.
Nesse, Randolphe M.; Williams, George C. (1994). Why We Get Sick: The New Science of Darwinian Medicine. Vintage Books. ISBN 0-8129-2224-7.
Nolen-Hoeksema, S (2013). Abnormal Psychology (6th ed.). McGraw-Hill Higher Education. ISBN 9780077499693. Retrieved 5 December 2014.
Parker, Gordon; Hadzi-Pavlovic, Dusan; Eyers, Kerrie (1996). Melancholia: A disorder of movement and mood: a phenomenological and neurobiological review. Cambridge: Cambridge University Press. ISBN 978-0-521-47275-3.
Sadock, Benjamin J.; Sadock, Virginia A. (2002). Kaplan and Sadocks Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry (9 |
Mood disorder | th ed.). Lippincott Williams & Wilkins. ISBN 978-0-7817-3183-6.
Semple, David; Smyth, Roger; Burns, Jonathan; Darjee, Rajan; McIntosh, Andrew (2007) [2005]. "13". Oxford Handbook of Psychiatry. Oxford University Press. ISBN 978-0-19-852783-1.
Sartorius, Norman (1993). "The ICD-10 Classification of Mental and Behavioural Disorders – Clinical descriptions and diagnostic guidelines" (PDF). www.who.int. World Health Organization. Retrieved 3 July 2021.{{cite web}}: CS1 maint: url-status (link)
Schacter, Daniel L.; Gilbert, Daniel T.; Wegner, Daniel M. (2011). "Chapter 14: Psychological Disorders". Psychology (2nd ed.). Worth Publishers. ISBN 9781429237192.
External links
Media related to Mood disorders at Wikimedia Commons |
Lymphangioleiomyomatosis | Lymphangioleiomyomatosis (LAM) is a rare, progressive and systemic disease that typically results in cystic lung destruction. It predominantly affects women, especially during childbearing years. The term sporadic LAM is used for patients with LAM not associated with tuberous sclerosis complex (TSC), while TSC-LAM refers to LAM that is associated with TSC.
Signs and symptoms
The average age of onset is the early to mid 30s. Exertional dyspnea (shortness of breath) and spontaneous pneumothorax (lung collapse) have been reported as the initial presentation of the disease in 49% and 46% of patients, respectively.Diagnosis is typically delayed 5 to 6 years. The condition is often misdiagnosed as asthma or chronic obstructive pulmonary disease. The first pneumothorax, or lung collapse, precedes the diagnosis of LAM in 82% of patients. The consensus clinical definition of LAM includes multiple symptoms:
Fatigue
Cough
Coughing up blood (rarely massive)
Chest pain
Chylous complications arising from lymphatic obstruction, including
Chylothorax
Chylous ascites
Chylopericardium
Chyloptysis
Chyluria
Chyle in vaginal discharge
Chyle in stool.
Angiomyolipomas (fatty kidney tumors) are present in about 30% of patients with sporadic LAM and up to 90% of patients with TSC-LAM. Angiomyolipomas can sometimes spontaneously bleed, causing pain or low blood pressure.
Cystic lymphangiomas or lymph nodes with hypodense centers, which mimic necrotizing lymphomas, ovarian or renal cancers, or other malignancies can occur in the retroperitoneum, pelvis or mediastinum.Lung destruction in LAM is a consequence of diffuse infiltration by neoplastic smooth muscle-like cells that invade all lung structures including the lymphatics, airway walls, blood vessels and interstitial spaces. The consequences of vessel and airway obstruction include chylous fluid accumulations, hemoptysis, airflow obstruction and pneumothorax. The typical disease course displays progressive dyspnea on exertion, spaced by recurrent pneumothoraces and in some patients, chylous pleural effusions or ascites.Most people have dyspnea on exertion with daily activities by 10 years after symptom onset. Many patients require supplemental oxygen over that interval.
Genetics
LAM occurs in two settings: in the disease tuberous sclerosis complex (TSC-LAM) and in a sporadic form, in women who do not have TSC (sporadic LAM). In both settings, genetic evidence indicates that LAM is caused by inactivating or “loss of function” mutations in the TSC1 or TSC2 genes, which were cloned in 1997 and 1993 respectively. The TSC1 gene is located on the long arm of chromosome 9 (9q34) and the TSC2 gene is located on the short arm of chromosome 16 (16p13). TSC-LAM occurs in women who have germline mutations in either the TSC1 or the TSC2 gene.Sporadic LAM is primarily associated with somatic TSC2 gene mutations. Germline and somatic mutations in LAM include many types of mutations spread across the genes, with no clear “hot spots,” including missense changes, in-frame deletions and nonsense mutations. Because of the large size of the genes (together they have more than 60 exons) and because mutations can be located virtually anywhere within the genes, mutation detection is often challenging.On a cellular basis, LAM cells carry bi-allelic inactivation of the TSC2 genes, consistent with the “two-hit” tumor suppressor gene model. The second hit event in LAM cells is often loss of the chromosomal region containing the wild-type copy of the TSC2 gene; this is referred to as loss of heterozygosity or LOH. LOH can be detected in microdissected LAM cells, in angiomyolipomas and lymph nodes from women with LAM, and in circulating LAM cells (cells in blood and urine).Angiomyolipomas and pulmonary LAM cells from women with the sporadic form of LAM carry identical mutations in TSC2. This, together with the fact that recurrent LAM after lung transplantation carries the same TSC2 mutations as the original LAM, has led to the "benign metastasis" hypothesis that LAM cells can migrate or metastasize from one site to another.
Pathophysiology
A variable percentage of cells within the LAM lesion contain mutational inactivation of the tuberous sclerosis complex (TSC1 or TSC2) tumor suppressor genes. TSC1 mutations cause a less severe clinical phenotype than TSC2 mutations. The discovery of TSC1/2 gene function as negative regulator of the mammalian target of rapamycin complex 1 (mTORC1) led to successful use of rapamycin analog sirolimus in clinical trials and FDA approval of sirolimus for treatment of LAM.
TSC1 and TSC2 form a tumor suppressor complex that regulates mammalian target of rapamycin (mTOR) signaling complex by directly controlling the activity of the small GTPase Rheb via the GTPase activating protein (GAP) domain of TSC2. Rheb binds to Raptor and controls the activity of mTOR complex 1 (mTORC1) that directly phosphorylates p70 S6 kinase (S6K1) and 4E-BP1. mTOR forms two physically and functionally distinct multiprotein complexes: the rapamycin-sensitive mTORC1 and the rapamycin-insensitive mTORC2. MTORC1 consists of five proteins including Raptor that positively regulate mTOR activity. MTORC2 consists of six proteins including mTOR and Rictor, which defines the activation level of mTORC2 and modulates the assembly of the actin cytoskeleton through Rho GTPases, and Rac1 is required for mTOR activation. In TSC2-null and human LAM cells, Rho GTPase activity is required for cell adhesion, motility, proliferation and survival. Loss of TSC1/TSC2 in LAM induces uncontrolled LAM cell growth and increases LAM cell viability. Upregulation of STAT1 and STAT3 and autophagy are known mediators of LAM cell viability and survival.
LAM cells behave, in many ways, like metastatic tumor cells. LAM cells appear to arise from an extrapulmonary source and migrate to the lung. Increased LAM cell migration and invasiveness is rescued by TSC2 re-expression. The cellular and molecular mechanisms of neoplastic transformation and lung parenchymal destruction by LAM cells remain unknown. Lung remodeling may be mediated by an imbalance between matrix degrading metalloproteinases (MMPs) and their endogenous inhibitors TIMPs. The invasive cell phenotype in LAM is associated with TIMP-3 downregulation and TSC2-dependent upregulation of MMPs.Clinical and histopathological evidence demonstrate the lymphatic involvement in LAM. The prevailing hypothesis is that LAM lesions secrete the lymphangiogenic factor VEGF-D, recruit lymphatic endothelial cells (LECs) that form lymphatic vessels and induce lung cysts. VEGF-D serum levels are increased in LAM compared to other cystic lung diseases, including pulmonary Langerhans cell histiocytosis, emphysema, Sjögrens syndrome, or Birt–Hogg–Dubé syndrome. VEGF-D levels correlate with the severity of LAM, evaluated as a measure of CT grade (the abundance of chylous effusions and lymphatic involvement). VEGF-D is a secreted homodimeric glycoprotein and a member of the VEGF family of growth factors, is known for its role in cancer lymphangiogenesis and metastasis. Proteolytic processing of VEGF-D affects cognate binding to VEGFR3. Histopathologically, LAM lesions are surrounded by cells that stain for VEGFR3, the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) and podoplanin. VEGF-D binds to the receptor protein tyrosine kinases VEGFR-2 and VEGFR-349 in humans, and to VEGFR3 in mice. Surprisingly, knock-out of VEGF-D in mice has little effect on lymphatic system development. Nevertheless, during tumorigenesis VEGF-D promotes formation of tumor lymphatic vessels and facilitates metastatic spread of cancer cells. However, little is known about a role of abnormal lymphatics and VEGF-D in LAM pathogenesis.
Diagnosis
LAM can come to medical attention in several ways, most of which trigger a chest CT. Thin-walled cystic change in the lungs may be found incidentally on CT scans of the heart, chest or abdomen (on the cuts that include lung bases) obtained for other purposes. HRCTs of TSC patients reveals that about 20% of women have cystic change by age 20 and about 80% of women have cystic changes after age 40. LAM is sometimes revealed by chest CT in patients who present with an apparent primary spontaneous pneumothorax, but more often CT scanning is not ordered (in the United States) until recurrences occur. Progressive dyspnea on exertion without the exacerbations and remissions that are characteristic of asthma or COPD sometimes prompt a chest CT. A review of the CT by an expert familiar with LAM may increase diagnostic accuracy. Chylothorax can also bring LAM to attention.
In some cases, a LAM diagnosis can be made with confidence on clinical grounds (without biopsy) in patients with typical cystic changes on high resolution CT scanning of the lung and findings of tuberous sclerosis, angiomyolipoma, lymphangioleiomyoma, chylothorax or serum VEGF-D > 800 pg/ml.If none of these clinical features are present, a biopsy may be necessary to make the diagnosis. Video-assisted thoracoscopic lung biopsy is the most definitive technique, but transbronchial biopsy has a yield of over 50% and can also be effective. The safety of the latter procedure in patients with diffuse cystic disease and the profusion of cystic change that predicts an informative biopsy are incompletely understood, however. Cytology of chylous fluids, aspirated abdominal nodes or lymphatic masses can also be diagnostic.
Diagram 1 outlines a proposed algorithm for the diagnosis of LAM.
Chest radiograph
The chest radiograph may appear relatively normal, even late in the disease, or may suggest hyperinflation only. As the disease progresses, the chest radiograph often demonstrates diffuse, bilateral and symmetric reticulonodular opacities, cysts, bullae or a "honeycomb" (i.e., pseudo fibrotic) appearance. Pleural effusion and pneumothorax may be apparent. Preservation of lung volumes in the presence of increased interstitial markings is a radiographic hallmark of LAM that helps distinguish it from most other interstitial lung diseases, in which alveolar septal and interstitial expansion tend to increase the lungs elastic recoil properties and decreased lung volumes.
Computed tomography
The high-resolution computed tomography (HRCT) chest scan is better than the chest radiograph to detect cystic parenchymal disease and is almost always abnormal at the time of diagnosis, even when the chest radiograph and pulmonary function assessments are normal. The typical CT shows diffuse round, bilateral, thin-walled cysts of varying sizes ranging from 1 to 45 mm in diameter. The numbers of cysts varies in LAM from a few to almost complete replacement of normal lung tissue. The profusion of cysts tends to be milder in patients with TSC-LAM than S-LAM, perhaps explained in part because TSC-LAM patients typically receive earlier screening. Pleural effusions are seen on CT in 12% of patients with S-LAM and 6% of patients with TSC-LAM. Other CT features include linear densities (29%), hilar or mediastinal lymphadenopathy (9%), pneumothorax, lymphangiomyoma, and thoracic duct dilation. Ground-glass opacities (12%) suggest the presence of interstitial edema due to lymphatic congestion. In patients with TSC, nodular densities on HRCT may represent multifocal micronodular pneumocyte hyperplasia (MMPH) made up of clusters of hyperplastic type II pneumocytes. MMPH may be present in males or females with TSC in the presence or absence of LAM, but not in patients with S-LAM. MMPH is not typically associated with physiologic or prognostic consequences, but one case of respiratory failure due to MMPH has been reported.
Ventilation-perfusion scans
In one study ventilation-perfusion scans were abnormal in 34 of 35 LAM patients. The most common abnormality was nonspecific diffuse heterogeneity, usually grossly matched. These authors also described an “unusual,” “speckling pattern” on the perfusion images in 74% of patients, consisting of “small, often peripheral collections of radioisotope.”
Positron emission tomography
LAM and AML lesions do not typically exhibit increased uptake of 18F-fluorodeoxyglucose on positron emission tomography (PET) scanning. Other neoplasms (or sources of inflammation) should therefore be considered in known or suspected LAM cases in which FDG-PET results are positive.
Abdominal imaging
Abnormalities on abdominal imaging, such as renal AML and enlarged lymphatic structures, are also common in LAM. Fat density within a renal mass is pathognomonic of AMLs. AMLs are more prevalent and more frequently bilateral and large in patients with TSC-LAM than in patients with S-LAM. AML size correlates with the prevalence of pulmonary cysts in patients with TSC. One study CT imaged 256 patients with S-LAM and 67 with TSC-LAM. Renal AMLs were present in 32% of patients with S-LAM and 93% of patients with TSC-LAM. Hepatic AMLs were present in 2% of patients with S-LAM and 33% of patients with TSC-LAM. Ascites was uncommon, seen in fewer than 10% of patients with LAM. Abdominal lymphangiomatosis, often containing both cystic and solid components, were seen in 29% of patients with S-LAM and 9% of patients with TSC-LAM.
Central nervous system imaging
Central nervous system abnormalities, such as cortical or subependymal tubers and astrocytomas, are common in patients with TSC, including those with TSC-LAM, but are not found in women with S-LAM. Moss and associates reported that women with S-LAM and TSC-LAM may have an increased incidence of meningioma, but the significance of that finding has been challenged.
Pulmonary function studies
Pulmonary function testing in patients with LAM may be normal or may reveal obstructive, restrictive or mixed patterns. Obstructive physiology is the most common abnormality. Quality-controlled lung function data were collected prospectively by the NHLBI Registry, a 5-year study of patients with LAM in centers around the United States. Spirometry revealed obstructive changes in about 57% of patients and normal results in 34%. Restriction, defined as a total lung capacity less than the lower limit of normal, was seen in 11%. Hyperinflation was present in about 6%. The average residual volume was 125% of predicted when measured by plethysmography, but was only 103% of predicted determined with gas dilution methods, suggesting significant air trapping in noncommunicating airspaces. Approximately 25% of patients with obstructive physiology may demonstrate bronchodilator responsiveness but may be less in more severe obstruction. The obstructive physiologic defect in LAM is primarily attributable to airflow obstruction. The earliest change in initial pulmonary function testing in various case series was abnormal gas transfer, as assessed by the diffusing capacity for carbon monoxide (DLCO), described in 82% to 97% of patients. It is not unusual for DLCO to be reduced out of proportion to forced expiratory volume in 1 second (FEV1). Reduction in DLCO and increase in residual volume are generally considered to be LAMs earliest physiologic manifestations.Cardiopulmonary exercise testing in a much larger cohort of patients with LAM revealed a reduced maximal oxygen consumption (VO2 max) and anaerobic threshold in 217 patients. Exercise-induced hypoxemia was found even in patients who did not have resting abnormalities in FEV1 and DLCO. In most patients, exercise was thought to be ventilation limited, owing to airflow obstruction and increased dead-space ventilation.Disease progression is usually accompanied by a progressive obstructive ventilatory defect. Decline in FEV1 is the most commonly used parameter to monitor disease progression. Although resting pulmonary hypertension appears to be unusual in LAM, pulmonary arterial pressure often rises with low levels of exercise, related in part to hypoxemia. One study reported an increase in intraparenchymal shunts in dyspneic patients with LAM, which may contribute to resting and exercise hypoxemia.
Pathology
Grossly, LAM lungs are enlarged and diffusely cystic, with dilated air spaces as large as several centimeters in diameter. Microscopic examination of the lung reveals foci of smooth muscle-like cell infiltration of the lung parenchyma, airways, lymphatics, and blood vessels associated with areas of thin-walled cystic change. LAM lesions often contain an abundance of lymphatic channels, forming an anastomosing meshwork of slit-like spaces lined by endothelial cells. LAM cells generally expand interstitial spaces without violating tissue planes but have been observed to invade the airways, the pulmonary artery, the diaphragm, aorta, and retroperitoneal fat, to destroy bronchial cartilage and arteriolar walls, and to occlude the lumen of pulmonary arterioles.There are two major cell morphologies in the LAM lesion: small spindle-shaped cells and cuboidal epithelioid cells. LAM cells stain positively for smooth muscle actin, vimentin, desmin, and, often, estrogen and progesterone receptors. The cuboidal cells within LAM lesions also react with a monoclonal antibody called HMB-45, developed against the premelanosomal protein gp100, an enzyme in the melanogenesis pathway. This immunohistochemical marker is very useful diagnostically, because other smooth muscle–predominant lesions in the lung do not react with the antibody. The spindle-shaped cells of the LAM lesion are more frequently proliferating cell nuclear antigen positive than the cuboidal cells, consistent with a proliferative phenotype. Compared with cigar-shaped normal smooth muscle cells, spindle-shaped LAM cells contain less abundant cytoplasm and are less eosinophilic. Estrogen and progesterone receptors are also present in LAM lesions, but not in adjacent normal lung tissue. LAM lesions express lymphatic markers LYVE-1, PROX1, podoplanin and VEGFR-3. The smooth muscle–like cells of AMLs are morphologically and immunohistochemically similar to LAM cells, including reactivity with antibodies directed against actin, desmin, vimentin, and HMB-45 as well as estrogen and progesterone receptors. Unlike the dilated airspaces in emphysema, the cystic spaces found in LAM may be partially lined with hyperplastic type II cells.
Treatment
An FDA-approved drug for treatment of LAM, the mTOR inhibitor sirolimus, is available for stabilization of lung function decline. Lung transplant remains the last resort for patients with advanced disease.
Pneumothorax
Pneumothoraces in LAM patients tend to recur, especially after conservative management such as observation, aspiration or simple tube thoracostomy. Over 65% of LAM patients develop pneumothorax during the course of their illness, averaging 3.5 pneumothoraces in those who have at least one pneumothorax. The LAM Foundation Pleural Consensus Group advocated the use of a pleural symphysis procedure with the first pneumothorax, given the greater than 70% chance of recurrence. Chemical sclerosis, mechanical abrasion, talc poudrage and pleurectomy have been effective in patients with LAM, but mechanical abrasion is preferred for those who may require pulmonary transplantation in the future. About half of LAM patients who have undergone transplant have had a prior pleurodesis procedure, and more than 75% of those had had prior bilateral pleurodesis. Although pleurodesis is not a contraindication to transplantation, it can result in increased perioperative bleeding.
Chylothorax
Chyle does not generally cause pleural inflammation or fibrosis. Small stable chylous effusions rarely require intervention once the LAM diagnosis is made. Shortness of breath may mandate possibly repeated drainage. Sirolimus is effective for chylous effusions and most experts believe it should be used as the first line of therapy. Imaging the source of the leak with heavy T2-weighted MRI or contrast lymphangiography is an advised for refractory effusions. Some leaks are amenable to embolization through catheters threaded from groin lymph nodes into the thoracic duct. Thoracic duct ligation can be considered, but since thoracic effusions sometimes originate from ascites that are siphoned into the chest by the bellows action of the thorax, it is important to rule out an abdominal source before considering this option. Pleural symphysis may be required to prevent nutritional and lymphocyte deficiencies that can result from repeated taps or persistent drainage. Chemical pleurodesis is generally an effective therapy for chylothorax, as is mechanical abrasion and talc poudrage.
Angiomyolipoma
Renal angiomyolipomas (AMLs) may require embolization or cauterization for control of bleeding, a complication that is thought to be more common when tumor diameter exceeds 4 cm. The extent of aneurysmal change may determine bleeding risk. Serial abdominal imaging should be performed to assess AML size at 6- to 12-month intervals, at least until trends in growth are clear. Nephron sparing partial resections may be considered for very large tumors. Nephrectomy is sometimes required for tumors with intravascular extension or other reasons, but is rarely the approach of choice for AMLs that can be managed by less invasive means. Everolimus is approved by the U.S. Food and Drug Administration (FDA) for AML treatment.
Lymphangioleiomyoma
Lymphangioleiomyomatoses are fluid-filled hypodense structures present in the retroperitoneal regions of the abdomen and pelvis in about 30% of LAM patients. They generally do not require intervention. Biopsy or resection can lead to prolonged leakage. mTOR inhibitors are effective at shrinking the size of lymphangioleiomyomatosis, and can lead to total resolution.
Management-other
Estrogen-containing medications can exacerbate LAM and are contraindicated. Agents that antagonize the effects of estrogen have not been proven to be effective for treatment, but no proper trials have been done. A trial of bronchodilators should be considered in LAM patients, because up to 17% to 25% have bronchodilator-responsive airflow obstruction. Oxygen should be administered to maintain oxyhemoglobin saturations of greater than 90% with rest, exercise and sleep. Bone densitometry should be considered in all patients who are immobilized and/or on antiestrogen therapies, and appropriate therapy instituted for osteoporotic patients. Proper attention should be paid to cardiovascular health following natural or induced menopause. Immunizations for pneumococcus and influenza should be kept up to date. Pulmonary rehabilitation seems to be particularly rewarding in young, motivated patients with obstructive lung disease, but studies to assess this interventions effect on exercise tolerance, conditioning and quality of life have not been done.
Medication
Sirolimus is an mTOR inhibitor that stabilizes lung function and improves some measures of life in LAM patients. It is approved by the FDA for use in LAM, based on the results of the Multicenter International LAM Efficacy and Safety of Sirolimus (MILES) Trial. MILES data supports the use of sirolimus in patients who have abnormal lung function (i.e. FEV1<70% predicted). Whether the benefits of treatment outweigh the risks for asymptomatic LAM patients with normal lung function is not clear, but some physicians consider treatment for declining patients who are approaching the abnormal range for FEV1. Sirolimus also appears to be effective for the treatment chylous effusions and lymphangioleiomyomatosis. The benefits of sirolimus only persist while treatment continues. The safety of long term therapy has not been studied.Potential side effects from mTOR inhibitors include swelling in the ankles, acne, oral ulcers, dyspepsia, diarrhea, elevation of cholesterol and triglycerides, hypertension and headache. Sirolimus pneumonitis and latent malignancy are more serious concerns, but occur infrequently. Sirolimus inhibits wound healing. It is important to stop therapy with the drug for 1–2 weeks before and after elective procedures that require optimal wound healing. Precautions must be taken to avoid prolonged sun exposure due to increased skin cancer risk.Treatment with another mTOR inhibitor, everolimus, was reported in a small, open-label trial to be associated with improvement in FEV1 and six-minute walk distance. Serum levels of VEGF-D and collagen IV were reduced by treatment. Adverse events were generally consistent with those known to be associated with mTOR inhibitors, although some were serious and included peripheral edema, pneumonia, cardiac failure and Pneumocystis jirovecii infection. Escalating doses of everolimus were used, up to 10 mg per day; higher than what is typically used clinically for LAM.
Serum VEGF-D concentration is useful, predictive and prognostic biomarker. Higher baseline VEGF-D levels predicts more rapid disease progression and a more robust treatment response.
Hormonal approaches to treatment have never been tested in proper trials. In the absence of proven benefit, therapy with progesterone, GnRh agonists (e.g., leuprorelin, goserelin) and tamoxifen are not routinely recommended. Doxycycline had no effect on the rate of lung function decline in a double blind trial.Sirolimus is often effective as first-line management for chylothorax. If chylous leakage or accumulations persist despite treatment, imaging with heavy T2 weighted MRI, MRI lymphangiography or thoracic duct lymphangiography can be considered. Pleural fusion procedures can be considered in refractory cases.
Prognosis
Survival estimates vary, dependent on mode of presentation or ascertainment, and have generally trended upward, probably due to earlier recognition through more widespread use of CT scanning. In a recent population-based cohort survey, median survival was found to be 29 years. Data from earlier, large case series indicated that 38% to 78% of patients were alive at 8.5 years from the time of disease onset.Patients typically develop progressive airflow obstruction. In a cohort of patients in the United Kingdom, 10 years after symptom onset, 55% of 77 patients were breathless walking on flat ground and 10% were housebound. The average annual rate of decline in FEV1 and DLCO in 275 patients studied in a single pulmonary function laboratory at the NHLBI was 75 ± 9 mL, and 0.69 ± 0.07 mL/min/mm Hg, respectively. In other series from Europe, the rate of decline in FEV1 was considerably higher, estimated at approximately 100 to 120 mL/yr. In the MILES trial, patients in the placebo group lost 134 cc/yr. There was some evidence in these studies that rate of decline in lung |
Lymphangioleiomyomatosis | function correlates with initial DLCO, with menopausal status and high baseline VEGF-D.
Estimates of median survival vary from 10 to 30 years, depending on whether hospital-based or population-based cohorts are studied.
Epidemiology
LAM is almost completely restricted to women. While lung cysts consistent with LAM are reported in some men with tuberous sclerosis, very few of these men develop symptoms. The prevalence of LAM is estimated using data from registries and patient groups and is between 3.4 and 7.8/million women. The number of new cases each year is between 0.23 and 0.31/million women/year in the US, UK and Switzerland. The variation between countries and between adjacent states in the US, suggest that a significant number of women with LAM remain either undiagnosed or their symptoms are attributed to other diseases. Adult women with tuberous sclerosis are more likely to develop LAM than women without tuberous sclerosis. Cohorts of patients with tuberous sclerosis have been screened for LAM using CT scanning. In a retrospective study of adults with tuberous sclerosis, CT demonstrated lung cysts in 42% of 95 women and 13% of 91 men. In general, lung cysts were larger and more numerous in women than in men. In a further retrospective study of women with TSC who underwent CT scanning to detect LAM, 25% of those in their 20s had lung cysts whereas 80% of women in their 40s were affected, suggesting that the development of LAM is age dependent at least in tuberous sclerosis-related LAM. Although the prevalence of tuberous sclerosis at 1 in 6000 births is much greater than that of LAM, most pulmonary clinics see more cases of sporadic than tuberous sclerosis-LAM: probably due to a combination of low levels of screening for LAM in tuberous sclerosis and in many, the absence of symptoms.Female sex and tuberous sclerosis are the only known risk factors. Although use of supplemental estrogen is not associated with development of LAM, one study suggested that use of estrogen-containing contraceptive pills was associated with earlier onset.It occurs in more than 30% of women with tuberous sclerosis complex (TSC-LAM), a heritable syndrome that is associated with seizures, cognitive impairment and benign tumors in multiple tissues. Most LAM patients who present for medical evaluation have the sporadic form of the disease (S-LAM), however, which is not associated with other manifestations of tuberous sclerosis complex.
Mild cystic changes consistent with LAM have been described in 10–15% of men with TSC, but symptomatic LAM in males is rare. Sporadic LAM occurs exclusively in women, with one published exception to date. Both TSC-LAM and S-LAM are associated with mutations in tuberous sclerosis genes.
Pregnancy
Pregnancy has been reported to exacerbate LAM in some cases. However, the risk has not been rigorously studied. In a survey of 318 patients who indicated that they had had at least one pregnancy, 163 responded to a second survey focusing on lung collapse. A total of 38 patients reported a pneumothorax with pregnancy, consistent with an incidence of pneumothorax in pregnancy of at least 10% (38 of 318). In one third of patients, the pneumothorax during pregnancy led to the LAM diagnosis. Pneumothoraces were almost twice as frequent on the right as on the left, and four women presented with bilateral spontaneous pneumothorax. Most pneumothoraces took place during the second and third trimesters. This study and others suggest that pregnancy is associated with pleural complications in LAM patients. Few women with a known LAM diagnosis choose to become pregnant and patients in whom LAM is diagnosed during pregnancy rarely have baseline pulmonary function tests available, complicating resolution of this question.
Society
The LAM Foundation was founded in 1995 as a grassroots organization to provide patient advocacy and research funding. Today, the LAM Foundation provides support and education for women with LAM and their families, engages doctors and scientists to continue to learn more about the disease, and raises funds for the continued study of LAM. It seeks safe and effective treatments, and ultimately a cure, for lymphangioleiomyomatosis. It is headquartered in Cincinnati, Ohio.
In popular culture
In "Lucky Thirteen", the fifth episode of the fifth season of House, Spencer (Angela Gots) was diagnosed with LAM, though later it was found to be a case of Sjögrens syndrome.
See also
PEComa
References
External links
American Thoracic Society (US): Patient Information Series – Lymphangioleiomyomatosis |
Tick-borne disease | Tick-borne diseases, which afflict humans and other animals, are caused by infectious agents transmitted by tick bites. They are caused by infection with a variety of pathogens, including rickettsia and other types of bacteria, viruses, and protozoa.
The economic impact of tick-borne diseases is considered to be substantial in humans, and tick-borne diseases are estimated to affect ~80 % of cattle worldwide.As of 2020 18 tick-borne pathogens have been identified in the United States according to the Centers for Disease Control and at least 27 are known globally.
New tick-borne diseases have been discovered in the 21st century, due in part to the use of molecular assays and next-generation sequencing.The occurrence of ticks and tick-borne illnesses in humans is increasing. Tick populations are spreading into new areas, in part due to climate change. Tick populations are also affected by changes in the populations of their hosts (e.g. deer, cattle, mice, lizards) and those hosts predators (e.g. foxes). Diversity and availability of hosts and predators can be affected by deforestation and habitat fragmentation.Because individual ticks can harbor more than one disease-causing agent, patients can be infected with more than one pathogen at the same time, compounding the difficulty in diagnosis and treatment.
As the incidence of tick-borne illnesses increases and the geographic areas in which they are found expand, health workers increasingly must be able to distinguish the diverse, and often overlapping, clinical presentations of these diseases.
Prevention
Exposure
Ticks tend to be more active during warmer months, though this varies by geographic region and climate. Areas with woods, bushes, high grass, or leaf litter are likely to have more ticks. Those bitten commonly experience symptoms such as body aches, fever, fatigue, joint pain, or rashes. People can limit their exposure to tick bites by wearing light-colored clothing (including pants and long sleeves), using insect repellent with 20%–30% N,N-Diethyl-3-methylbenzamide (DEET), tucking their pants legs into their socks, checking for ticks frequently, and washing and drying their clothing (in a hot dryer).According to the World Health Organization, tick-to-animal transmission is difficult to prevent because animals do not show visible symptoms; the only effective prevention relies on killing ticks on the livestock production facility.
Tick removal
Ticks should be removed as soon as safely possible once discovered. They can be removed either by grasping tweezers as close to the mouth as possible and pulling without rotation; some companies market grooved tools that rotate the hypostome to facilitate removal. Chemical methods to make the tick self-detach, or trying to pull the tick out with one’s fingers, are not efficient methods.
Diagnosis
In general, specific laboratory tests are not available for rapid diagnosis of tick-borne diseases. Due to their seriousness, antibiotic treatment is often justified based on clinical presentation alone.
Assessing risk
For a person or pet to acquire a tick-borne disease requires that the individual gets bitten by a tick and that the tick feeds for a sufficient period of time. The feeding time required to transmit pathogens differs for different ticks and different pathogens. Transmission of the bacterium that causes Lyme disease is well understood to require a substantial feeding period. In general, soft ticks (Argasidae) transmit pathogens within minutes of attachment because they feed more frequently, whereas hard ticks (Ixodidae) take hours or days, but the latter are more common and harder to remove.For an individual to acquire infection, the feeding tick must also be infected. Not all ticks are infected. In most places in the US, 30-50% of deer ticks will be infected with Borrelia burgdorferi (the agent of Lyme disease). Other pathogens are much more rare. Ticks can be tested for infection using a highly specific and sensitive qPCR procedure. Several commercial labs provide this service to individuals for a fee. The Laboratory of Medical Zoology (LMZ), a nonprofit lab at the University of Massachusetts, provides a comprehensive TickReport for a variety of human pathogens and makes the data available to the public. Those wishing to know the incidence of tick-borne diseases in their town or state can search the LMZ surveillance database.
Examples
Major tick-borne diseases include:
Bacterial
Lyme disease or borreliosis
Organism: Borrelia burgdorferi sensu lato (bacterium)
Vector: at least 15 species of ticks in the genus Ixodes, including deer tick (Ixodes scapularis (=I. dammini), I. pacificus, I. ricinus (Europe), I. persulcatus (Asia))
Endemic to: The Americas and Eurasia
Symptoms: Fever, arthritis, neuroborreliosis, erythema migrans, cranial nerve palsy, carditis, fatigue, and influenza-like illness
Treatment: Antibiotics - amoxicillin in pregnant adults and children), (doxycycline in other adults
Relapsing fever (tick-borne relapsing fever, different from Lyme disease due to different Borrelia species and ticks)
Organisms: Borrelia species such as B. hermsii, B. parkeri, B. duttoni, B. miyamotoi
Vector: Ornithodoros species
Regions : Primarily in Africa, Spain, Saudi Arabia, Asia in and certain areas of Canada and the western United States
Symptoms: Relapsing fever typically presents as recurring high fevers, flu-like symptoms, headaches, and muscular pain, with less common symptoms including rigors, joint pain, altered mentation, cough, sore throat, painful urination, and rash
Treatment: Antibiotics are the treatment for relapsing fever, with doxycycline, tetracycline, or erythromycin being the treatment of choice.
Typhus Several diseases caused by Rickettsia bacteria (below)
Rocky Mountain spotted fever
Organism: Rickettsia rickettsii
Vector: Wood tick (Dermacentor variabilis), D. andersoni
Region (US): East, Southwest
Vector: Amblyomma cajennense
Region (Brazil): São Paulo, Rio de Janeiro, Minas Gerais.
Symptoms:Fever, headache, altered mental status, myalgia, and rash
Treatment: Antibiotic therapy, typically consisting of doxycycline or tetracycline
Helvetica spotted fever
Organism: Rickettsia helvetica
Region(R. helvetica): Confirmed common in ticks in Sweden, Switzerland, France, and Laos
Vector/region(s)#1: Ixodes ricinus is the main European vector.
Symptoms: Most often small red spots, other symptoms are fever, muscle pain, headache and respiratory problems
Treatment: Broad-spectrum antibiotic therapy is needed, phenoxymethylpenicillin likely is sufficient.
Human granulocytic anaplasmosis (formerly human granulocytic ehrlichiosis or HGE)
Organism: Anaplasma phagocytophilum (formerly Ehrlichia phagocytophilum or Ehrlichia equi)
Vector: Lone star tick (Amblyomma americanum), I. scapularis
Region (US): South Atlantic, South-central
Bartonella: Bartonella transmission rates to humans via tick bite are not well established but Bartonella is common in ticks. For example: 4.76% of 2100 ticks tested in a study in Germany
Tularemia
Organism: Francisella tularensis, A. americanum
Vector: D. variabilis, D. andersoni
Region (US): Southeast, South-central, West, widespread
Viral
Tick-borne meningoencephalitis
Organism: TBEV (FSME) virus, a flavivirus from family Flaviviridae
Vector: deer tick (Ixodes scapularis), Ixodes ricinus (Europe), Ixodes persulcatus (Russia + Asia))
Endemic to: Europe and northern Asia
Powassan virus/deer tick virusOrganism: Powassan virus (POWV), a flavivirus from family Flaviviridae. Lineage 2 POWV is also known as deer tick virus (DTV)
Vector: Ixodes cookei, Ix. scapularis, Ix. marxi, Ix. spinipalpusm, Dermacentor andersoni, and D. variabilis
Endemic to: North America and eastern Russia
Colorado tick fever
Organism: Colorado tick fever virus (CTF), a coltivirus from the Reoviridae
Vector: Dermacentor andersoni
Region: US (West)
Crimean-Congo hemorrhagic fever
Organism: CCHF virus, a nairovirus, from the Bunyaviridae
Vector: Hyalomma marginatum, Rhipicephalus bursa
Region: Southern part of Asia, Northern Africa, Southern Europe
Severe febrile illnessOrganism: Heartland virus, a phlebovirus, from the Bunyaviridae
Vector: Lone star tick (Amblyomma americanum)
Region: Missouri and Tennessee, United States
Severe febrile illness, headaches, coma in 1/3 patientsOrganism: tentatively Alongshan virus, jingmenvirus group in the flavivirus family
Vector: tick (likely Ixodes persulcatus, Ixodes ricinus), mosquitoes
Region: Inner Mongolia but potentially more widespread
Protozoan
Babesiosis
Organism: Babesia microti, Theileria equi
Vector: Ixodes scapularis (deer tick), I. pacificus (western black-legged tick)
Region (US): Northeast, West Coast
Cytauxzoonosis
Organism: Cytauxzoon felis
Vector: Amblyomma americanum (Lone star tick)
Region (US): South, Southeast
Toxin
Tick paralysis
Cause: Toxin
Vector (US): Dermacentor andersoni (Rocky Mountain wood tick), D. variabilis (American dog tick or wood tick)
Region (US): D. andersoni: East, D. variabilis: East, West coast
Vector (Australia): Ixodes holocyclus (Australian paralysis tick)
Region (Australia): East
Allergies
Alpha-gal allergy - Alpha-gal syndrome is likely caused by a hypersensitivity reaction to the Alpha-gal (Galactose-alpha-1,3-galactose) sugar molecule introduced by ticks while feeding on a human host. The immune reaction can leave people with an allergy to red meat and other mammalian derived products.
See also
Arbovirus
List of diseases spread by invertebrates
List of insect-borne diseases
Mobovirus
Mosquito-borne disease
Robovirus
Sandfly-borne disease
Tibovirus
Ticks of domestic animals
References
External links
Tick-Borne Diseases: Recommendations for Workers and Employers—National Institute for Occupational Safety and Health
Tickborne Diseases—National Center for Infectious Diseases (CDC)
Tickborne Disease Website—Massachusetts Department of Public Health
Ixodes Scapularis—3D animation of Deer or Blacklegged Tick from US Army site
Parasitic Insects, Mites and Ticks: Genera of Medical and Veterinary Importance Wikibooks |
Microgyrus | A microgyrus is an area of the cerebral cortex that includes only four cortical layers instead of six.
Microgyria are believed by some to be part of the genetic lack of prenatal development which is a cause of, or one of the causes of, dyslexia.
Albert Galaburda of Harvard Medical School noticed that language centers in dyslexic brains showed microscopic flaws known as ectopias and microgyria (Galaburda et al., 2006, Nature Neuroscience 9(10): 1213–1217). Both affect the normal six-layer structure of the cortex. These flaws affect connectivity and functionality of the cortex in critical areas related to sound and visual processing. These and similar structural abnormalities may be the basis of the inevitable and hard to overcome difficulty in reading.
References
External links
The neurological basis of developmental dyslexia
Another article on the subject
Birthdates of neurons in induced microgyria |
Diabetic foot ulcer | Diabetic foot ulcer is a major complication of diabetes mellitus, and probably the major component of the diabetic foot.
Wound healing is an innate mechanism of action that works reliably most of the time. A key feature of wound healing is stepwise repair of lost extracellular matrix (ECM) that forms the largest component of the dermal skin layer. But in some cases, certain disorders or physiological insult disturbs the wound healing process. Diabetes mellitus is one such metabolic disorder that impedes the normal steps of the wound healing process. Many studies show a prolonged inflammatory phase in diabetic wounds, which causes a delay in the formation of mature granulation tissue and a parallel reduction in wound tensile strength.Treatment of diabetic foot ulcers should include: blood sugar control, removal of dead tissue from the wound, wound dressings, and removing pressure from the wound through techniques such as total contact casting. Surgery in some cases may improve outcomes. Hyperbaric oxygen therapy may also help but is expensive.It occurs in 15% of people with diabetes, and precedes 84% of all diabetes-related lower-leg amputations.
Risk factors
Risk factors implicated in the development of diabetic foot ulcers are infection, older age, diabetic neuropathy, peripheral vascular disease, cigarette smoking, poor glycemic control, previous foot ulcerations or amputations, and ischemia of small and large blood vessels. Prior history of foot disease, foot deformities that produce abnormally high forces of pressure, callus at pressure areas renal failure, oedema, impaired ability to look after personal care (e.g. visual impairment) are further risk factors for diabetic foot ulcer.People with diabetes often develop diabetic neuropathy due to several metabolic and neurovascular factors. Peripheral neuropathy causes loss of pain or feeling in the toes, feet, legs, and arms due to distal nerve damage and low blood flow. Autonomic neuropathy causes Sudomotor dysfunction and dryness of the skin. Blisters and sores may appear on numb areas of the feet and legs, such as metatarsophalangeal joints and the heel region, as a result of pressure or injury which may go unnoticed and eventually become a portal of entry for bacteria and infection.
Pathophysiology
Extracellular matrix
Extra cellular matrix (or "ECM") is the external structural framework that cells attach to in multicellular organisms. The dermis lies below the epidermis, and these two layers are collectively known as the skin. Dermal skin is primarily a combination of fibroblasts growing in this matrix. The specific species of ECM of connective tissues often differ chemically, but collagen generally forms the bulk of the structure.Through the interaction of a cell with its extracellular matrix (transmitted through the anchoring molecules classed as integrins) there forms a continuous association between the cell interior, cell membrane and its extracellular matrix components that helps drive various cellular events in a regulated fashion. Wound healing is a localized event involving the reaction of cells to the damage sustained.The cells break down damaged ECM and replace it, generally increasing in number to react to the harm. The process is activated, though perhaps not exclusively, by cells responding to fragments of damaged ECM, and the repairs are made by reassembling the matrix by cells growing on and through it. Because of this, extracellular matrix is often considered as a conductor of the wound healing symphony. In the Inflammatory phase, neutrophils and macrophages recruit and activate fibroblasts which in subsequent granulation phase migrate into the wound, laying down new collagen of the subtypes I and III.In the initial events of wound healing, collagen III predominates in the granulation tissue which later on in remodeling phase gets replaced by collagen I giving additional tensile strength to the healing tissue. It is evident from the known collagen assembly that the tensile strength is basically due to fibrillar arrangement of collagen molecules, which self-assemble into microfibrils in a longitudinal as well as lateral manner producing extra strength and stability to the collagen assembly. Metabolically altered collagen is known to be highly inflexible and prone to break down, particularly over pressure areas. Fibronectin is the major glycoprotein secreted by fibroblasts during initial synthesis of extracellular matrix proteins. It serves important functions, being a chemo-attractant for macrophages, fibroblasts and endothelial cells.The basement membrane that separates the epidermis from the dermal layer and the endothelial basement membrane mainly contains collagen IV that forms a sheet and binds to other extracellular matrix molecules like laminin and proteoglycans. In addition to collagen IV, the epidermal and endothelial basement membrane also contains laminin, perlecan and nidogen. Hyaluronic acid, a pure glycosaminoglycan component, is found in high amounts in damaged or growing tissues. It stimulates cytokine production by macrophages and thus promotes angiogenesis. In normal skin chondroitin sulfate proteoglycan is mainly found in the basement membrane, but in healing wounds they are up-regulated throughout the granulation tissue especially during the second week of wound repair where they provide a temporary matrix with highly hydrative capacity. Binding of growth factors is clearly an important role of perlecan in wound healing and angiogenesis. Poor wound healing in diabetes mellitus may be related to perlecan expression. High levels of glucose can decrease perlecan expression in some cells, probably through transcriptional and post-transcriptional modification. Wound healing phases especially, granulation, re-epithelization and remodelling exhibit controlled turnover of extracellular matrix components.
Altered metabolism
Diabetes mellitus is a metabolic disorder and hence the defects observed in diabetic wound healing are thought to be the result of altered protein and lipid metabolism and thereby abnormal granulation tissue formation. Increased glucose levels in the body end up in uncontrolled covalent bonding of aldose sugars to a protein or lipid without any normal glycosylation enzymes. These stable products then accumulate over the surface of cell membranes, structural proteins and circulating proteins. These products are called advanced glycation endproducts (AGEs) or Amadori products. Formation of AGEs occurs on extracellular matrix proteins with slow turnover rate. AGEs alter the properties of matrix proteins such as collagen, vitronectin, and laminin through AGE-AGE intermolecular covalent bonds or cross-linking. AGE cross-linking on type I collagen and elastin results in increased stiffness. AGEs are also known to increase synthesis of type III collagen that forms the granulation tissue. AGEs on laminin result in reduced binding to type IV collagen in the basement membrane, reduced polymer elongation and reduced binding of heparan sulfate proteoglycan.
Impaired NO synthesis
Nitric oxide is known as an important stimulator of cell proliferation, maturation and differentiation. Thus, nitric oxide increases fibroblast proliferation and thereby collagen production in wound healing. Also, L-arginine and nitric oxide are required for proper cross linking of collagen fibers, via proline, to minimize scarring and maximize the tensile strength of healed tissue. Endothelial cell specific nitric oxide synthase (EcNOS) is activated by the pulsatile flow of blood through vessels. Nitric oxide produced by EcNOS, maintains the diameter of blood vessels and proper blood flow to tissues. In addition to this, nitric oxide also regulates angiogenesis, which plays a major role in wound healing. Thus, diabetic patients exhibit reduced ability to generate nitric oxide from L-arginine. Reasons that have been postulated in the literature include accumulation of nitric oxide synthase inhibitor due to high glucose associated kidney dysfunction and reduced production of nitric oxide synthase due to ketoacidosis observed in diabetic patients and pH dependent nature of nitric oxide synthase.Structural and functional changes in fibroblasts
Diabetic ulcer fibroblasts show various morphological differences compared to fibroblasts from age matched controls. Diabetic ulcer fibroblasts are usually large and widely spread in the culture flask compared to the spindle shaped morphology of the fibroblasts in age-matched controls. They often show dilated endoplasmic reticulum, numerous vesicular bodies and lack of microtubular structure in transmission electron microscopy study. Therefore, interpretation of these observations would be that in spite of high protein production and protein turnover in diabetic ulcer fibroblasts, vesicles containing secretory proteins could not travel along the microtubules to release the products outside. Fibroblasts from diabetic ulcer exhibit proliferative impairment that probably contributes to a decreased production of extracellular matrix proteins and delayed wound contraction and impaired wound healing.Increased matrix metalloproteinases (MMP) activity
In order for a wound to heal, extracellular matrix not only needs to be laid down but also must be able to undergo degradation and remodeling to form a mature tissue with appropriate tensile strength. Proteases, namely matrix metalloproteinases are known to degrade almost all the extracellular matrix components. They are known to be involved in fibroblast and keratinocyte migration, tissue re-organization, inflammation and remodeling of the wounded tissue. Due to persistently high concentrations of pro-inflammatory cytokines in diabetic ulcers, MMP activity is known to increase by 30 fold when compared to acute wound healing. MMP-2 and MMP-9 show sustained overexpression in chronic non-healing diabetic ulcers. Balance in the MMP activity is usually achieved by tissue inhibitor of metalloproteinases (TIMP). Rather than absolute concentrations of either two, it is the ratio of MMP and TIMP that maintains the proteolytic balance and this ratio is found to be disturbed in diabetic ulcer. In spite of these findings, the exact mechanism responsible for increased MMP activity in diabetes is not known yet. One possible line of thought considers Transforming growth factor beta (TGF-β) as an active player. Most MMP genes have TGF-β inhibitory element in their promoter regions and thus TGF–β regulates the expression of both MMP and their inhibitor TIMP. In addition to the importance of cell-cell and cell-matrix interactions, all phases of wound healing are controlled by a wide variety of different growth factors and cytokines. To mention precisely, growth factors promote switching of early inflammatory phase to the granulation tissue formation. Decrease in growth factors responsible for tissue repair such as TGF-β is documented in diabetic wounds. Thus, reduced levels of TGFβ in diabetes cases lower down the effect of inhibitory regulatory effect on MMP genes and thus cause MMPs to over express.
Biomechanics
Complications in the diabetic foot and foot-ankle complex are wider and more destructive than expected and may compromise the structure and function of several systems: vascular, nervous, somatosensory, musculoskeletal. Thus, deeper comprehension of the alteration of gait and foot biomechanics in the diabetic foot is of great interest and may play a role in the design and onset of preventive as well as therapeutic actions.Briefly, the effect of diabetes on the main structures of the foot-ankle complex can be summarised as:
effects on the skin: skin – and the soft tissues immediately underneath the skin – undergo greater compression and shear loading than usual, thus explaining the onset of tissue damage so deeply correlated to traumatic ulceration processes. Besides this, skin of the diabetic foot loses autonomic nervous control and consequently reduced hydration, making it less elastic and thus more vulnerable to the action of increased mechanical stress;
effects on tendons and ligaments: protein glycosylation and the resulting collagen abnormalities lead to greater transversal section – i.e. thickening – of tendons and ligaments and a greater coefficient of elasticity. Particularly impacted by this process are Plantar Fascia and Achilles Tendon. Both causes lead to increased stiffness of those structures;
effects on cartilage: similar to what happens to tendons and ligaments, cartilage changes its composition mainly due to the modification of collagen fibers. This increases its stiffness and decreases the range of motion of all joints in the foot and ankle.
effects on muscles: Diabetes mellitus causes severe damage to nerve conduction, thus causing a worsening in the management of the related muscle fibers. As a consequence, both intrinsic and extrinsic muscles of the foot-ankle complex are damaged in structure (reduction of muscle volume) and function (reduction of muscle strength);
effects on the peripheral sensory system: impaired nerve conduction has a dramatic effect on the peripheral sensory system since it leads to loss of protective sensation under the sole of the foot. This exposes the diabetic foot to thermal or mechanical trauma, and to the late detection of infection processes or tissue breakdown;
effects on foot morphology (deformities): due to most of the above alterations, a significant imbalance of peripheral musculature and soft tissue occur in the foot which seriously alters its morphology and determines the onset of foot deformities. Most common deformities of the diabetic foot are represented by a high longitudinal arch (rigid cavus foot), hammer toes and hallux valgus. A completely different morphologic degeneration is represented by neuropathic arthropathy, whose analysis is not part of this discussion.
Diagnosis
Assessment of diabetic foot ulcer includes identifying risk factors such as diabetic peripheral neuropathy, noting that 50 percent of people are asymptomatic, and ruling out other causes of peripheral neuropathy such as alcohol use disorder and spinal injury.The location of the ulcer, its size, shape, depth and whether the tissue is granulating or sloughy needs to be considered. Further considerations include whether there is malodour, condition of the border of the wound and palpable bone and sinus formation should be investigated. Signs of infection require to be considered such as development of grey or yellow tissue, purulent discharge, unpleasant smell, sinus, undermined edges and exposure of bone or tendon.Identification of diabetic foot in medical databases, such as commercial claims and prescription data, is complicated by the lack of a specific ICD-9 code for diabetic foot and variation in coding practices. The following codes indicate ulcer of the lower limb or foot:
707.1 Ulcer of lower limbs, except pressure ulcer
707.14 Ulcer of heel and midfoot
707.15 Ulcer of other part of foot
707.19 Ulcer of other part of lower limbOne or more codes, in combination with a current or prior diagnosis of diabetes may be sufficient to conclude diabetic foot:
250.0 Diabetes Mellitus
250.8 Diabetes with other specified manifestations
Classification
Diabetic foot ulcer is a complication of diabetes. Diabetic foot ulcers are classified as either neuropathic, neuroischaemic or ischaemic.Doctors also use the Wagner Grades to describe the severity of an ulcer. The purpose of the Wagner Grades is to allow specialists to better monitor and treat diabetic foot ulcers. This grading system classifies Diabetic foot ulcers using numbers, from 0 to 5.
Wagner Grades 0 through 5 are as follows:
0. No diabetic foot ulcer is present, but there is a high risk of developing one.
1. A surface ulcer involves full skin thickness, but does not yet involve the underlying tissues.
2. A deep ulcer penetrates past the surface, down to the ligaments and muscle. There is no abscess or bone involved yet.
3. A deep ulcer occurs with inflammation of subcutaneous connective tissue or an abscess. This can include infections in the muscle, tendon, joint, and/or bone.
4. The tissue around the area of the ulcer (limited to the toes and forefoot) has begun to decay. This condition is called gangrene.
5. Gangrene has spread from the localized area of the ulcer to become extensive. This involves the whole foot.
Prevention
Steps to prevent diabetic foot ulcers include frequent review by a foot specialist and multidisciplinary team, good foot hygiene, diabetic socks and shoes, as well as avoiding injury. Foot-care education combined with increased surveillance can reduce the incidence of serious foot lesions.There is no high quality researches that evaluate complex intervention of combining two or more preventive strategies in preventing diabetic foot ulcer.
Monitoring and prediction
People with loss of feeling in their feet should inspect their feet on a daily basis, to ensure that there are no wounds starting to develop. Monitoring a persons feet can help in predicting the likelihood of developing ulcers.A common method for this is using a special thermometer to look for spots on the foot that have higher temperature which indicate the possibility of an ulcer developing. At the same time there is no strong scientific evidence supporting the effectiveness of at-home foot temperature monitoring.The current guideline in the United Kingdom recommends collecting 8-10 pieces of information for predicting the development of foot ulcers. A simpler method proposed by researchers provides a more detailed risk score based on three pieces of information (insensitivity, foot pulse, previous history of ulcers or amputation). This method is not meant to replace people regularly checking their own feet but complement it.
Footwear
Diabetic shoes, insoles and socks are personalised products that relieve pressure on the foot in order to prevent ulcers. The evidence for special footwear to treat foot ulcers is poor but their effectiveness for prevention is well-established. Design features of footwear that are effective in reducing pressure are arch supports, cushioned cut-outs around points at risk of damage, and cushioning at the ball of the foot. Technology for measuring the pressure within the shoes is recommended during designing diabetic footwear.People with loss of feeling in their feet should not walk around barefoot, but use proper footwear at all times.
Treatment
Foot ulcers in diabetes require multidisciplinary assessment, usually by diabetes nurse specialist, a tissue viability nurse, podiatrists, diabetes specialists and surgeons. An aim to improve glycaemic control, if poor, forms part of the management, to slow disease progression. Individuals who have sausage shaped toes, a positive probe to bone test, evidence suggesting osteomyelitis, suspected charcot neuroarthropathy, or those whose ulcers do not improve within 4 weeks of standard care and where there is evidence that exudate is of synovial membrane in origin. When osteomyelitis is suspected to be involved in the foot ulcer, but not evidenced on an x-ray, an MRI scan should be obtained.With regards to infected foot ulcers, the presence of microorganisms is not in itself enough to determine whether an infection is present. Signs such as inflammation and purulence are the best indicators of an active infection. The most common organism causing infection is staphylococcus. The treatment consists of debridement, appropriate bandages, managing peripheral arterial disease and appropriate use of antibiotics (against pseudomonas aeruginosa, staphylococcus, streptococcus and anaerobe strains), and arterial revascularisation.
Fespixon Cream(ON101)
There was a novel topical medication developed by a Taiwanese company, Oneness Biotech Co. Ltd (4743:Taipei), called ON101(officially named Fespixon cream(速必一) later), which showed promising efficacy on diabetic foot ulcer healing. During a 3rd phase clinical trial of 236 patients, it showed superior complete healing rate with 60.7% in 16 weeks in average, comparing to aquacel with 35.1%. Its active components were PA-F4(from Plectranthus amboinicus) and S1(from Centella asiatica).Fespixon Cream(ON101) is a first-in-class macrophage-regulating new drug for the chronic wounds. It can effectively regulate the immune environment in the DFU (hyperglycemia causes dermatological immunopathy on DM patients) by suppressing M1 φ overexpression and increase M2 φ to transit the inflammation stage to proliferation stage and to resolve DFU chronicity. On 2021 February, it was approved by Taiwan Food and Drug Administration to be launched in Taiwan market.
Antibiotics
The length of antibiotic courses depend on the severity of the infection and whether bone infection is involved but can range from 1 week to 6 weeks or more. Current recommendations are that antibiotics are only used when there is evidence of infection and continued until there is evidence that the infection has cleared, instead of evidence of ulcer healing. Choice of antibiotic depends on common local bacterial strains known to infect ulcers. Microbiological swabs are believed to be of limited value in identifying causative strain. Microbiological investigation is of value in cases of osteomyelitis. Most ulcer infections involve multiple microorganisms.There is limited safety and efficacy data of topical antibiotics in treating diabetic foot ulcers.
Wound dressings
There are many types of dressings used to treat diabetic foot ulcers such as absorptive fillers, hydrogel dressings, and hydrocolloids. There is no good evidence that one type of dressing is better than another for diabetic foot ulcers. In selecting dressings for chronic non healing wounds it is recommended that the cost of the product be taken into account.Hydrogel dressings may have shown a slight advantage over standard dressings, but the quality of the research is of concern. Dressings and creams containing silver have not been properly studied nor have alginate dressings. Biologically active bandages that combine hydrogel and hydrocolloid traits are available, however more research needs to be conducted as to the efficacy of this option over others.
Total contact casting
Total contact casting (TCC) is a specially designed cast designed to take weight of the foot (off-loading) in patients with DFUs. Reducing pressure on the wound by taking weight of the foot has proven to be very effective in DFU treatment. DFUs are a major factor leading to lower leg amputations among the diabetic population in the US with 85% of amputations in diabetics being preceded by a DFU. Furthermore, the 5 year post-amputation mortality rate among diabetics is estimated at 45% for those with neuropathic DFUs.TCC has been used for off-loading DFUs in the US since the mid-1960s and is regarded by many practitioners as the "reference standard" for off-loading the bottom surface (sole) of the foot.TCC helps patients to maintain their quality of life. By encasing the patients complete foot — including the toes and lower leg — in a specialist cast to redistribute weight and pressure from the foot to the lower leg during everyday movements, patients can remain mobile. The manner in which TCC redistributes pressure protects the wound, letting damaged tissue regenerate and heal. TCC also keeps the ankle from rotating during walking, which helps prevent shearing and twisting forces that can further damage the wound.Effective off loading is a key treatment modality for DFUs, particularly those where there is damage to the nerves in the feet (peripheral neuropathy). Along with infection management and vascular assessment, TCC is vital aspect to effectively managing DFUs. TCC is the most effective and reliable method for off-loading DFUs.A 2013 meta-analysis by the Cochrane Collaboration compared the effectiveness of non-removable pressure relieving interventions, such as casts, with therapeutic shoes, dressings, removable pressure relieving orthotic devices, and surgical interventions. Non-removable pressure relieving interventions, including non-removable casts with an Achilles tendon lengthening component, were found to be more effective at healing foot ulcers related to diabetes that therapeutic shoes and other pressure relieving approaches.TCC systems include TCC-EZ (Integra LifeSciences) and Cutimed Off-loader (BSN Medical).
Hyperbaric oxygen
In 2015, a Cochrane review concluded that for people with diabetic foot ulcers, hyperbaric oxygen therapy reduced the risk of amputation and may improve the healing at 6 weeks. However, there was no benefit at one year and the quality of the reviewed trials was inadequate to draw strong conclusions.
Negative pressure wound therapy
This treatment uses vacuum to remove excess fluid and cellular waste that usually prolong the inflammatory phase of wound healing. Despite a straightforward mechanism of action, results of negative pressure wound therapy studies have been inconsistent. Research needs to be carried out to optimize the parameters of pressure intensity, treatment intervals and exact timing to start negative pressure therapy in the course of chronic wound healing.There is low-certainty evidence that negative pressure wound therapy would improve wound healing in diabetic foot ulcers.
Other treatments
Ozone therapy – there is only limited and poor-quality information available regarding the effectiveness of ozone therapy for treating foot ulcers in people with diabetes.Growth factors - there is some low-quality evidence that growth factors may increase the likelihood that diabetic foot ulcers will heal completely.Continuous diffusion of oxygen (CDO) - CDO delivers continuous oxygen to an occluded, moist wound site at much lower flow rates of 3–12 mL/h for 24 h 7 days a week for up to several weeks or months, depending on the wound status.Phototherapy - there is very weak evidence to suggest that people with foot ulcers due to diabetes may have improved healing. There is no evidence to suggest that phototherapy improves the quality of life for people with foot ulcers caused by diabetes.Sucrose-octasulfate impregnated dressing is recommended by the International Working Group on the Diabetic Foot Ulcer (IWGDF) for the treatment of non-infected, neuro-ischaemic diabetic foot ulcers that do not show an improvement with a standard of care regimenAutologous combined leucocyte, platelet and fibrin as an adjunctive treatment, in addition to best standard of care is also recommended by IWGDF However, there is only low quality evidence that such treatment is effective in treating diabetic foot ulcer.There is limited evidence that granulocyte colony-stimulating factor may not hasten the resolution of diabetic foot ulcer infection. However, it may reduce the need for surgical interventions such as amputations and hospitalizations.It is unknown that whether intensive or conventional blood glucose control is better for diabetic foot ulcer healing.A 2020 Cochrane systematic review evaluated the effects of nutritional supplements or special diets on healing foot ulcers in people with diabetes. The review authors concluded that its uncertain whether or not nutritional interventions have an effect on foot ulcer healing and that more research is needed to answer this question.Skin grafting and tissue replacements can help to improve the healing of diabetic foot ulcer.A 2021 systematic review concluded that there was no strong evidence about the effects of psychological therapies on diabetic foot ulcer healing and recurrence.
Epidemiology
Approximately 15 percent of people with diabetes experience foot ulcers, and approximately 84 percent of lower limb amputations have a history of ulceration with only approximately half of amputees surviving for more than 2 years. 56 percent of individuals with foot ulcers who do not have an amputations survive for 5 years. Foot ulcers and amputations significantly reduce the quality of life. Approximately 8.8 percent of hospital admissions of diabetic patients are for foot related problems, and such hospital admissions are about 13 days longer than for diabetics without foot related admissions. Approximately 35 to 40 percent of ulcers recur within 3 years and up to 70 percent recur within 5 years. Diabetic foot disease is the leading cause of non-traumatic lower limb amputations.
Research
Stem cell therapy may represent a treatment for promoting healing of diabetic foot ulcers. Diabetic foot ulcers develop their own, distinctive microbiota. Investigations into characterizing and identifying the phyla, genera and species of nonpathogenic bacteria or other microorganisms populating these ulcers may help identify one group of microbiota that promotes healing.The recent advances in epigenetic modifications, with special focus on aberrant macrophage polarisation is giving increasing evidences that epigenetic modifications might play a vital role in changing the treatment of diabetic foot ulcer in the near future.
References
== External links == |
Tethered spinal cord syndrome | Tethered cord syndrome (TCS) refers to a group of neurological disorders that relate to malformations of the spinal cord. Various forms include tight filum terminale, lipomeningomyelocele, split cord malformations (diastematomyelia), occult, dermal sinus tracts, and dermoids.
All forms involve the pulling of the spinal cord at the base of the spinal canal, literally a tethered cord. The spinal cord normally hangs loose in the canal, free to move up and down with growth, and with bending and stretching. A tethered cord, however, is held taut at the end or at some point in the spinal canal. In children, a tethered cord can force the spinal cord to stretch as they grow. In adults the spinal cord stretches in the course of normal activity, usually leading to progressive spinal cord damage if untreated. TCS is often associated with the closure of a spina bifida. It can be congenital, such as in tight filum terminale, or the result of injury later in life.
Signs and symptoms
In children, symptoms may include:
Lesions, hairy patches, dimples, hemangiomas, or fatty tumours on the lower back
Foot and spinal deformities
Weakness in the legs (loss of muscle strength and tone)
Change in or abnormal gait including awkwardness while running or wearing the tips or side of one shoe
Low back pain
Scoliosis (abnormal curvature of the spine to the left or right)
Urinary irregularities (incontinence or retention)Tethered spinal cord syndrome may go undiagnosed until adulthood, when sensory, motor, bowel, and bladder control issues emerge. This delayed presentation of symptoms relates to the degree of strain on the spinal cord over time.
Tethering may also develop after spinal cord injury. Scar tissue can block the flow of fluids around the spinal cord. Fluid pressure may cause cysts to form in the spinal cord, a condition called syringomyelia. This can lead to additional loss of movement or feeling, or the onset of pain or autonomic nervous system symptoms.
In adults, onset of symptoms typically include:
Severe pain (in the lower back and radiating into the legs, groin, and perineum)
Bilateral muscle weakness and numbness
Loss of feeling and movement in lower extremities
Urinary irregularities (incontinence or retention)
Bowel control issuesNeurological symptoms can include a mixed picture of upper and lower motor neuron findings, such as amyotrophy, hyperreflexia or hyporeflexia, a positive stretch sign, and pathologic plantar response, occurring in the same limb. Profound sensory changes, such as loss of pain, temperature, and proprioceptive sensations, are common. Last, progressive symptoms of a neuropathic bladder are noted on over 70% of adult patients, versus only 20% to 30% of children. These symptoms include urinary frequency and urgency, feeling of incomplete voiding, poor voluntary control, nocturia, and urge and stress incontinence. Chronic recurrent infections are common and occasionally lead to nephrolithiasis (kidney stones), kidney failure, or kidney transplantation. Female patients also give a history of ineffective labor and postpartum rectal prolapse, presumably due to an atonic pelvic floor.
Related disorders
Kyphosis
Scoliosis
Brain herniation
Spina Bifida
Ehlers-Danlos syndrome
Klippel-Feil syndrome
Syringomyelia
Cause
Tethered spinal cord can be caused by various conditions but the main cause is when tissue attachments limit the movement of the spinal cord in the spinal column which causes abnormal stretching of the cord. The tethered spinal cord syndrome is correlated with having the causes:
Spina bifida
Occulta
Mylomeningocele
Meningocele
History of spinal trauma
History of spinal surgery
Tumor(s) in the spinal column
Thickened and/or tight filum terminale
Lipoma(s) in the spinal column
Dermal Sinus Tract (congenital deformity)
Diastematomyelia (split spinal cord)Tethered spinal cord is a disorder and not a mechanism so it does not spread to other people and there are no measures that can be done to prevent it beforehand. The only preventative measure that is successful is to surgically untether the spinal cord though there might already be irreversible damage.
Spina bifida
In tethered spinal cord cases spina bifida can be accompanied by tethering of the spinal cord but in rare cases with Spina bifida occulta. Tethering of the spinal cord tends to occur in the cases of Spina bifida with mylomeningocele. In most people the spine grows faster than the spinal cord during development which causes the end of the spinal cord to appear to rise relative to the bony spine next to it. By the time of birth the spinal cord is located between L1 and L2. In a baby with Spina bifida the spinal cord is still attached to the skin around it preventing it from rising properly. This occurs because the spinal cord in a child with Spina bifida is low lying and tethered at the bottom. At the time of birth the mylomeningocele is separated from the skin but the spinal cord is still stuck in the same place. As the child begins to grow the spinal cord remains in the same place becoming stretched out causing the tight cord and the tethering at the end. With this type of tethering there is an interference with the blood supply to the nerves and body which can then cause the deterioration of the body causing orthopedic, neurological, and urological problems. With milder forms of Spina bifida such as Occulta, may be related to the degree of strain on the cord which can become worse with physical activity, injury, pregnancy, bone spurs, or spinal stenosis. The tethered cord in this case might not be diagnosed until adulthood when it worsens and can still cause neurological, orthopedic, and urological dysfunctions.
Mechanism
Tethered spinal cord syndrome is a clinical entity which is manifested by progressive motor and sensory changes in:
legs
incontinence
back of leg pain
scoliosisIn order to understand the pathophysiology that is involved in a tethered spinal cord, the reduction/oxidation ratio has to be used in vivo of cytochrome alpha and alpha 3 to signal the oxidative metabolic functioning in humans. Studies have found that marked metabolic and electrophysiological susceptibility to hypoxic stress to the lumbar and sacral portion of the spinal cord under traction with various weights. Similar effects were found in redox behavior of tethered spinal cord during the surgical procedures to repair it. This can be due to impairment of mitochondrial oxidative metabolism under constant or intermittent stretching. The act of prolonged stretching can lead to structural damage to the neural perikarya and eventually the axons in neurons. The untethering process can improve the oxidative metabolism and can help to repair injured neurons.
Diagnosis
For children younger than eight weeks of age (and possibly in utero), a tethered cord may be observed using ultrasonography. Ultrasonography may still be useful through age 5 in limited circumstances.
MRI imaging appears to be the gold standard for diagnosing a tethered cord.A tethered cord is often diagnosed as a "low conus." The conus medullaris (or lower termination of the spinal cord) normally terminates at or above the L1-2 disk space (where L1 is the first, or topmost lumbar vertebra). After about 3 months of age, a conus below the L1-2 disk space may indicate a tethered cord and termination below L3-4 is unmistakably tethered. "Cord tethering is often assumed when the conus is below the normal L2-3 level.
TCS, however, is a clinical diagnosis that should be based on "neurological and musculoskeletal signs and symptoms. Imaging features are in general obtained to support rather than make the diagnosis." This is especially true for cases of occult tethered cord, where the patient has the symptoms of tethered cord syndrome but MRI reveals the conus to be above the L2 level. Clinical evaluation may include a simple rectal examination and may also include invasive or non-invasive urological examination. "Bladder dysfunction occurs in ~40% of patients affected by tethered cord syndrome. ... [I]t may be the earliest sign of the syndrome."
Treatment
Because neurological deficits are generally irreversible, early surgery is recommended when symptoms begin to worsen. In children, early surgery is recommended to prevent further neurological deterioration, including but not limited to chronic urinary incontinence.
In adults, surgery to detether (free) the spinal cord can reduce the size and further development of cysts in the cord and may restore some function or alleviate other symptoms. Although detethering is the common surgical approach to TCS, another surgical option for adults is a spine-shortening vertebral osteotomy. A vertebral osteotomy aims to indirectly relieve the excess tension on the spinal cord by removing a portion of the spine, shortening it. This procedure offers a unique benefit in that the spinal cord remains fixated to the spine, preventing retethering and spinal cord injury as possible surgical complications. However, its complexity and limited “track record” presently keeps vertebral osteotomies reserved as an option for patients who have failed in preventing retethering after detethering procedure(s).Other treatment is symptomatic and supportive. Medications such as NSAIDs, opiates, synthetic opiates, COX-2 inhibitors, and off-label applications of tricyclic antidepressants combined with anti-seizure compounds have yet to prove they are of value in treatment of this afflictions pain manifestations. There is anecdotal evidence that TENS units may benefit some patients.
Treatment may be needed in adults who, while previously asymptomatic, begin to experience pain, lower back degeneration, scoliosis, neck and upper back problems and bladder control issues. Surgery on adults with minimal symptoms is somewhat controversial. For example, a website from the Columbia University Department of Neurosurgery says, "For the child that has reached adult height with minimal if any symptoms, some neurosurgeons would advocate careful observation only." However, surgery for those who have worsening symptoms is less controversial. If the only abnormality is a thickened, shortened filum, then a limited lumbosacral laminectomy with division of the filum may be sufficient to relieve the symptoms.This syndrome was first noticed in the late 19th century. While information has been available for years, little widespread blind research has been done. More research has been called for, and doctors have conducted many studies with good results. There is a low morbidity rate, and no complications have been documented other than those typical of any type of back surgery. The association of this condition with others has been noticed, and needs further research to understand such relationships. TCS is causally linked to Chiari malformation and any affirmative diagnosis of TCS must be followed by screening for Chiaris several degrees. TCS may also be related to Ehlers–Danlos syndrome, or Klippel–Feil syndrome, which should also be screened for upon a positive TCS diagnosis. Spinal compression and the resulting relief is a known issue with this disorder. Like with the early-onset form, this disease form is linked to the Arnold–Chiari malformation, in which the brain is pulled or lowers into the top of the spine.
Prognosis
The disorder progresses with age, but the aforementioned treatments can help prevent or sometimes relieve symptoms. With treatment, individuals with tethered spinal cord syndrome have a normal life expectancy. Studies have shown surgery can help improve low back pain, urinary symptoms leg weakness and walking distance. However, most neurological and motor impairments are irreversible.
References
External links
National institute of Health page |
Aortic rupture | Aortic rupture is the rupture or breakage of the aorta, the largest artery in the body. Aortic rupture is a rare, extremely dangerous condition. The most common cause is an abdominal aortic aneurysm that has ruptured spontaneously. Aortic rupture is distinct from aortic dissection, which is a tear through the inner wall of the aorta that can block the flow of blood through the aorta to the heart or abdominal organs.
An aortic rupture can be classified according to its cause into one of the following main types:
Traumatic aortic rupture
Aortic rupture secondary to an aortic aneurysm
Signs and symptoms
Symptoms
Tearing pain, located in the abdomen, flank, groin, or back
Loss of consciousness
Signs
Low blood pressure from hypovolemic shock
Fast heart rate
Blue discoloration of the skin
Altered mental status
Bruising of the flank, a sign of retroperitoneal bleeding.
Death
Causes
The most common cause of aortic rupture is a ruptured aortic aneurysm. Other causes include trauma and iatrogenic (procedure-related) causes.
Mechanism
The wall of the aorta is an elastic structure which requires integrity. Rupture results from either loss of wall strength to the point at which systemic pressure is greater than wall strength, or external destruction of the wall of the aorta, by a tumor or traumatic means. The bleeding can be retroperitoneal or intraperitoneal, or the rupture can create an aortocaval (between the aorta and inferior vena cava) or aortoenteric (between the aorta and intestine) fistula.
Diagnosis
The condition is often suspected in patients close to death with abdominal trauma or with relevant risk-factors. Diagnosis may be confirmed by ultrasound or X-ray computed tomography (CT) scan.
Prevention
Prevention of aortic rupture begins with screening for disease of the aorta. If indicated, treatment with EVAR or open repair of the diseased aorta can limit the risk of aortic rupture.
Treatment
Aortic ruptures can be repaired surgically via open aortic surgery or using endovascular therapy (EVAR), regardless of cause, just as non-ruptured aortic aneurysms are repaired. An aortic occlusion balloon can be placed to stabilize the patient and prevent further blood loss prior to the induction of anesthesia.
Prognosis
An aortic rupture is a catastrophic medical emergency. People rarely survive such an injury. Mortality from aortic rupture is up to 90%. 65–75% of patients die before they arrive at hospital and up to 90% die before they reach the operating room.
== References == |
Retrolisthesis | A retrolisthesis is a posterior displacement of one vertebral body with respect to the subjacent vertebra to a degree less than a luxation (dislocation). Retrolistheses are most easily diagnosed on lateral x-ray views of the spine. Views where care has been taken to expose for a true lateral view without any rotation offer the best diagnostic quality.
Retrolistheses are found most prominently in the cervical spine and lumbar region but can also be seen in the thoracic area.
Classification
Retrolisthesis can be classified as a form of spondylolisthesis, since spondylolisthesis is often defined in the literature as displacement in any direction. Yet, medical dictionaries usually define spondylolisthesis specifically as the forward or anterior displacement of a vertebra over the vertebra inferior to it (or the sacrum). Retrolisthesis is also called retrospondylolisthesis.
Signs and symptoms
Retrolisthesis may lead to symptoms of greatly varying intensity and distribution. This is because of the variable nature of the impact on nerve tissue and of the mechanical impact on the spinal joints themselves.Structural instability may be experienced as a local uneasiness through to a more far reaching structural compensatory distortion involving the whole spine. If the joints are stuck in a retrolisthesis configuration there may also be changes to range of motion.Pain may be experienced as a result of irritation to the sensory nerve roots by bone depending on the degree of displacement and the presence of any rotatory positioning of the individual spinal motion segments. The soft tissue of the disc is often caused to bulge in retrolistheses. These cannot be determined by plain films, as the x-ray passes through the soft tissue. A study by Giles et al., stated that sixteen of the thirty patients (53%) had retrolisthesis of L5 on S1 ranging from 2–9 mm; these patients had either intervertebral disc bulging or protrusion on CT examination ranging from 3–7 mm into the spinal canal. Fourteen patients (47%) without retrolisthesis (control group) did not show any retrolisthesis and the CT did not show any bulge/protrusion. On categorizing x-ray and CT pathology as being present or not, the well positioned i.e. true lateral plain x-ray film revealed a sensitivity and specificity of 100% ([95% Confidence Interval. = [89%–100%]) for bulge/protrusion in this preliminary study.” (7)Spinal cord compressions are also possible with patients experiencing pain, rigidity and neurologic signs that may follow some distance along nerves to cause symptoms at some distance from the location of the retrolisthesis.
Diagnosis
Complete Retrolisthesis - The body of one vertebra is posterior to both the vertebral body of the segment of the spine above as well as below.Stairstepped Retrolisthesis - The body of one vertebra is posterior to the body of the spinal segment above, but is anterior to the one below.Partial Retrolisthesis - The body of one vertebra is posterior to the body of the spinal segment either above or below. (3)
Grading
Since the vertebral body in a retrolisthesis moves in a posterior direction, the grading used for spondylolistheses is of little use. It is however useful to divide the anterior to posterior dimension of the intervertebral foramina (IVF) (4) into four equal units. A posterior displacement of up to ¼ of the IVF is graded as Grade 1, ¼ to ½ as Grade 2, ½ to ¾ as Grade 3, ¾ to total occlusion of the IVF as Grade 4. Alternatively, a measurement of the amount of displacement can also made by measuring the bone displacement in millimetres.Retrolistheses can be caused by injury and the resulting instability of the connecting soft tissues especially ligaments, discs, muscles, tendons and fascia. They may also involve muscles through spasm as a result of nerve malfunction due to pressure caused by the posterior displacement of the vertebra encroaching on the contents of the IVF. The IVFs contents include spinal (sensory and motor) nerves, arteries, veins and lymphatic vessels which cater to the nutritional and waste removal needs of the spinal cord.Degenerative spinal changes are often seen at the levels where a retrolisthesis is found. These changes are more pronounced as time progresses after injury, and are evidenced by end plate osteophytosis, disc damage, disc narrowing, desiccation and disc bulging. “A retrolisthesis hyperloads at least one disc and puts shearing forces on the anterior longitudinal ligament, the annular rings, nucleus pulposus, cartilage end plates and capsular ligaments. The bulging, twisting and straining tissues attached to the endplates pull, push and stretch it. It is worsened with time, becoming irreversible.” This is the etiology of degenerative joint disease. (5)
Associated radiological findings include a vacuum phenomenon (in the nucleus pulposis of the adjacent intervertebral disc), reduction of disc height with corresponding loss of the disc space, marginal sclerosis of the adjacent vertebral bodies, osteophyte formation and apophyseal joint instability. With a retrolisthesis there is always a less than ideal positioning of spinal segments. There is also always a reduced anterior to posterior dimension of the spinal canal compared to the way it is supposed to be. The greater the posterior displacement, the more significant it is for producing a dysfunctional spinal cord or even a cauda equina syndrome.
Joint stability
Joint stability is easily evaluated by the use of flexion and extension lateral x-ray views of the spine.
A summary of part of the DRE tables (6) give a guide as to the implications of the joint instability. If either translation or angular change is determined from flexion to extension to the degree shown in the table below, then Category IV instability is present. See also Joint stability.Translation is a gliding motion where one bone of a joint glides over its neighbour.
Management
References
6. Hadley, Lee A. (MD), (1973) “Anatomicoroentgenographic Studies of the Spine”. 390.7. Cocchiarella L., Andersson, G. “American Medical Association Guides to the Evaluation of Permanent Impairment”, 5th edition, Tables 15- 3, 15-4, 15-5.8. Giles, L.G.F.; Muller R.; and Winter G.J. (2006) “Lumbosacral disc bulge or protrusion suggested by lateral lumbosacral plain x-ray film – preliminary results.” Journal of Bone and Joint Surgery. British Volume, Vol 88-B, Issue SUPP_III, 450. |
Bicornuate uterus | A bicornuate uterus or bicornate uterus (from the Latin cornū, meaning "horn"), is a type of mullerian anomaly in the human uterus, where there is a deep indentation at the fundus (top) of the uterus.
Pathophysiology
A bicornuate uterus develops during embryogenesis. It occurs when the proximal (upper) portion of the paramesonephric ducts does not fuse, but the distal portion that develops into the lower uterine segment, cervix, and upper vagina fuses normally.
Diagnosis
Diagnosis of bicornuate uterus typically involves imaging of the uterus with 2D or 3D ultrasound, hysterosalpingography, or magnetic resonance imaging (MRI). On imaging, a bicornuate uterus can be distinguished from a septate uterus by the angle between the cornua (intercornual angle): less than 75 degrees in a septate uterus, and greater than 105 degrees in a bicornuate uterus. Measuring the depth of the cleft between the cornua (fundal cleft) may also assist in diagnosis; a cleft of over 1 centimetre (0.39 in) is indicative of bicornuate uterus.
Classification
Bicornuate uterus is typically classified based on whether or not the division extends to the external cervical os. Bicornuate uteri with a division above the os are called bicornuate unicollis and those with a divided os are called bicornuate bicollis. There is a continuous range of the degree and location of the fusion of the paramesonephric ducts, and existence of a spectrum, rather than a fixed number of types corresponding to strict medical definitions.
Two processes that occur during the embryonic development of the paramesonephric ducts — fusion and reabsorption — can be affected to different degrees.There is also a hybrid bicornuate uterus: External fundal depressions of variable depths associated with a septate uterus can be seen by laparoscopy, indicating the coexistence of the two anomalies. These cases are candidates for hysteroscopic metroplasty under appropriate sonographic and/or laparoscopic monitoring.An obstructed bicornuate uterus showing uni or bilateral obstruction might also be possible. The unilateral obstruction is more difficult to diagnose than the bilateral obstructive. A delay in the diagnosis can be problematic and compromise the reproductive abilities of those cases.
Treatment
Bicornuate uterus typically requires no treatment. In those who do need treatment, metroplasty is the surgical correction of choice. Women who have recurrent miscarriage with no other explanation may benefit from surgery.
Epidemiology
The occurrence of all types of paramesonephric duct abnormalities in women is estimated around 0.4%. A bicornuate uterus is estimated to occur in 0.1–0.6% of women in the US. It is possible that this figure is an underestimate, since subtle abnormalities often go undetected. Some intersex individuals whose external genitalia are perceived as being male may nonetheless have a variably shaped uterus. Women exposed in utero to diethylstilbestrol (DES) are at risk for this abnormality.
In pregnancy
A bicornuate uterus is an indication for increased surveillance of a pregnancy, though most women with a bicornuate uterus are able to have healthy pregnancies. Women with a bicornuate uterus are at an increased risk of recurrent miscarriage, preterm birth, malpresentation, disruptions to fetal growth, premature rupture of membranes, placenta previa and retained placenta (which can lead to postpartum hemorrhage). This is due to the distortion of the normal shape of the uterus, distortion of the cervix leading to cervical insufficiency, or under-vascularization of the endometrium as the pregnancy requires more blood supply. In some cases, the nonpregnant horn can rupture during labor, necessitating emergency surgery.Fetuses developing in bicornuate uteri are more likely to present breech or transverse, with the fetal head in one horn and the feet in the other. This will often necessitate cesarean delivery. If the fetus is vertex (head down), the two horns may not contract in coordination, or the horn that does not contain the pregnancy may interfere with contractions and descent of the fetus, causing obstructed labor.
Effect on intrauterine device usage
Usage of intrauterine device (IUD) with copper requires one IUD in each horn to be effective in case of bicornuate uterus. The same practice is generally applied when using IUD with progestogen due to lack of evidence of efficacy with only one IUD. Evidence is lacking regarding progestogen IUD usage for menorrhagia in bicornuate uterus, but a case report showed good effect with a single IUD.
References
== External links == |
Skull fracture | A skull fracture is a break in one or more of the eight bones that form the cranial portion of the skull, usually occurring as a result of blunt force trauma. If the force of the impact is excessive, the bone may fracture at or near the site of the impact and cause damage to the underlying structures within the skull such as the membranes, blood vessels, and brain.
While an uncomplicated skull fracture can occur without associated physical or neurological damage and is in itself usually not clinically significant, a fracture in healthy bone indicates that a substantial amount of force has been applied and increases the possibility of associated injury. Any significant blow to the head results in a concussion, with or without loss of consciousness.
A fracture in conjunction with an overlying laceration that tears the epidermis and the meninges, or runs through the paranasal sinuses and the middle ear structures, bringing the outside environment into contact with the cranial cavity is called a compound fracture. Compound fractures can either be clean or contaminated.
There are four major types of skull fractures: linear, depressed, diastatic, and basilar. Linear fractures are the most common, and usually require no intervention for the fracture itself. Depressed fractures are usually comminuted, with broken portions of bone displaced inward—and may require surgical intervention to repair underlying tissue damage. Diastatic fractures widen the sutures of the skull and usually affect children under three. Basilar fractures are in the bones at the base of the skull.
Types
Linear fracture
Linear skull fractures are breaks in the bone that transverse the full thickness of the skull from the outer to inner table. They are usually fairly straight with no bone displacement. The common cause of injury is blunt force trauma where the impact energy transferred over a wide area of the skull.Linear skull fractures are usually of little clinical significance unless they parallel in close proximity or transverse a suture, or they involve a venous sinus groove or vascular channel. The resulting complications may include suture diastasis, venous sinus thrombosis, and epidural hematoma. In young children, although rare, the possibility exists of developing a growing skull fracture especially if the fracture occurs in the parietal bone.
Depressed fracture
A depressed skull fracture is a type of fracture usually resulting from blunt force trauma, such as getting struck with a hammer, rock or getting kicked in the head. These types of fractures—which occur in 11% of severe head injuries—are comminuted fractures in which broken bones displace inward. Depressed skull fractures present a high risk of increased pressure on the brain, or a hemorrhage to the brain that crushes the delicate tissue.Compound depressed skull fractures occur when there is a laceration over the fracture, putting the internal cranial cavity in contact with the outside environment, increasing the risk of contamination and infection. In complex depressed fractures, the dura mater is torn. Depressed skull fractures may require surgery to lift the bones off the brain if they are pressing on it by making burr holes on the adjacent normal skull.
Diastatic fracture
Diastatic fractures occur when the fracture line transverses
one or more sutures of the skull causing a widening of the suture. While this type of fracture is usually seen in infants and young children as the sutures are not yet fused it can also occur in adults. When a diastatic fracture occurs in adults it usually affects the lambdoidal suture as this suture does not fully fuse in adults until about the age of 60. Most adult diastatic fractures are caused by severe head injuries. Due to the trauma, diastatic fracture occurs with the collapse of the surrounding head bones. It crushes the delicate tissue, similarly to a depressed skull fracture.Diastatic fractures can occur with different types of fractures and it is also possible for diastasis of the cranial sutures to occur without a concomitant fracture. Sutural diastasis may also occur in various congenital disorders such as cleidocranial dysplasia and osteogenesis imperfecta.
Basilar fracture
Basilar skull fractures are linear fractures that occur in the floor of the cranial vault (skull base), which require more force to cause than other areas of the neurocranium. Thus they are rare, occurring as the only fracture in only 4% of severe head injury patients.
Basilar fractures have characteristic signs: blood in the sinuses; cerebrospinal fluid rhinorrhea (CSF leaking from the nose) or from the ears (cerebrospinal fluid otorrhea); periorbital ecchymosis often called raccoon eyes (bruising of the orbits of the eyes that result from blood collecting there as it leaks from the fracture site); and retroauricular ecchymosis known as "Battles sign" (bruising over the mastoid process).
Growing fracture
A growing skull fracture (GSF) also known as a craniocerebral erosion or leptomeningeal cyst due to the usual development of a cystic mass filled with cerebrospinal fluid is a rare complication of head injury usually associated with linear skull fractures of the parietal bone in children under 3. It has been reported in older children in atypical regions of the skull such as the basioccipital and the base of the skull base and in association with other types of skull fractures. It is characterized by a diastatic enlargement of the fracture.Various factors are associated with the development of a GSF. The primary causative factor is a tear in the dura mater. The skull fracture enlarges due, in part, to the rapid physiologic growth of the brain that occurs in young children, and brain cerebrospinal fluid (CSF) pulsations in the underlying leptomeningeal cystic mass.
Cranial burst fracture
A cranial burst skull fracture, usually occurring with severe injuries in infants less than 1 year of age, is a closed, diastatic skull fracture with cerebral extrusion beyond the outer table of the skull under the intact scalp.Acute scalp swelling is associated with this type of fracture. In equivocal cases without immediate scalp swelling the diagnosis may be made via the use of magnetic resonance imaging thus insuring more prompt treatment and avoiding the development of a "growing skull fracture".
Compound fracture
A fracture in conjunction with an overlying laceration that tears the epidermis and the meninges—or runs through the paranasal sinuses and the middle ear structures, putting the outside environment in contact with the cranial cavity—is a compound fracture.Compound fractures may either be clean or contaminated. Intracranial air (pneumocephalus) may occur in compound skull fractures.The most serious complication of compound skull fractures is infection. Increased risk factors for infection include visible contamination, meningeal tear, loose bone fragments and presenting for treatment more than eight hours after initial injury.
Compound elevated fracture
A compound elevated skull fracture is a rare type of skull fracture where the fractured bone is elevated above the intact outer table of the skull. This type of skull fracture is always compound in nature. It can be caused during an assault with a weapon where the initial blow penetrates the skull and the underlying meninges and, on withdrawal, the weapon lifts the fractured portion of the skull outward. It can also be caused by the skull rotating while being struck in a case of blunt force trauma, the skull rotating while striking an inanimate object as in a fall, or it may occur during transfer of a patient after an initial compound head injury.
Anatomy
The human skull is anatomically divided into two parts: the neurocranium, formed by eight cranial bones that houses and protect the brain—and the facial skeleton (viscerocranium) composed of fourteen bones, not including the three ossicles of the inner ear. The term skull fracture typically means fractures to the neurocranium, while fractures of the facial portion of the skull are facial fractures, or if the jaw is fractured, a mandibular fracture.The eight cranial bones are separated by sutures : one frontal bone, two parietal bones, two temporal bones, one occipital bone, one sphenoid bone, and one ethmoid bone.The bones of the skull are in three layers: the hard compact layer of the external table (lamina externa), the diploë (a spongy layer of red bone marrow in the middle, and the compact layer of the inner table (Lamina interna).Skull thickness is variable, depending on location. Thus the traumatic impact required to cause a fracture depends on the impact site. The skull is thick at the glabella, the external occipital protuberance, the mastoid processes, and the external angular process of the frontal bone. Areas of the skull that are covered with muscle have no underlying diploë formation between the internal and external lamina, which results in thin bone more susceptible to fractures.Skull fractures occur more easily at the thin squamous temporal and parietal bones, the sphenoid sinus, the foramen magnum (the opening at the base of the skull that the spinal cord passes through), the petrous temporal ridge, and the inner portions of the sphenoid wings at the base of the skull. The middle cranial fossa, a depression at the base of the cranial cavity forms the thinnest part of the skull and is thus the weakest part. This area of the cranial floor is weakened further by the presence of multiple foramina; as a result this section is at higher risk for basilar skull fractures to occur. Other areas more susceptible to fractures are the cribriform plate, the roof of orbits in the anterior cranial fossa, and the areas between the mastoid and dural sinuses in the posterior cranial fossa.
Prognosis
Children with a simple skull fracture without other concerns are at low risk of a bad outcome and rarely require aggressive treatment.The presence of a concussion or skull fracture in people after trauma without intracranial hemorrhage or focal neurologic deficits was indicated in long term cognitive impairments and emotional lability at nearly double the rate as those patients without either complication.Those with a skull fracture were shown to have "neuropsychological dysfunction, even in the absence of intracranial pathology or more severe disturbance of consciousness on the GCS".
See also
Le Fort facial fracture
Facial fracture
Mandibular fracture
References
Bibliography
Forensic Neuropathology By Jan E. Leestma Publisher: CRC Press; 2 edition (October 14, 2008) Language: English ISBN 0-8493-9167-9 ISBN 978-0849391675
Neuroimaging: Clinical and Physical Principles By Robert A. Zimmerman, Wendell A. Gibby, Raymond F. Carmody Publisher: Springer; 1st edition (January 15, 2000) Language: English ISBN 0387949631 ISBN 978-0-387-94963-5
External links
Medscape: Imaging in Skull Fractures
Growing skull fracture at Medpix
"Tutorial: CT in Head Trauma"
Head Trauma at Emedicine.com
Skull Fractures at MedPix |
Benign neonatal sleep myoclonus | Benign neonatal sleep myoclonus (BNSM) is the occurrence of myoclonus (jerky movements) during sleep. It is not associated with seizures.BNSM occurs in the first few weeks of life, and usually resolves on its own within the first 3-4 months of life. It often worries parents because it can appear like seizures, but is not. Features that can help distinguish this condition from seizures include: The myoclonic movements only occur during sleep, when baby is woken up the myoclonic movements stop, normal EEG, normal neurological examination, normal developmental examination. The myoclonic jerks occur during non-REM sleep.
References
== External links == |
Iridodonesis | Iridodonesis () is the vibration or agitated motion of the iris with eye movement. This may be caused by lens subluxation, the incomplete or partial dislocation of the lens; or by aphakia, the absence of a lens. The term originated from irido- (Latin: iris) + doneo (Greek: δονεο, to shake to and fro).
See also
Phacodonesis
References
External links
An example of iridodonesis on YouTube |
Cranioschisis | Cranioschisis (Greek: κρανιον kranion, "skull", and σχίσις schisis, "split"), or dysraphism, is a neural tube defect involving the skull. In this defect, the cranium fails to close completely (especially at the occipital region). Thus, the brain is exposed to the amnios and eventually degenerates, causing anencephaly.Craniorachischisis is on the extreme end of the dysraphism spectrum, wherein the entire length of the neural tube fails to close.
See also
Rachischisis
Spina bifida
== References == |
Pseudomyxoma peritonei | Pseudomyxoma peritonei (PMP) is a clinical condition caused by cancerous cells (mucinous adenocarcinoma) that produce abundant mucin or gelatinous ascites. The tumors cause fibrosis of tissues and impede digestion or organ function, and if left untreated, the tumors and mucin they produce will fill the abdominal cavity. This will result in compression of organs and will destroy the function of the colon, small intestine, stomach, or other organs. Prognosis with treatment in many cases is optimistic, but the disease is lethal if untreated, with death occurring via cachexia, bowel obstruction, or other types of complications.
This disease is most commonly caused by an appendiceal primary cancer (cancer of the appendix); mucinous tumors of the ovary have also been implicated, although in most cases ovarian involvement is favored to be a metastasis from an appendiceal or other gastrointestinal source. Disease is typically classified as low- or high-grade (with signet ring cells). When disease presents with low-grade histologic features the cancer rarely spreads through the lymphatic system or through the bloodstream.
Signs and symptoms
Signs and symptoms of pseudomyxoma peritonei may include abdominal or pelvic pain and/or bloating, distension, digestive disorders, weight changes, increased girth, and infertility.
Cause
The primary tumor appears to arise from the MUC2 expressing goblet cells and most commonly from these cells in the appendix. The K-Ras and p53 genes may be involved in the oncogenesis. It may be diagnosed with a range of conditions. While the majority of these cases are associated with appendiceal carcinomas, other conditions may also be found, including disseminated peritoneal adenomucinosis (DPAM), peritoneal carcinomas, several mucinous tumors (mucinous adenocarcinoma, mucinous cystadenoma, and mucinous cystadenocarcinoma), as well as other disease states. Other primary sites that have been reported include colon, rectum, stomach, gallbladder, bile ducts, small intestine, urinary bladder, lung, breast, fallopian tubes, and the pancreas.
Diagnosis
This disease is often discovered during surgery for other conditions, e.g., hernia repair, following which an experienced pathologist can confirm the diagnosis. Advanced stages may present as tumors palpable on the abdomen or distention of the belly ("jelly belly" is sometimes used as a slang term for the condition). Due to the rarity of this disease, it is important to obtain an accurate diagnosis so that appropriate treatment may be obtained from a Gastro intestinal cancer surgeon. Diagnostic tests may include CT scans, examination of tissue samples obtained through laparoscopy, and the evaluation of tumor markers. In most cases a colonoscopy is unsuitable as a diagnostic tool because in most cases appendix cancer invades the abdominal cavity but not the colon (however, spread inside the colon is occasionally reported). PET scans may be used to evaluate high-grade mucinous adenocarcinoma, but this test is not reliable for detecting low-grade tumors because those do not take up the dye which shows up on scans. New MRI procedures are being developed for disease monitoring, but standard MRIs are not typically used as a diagnostic tool. Diagnosis is confirmed through pathology.
Classification
There is substantial debate regarding histopathologic classification of pseudomyxoma peritonei. In 1995, Ronnett et al. proposed separating pseudomyxoma peritonei cases into two diagnostic categories: adenoma (disseminated peritoneal adenomucinosis, DPAM) or carcinoma (peritoneal mucinous carcinomatosis, PMCA) with a third category reserved for cases with intermediate features. In this classification system, cases of DPAM were characterized by peritoneal lesions composed of abundant extracellular mucin containing scant simple to focally proliferative mucinous epithelium with little cytologic atypia or mitotic activity (in other words, most cells looked fairly normal and there was no evidence of mitosis which would indicate that cells were rapidly dividing), with or without an associated appendiceal mucinous adenoma. Cases of PMCA were characterized by peritoneal lesions composed of more abundant mucinous epithelium with the architectural and cytologic features of carcinoma (irregular cells, evidence that cells were rapidly dividing, and other criteria), with or without an associated primary mucinous adenocarcinoma. Bradley et al. (2007) argued that continued use of non-malignant terms, i.e., adenoma, for those frequent cases with low-grade features (such as DPAM), is misleading because pseudomyxoma peritonei is a disease state that results from invasion of the abdominal cavity by cells with uncontrolled growth. Bradley states that an adenoma, by definition, is a tumor confined to the appendiceal mucosa with absolutely no evidence of invasion beyond the muscularis mucosae.
The term mucinous adenocarcinoma is used in different contexts depending on the reference material used by the pathologist for disease classification. For example, neoplasms characterized by high-grade features, invasive glands and or signet ring cells, are termed adenocarcinoma in pathology literature. However, some pathologists (e.g., Odze and Goldblum, Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas, 2nd ed.) also use the term mucinous adenocarcinoma when referring to low-grade, well-differentiated tumors lacking high-grade features. Low-grade mucinous adenocarcinoma is used by the American Joint Committee on Cancer and World Health Organization and is nearly or completely synonymous with the DPAM designation. For low-grade mucinous adenocarcinoma, disease may be designated as "benign" because tumors do not invade deeply into tissue and rarely metastasize to parenchyma of organs; this designation may be misleading and confusing to the layperson because pseudomyxoma peritonei is not a harmless condition, fatal if untreated. High-grade or poorly differentiated mucinous adenocarcinoma has a generally poorer prognosis, though surgical treatment with heated intra-peritoneal chemotherapy (HIPEC) is yielding promising outcomes (see surgical treatment).
Immunohistochemistry
Immunohistochemical features:
Diffuse expression of SATB2, CK20, CDX2, and mCEA
Sometimes patchy CK7; negative PAX8
High-grade neoplasms may show loss of DPC4 (10%)
Treatment
Treatment is variable, both due to its rarity and to its frequently slow-growing nature. Treatment ranges from watchful waiting to debulking and hyperthermic intraperitoneal chemotherapy (HIPEC, also called intraperitoneal hyperthermic chemotherapy, IPHC) with cytoreductive surgery.
Surgical
The standard of care for mucinous adenocarcinoma with clinical condition PMP involves cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), performed by surgical oncologists who specialize in treating PMP. Some surgeons also apply early post-operative intraperitonial chemotherapy (EPIC), adjunct to surgical cytoreduction and HIPEC. In situations where surgery is not required immediately, patients can be monitored via CT scans, tumor marker laboratory tests, and physical symptoms, to determine when, and if, surgery is warranted. Although some surgical procedures may be rather extensive, patients can and do recover from surgery, and the majority of these patients can and do live productive lives.In debulking, the surgeon attempts to remove as much tumor as possible. CRS or cytoreductive surgery involves surgical removal of the peritoneum and any adjacent organs which appear to have tumor seeding. Since the mucus tends to pool at the bottom of the abdominal cavity, it is common to remove the ovaries, fallopian tubes, uterus, and parts of the large intestine. Depending upon the spread of the tumor, other organs might be removed, including but not limited to the gallbladder, spleen, and portions of the small intestine and/or stomach. For organs that cannot be removed safely (like the liver), the surgeon strips off the tumor from the surface.
Chemotherapy
Chemotherapy (typically utilising the chemotherapeutic agent Mitomycin C) may be infused directly into the abdominal cavity after cytoreductive surgery (surgery removing all visible disease to kill remaining microscopic cancerous tumors and free floating cells). The heated chemotherapy (HIPEC) is perfused throughout the abdominal cavity for an hour or two as the last step in the surgery, or ports are installed to allow circulation and/or drainage of the chemicals for one to five days after surgery, known as early postoperative intraperitoneal chemotherapy (EPIC). EPIC may be given in multiple cycles for several months after surgery.Systemic chemotherapy may be administered as additional or adjuvant treatment. Due to the increased availability of new chemotherapies developed for colorectal cancer patients, some patients have experienced stability in tumor growth with systemic chemotherapy. Systemic chemotherapy is generally reserved for patients with advanced disease, recurrent disease, or disease that has spread to the lymph nodes or distant sites.This disease may recur following surgery and chemotherapy. Periodic post operative CT scans and tumor marker laboratory tests are used to monitor patients for disease progression.
Epidemiology
The overall incidence was previously estimated at 0.5 to 1 cases per 100,000 people per year. Recent research in Europe indicates that the previous estimate of 1-2 persons per million may be underestimating the actual rate by approximately half, with the real incidence being approximately 3.2 persons per million, and the prevalence being 22 persons per million. It is slightly more common in women than men (male:female ratio of approximately 1:1.3,), although the actual ratio is difficult to identify due to potential misdiagnoses and possibly inclusion bias in reported studies. The median age at presentation is typically about 50 years with a range of 20–25 years, but PMP may strike persons of any age.
History
The first case was described by Carl F. Rokitansky in 1842. Werth in 1884 coined the term pseudomyxoma peritonei, describing it in association with a mucinous ovarian tumor. In 1901 Frankel described the first case associated with a cyst of the appendix. Audrey Hepburn died of pseudomyxoma peritonei in 1993.
See also
Pseudomyxoma Survivor
References
== External links == |
Pronator teres syndrome | Pronator teres syndrome is a compression neuropathy of the median nerve at the elbow.
It is rare compared to compression at the wrist (carpal tunnel syndrome) or isolated injury of the anterior interosseous branch of the median nerve (anterior interosseous syndrome).
Symptoms
Compression of the median nerve in the region of the elbow or proximal part of the forearm can cause pain and/or numbness in the distribution of the distal median nerve, and weakness of the muscles innervated by the anterior interosseous nerve: the flexor pollicis longus ("FPL"), the flexor digitorum profundus of the index finger ("FDP IF"), and the pronator quadratus ("PQ").
The pain tends to be at the wrist joint, in the distribution of the terminal branch of the anterior interosseous nerve, and is exacerbated by sustained pronation (i.e., wrist down).
The weakness of the FPL and FDP IF is painless, but causes people to "drop things" and have a sense of loss of dexterity. Pinching with the wrist flexed magnifies the expression of this weakness, by reducing resting tension on the muscles of pinch. For instance, "child-proof" prescription pill bottles may be difficult to open. People easily adapt to this weakness without conscious effort or self-awareness, by using 1) the next muscles down, which are innervated by a different nerve, or 2) using ligaments to give resistance, pinching laterally against the index finger or against the side of the end of the thumb, or 3) by what is called "tenodesis," which in this case is extension of the wrist joint, which tightens the muscles on the palm side of the hand. These adaptations on a moment-to-moment basis do not cause problems, but over time in loose-jointed patients, such as many women and people with collagen disorders such as Ehlers Danlos Syndrome, the adaptations can cause soft tissue failures that can become painful, particularly at the base of the thumb and in the proximal forearm (i.e., "Tennis Elbow" in a non-tennis player).
Causes
The most common cause is entrapment of the median nerve between the two heads of the pronator teres muscle. Other causes are compression of the nerve from the fibrous arch of the flexor superficialis, or the thickening of the bicipital aponeurosis.
Anatomy
The median nerve passes through the cubital fossa and passes between the two heads of pronator teres muscle into the forearm. It then runs between flexor digitorum superficialis and flexor digitorum profundus muscles and enters the hand through the carpal tunnel.It innervates most of the flexor muscles in the forearm and hand. Its sensory component supplies the skin of the palm, thumb, index and middle finger as well as half the ring finger, and, importantly and often forgotten, the bones of the wrist.
In the proximal forearm it gives rise to the anterior interosseous nerve which innervates the flexor of the thumb (FPL), the flexor digitorum profundus of the index finger (FDP IF), and the pronator quadratus, and terminates in a sensory branch to the bones of the wrist, i.e., the carpal tunnel. Compression of the proximal median nerve results in weakness of these three muscles, and can cause aching pain in the wrist on the basis of the sensory nerve to the carpal bones.
Diagnosis
The most common chief complaint is intermittent pain in the wrist, associated with sustained pronation, frequently misinterpreted by patients and providers as "tendonitis." This is usually accompanied by the perception of "hand weakness," and "dropping things." The characteristic physical finding is tenderness over the proximal median nerve, with ensuing numbness in the hand in less than a minute, and/or numbness in the hand with resisted pronation of the forearm in less than a minute.The flexor pollicis longus and FDP of the index finger are weak, leading to impairment of pinching firmly. This reflects involvement of the anterior interosseous nerve.Sensory changes may be found in the first three fingers as well as in the palm, indicating impairment of the median nerve proximal to the flexor retinaculum, but tend to involve the sensation of the entire hand going numb at night, with any pressure on the median nerve on the areas at the inside of the elbow.The clinical and electrophysiological features of pronator teres syndrome are quite different from patients with carpal tunnel syndrome or pure anterior interosseous syndrome, and are typically normal. Proper localisation is crucial to treatment options.Conduction velocity of the median nerve in the proximal forearm may be slow but the distal latency and sensory nerve action potential at the wrist are normal.Although MRI may show denervation atrophy of the affected muscles, its role in the evaluation of pronator teres syndrome is unclear.
If the EMG or the MRI are abnormal for the pronator teres muscle and the flexor carpi radialis, this implies that the problem is at or proximal to the elbow, as the takeoff of the nerves to these muscles occurs proximal to the elbow.
Treatment
Injection of corticosteroids into the pronator teres muscle may produce relief of symptoms.Massage therapy can also provide relief for individuals experiencing this condition.Surgical decompression can provide benefit in selected cases.
References
== External links == |
Variegate porphyria | Variegate porphyria, also known by several other names, is an autosomal dominant porphyria that can have acute (severe but usually not long-lasting) symptoms along with symptoms that affect the skin. The disorder results from low levels of the enzyme responsible for the seventh step in heme production. Heme is a vital molecule for all of the bodys organs. It is a component of hemoglobin, the molecule that carries oxygen in the blood.
Signs and symptoms
When symptoms occur, they can include acute attacks (similar to acute intermittent porphyria) or skin damage. Acute attacks usually begin in adulthood and cause abdominal pain, vomiting, diarrhoea and constipation. During an attack, a person may also experience muscle weakness, seizures, and mental changes such as anxiety and hallucinations. These signs and symptoms are triggered by nongenetic factors such as certain drugs, dieting or fasting, certain hormones and stress.Some people with variegate porphyria have skin that is overly sensitive to sunlight (photosensitive). Areas of skin exposed to the sun develop severe blistering, scarring, changes in pigmentation, and increased hair growth. Exposed skin becomes fragile and is easily damaged.Rarely, the signs and symptoms of variegate porphyria can begin in infancy or early childhood. In such cases, the signs and symptoms are usually more severe than those starting later in life.
Genetics
Mutations in the PPOX gene cause variegate porphyria. The PPOX gene makes a membrane bound mitochondrial enzyme called protoporphyrinogen oxidase, which is critical to the chemical process that leads to heme production. The activity of this enzyme is reduced by 50 percent in most people with variegate porphyria. In severe cases that begin early in life, the enzyme is almost completely inactive. Nongenetic factors such as certain drugs, stress, and others listed above can increase the demand for heme and the enzymes required to make heme. The combination of this increased demand and reduced activity of protoporphyrinogen oxidase disrupts heme production and allows byproducts of the process to accumulate in the liver, triggering an acute attack.Variegate porphyria is inherited in an autosomal dominant pattern, which means the defective gene is located on an autosome, and inheriting one copy of the defective gene from an affected parent is sufficient to cause the disorder. More severe cases result from inheriting two copies of the defective gene.The entire PPOX gene has about 8kb with 13 exon sequences. It was successfully cloned from a cDNA library in 1995 revealing that, after processing, it is 477 nucleotides long. It has previously been thought that the PPOX gene was located on human chromosome 14, however mapping experiments (FISH) have shown that it is near 1q23. An additional aggravating mutation affecting variegate porphyria can be found at 6p21.3 on the HFE gene.A 2006 clinical, biochemical and mutational study of eight Swiss variegate porphyria patients and their families found four novel PPOX gene mutations believed to be unique to the Swiss population.
Diagnosis
Diagnosis is by finding raised urine porphyrins, raised faecal porphyrins, markedly raised plasma porphyrins (pathognomic) and finding photosensitive cutaneous lesions on clinical examination.
Treatment
Liver transplant has been used in the treatment of this condition.
Epidemiology
In South Africa, the prevalence of variegate porphyria is approximately 1 in 300. In Finland, the prevalence is approximately 1 in 75,000.It is also found in Argentina, Sweden, and Australia.
References
This article incorporates public domain text from The U.S. National Library of Medicine
External links
Variegate porphyria at NIHs Office of Rare Diseases |
Mauriac syndrome | Mauriac syndrome is a rare complication of type 1 diabetes characterized by extreme liver enlargement due to glycogen deposition, along with growth failure and delayed puberty. It occurs in some children and adolescents with type 1 diabetes irrespective of their glycemic control.
History
Mauriac syndrome was first described in 1930 by Pierre Mauriac. It was described as a syndrome of growth failure and delayed puberty in children with poorly-controlled type I diabetes.
Signs and symptoms
Patients with Mauriac syndrome may present with obesity, hepatomegaly, cushingoid facies, and elevated liver enzymes. Patients usually have growth failure and delayed puberty, which should warn the physician about insufficient management of the patients diabetes. These symptoms can be reversed with good glycemic control.
Genetics
Abnormally high blood sugar levels are relatively common among patients with type I diabetes, but Mauriac syndrome is rare. This suggests that high blood sugar is not the only factor necessary to cause the syndrome. A study of an adolescent boy with severe Mauriac syndrome found a mutation in PHKG2, which is the catalytic subunit of the enzyme glycogen phosphorylase kinase (PhK). PhK is a large enzyme complex responsible for the activation of glycogen phosphorylase, the first enzyme in the pathway of glycogen metabolism. This childs mutation inhibited glycogen metabolism and caused increased glycogen deposition in the liver. The childs mother had the mutant enzyme, but no liver enlargement. The childs father had type 1 diabetes. Neither parent had Mauriac syndrome. The study suggests that both the mutant enzyme and an abnormally high blood glucose level were necessary to cause Mauriac syndrome.
Treatment
Symptoms are improved when patient attain tighter control of their blood sugars. The generally accepted therapeutic approach is intensified multiple insulin injection therapy; however, this may cause development of retinopathy if the blood sugars are adjusted too quickly. In one study, a patient was transferred to continuous insulin delivery, which resulted in improvement of his symptoms and greater control of his blood sugars.
== References == |
Anonychia | Anonychia is the absence of fingernails or toenails, an anomaly which may be the result of a congenital ectodermal defect, ichthyosis, severe infection, severe allergic contact dermatitis, self-inflicted trauma, Raynaud phenomenon, lichen planus, epidermolysis bullosa, or severe exfoliative diseases.: 784
Congenital form
This is rare and is usually due to mutations in the R-spondin 4 (RSPO4) gene which is located on the short arm of chromosome 20 (20p13). Clinically it is manifest by the absence (anonychia) or hypoplasia (hyponychia) of finger- or toenails.
See also
List of cutaneous conditions
References
== External links == |
Dextrocardia | Dextrocardia (from Latin dextro, meaning "right hand side," and Greek kardia, meaning "heart") is a rare congenital condition in which the apex of the heart is located on the right side of the body, rather than the more typical placement towards the left. There are two main types of dextrocardia: dextrocardia of embryonic arrest (also known as isolated dextrocardia) and dextrocardia situs inversus. Dextrocardia situs inversus is further divided.
Classification
Dextrocardia of embryonic arrest
In this form of dextrocardia, the heart is simply placed further right in the thorax than is normal. It is commonly associated with severe defects of the heart and related abnormalities including pulmonary hypoplasia.
Dextrocardia situs solitus
Dextrocardia refers to a heart positioned in the right side of the chest. Situs solitus describes viscera that are in the normal position, with the stomach on the left side.
Dextrocardia situs inversus
Dextrocardia situs inversus refers to the heart being a mirror image situated on the right side. For all visceral organs to be mirrored, the correct term is dextrocardia situs inversus totalis.Although statistically people with dextrocardia do not have any medical problems from the disorder, they may be prone to a number of bowel, esophageal, bronchial and cardiovascular disorders (such as double outlet right ventricle, endocardial cushion defect and pulmonary stenosis). Certain cardiovascular and pulmonary disorders related to dextrocardia can be life-threatening if left unchecked.Kartagener syndrome may also be present in patients with dextrocardia but this must be in the setting of situs inversus and may include male infertility.
Dextrocardia with situs ambiguus
In contrast to dextrocardia situs inversus which is only rarely associated with congenital heart disease, dextrocardia situs ambiguus is often associated with intracardiac anomalies. Dextrocardia situs ambiguus presents a surgical challenge not per se due to associated cardiac malformation, but because achieving adequate exposure is difficult. Right sided structures such as right atrium, right ventricle and tricuspid valve are oriented posteriorly in dextrocardia situs ambiguus (in contrast to dextrocardia with situs inversus). This presents a challenge to the surgeons operating on the right-sided cardiac structures in a case of dextrocardia situs ambiguus.
Diagnosis
Medical diagnosis of the two forms of congenital dextrocardia can be made by ECG or imaging.
Technical dextrocardia
Technical dextrocardia refers to an ECG reading that has no basis in the patients anatomy. This apparent presentation is typically caused by the accidental lead placement of the left and right arm electrodes. Usually, this would show as an extreme axis deviation.
Management
ECG leads must be placed in reversed positions on a person with dextrocardia. In addition, when defibrillating someone with dextrocardia, the pads should be placed in reverse positions. That is, instead of upper right and lower left, pads should be placed upper left and lower right.When heart transplantation is required in a person with situs inversus, reconstruction of the venous pathways to accommodate a normal donor heart is a major, but not insurmountable, challenge.
Epidemiology
Dextrocardia is estimated to occur in approximately 1 in 12,019 pregnancies.A Japanese study of 1,753 fetal cardiac echocardiograms over five years revealed only two cases.
References
External links
Dextrocardia at NIHs Office of Rare Diseases
Dextrocardia with situs inversus at NIHs Office of Rare Diseases |
Natural killer cell enteropathy | Natural killer cell enteropathy, also termed NK cell enteropathy (NKCE), and a closely related disorder, lymphomatoid gastropathy (LG), are non-malignant diseases in which one type of lymphocyte, the natural killer cell (i.e. NK cell), proliferates excessively in the gastrointestinal tract (GI tract). This proliferation causes red, sore-like spots, raised lesions, erosions, and ulcers in the mucosal layer surrounding the GI tract lumen. Both disorders cause either no or only vague symptoms of GI tract disturbances such as nausea, vomiting, and bleeding.In 2006, a persistent but apparently benign disease that involved the proliferation of NK cells at multiple sites throughout the intestines was described. This disorder appeared similar to and easily mistaken for a highly malignant disease, extranodal NK/T-cell lymphoma, nasal type. In 2010, a similarly non-malignant disorder that involved the proliferation of NK cells in the stomach was described. The disease mimicked gastrointestinal lymphomas. Since these first descriptions, several case series and case reports have been published on these enteropathies.The two NK cell proliferation diseases have been termed NK cell enteropathy and lymphomatoid gastropathy with NKCE being seen mostly in the United States and Korea and LG being seen mostly in Japan. Besides this geographical difference, the only other critical difference between the two diseases is that the lesions in NKCE occur in the small intestine, colon, stomach, and/or esophagus while those of LG are limited to the stomach. Since the pathophysiological features of the two diseases are virtually identical, NKCE and LG are now commonly viewed as manifestations of the same disease.Only 36 patients with NKCE or LG have been reported as of January 2019. Nonetheless, these diseases are emerging as important clinical entities because they 1) are newly described and likely to be diagnosed more often as they become better known and 2) have been mistaken for, and treated as, various types of pre-malignant and malignant lymphomas of the GI tract. Given the radical differences in the prognoses and treatments of NKCE and LG compared to the lymphomas that they can mimic, the evaluation of many lymphocyte-proliferating disorders of the GI tract must consider and rule out the possibility that they are NKCE or LG rather than a pre-malignant disorder or malignant lymphoma.
Presentation
Most cases of NKCE and LG have been reported in middle-aged or older individuals. Patients diagnosed with NKCE (medium age 46 years) have presented with vague abdominal pain, indigestion, vomiting, diarrhea, constipation, weight loss, anemia, and/or GI bleeding. Two patients complained of biliary colic (i.e. gallbladder pain) and were found to have typical lesions of NKCE in their cystic ducts. These two cases indicate that NKCE involvement is not totally limited to the alimentary canal. Three of 15 individuals diagnosed with NKCE disease reported no symptoms, their disease being found on endoscopy conducted for screening purposes. Typically, patients diagnosed with LG (medium age 58 years) have been asymptomatic at presentation with their disease being detected during GI tract examinations done for other reasons. Three of twenty patients diagnosed with LG complained of pain or discomfort in the upper abdominal region. Symptomatic individuals with either disease generally have a long history of persistent or intermittent symptoms.
Pathophysiology
NK cells normally occupy the GI tract where they contribute to innate immunity by becoming active in killing pathogen-infected and cancerous cells. The proliferating lymphocytes in NKCE and LG express CD56 and CD7 proteins on their cell surface membrane, CD3γ protein in their cytoplasm, and granzyme B, perforin, and T-cell intracellular antigen-1 cytotoxic proteins within their cytoplasmic granules. This pattern of protein expression identifies these cells as NK cells that, because of their expression of the cytotoxic granule-bound proteins, have been activated. However, the cause(s) for the activation of these cells as wells as for their rapid proliferation to produce NKCE and LG is unknown. To date, no evidence of NK cell clonality (i.e. cells developing from a single precursor) or for these cells to bear gene mutations or chromosome abnormalities have been reported in NKCE or LG. These findings help distinguish LB and NKCE from many lymphomas and support the conclusion that neither disease is malignant. The NK cells in LG and NKCE are not infected with the Epstein-Barr virus (EBV), as evidenced by their failure to express this viruss latency proteins and latency ncRNAs. This finding indicates that EBV is not the cause for the NK cell activation and excessive proliferation seen in NKCE and LG and distinguishes these diseases from malignant diseases they can mimic such as extranodal NK/T-cell lymphoma, nasal type. In isolated reports, LG has occurred in individuals with Helicobacter pylori infection of the stomach or a history of stomach cancer, while NKCE has been reported to occur in patients with gluten sensitivity or circulating anti-gliadin antibodies. Both of the latter conditions are associated with the development of GI tract lymphomas. However, the relationship of any of these findings to the etiology of LB and NKCE is unclear.
Histology
Biopsies of NKCE tissues reveal atypical medium to large lymphocytes identified by immunohistochemistry to be NK cells that are multiplying at a moderately rapid rate and that lack evidence of being infected by the Epstein-Barr virus. These cells are located primarily in the lamina propria, i.e. loose connective tissue lying just below the epithelium lining the GI tract. There is generally little invasion of these cells into the epithelium, submucosa, or glands of the GI tract, and the lesions almost always show a complete absence of vascular injury due to invasion by these cells. The lesions in LG closely resemble those of NKCE.
Diagnosis
The diagnoses of NKCE and LG depends on clinical and pathological findings indicating that the two diseases: a) are indolent and non-malignant; b) usually manifested by mild, vague, or no symptoms; c) localize to the GI tract without involvement of the head, neck, or organs such as the liver and spleen; d) consist of one or more lesions localized primarily to the lamina propria of the esophagus, stomach, small intestine, and/or large intestine (for NKCE} or to the stomach (for LG); and e) involve lesions which contain medium-to large-sized, atypical, and non-clonal lymphocytes that are activated NK cells (see Pathophysiology section) which proliferate at moderately rapid rates (as gauged by, e.g. analysis of their Ki-67 protein levels), lack evidence of Epstein-Barr virus infection, gene mutations, or chromosome abnormalities, and show little evidence of centering around, and destroying, blood vessels.
Differential diagnosis
In early studies, aggressive chemotherapy with or without bone marrow translanton and gastric resections were used to treat NKCE and LG, respectively, based on the assumptions that these diseases were malignant. Since there was no evidence that these treatments influenced the underlying disease and since NKCE and LG are essentially benign disorders, they must be distinguished from the malignant diseases which they mimic. Three malignant or potentially premalignant diseases which can closely resemble NKCE and LG along with some clinical and laboratory findings which differentiate them from NKCE and LT are:
Extranodal NK/T cell lymphoma, nasal type: This disease can closely mimic NKCE and, to a lesser extent, LG. In contrast to NKCE and LG, extranodal NK/T cell lymphoma, nasal type: is malignant and often aggressive; causes serious, persistent, and often progressive GI tract and other symptoms; commonly involves the head and neck areas and/or multiple organs outside of the GI tract; is deeply invasive, extending beyond the lamina propia of the GI tract; and consists of lesions which contain malignant Epstein-Barr virus-infected NK cells that have numerous gene mutations and chromosome abnormalities and that center around and destroy blood vessels.
Monomorphic epitheliotropic intestinal T cell lymphoma (MEITL): MEITL is a malignant and extremely aggressive GI tract disease. It is manifested by serious, sometimes life-threatening GI tract symptoms such as GI tract obstructions and perforations; is usually localized to the small intestine but may involve other areas of the GI tact; is invasive, e.g. spreads to the submucosa; commonly metastasizes to GI tract lymph nodes; and is composed of lesions which contain Epstein-Barr virus-negative homogenously appearing, medium-sized, malignant T cells that may have mutations or other genetic abnormalities in their STAT5B, JAK3, TP53, SETD2, BRAF, KRAS, GNA12, CREBBP, and/or Myc genes.
Indolent T cell lymphoproliferative disorder of the gastrointestinal tract: This recently described disease, while generally considered benign, has in rare cases been lethal with disease spreading to the bone marrow and blood. This disease is a potentially precancerous condition. Indolent T-cell lymphoproliferative disorder almost always presents with significant GI tract severe symptoms (chronic diarrhea, weight loss, abdominal pain, and/or GI bleeding); involves multiple lesions, most commonly located in the small intestine, colon, and, rarely, stomach, esophagus, and oral cavity; exhibits lesions that resemble those of NKCE and LG but involve infiltrations of T-cells that unlike the NK cells of NKCE and LG, are slowly proliferating, homogenously small-sized, CD56-negative, usually express CD4 and CD8, are not infected by the Epstein-Barr virus, are clonal in nature based on their T-cell receptor rearrangements, and, while located primarily in the lamina propria, may infiltrate into nearby submucosal tissue.Other diseases which NKCE and LG may superficially resemble and require consideration as being in their differential diagnoses include: peripheral T-cell lymphoma not otherwise specified, T cell lymphomas that consist of mature T cells and occur in the GI tact, MALT lymphoma of the stomach, and other types of stomach lymphomas.
Treatment
Patients with NKCE or LG should be treated for symptom relief but, as currently recommended, not for the underlying NK cell proliferative disease. Regular follow-ups that include repeated endoscopic analyses of their GI tracts and tests for the spreading of the disease to other organs are recommended to insure the original diagnosis is correct.
Prognosis
NKCE and LG usually follow a persistent or regressing-relapsing coarse but uncommonly spontaneously relapses without a recurrence even in cases that have been mistreated with chemotherapy, bone marrow transplantation, or gastric resection. Patients with LG are less likely to have persistent or regressing-relapsing coarse. Symptoms of the disease usually remain vague and mild.
== References == |
Dysgraphia | Dysgraphia is a learning disability of written expression, that affects the ability to write, primarily handwriting, but also coherence. It is a specific learning disability (SLD) as well as a transcription disability, meaning that it is a writing disorder associated with impaired handwriting, orthographic coding and finger sequencing (the movement of muscles required to write). It often overlaps with other learning disabilities and neurodevelopmental disorders such as speech impairment, attention deficit hyperactivity disorder (ADHD) or developmental coordination disorder (DCD).In the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), dysgraphia is characterized as a learning disability in the category of written expression, when ones writing skills are below those expected given a persons age measured through intelligence and age-appropriate education. The DSM is unclear in whether writing refers only to the motor skills involved in writing, or if it also includes orthographic skills and spelling.Dysgraphia should be distinguished from agraphia (sometimes called acquired dysgraphia), which is an acquired loss of the ability to write resulting from brain injury, progressive illness, or a stroke.The prevalence of dysgraphia throughout the world is not known, due to difficulties in diagnosis and lack of research.
Etymology
The word dysgraphia comes from the Greek words dys meaning "impaired" and γραφία graphía meaning "writing by hand".
Development
There are at least two stages in the act of writing: the linguistic stage and the motor-expressive-praxic stage. The linguistic stage involves the encoding of auditory and visual information into symbols for letters and written words. This is mediated through the angular gyrus, which provides the linguistic rules which guide writing. The motor stage is where the expression of written words or graphemes is articulated. This stage is mediated by Exners writing area of the frontal lobe.The condition can cause individuals to struggle with feedback and anticipating and exercising control over rhythm and timing throughout the writing process.People with dysgraphia can often write on some level and may experience difficulty with other activities requiring reciprocal movement of their fingers and other fine motor skills, such as; tying shoes, fastening buttons or playing certain musical instruments. However, dysgraphia does not affect all fine motor skills. People with dysgraphia often have unusual difficulty with handwriting and spelling which in turn can cause writing fatigue. Unlike people without transcription disabilities, they tend to fail to preserve the size and shape of the letters they produce if they cannot look at what they are writing. They may lack basic grammar and spelling skills (for example, having difficulties with the letters p, q, b, and d), and often will write the wrong word when trying to formulate their thoughts on paper. The disorder generally emerges when the child is first introduced to writing. There is accumulating evidence that in many cases individuals with SLDs and DCD do not outgrow their disorders. Accordingly, it has been found that adults, teenagers, and children alike are all subject to dysgraphia. Studies have shown that higher education students with developmental dysgraphia still experience significant difficulty with hand writing, fine motor skills and motor-related daily functions when compared to their peers without neurodevelopmental disorders.
Classification
Dysgraphia is nearly always accompanied by other learning disabilities and/or neurodevelopmental disorders such as dyslexia, attention deficit disorder or oral and written language learning disability (OWL LD) and this can impact the type of dysgraphia a person has. Tourette syndrome, ASD and dyspraxia are also common diagnoses among dysgraphic individuals. Developmental dysgraphia was originally described as being a disorder that occurs solely in dyslexic individuals. Dysgraphia was not studied as a separate entity until mid-20th century when researchers discovered there were different types that occur without dyslexia. Dyslexics and dysgraphics experience similar synchronization difficulties and issues with spelling. However, dyslexia does not seem to impair physical writing ability or dramatically impact fine motor skills and dysgraphia does not impact reading comprehension. Methods for evaluating, managing and remedying dysgraphia are still evolving, but there are three principal subtypes of dysgraphia that are recognized. There is little information available about different types of dysgraphia and there are likely more subtypes than the ones listed below. Some people may have a combination of two or more of these, and individual symptoms may vary in presentation from what is described here. Most common presentation is a motor agraphia resulting from damage to some part of the motor cortex in the parietal lobes.
Dyslexic
There are several features that distinguish dyslexic-dysgraphia (sometimes called linguistic dysgraphia) from the other types. People with dyslexic-dysgraphia typically have poor oral and written spelling that is typically phonemic in nature. Their spontaneously written work is often illegible, has extra or deleted syllables or letters, and contains unnecessary capitalization or large spaces in the middle of words which can make each individual word unrecognizable. They may also insert symbols that do not resemble any letter of the alphabet. Writing production generally requires long periods of contemplation and correction.Dyslexic-dysgraphic individuals have fairly good copied work, and their ability to draw is also preserved. Their finger tapping speed (a method for identifying fine motor problems) is normal, indicating that the deficit does not likely stem from cerebellar damage. Impaired verbal executive functioning has also been related to this form of the disorder.One study found that boys with ADHD and dysgraphia struggle primarily with motor planning rather than have a linguistic impairment but the prevalence of linguistic/dyslexic-dysgraphia compared to other subtypes is uncertain.
Motor
Motor dysgraphia (sometimes called peripheral dysgraphia) is due to deficient fine motor skills, poor dexterity, poor muscle tone or unspecified motor clumsiness. Motor dysgraphia impairs both motor patterns and motor memory. Letter formation may be acceptable in very short samples of writing, but this requires extreme effort and an unreasonable amount of time to accomplish, and it cannot be sustained for a significant length of time, as it can cause arthritis-like tensing of the hand. Overall, their written work is poor to illegible even if copied by sight from another document, and drawing is impaired. Oral spelling for these individuals is normal, and their finger tapping speed is below normal. This shows that there are problems within the fine motor skills of these individuals. People with developmental coordination disorder may be dysgraphic and motor-dysgraphia may serve as a marker of dyspraxia. Motor-dysgraphics struggle with proper finger grip and writing is often slanted due to holding a pen or pencil incorrectly. Average writing speed is slower than that of non-dysgrapic individuals, but this seems to improve with age. Motor skill deficits appears to be a common cause of dysgraphia; 78% of children with the disorder present kinematic difficulties, while 58% of them display issues with pressure skills.
Spatial
A person with spatial dysgraphia has a defect in the understanding of space. This impaired spatial perception causes illegible spontaneously written work, illegible copied work, abnormal spacing between letters and majorly impaired drawing abilities. They have normal oral spelling and normal finger tapping speed, suggesting that this subtype is not fine motor based. Symptoms in actuality may vary in presentation from what is listed here. Spatial dysgraphia may develop in individuals with lesions on the right hemisphere of the brain.
Miscellaneous
Other subtypes and informal classification systems have been proposed by researchers; this includes but is not limited to phonological dysgraphia, deep dysgraphia and surface dysgraphia.
Signs and symptoms
The symptoms to dysgraphia are often overlooked or attributed to the student being lazy, unmotivated, careless or anxious. The condition may also be dismissed as simply being an expression of attention deficiency or having delayed visual-motor processing. In order to be diagnosed with dysgraphia, one must have a cluster, but not necessarily all, of the following symptoms:
The symptoms of dysgraphia can change as one ages. Dysgraphia may cause students emotional trauma often due to the fact that no one can read their writing, and they are aware that they are not performing to the same level as their peers. Emotional problems that may occur alongside dysgraphia include impaired self-esteem, lowered self-efficacy, reduced motivation, poorer social functioning, heightened anxiety, and depression. They may put in extra efforts in order to have the same achievements as their peers, but often get frustrated because they feel that their hard work does not pay off. Dysgraphia is a hard disorder to detect as it does not affect specific ages, gender, or intelligence. The main concern in trying to detect dysgraphia is that people hide their disability behind their verbal fluency/comprehension and strong syntax coding because they are ashamed that they cannot achieve the same goals as their peers. Having dysgraphia is not related to a lack of cognitive ability, and it is not uncommon in intellectually gifted individuals, but due to dysgraphia their intellectual abilities are often not identified.
Associated conditions
There are some common problems not related to dysgraphia but often associated with dysgraphia, the most common of which is stress. Developing an aversion to writing is another common issue. Often children (and adults) with dysgraphia will become extremely frustrated with the task of writing specially on plain paper (and spelling); younger children may cry, pout, or refuse to complete written assignments. This frustration can cause the student a great deal of stress and can lead to stress-related illnesses. This can be a result of any symptom of dysgraphia.
Causes
The underlying causes of the disorder are not fully understood But dysgraphia is as well known to be a biologically based disorder with genetic and brain bases. More specifically, it is a working memory problem caused by specific neurodevelopmental dysfunction. In dysgraphia, individuals fail to develop normal connections among different brain regions needed for writing. People with dysgraphia have difficulty in automatically remembering and mastering the sequence of motor movements required to write letters or numbers. Dysgraphia is also in part due to underlying problems in orthographic coding, the orthographic loop, and graphmotor output (the movements that result in writing) by ones hands, fingers and executive functions involved in letter writing. The orthographic loop is when written words are stored in the minds eye, connected through sequential finger movement for motor output through the hand with feedback from the eye.Family history of specific learning disabilities may play a role. Children with developmental dysphasia, developmental dysgraphia and developmental dyslexia may be more likely to have family members with one of these conditions. Genetic studies suggest that verbal executive function tasks, orthographic skills, and spelling ability may have a genetic basis. Genes on chromosomes 6 and 15 may play some role with SLDs as they have linked to poorer reading, poorer spelling and lower phonemic awareness.
Diagnosis
Unlike specific learning disabilities and neurodevelopmental disorders that have been more extensively studied, there is no gold standard for diagnosing dysgraphia. This is likely due to writing systems often differing substantially between countries and languages and there being considerable heterogeneity among the therapists who are charged with diagnosing dysgraphia. Consequently, there are several tests that are used to diagnose dysgraphia like Ajuriaguerra scale, BHK for children or teenagers, the Minnesota Handwriting Assessment, ETCH, SCRIPT, DASH and HHE scale.With devices like drawing tablets, it is now possible to measure the position, tilt, and pressure in real time. From these features, it is possible to compute automatic features like speed and shaking and train a classifier to diagnose automatically children with atypical writing. The features extracted have different importances in the classification through development and allow to characterize different subtypes of dysgraphia that could have different origins, outcomes and could require different remediation strategies.It is not uncommon for dysgraphic individuals to be intellectually gifted, possess a rich vocabulary and have strong comprehension of language when speaking or reading, though their disorder is often not detected or treated; which may also be in part to developmental dyslexia receiving far more academic and medical attention than developmental dysgraphia. In addition, gifted children with transcription disabilities seldom receive programming for their intellectual talents due to their difficulties in completing written assignments.
Treatment
Treatment for dysgraphia varies and may include treatment for motor disorders to help control writing movements. Helping dysgraphic students overcome writing avoidance and accept the purpose and necessity of writing may be needed. The use of occupational therapy can be effective in the school setting, and teachers should be well informed about dysgraphia to aid in carry-over of the occupational therapists interventions. Treatments may address impaired memory or other neurological problems. Some physicians recommend that individuals with dysgraphia use computers to avoid the problems of handwriting. Dysgraphia can sometimes be partially overcome with appropriate and conscious effort and training. The International Dyslexia Association suggests the use of kinesthetic memory through early training by having the child overlearn how to write letters and to later practice writing with their eyes closed or averted to reinforce the feel of the letters being written. They also suggest teaching the students cursive writing as it has fewer reversible letters and can help lessen spacing problems, at least within words, because cursive letters are generally attached within a word.
Prevalence
It has been estimated that up to 10% of children in the world are affected by disabilities like dysgraphia, dyslexia, dyscalculia and dyspraxia. Estimates on the true prevalence of dysgraphia are not available due to lack of research on the disorder.
School
There is no special education category for students with dysgraphia; in the United States, The National Center for Learning Disabilities suggests that children with dysgraphia be handled in a case-by-case manner with an Individualized Education Program, or provided individual accommodation to provide alternative ways of submitting work and modify tasks to avoid the area of weakness. Students with dysgraphia often cannot complete written assignments that are legible, appropriate in length and content, or within given time. It is suggested that students with dysgraphia receive specialized instructions that are appropriate for them. Children will mostly benefit from explicit and comprehensive instructions, help translating across multiple levels of language, and review and revision of assignments or writing methods. Direct, explicit instruction on letter formation and guided practice will help students achieve automatic handwriting performance before they use letters to write words, phrases, and sentences. Some older children may benefit from the use of a personal computer or a laptop in class so that they do not have to deal with the frustration of falling behind their peers.It is also suggested by Berninger that teachers with dysgraphic students decide if their focus will be on manuscript writing (printing) or keyboarding. In either case, it is beneficial that students are taught how to read cursive writing as it is used daily in classrooms by some teachers. It may also be beneficial for the teacher to come up with other methods of assessing a childs knowledge other than written tests; an example would be oral testing. This causes less frustration for the child as they are able to get their knowledge across to the teacher without worrying about how to write their thoughts. Dysgraphic students may benefit from special accommodation by their teachers when being required to write. Accommodations that may be helpful include but are not limited to; offering larger pencils or pencils with special grips, supplying paper with raised lines to provide tactile feedback, allowing extra time for classwork assignments, scaling down large written assignments and breaking down long written assignments into multiple shorter assignments.The number of students with dysgraphia may increase from 4 percent of students in primary grades, due to the overall difficulty of handwriting, and up to 20 percent in middle school because written compositions become more complex. With this in mind, there are no exact numbers of how many individuals have dysgraphia due to its difficulty to diagnose and exact prevalence depends on the definition of dysgraphia. There are slight gender differences in association with written disabilities; overall it is found that males are more likely to be impaired with handwriting, composing, spelling, and orthographic abilities than females.The Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) does not use the term dysgraphia but uses the phrase "an impairment in written expression" under the category of "specific learning disorder". This is the term used by most doctors and psychologists. To qualify for special education services, a child must have an issue named or described in the Individuals with Disabilities Education Act (IDEA). While IDEA does not use the term "dysgraphia", it describes it under the category of "specific learning disability". This includes issues with understanding or using language (spoken or written) that make it difficult to listen, think, speak, read, write, spell or to do mathematical calculations.
See also
Agraphia
Character amnesia
Developmental disability
Dyscravia
Learning disability
Lists of language disorders
References
Further reading
External links
NINDS Dysgraphia Information Page |
Necrobiotic xanthogranuloma | Necrobiotic xanthogranuloma (also known as "necrobiotic xanthogranuloma with paraproteinemia") is a multisystem disease that affects older adults, and is characterized by prominent skin findings.: 707
See also
List of cutaneous conditions
References
== External links == |
Laryngopharyngeal reflux | Laryngopharyngeal reflux (LPR) is the retrograde flow of gastric contents into the larynx, oropharynx and/or the nasopharynx. LPR causes respiratory symptoms such as cough and wheezing and is often associated with head and neck complaints such as dysphonia, globus pharyngis, and dysphagia. LPR may play a role in other diseases, such as sinusitis, otitis media, and rhinitis, and can be a comorbidity of asthma. While LPR is commonly used interchangeably with gastroesophageal reflux disease (GERD), it presents with a different pathophysiology.LPR reportedly affects approximately 10% of the U.S. population. However, LPR occurs in as many as 50% of individuals with voice disorders.
Signs and symptoms
Extraesophageal symptoms result from exposure of the upper aerodigestive tract to gastric contents. This causes a variety of symptoms, including hoarseness, postnasal drip, sore throat, difficulty swallowing, indigestion, wheezing, globus pharyngeus, and chronic throat-clearing. Some people with LPR have heartburn, while others have little to no heartburn as refluxed stomach contents do not remain in the esophagus long enough to irritate the surrounding tissue. Individuals with more severe forms of LPR may experience abrasion of tooth enamel due to intermittent presence of gastric contents in the oral cavity.Additionally, LPR can cause inflammation in the vocal tract which results in the symptom of dysphonia or hoarseness. Hoarseness is considered to be one of the primary symptoms of LPR and is associated with complaints such as strain, vocal fatigue, musculoskeletal tension, and hard glottal attacks, all of which can reduce a persons ability to communicate effectively. Moreover, LPR patients may try to compensate for their hoarseness by increasing muscular tension in their vocal tract. This hyper-functional technique adopted in response to the inflammation caused by LPR can lead to a condition called muscle tension dysphonia and may persist even after the hoarseness and inflammation has disappeared. A speech-language pathologist will often need to be involved to help resolve this maladaptive, compensatory pattern through the implementation of voice therapy.LPR presents as a chronic and intermittent disease in children. LPR in children and infants tends to manifest with a unique set of symptoms. Symptoms seen in children with LPR include a cough, hoarseness, stridor, sore throat, asthma, vomiting, globus sensation, wheezing, aspiration and recurrent pneumonia. Common symptoms of LPR in infants include wheezing, stridor, persistent or recurrent cough, apnea, feeding difficulties, aspiration, regurgitation, and failure to thrive. Moreover, LPR in children is commonly concomitant with laryngeal disorders such as laryngomalacia, subglottic stenosis, and laryngeal papillomatosis.
Relationship to GERD
LPR is often regarded as a subtype of GERD that occurs when stomach contents flow upward through the esophagus and reach the level of the larynx and pharynx. However, LPR is associated with a distinct presentation of symptoms. LPR and GERD frequently differ in the relative prevalence of heartburn and throat clearing. While heartburn is present in over 80% of GERD cases, it occurs in only 20% of LPR cases. Throat clearing shows the opposite prevalence pattern, occurring in approximately 87% of LPR cases and in fewer than 5% of GERD cases. Unlike GERD, LPR also poses a risk for bronchitis or pneumonitis as reflux of stomach acid to the level of the larynx can result in aspiration. LPR is also commonly associated with erythema, or redness, as well as edema in the tissues of the larynx that are exposed to gastric contents. In contrast, most cases of GERD are nonerosive, with no apparent injury to the mucosal lining of the esophageal tissue exposed to the refluxed material.Differences in the molecular structure of the epithelial tissue lining the laryngopharyngeal region may be partly responsible for the different symptomatic manifestations of LPR in comparison to GERD. In contrast to the resistant stratified squamous epithelium lining the esophagus, the larynx is lined by ciliated respiratory epithelium, which is more fragile and susceptible to damage. While the epithelium lining the esophagus is capable of withstanding as many as 50 instances of exposure to gastric contents each day, which is the uppermost estimate considered to be within the range of normal physiologic functioning, injury to laryngeal epithelium can occur following exposure to only small amounts of acidic gastric contents.
Diagnosis
LPR presents with non-specific symptoms and signs that make differential diagnosis difficult to achieve. Furthermore, symptoms of the disorder overlap greatly with symptoms of other disorders. Therefore, LPR is under-diagnosed and under-treated. As there are multiple potential etiologies for the respiratory and laryngeal symptoms of LPR, diagnosing LPR based on symptoms alone is unreliable. Laryngoscopic findings such as erythema, edema, laryngeal granulomas, and interarytenoid hypertrophy have been used to establish the diagnosis; however, these findings are nonspecific and have been described in the majority of asymptomatic subjects undergoing laryngoscopy. Response to acid-suppression therapy has been suggested as a diagnostic tool for confirming diagnosis of LPR, but studies have shown that the response to empirical trials of such therapy (as with proton-pump inhibitors) in these patients is often disappointing. Several studies have emphasized the importance of measuring proximal esophageal, or ideally pharyngeal acid exposure, in patients with clinical symptoms of LPR to document reflux as the cause of the symptoms.Additionally, several potential biomarkers of LPR have been investigated. These include inflammatory cytokines, carbonic anyhydrase, E-cadherin and mucins; however, their direct implications in LPR are still being established. The presence of pepsin, an enzyme produced in the stomach, in the hypopharynx has also become an increasingly researched biomarker for LPR. Research suggests that the stomach enzyme pepsin plays a crucial role in the complex mechanism behind LPR. Once present in the larynx pepsin is active at a low pH, but persists even when inactive. Pepsin can manifest both extracellularly and intracellularly; however, damage is realized differently in these two environments. Intracellularly, pepsin enters the laryngeal tissue through endocytosis and causes damage that accumulates over time. Pepsin has implications on cellular transcription and therefore, gene expression, which subsequently leads to the recruitment of inflammatory cells, but inhibition of protective mechanisms such as growth factors. Structurally, pepsin plays a role in increasing viscosity of the vibratory portion of the vocal folds and decreasing cellular water retention, which reduces the overall thickness of the vocal folds. These morphological changes result in decreased vibratory amplitude, increasing demands for initiating vibration and ultimately, impacting voice quality.Before a diagnosis can be made, a physician will need to record the patients medical history and ask for details about the presenting symptoms. Questionnaires such as the Reflux Symptom Index (RSI), Quality-of-Life Index (QLI) for LPR, Glottal Closure/Function Index (GCI) and Voice Handicap Index (VHI) can be administered to gain information about the patients medical history as well as their symptomatology. A physical examination will then need to be performed with particular concentration around the head and neck. A scope with a specialized camera lens made of fiber optic strands is gently fed down the throat and feeds back images to a monitor. This provides a clear view of the throat and larynx. Signs of LPR include redness, swelling, and obvious irritation. Other, more invasive tests, such as fibre-optic transnasal laryngoscopy, 24-hour ambulatory dual probe pHmetry, pharyngeal pHmetry, transnasal esophagoscopy (TNE) and biopsy may be used. A noninvasive test for diagnosis of LPR is the collection of refluxate where the refluxed material is collected and analyzed. Another noninvasive diagnostic test that can be used is an empirical trial of proton-pump inhibitor therapy; however, this test is mostly successful in diagnosing GERD.There is no agreed-upon assessment technique to identify LPR in children. Of the debated diagnostic tools, multichannel intraluminal impedance with pH monitoring (MII-pH) is used as it recognizes both acid and non-acid reflux. A more common technique that is used is 24-hour dual probe pH monitoring. Both of these tools are expensive and are therefore not widely used.
Treatment
Management of symptoms for patients within this subgroup of the GERD spectrum is difficult. Once these patients are identified, behavioural and dietary changes are advised. Dietary modifications may include limiting the intake of chocolate, caffeine, acidic food and liquids, gaseous beverages and foods high in fat. Behavioral changes may include weight loss, cessation of smoking, limiting alcohol consumption and avoiding the ingestion of food shortly before bed. Lifestyle changes in children diagnosed with LPR include dietary modifications to avoid foods that will aggravate reflux (e.g., chocolate or acidic and spicy food), altering positioning (e.g., sleeping on your side), modifying the textures of foods (e.g., thickening feeds to heighten awareness of the passing bolus), and eliminating the intake of food before bed.Proton pump inhibitors (PPIs) are the leading pharmaceutical intervention chosen for the relief and reduction of LPR and are typically recommended for ongoing use twice a day for a period of 3–6 months. PPIs have been shown to be ineffective in very young children and are of uncertain efficacy in older children, for whom their use has been discouraged.
While PPIs may provide limited clinical benefits in some adults, there is insufficient evidence to support routine use. Many studies show that PPIs are not more effective than placebos in treating LPR.When medical management fails, Nissen fundoplication can be offered. However, patients should be advised that surgery may not result in complete elimination of LPR symptoms and even with immediate success, recurrence of symptoms later on is still possible.One way to assess treatment outcomes for LPR is through the use of voice quality measures. Both subjective and objective measures of voice quality can be used to assess treatment outcomes. Subjective measures include scales such as the Grade, Roughness, Breathiness, Asthenia, Strain Scale (GRBAS); the Reflux Symptom Index; the Voice Handicap Index (VHI); and a voice symptom scale. Objective measures often rely on acoustic parameters such as jitter, shimmer, signal-to-noise ratio, and fundamental frequency, among others. Aerodynamic measures such as vital capacity and maximum phonation time (MPT) have also been used as an objective measure. However, there is not yet a consensus on how best to use the measures or which measures are best to assess treatment outcomes for LPR.
Procedures
There is tentative evidence from non-controlled trials that oral neuromuscular training may improve symptoms. This has been approved by the UK National Health Service (NHS) for supply on prescription from 1 May 2022.
History
LPR was not discussed as a separate condition from GERD until the 1970s and 1980s. However, at around the same time that GERD was first recognized as a clinical entity in the mid-1930s, a link between gut symptoms and airway disease was suggested. Later, acid-related laryngeal ulcerations and granulomas were reported in 1968. Subsequent studies suggested that acid reflux might be a contributory factor in other laryngeal and respiratory conditions. In 1979, the link between these airway symptoms and reflux of gastric contents was first documented. At the same time, treatment of reflux disease results was shown to eliminate these airway symptoms.
== References == |
Hyperlysinemia | Hyperlysinemia is an autosomal recessive metabolic disorder characterized by an abnormal increase of lysine in the blood, but appears to be benign. It is caused by mutations in AASS, which encodes α-aminoadipic semialdehyde synthase.Hyperlysinemia is associated with ectopia lentis (a displacement or malposition of the eyes crystalline lens) in humans.
Genetics
Hyperlysinemia is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.
Diagnosis
Treatment
See also
Saccharopinuria
References
== External links == |
Verrucous perforating collagenoma | Verrucous perforating collagenoma is a very rare skin disorder which presents (clinically) with verrucous papules with a transepidermal elimination of collagen.
See also
Linear verrucous epidermal nevus
List of cutaneous conditions
== References == |
Aarskog–Scott syndrome | Aarskog–Scott syndrome is a rare disease inherited as X-linked and characterized by short stature, facial abnormalities, skeletal and genital anomalies. This condition mainly affects males, although females may have mild features of the syndrome.
Signs and symptoms
People with Aarskog–Scott syndrome often have distinctive facial features, such as widely spaced eyes (hypertelorism), a small nose, a long area between the nose and mouth (philtrum), and a widows peak hairline. They frequently have mild to moderate short stature during childhood, but their growth usually catches up with that of their peers during puberty. Hand abnormalities are common in this syndrome and include short fingers (brachydactyly), curved pinky fingers (fifth finger clinodactyly), webbing of the skin between some fingers (cutaneous syndactyly), and a single crease across the palm. Other abnormalities in people with Aarskog–Scott syndrome include heart defects and a split in the upper lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate).Most males with Aarskog–Scott syndrome have a shawl scrotum, in which the scrotum surrounds the penis instead of hanging below. Less often, they have undescended testes (cryptorchidism) or a soft out-pouching around the belly-button (umbilical hernia) or in the lower abdomen (inguinal hernia).The intellectual development of people with Aarskog–Scott syndrome varies widely. Some may have mild learning and behavior problems, while others have normal intelligence. In rare cases, severe intellectual disability has been reported.
Genetics
Mutations in the FGD1 gene are the only known genetic cause of Aarskog-Scott syndrome. The FGD1 gene provides instructions for making a protein that turns on (activates) another protein called Cdc42, which transmits signals that are important for various aspects of development before and after birth.Mutations in the FGD1 gene lead to the production of an abnormally functioning protein. These mutations disrupt Cdc42 signaling, leading to the wide variety of abnormalities that occur in people with Aarskog-Scott syndrome.Only about 20 percent of people with this disorder have identifiable mutations in the FGD1 gene. The cause of Aarskog-Scott syndrome in other affected individuals is unknown.
Pathophysiology
The Aarskog–Scott syndrome is due to mutation in the FGD1 gene. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates Cdc42, a member of the Rho (Ras homology) family of the p21 GTPases. By activating Cdc42, FGD1 protein stimulates fibroblasts to form filopodia, cytoskeletal elements involved in cellular signaling, adhesion, and migration. Through Cdc42, FGD1 protein also activates the c-Jun N-terminal kinase (JNK) signaling cascade, a pathway that regulates cell growth, apoptosis, and cellular differentiation.Within the developing mouse skeleton, FGD1 protein is expressed in precartilaginous mesenchymal condensations, the perichondrium and periosteum, proliferating chondrocytes, and osteoblasts. These results suggest that FGD1 signaling may play a role in the biology of several different skeletal cell types including mesenchymal prechondrocytes, chondrocytes, and osteoblasts. The characterization of the spatiotemporal pattern of FGD1 expression in mouse embryos has provided important clues to the understanding of the pathogenesis of Aarskog–Scott syndrome.It appears likely that the primary defect in Aarskog–Scott syndrome is an abnormality of FGD1/Cdc42 signaling resulting in anomalous embryonic development and abnormal endochondral and intramembranous bone formation.
Diagnosis
Genetic testing may be available for mutations in the FGDY1 gene. Genetic counseling is indicated for individuals or families who may carry this condition, as there are overlapping features with fetal alcohol syndrome.Other examinations or tests can help with diagnosis. These can include:
detailed family history
conducting a detailed physical examination to document morphological features
testing for genetic defect in FGDY1
x-rays can identify skeletal abnormalities
echo cardiogram can screen for heart abnormalities
CT scan of the brain for cystic development
X-ray of the teeth
Ultrasound of abdomen to identify undescended testis
Treatment
Similar to all genetic diseases Aarskog–Scott syndrome cannot be cured, although numerous treatments exist to increase the quality of life.Surgery may be required to correct some of the anomalies, and orthodontic treatment may be used to correct some of the facial abnormalities. Trials of growth hormone have been effective to treat short stature in this disorder.
Prognosis
Some people may have some mental slowness, but children with this condition often have good social skills. Some males may have problems with fertility.
History
The syndrome is named for Dagfinn Aarskog, a Norwegian pediatrician and human geneticist who first described it in 1970, and for Charles I. Scott, Jr., an American medical geneticist who independently described the syndrome in 1971.
References
Jones, Kenneth Lyons (2005). Smiths Recognizable Patterns of Human Malformation (6th ed.). Philadelphia: WB Saunders. ISBN 978-0-7216-2359-7.
Orrico A.; Galli L.; Cavaliere ML.; et al. (2004). "Phenotypic and molecular characterisation of the Aarskog–Scott syndrome: a survey of the clinical variability in light of FGD1 mutation analysis in 46 patients". Eur. J. Hum. Genet. 12 (1): 16–23. doi:10.1038/sj.ejhg.5201081. PMID 14560308.
External links
Aarskog–Scott syndrome, detailed up-to-date information in OMIM (Online Mendelian Inheritance in Man)
Aarskogs syndrome at Who Named It? |
Remitting seronegative symmetrical synovitis with pitting edema | Remitting seronegative symmetrical synovitis with pitting edema (or sometimes RS3PE) is a rare syndrome identified by symmetric polyarthritis, synovitis, acute pitting edema (swelling) of the back of the hands and/or feet, and a negative serum rheumatoid factor. If no underlying disorder can be identified (idiopathic RS3PE), this entity has an excellent prognosis and responds well to treatment.RS3PE typically involves the joints of the extremities, specifically the metacarpophalangeal and proximal interphalangeal joints, wrists, shoulders, elbows, knees and ankles.
It is more common in older adults, with the mean age between 70 and 80 years in most studies.
It occurs more often in men than in women with a 2:1 ratio.
It is unknown how common this condition is.
Signs and symptoms
Individuals affected by RS3PE typically have repeated episodes of inflammation of the lining of their synovial joints and swelling of the end portion of the limbs. The arms and hands are more commonly affected than the legs and feet. Both sides are usually involved though RS3PE can affect only one side in certain cases.
Causes
RS3PE is a constellation of symptoms that can be caused by many other conditions. Since there is no definitive diagnostic test, other conditions have to be ruled out before this rare condition can be diagnosed.
The main differential diagnosis is polymyalgia rheumatica (PMR), although pain, stiffness and weakness at the level of the shoulders and pelvic girdle with associated systemic symptoms (fever, malaise, fatigue, weight loss) is more typical of PMR. Prospective studies have found a subgroup of PMR patients with hand edema, as well as other similarities. Thus, RS3PE has been proposed as a condition related to PMR or even that they are both part of the same disorder. However, PMR typically requires protracted courses of steroids, whereas corticosteroids can be tapered more quickly with persisting remission in RS3PE.Other rheumatological disorders that can cause the features typical for RS3PE include late onset (seronegative) rheumatoid arthritis, acute sarcoidosis, ankylosing spondylitis and other spondyloarthropathies such as psoriatic arthropathy, mixed connective tissue disease, chondrocalcinosis and arthropathy due to amyloidosis.RS3PE has been documented in patients with cancers (Non-Hodgkins lymphoma, gastric cancer, pancreatic cancer, lung cancer, breast cancer, colon cancer, prostate cancer and bladder cancer, among others), in whom it might represent a paraneoplastic manifestation.
Other underlying disorders include vasculitides such as polyarteritis nodosa.Other causes of edema include heart failure, hypoalbuminemia, nephrotic syndrome and venous stasis. The key distinguishing feature is that these conditions dont tend to manifest with pitting edema at the back of the hands.
Pathogenesis
The disease mechanism (pathophysiology) of RS3PE remains unknown. One study suggested a possible role for vascular endothelial growth factor. A study using magnetic resonance imaging found that tenosynovitis of the extensors of the hands and feet is the major contributor to edema.
Diagnosis
Ultrasonography and magnetic resonance imaging of the hands and/or feet have been proposed as useful diagnostic investigations in RS3PE.Some studies linked RS3PE to HLA-B27 whereas others have not.
Treatment
RS3PE responds excellently to low dose corticosteroids, with sustained and often complete remission. Non-steroidal anti-inflammatory drugs (NSAIDs) have also been used. Hydroxychloroquine has proven effective in some cases.
History
In a 1985 paper published in the Journal of the American Medical Association, McCarty and colleagues first described a case series of patients with this disorder, for which they coined the abbreviation RS3PE. RS3PE was initially thought to represent a form of seronegative rheumatoid arthritis but is now believed to be a separate syndrome.
== References == |
Uveitic glaucoma | Uveitic glaucoma (or uveitis glaucoma, or anterior uveitic glaucoma, or anterior noninfectious uveitic glaucoma, or uveitis associated with glaucoma, or iritic glaucoma) is most commonly a progression stage of noninfectious anterior uveitis or iritis.
Noninfectious anterior uveitis is an inflammation of the anterior (front) part of the eye and is instigated by autoimmune or other noninfectious causes (noninfectious uveitis can also affect the posterior segments of the eye, and then is called posterior, pan or intermediate uveitis). The onset of noninfectious uveitis occurs in patients in their thirties, with up to 10% of cases diagnosed in children under the age of 16. The condition may persist as a chronic disease.
Noninfectious uveitis is the most common form of uveitis in developed countries. Approximately 30% of uveitis patients develop glaucoma as a result of the inflammation that occurs in uveitis, as a complication of steroid treatment or a combination of both.Uveitis, as well as steroid treatment for uveitis, can cause an increased resistance to the flow of aqueous humour (the clear liquid suspended between the lens and the cornea) from the eye. This leads to an excess of fluid buildup, which exerts elevated pressure on the inside parts of the eye, or elevated intraocular pressure (IOP). Elevated intraocular pressure can in turn lead to optic nerve damage and glaucoma.
Based on epidemiological studies of uveitis, approximately 34-94/100,000 people will develop uveitic glaucoma (see Epidemiology section). Uveitic glaucoma patients are at significantly higher risk for visual field loss in the long term compared to patients who only have uveitis. Patients with uveitic glaucoma also experience a particularly high burden of care.
Signs and symptoms
Because uveitic glaucoma is a progressive stage of anterior non infectious uveitis, uveitic glaucoma involves signs and symptoms of both glaucoma and uveitis.
Patients with acute non infectious anterior uveitis may experience the following symptoms: pain, blurry vision, headache, photophobia (discomfort or pain due to light exposure), or the observance of haloes around lights.
An ophthalmologist may be able to observe the main sign of active noninfectious anterior uveitis, which is the presence of immune cells (anterior chamber cells, or ACCs) floating within the anterior segment of the eye (see "Noninfectious anterior uveitis" in Diagnosis section). The ophthalmologist also may observe peripheral anterior synechiae (PAS), or adhesions between the iris and trabecular meshwork, the tissue responsible for draining aqueous humour from the eye.Patients with uveitis who also experience symptoms of glaucoma may have uveitic glaucoma.
In an eye with uveitic glaucoma, the following glaucoma signs may be observed: elevated intraocular pressure, scotomas in the field of vision, defects in the fiber layer of the retinal nerve, and/or excavation (a regional deformation or depression of the optic nerve). Pupillary blocks, or the obstruction of "the flow of aqueous humor from the posterior chamber to the anterior chamber" due to a "functional block between the pupillary portion of the iris and the lens" may also be detected. Finally, the ophthalmologist may observe peripheral anterior synechiae (PAS), or adhesions between the iris and trabecular meshwork.The dual presence of glaucoma and uveitis symptoms points to a diagnosis of uveitic glaucoma.
Causes
Uveitic glaucoma is a progressive stage of anterior noninfectious uveitis. Patients diagnosed with anterior noninfectious uveitis may also develop glaucoma; in this case the condition is termed uveitic glaucoma. Uveitic glaucoma can arise from the inflammation that occurs in uveitis; from steroid treatment for uveitis; or a combination of both.
Uveitis inflammation
The inflammatory response associated with uveitis may lead to glaucoma. Active anterior uveitis flare-ups may develop quickly; in these cases, the inflammation can damage the tissues in the front part of the eye. Anterior uveitis may also be chronic; in these cases, repeated inflammation can cause progressive, accumulating damage to the eye tissues.
In all cases — acute one-time episodes, recurrent chronic inflammation or acute-on-chronic inflammation — damage to the eye tissues can cause increased resistance to the outflow of aqueous humour from the eye, which then increases the pressure inside the eye. In some chronic uveitis cases, the pressure inside the eye waxes and wanes due to the uveitis flare-ups.Elevated pressure inside the eye can lead to irreversible optic nerve damage and glaucoma.
Steroid treatment for uveitis
Topical corticosteroids are the first-line treatment for an active flare-up of noninfectious anterior uveitis, and the only effective treatment available for active inflammation. However, steroid treatment for uveitis can lead to uveitic glaucoma. Corticosteroids increase the fluid pressure inside the eye by increasing resistance to the outflow of aqueous humour, which can cause optic nerve damage and glaucoma. Steroid treatment can therefore cause or worsen uveitic glaucoma.Elevated pressure inside the eye typically develops 2 to 6 weeks after starting corticosteroid therapy, but can occur at any time during corticosteroid therapy and may continue for weeks after steroid use has been stopped. According to the Glaucoma Research Foundation, the risk of developing chronic steroid-induced glaucoma increases with every week of steroid use.Around 90% of patients with open angle glaucoma experience a steroid response of elevated intraocular pressure following steroid treatment. Therefore, once uveitis patients have developed uveitic glaucoma, they should ideally avoid steroids wherever possible.
Combination of uveitis inflammation and steroid treatment
In some cases, uveitis inflammation and steroid treatment both contribute to elevated pressure inside the eye, which leads to optic nerve damage and glaucoma.
Pathogenesis
Uveitic glaucoma as a result of recurring uveitic inflammation
Uveitic glaucoma can develop as a complication of anterior uveitis resulting from the inflammatory response associated with the disease. The inflammatory response can be characterized by occlusion of the trabecular meshwork, or blocking of the tissue that is responsible for draining aqueous humour from the eye. Another characteristic that presents in some patients is peripheral anterior synechiae (PAS), or adhesions between the iris and trabecular meshwork. These two characteristics of the inflammatory uveitic response can lead to an increase in intraocular pressure, and consequently to irreversible optic nerve damage and glaucoma.
Noninfectious uveitis is characterized by an inflammatory process that may be acute, recurrent, chronic or acute-on-chronic. Uveitic glaucoma is associated with an aggressive disease course caused by very high levels of intraocular pressure that wax and wane. When uveitis is acute, the onset of inflammation is rapid, with obstruction of intertrabecular spaces. When uveitis is chronic, recurrent bouts lead to tissue destruction from direct inflammation. Obstruction of the intertrabecular spaces characteristic of acute onset uveitis, as well as the repeated inflammation characteristic to chronic uveitis, can lead to elevated intraocular pressure. This can consequently cause optic nerve damage and glaucoma.
Uveitic glaucoma as a response to steroid treatment of uveitis
Uveitic glaucoma can also develop as a response to steroid treatment of uveitis. Corticosteroids cause a rise in the fluid pressure inside the eye. While the pathogenesis of corticosteroid-induced ocular hypertension is not fully understood, it likely involves swelling and remodeling (alterations to the extracellular matrix) of the trabecular meshwork, which leads to increased resistance to aqueous humour outflow and an increase in intraocular pressure. Another possible mechanism by which corticosteroids increase fluid pressure inside the eye is as follows:
Corticosteroids inhibit (partly prevent and slow) the breakdown of glycosaminoglycans (GAGs) in the trabecular meshwork.
GAGs accumulate in the meshwork.
Fluid drainage is decreased.
Fluid pressure in the eye is increased.It has also been suggested that corticosteroids may be capable of modifying the trabecular meshwork cells, modulating their size as well as their cytoskeletal arrangement, which in turn could limit fluid drainage.
Diagnosis
Uveitic glaucoma is a progression stage of noninfectious acute anterior uveitis. In order to diagnose uveitic glaucoma, a dual diagnosis of non-infectious anterior uveitis and glaucoma is required. A thorough examination of the eye by an ophthalmologist is performed in order to diagnose uveitic glaucoma.
Noninfectious anterior uveitis
[Main article: Uveitis]
The main diagnostic sign of noninfectious acute anterior uveitis is the presence of anterior chamber cells (ACCs), or immune cells, in the anterior, or front, chamber of the eye. The anterior chamber of healthy eyes does not contain any immune cells, hence the main indicator of noninfectious anterior uveitis is the presence of immune blood cells inside the anterior chamber of the eye. The more cells found floating in the anterior chamber, the more severe the uveitis.The quantity of immune cells present in the anterior chamber can be determined via a slit lamp examination.In 2005, an International Working Group on SUN (Standardization of Uveitis Nomenclature) took steps towards standardizing the methods for reporting clinical data in the field of uveitis. One of their products was a grading scheme for anterior chamber cells.
In 2021, a new slit lamp–based ACC assessment method, TGIS (Tarsier Grading Image Scale), was developed. TGIS uses a visual analog scale to enable pattern recognition-based evaluation of ACC density during a uveitic flare-up. This is achieved by graphically representing a high-power field slit beam through the anterior chamber, from the cornea to the lens surface.
Another important clinical measurement of ocular inflammation is flare. Flare is the leakage of various proteins (such as fibrin and cytokines) into the ocular anterior chamber, as a manifestation of inflammation. It will usually have a "milky" appearance. Flare can also be observed via slit lamp examination.
Glaucoma
[Main article: Glaucoma]
Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss.Glaucoma is challenging to diagnose and relies on several different methods of assessment to determine the level of optic nerve damage. These may include tonometry, a procedure to determine pressure inside the eye; a visual field test, which assesses peripheral vision; and imaging tests of the optic nerve.
Treatment
Treatment for uveitic glaucoma requires addressing the noninfectious anterior uveitis as well as the glaucoma present in uveitic glaucoma patients. Most urgently, the inflammation associated with uveitis must be identified and treated, to ensure as little damage to the eye as possible. Secondly, the elevated intraocular pressure associated with glaucoma must be treated. Steroid treatment may be discouraged because of the associated side effects.
Treatment of noninfectious anterior uveitis
Topical corticosteroid eyedrops are first-line treatment for uveitis and represent the only approved topical treatment for active non-infectious anterior uveitis. They are the only effective treatment for the short term available today. Corticosteroids can also be administered via periocular injection or intravitreal (IVT) injection. In more severe cases, treatment may be administered systemically via oral or intravenous corticosteroids.
Other treatments, including systemic immunosuppressive agents — which require close monitoring — may be considered where corticosteroids are ineffective or if there are concerns regarding side effects. Immunosuppressive agents include T-cell inhibitors such as cyclosporine and tacrolimus; antimetabolites such as azathioprine, methotrexate, mycophenolate mofetil, and leflunomide; alkylating agents such as cyclophosphamides and chlorambucil; and biological drugs such as adalimumab.
Most uveitis patients are treated with local steroids in the acute phase but may also need long-term treatment with lower-dose steroids as a preventive measure between flare-ups. This precaution is employed in order to minimize the use of topical corticosteroids, due to their severe ocular side effects.
Despite significant advances in therapeutics, the prevalence of blindness secondary to uveitis has not been reduced in the U.S. for the past 30 years.
Challenges related to steroid treatment of noninfectious anterior uveitis
Steroid treatment for uveitis can lead to uveitic glaucoma. Corticosteroids increase the fluid pressure inside the eye (by increasing the resistance to the outflow of aqueous humour), which can cause optic nerve damage and glaucoma. Steroid treatment can therefore cause or worsen uveitic glaucoma.Studies show that 40% to 50% of patients treated with the corticosteroid triamcinolone via intravitreal injection developed clinically significant ocular hypertension. Corticosteroid-induced ocular hypertension typically develops 2 to 6 weeks after starting therapy but can occur at any time during corticosteroid therapy and may persist for weeks after corticosteroids have been discontinued. According to the Glaucoma Research Foundation, "every week of steroid use averaged over a lifetime leads to a 4% increased risk of chronic steroid[-induced] glaucoma".In addition, around 90% of patients with pre-existing open angle glaucoma develop an additional adverse response to steroid treatment.
Treatment of uveitic glaucoma
Glaucoma medications, glaucoma surgery and steroids are the primary options for addressing uveitic glaucoma. Approximately 30% of uveitic glaucoma patients require surgical intervention due to insufficient intraocular pressure control while on maximum medicinal therapy.Available surgical interventions to treat the glaucoma in uveitic glaucoma patients pose a high risk to the eye, with a lower success rate compared to glaucoma surgeries in non-uveitic eyes. Steroids for treating uveitic glaucoma patients also carry high risks.
Because of the risks inherent in steroid treatment and the ineffectiveness of surgical interventions for uveitic glaucoma, there is currently no approved treatment for uveitic patients who also have glaucoma.
A steroid-free medication for uveitis in uveitic glaucoma patients, formulated by Tarsier Pharma, is currently undergoing clinical trials [see Research section].
Challenges related to surgical treatment of uveitic glaucoma
Uveitic glaucoma patients respond poorly to glaucoma surgery; surgery in uveitic glaucoma patients commonly has complications. These complications are caused by either the surgical wound healing improperly or unhealthy levels of pressure inside the eye.Glaucoma surgery usually leads to increased levels of inflammation in the eyes. This is an undesirable consequence, especially in uveitis patients, who already have a high tendency to develop inflammation. Because of this, 80% of uveitis experts report that glaucoma surgeries for uveitic glaucoma patients are likely to fail. Surgery in an eye with uveitis is associated with a higher complication rate, and in some cases surgeries such as valve implantation are too complicated to perform.
Prognosis for uveitic glaucoma patients
About 30% of uveitis patients also develop uveitic glaucoma. Uveitic glaucoma patients are at significantly higher risk for visual field loss in the long term (>5 years) compared to patients who only have uveitis. A patient who only has glaucoma (without uveitis) will, on average, become blind in one eye within 20 years of glaucoma onset. This is especially devastating given that the majority of uveitic glaucoma patients are diagnosed with uveitis at a relatively young age (in their thirties). Thus developing glaucoma at a young age and the cumulative damage of uveitis flare-ups put these patients at high risk of losing their eyesight.
The burden of care for uveitis glaucoma patients is also higher than that of uveitis patients without glaucoma. On average, doctors report 60% more visits from uveitic glaucoma patients than non-glaucomatous uveitis patients. Doctor visits are 40% longer for patients with uveitic glaucoma than for uveitis patients without glaucoma.
Epidemiology
According to epidemiological studies, the prevalence of uveitis is estimated at 115-316 occurrences in 100,000 people. About 30% of patients with non-infectious anterior uveitis also develop glaucoma. Accordingly, 34-94 people in every 100,000 patients with uveitis will develop glaucoma.
Research
Steroid-free medication for uveitis and uveitic glaucoma
A steroid-free eyedrop medication for uveitis and uveitic glaucoma patients, TRS01, is undergoing clinical investigation (as of May 2022). TRS01 is intended as an anti-inflammatory medication for uveitis and uveitic glaucoma that is not anticipated to contribute to elevated intraocular pressure and glaucoma. Up to May 2022, two Phase I/II clinical trials testing TRS01 have been completed. Several dozen patients have undergone these trials. TRS01 is now being investigated in a Phase III clinical trial in patients with noninfectious anterior uveitis, including some with uveitic glaucoma.
== References == |
Generalized epilepsy with febrile seizures plus | Generalized epilepsy with febrile seizures plus (GEFS+) is a syndromic autosomal dominant disorder where affected individuals can exhibit numerous epilepsy phenotypes. GEFS+ can persist beyond early childhood (i.e., 6 years of age). GEFS+ is also now believed to encompass three other epilepsy disorders: severe myoclonic epilepsy of infancy (SMEI), which is also known as Dravets syndrome, borderline SMEI (SMEB), and intractable epilepsy of childhood (IEC). There are at least six types of GEFS+, delineated by their causative gene. Known causative gene mutations are in the sodium channel α subunit genes SCN1A, an associated β subunit SCN1B, and in a GABAA receptor γ subunit gene, in GABRG2 and there is another gene related with calcium channel the PCDH19 which is also known as Epilepsy Female with Mental Retardation. Penetrance for this disorder is estimated at 60%.
Signs and symptoms
Individuals with GEFS+ present with a range of epilepsy phenotypes. These include febrile seizures that end by age 6 (FS), such seizures extending beyond age 6 that may include afebrile tonic-clonic, myoclonic, absence, atonic seizures and myoclonic-astatic epilepsy. Individuals may also present with SMEI, characterized by generally tonic-clonic seizures, impaired psychomotor development, myoclonic seizures, ataxia, and poor response to many anticonvulsants.
Pathophysiology
Type 1
GEFS+ type 1 is a subtype of GEFS+ in which there are mutations in SCN1B, a gene encoding a sodium channel β subunit. The β subunit is required for proper channel inactivation. There are two known mutations in SCN1B that lead to GEFS+ (Figure 1). The first and best characterized of these mutations is C121W. This mutation alters a cysteine involved in a disulfide bond in the extracellular N-terminus of the protein. This extracellular region is similar to the cell adhesion molecule contactin and other cell adhesion molecules. It is believed that the disulfide bond disrupted by the C121W mutation is required for the proper folding of this N-terminus motif. Coexpression of SCN1B with sodium channel α subunits in oocytes and other cells results in channels that inactivate more slowly. Expression of C121W mutant along with wild-type α subunits produces current indistinguishable from that through α subunits alone. Further investigation of this mutation has indicated that it results in decreased frequency dependent rundown and, thus, likely hyperexcitability when compared to cells expressing the wild-type subunit. This mutation also disrupts the subunits ability to induce cellular aggregation. The importance of this last fact is unclear, though it is presumed that proper channel aggregation within cells and cell-cell contact are required for normal neuronal function.A second mutation has been found in one kindred with GEFS+ type 1. This mutation is in a splice acceptor site of exon 3. The loss of this acceptor site reveals a downstream cryptic acceptor site and a protein missing 5 amino acids in the N-terminus (I70_E74del). This mutation has not been further characterized.
Type 2
A second subtype of GEFS+, type 2, is the result of mutations in SCN1A, a gene encoding a sodium channel α subunit. There are currently almost 90 known mutations in the SCN1A gene throughout the entirety of the channel (see table 1). These mutations result in almost any imaginable mutation type in the gene, short of duplications. The results of these mutations are highly variable, some producing functional channels while others result in non-functional channels. Some functional channels result in membrane hyperexcitability while others result in hypoexcitability. Most of the functional mutant channels result in hyperexcitability due to decreased frequency dependent rundown. An example of this is the D188V mutation. A 10 Hz stimulation of wild-type channels causes current to decrease to approximately 70% of maximum whereas the same stimulation of mutant channels results in rundown to 90% of maximum. This is caused by an expedited recovery from inactivation for mutant channels versus wild-type. The D188V mutant, for example, recovers to 90% maximal current in 200ms while wild-type channels are unable to recover to this degree in >1000ms. Some other functional mutations that lead to hyperexcitability do so by other means, such as decreasing the rate of entrance into the slow inactivated state.Some of the other functional mutations are believed to result in hypoexcitability. The R859C mutation, for example, has a more depolarized voltage dependence of activation, meaning that the membrane must be more depolarized for the channel to open. This mutant also recovers more slowly from inactivation. The nonfunctional channels are believed to produce similar changes in cell excitability. Likewise, many of the nonsense mutations likely result in nonfunctional channels and hypoexcitability, though this has yet to be tested. It is also unclear how this membrane hypoexcitability leads to the GEFS+ phenotype.
Type 3
Patients with GEFS+ type 3 have mutations in the GABRG2 gene, which encodes the GABAA γ2 subunit (figure 2). The first mutation discovered in GABRG2 was K289M, in the extracellular region linking membrane-spanning domains M2 and M3. Oocytes injected with α1, β2, and γ2 subunits produce large GABA inducible currents whereas those injected with K289M mutant instead of wild-type subunits produce currents much smaller (about 10% of wild-type). This abnormal current is not the result of non-incorporation of mutant subunits since mutant containing receptors are still sensitive to benzodiazepines, a property for which functional γ subunits are required. Because of these results, it is believed that the GEFS+ phenotype in these individuals is a result of hyperexcitability.Concurrent with the previous mutation, a second group found a second mutation in GABRG2 associated with GEFS+. This mutation, R43Q, is located in the one of two benzodiazepine binding-sites located in the extracellular N-terminus. Benzodiazepines, such as Diazepam, potentiate GABA induced current. This potentiation is abolished in cells expressing the R43Q mutant subunit instead of the wild-type γ subunit. This mutation does not affect the subunits ability to coassemble into function receptors as it still confers resistance to GABA current blockade by zinc. As with the previous mutation, this mutation is expected to result in neuronal hyperexcitability.The final known GEFS+ type 3 mutation is a nonsense mutation, Q351X, located in the intracellular region linking the third and fourth membrane spanning segments. When this mutant subunit is expressed in cells with wild-type α and β subunits it produces non-functional receptors. Since wild-type α and β subunits expressed alone are able to produce GABA inducible current this indicates that the mutation either prevents both coassembly of the mutant and wild-type subunits but also coassembly of the wild-type α and β subunits or prevents proper trafficking of the formed receptor to the membrane. Fusion of GFP onto this mutated subunit has indicated that it is localized to the endoplasmic reticulum instead of the cell membrane. As with other known GEFS+ type 3 mutation, Q351X likely results in neuronal hyperexcitability.
SCN2A mutations
The final type of GEFS+ is caused by mutations in the SCN2A gene, which encodes a sodium channel α subunit. The first associated mutation in this gene is R187W, located on the intracellular region linking membrane spanning units two and three in the first domain (D1S2-S3, figure 3). Patients with this mutation have both febrile and afebrile seizures. Electrophysiological examination of this mutant revealed that it increases the time constant for inactivation, presumably increasing sodium current and leading to hyperexcitability. However, this mutation also yields channels that inactivate at more hyperpolarized potentials relative to wild-type channels, indicative of hypoexcitability. Whether the result on membrane excitability of this mutation is hyperexcitability or hypoexcitability is, as yet, unclear.The second known mutation in SCN2A associated with GEFS+ is R102X. This mutation is located in the intracellular N-terminus (figure 3) and results in SMEI in patients. The result of this mutation is completely non-functional channels and membrane hypoexcitability. The truncated mutant protein also seems to cause wild-type channels to inactivate at more hyperpolarized potentials, indicating that it also acts in a dominant negative manner.
Management
Long term management is by use of anticonvulsant medication, principally valproate, stiripentol, topiramate or clobazam. Ketogenic diet has also been found useful in certain cases Management of breakthrough seizures is by benzodiazepine such as midazolam.
See also
Febrile seizures
Idiopathic generalized epilepsy
Dravet Syndrome Foundation
International Dravet Epilepsy Action League
References
== External links == |
Anterior cerebral artery syndrome | Anterior cerebral artery syndrome is a condition whereby the blood supply from the anterior cerebral artery (ACA) is restricted, leading to a reduction of the function of the portions of the brain supplied by that vessel: the medial aspects of the frontal and parietal lobes, basal ganglia, anterior fornix and anterior corpus callosum.Depending upon the area and severity of the occlusion, signs and symptoms may vary within the population affected with ACA syndrome. Blockages to the proximal (A1) segment of the vessel produce only minor deficits due to the collateral blood flow from the opposite hemisphere via the anterior communicating artery. Occlusions distal to this segment will result in more severe presentation of ACA syndrome. Contralateral hemiparesis and hemisensory loss of the lower extremity is the most common symptom associated with ACA syndrome.
Signs and symptoms
Hemiparesis or hemiplegia contralaterally, involving primarily the lower limbs and pelvic floor musculature
Sensory deficits contralaterally, involving primarily the leg and perineum
Apraxia (due to branches to the supplementary motor area and corpus callosum)
Disconnection syndrome (due to callosal branches)
Anosmia (due to branches of the olfactory bulb and olfactory tract)
Urinary incontinence
Grasp reflex and or sucking reflex contralaterally (if circle of Willis compromised)
Diagnosis
Once an acute ischemic stroke is suspected, the standard evaluation includes performing routine airway, breathing and circulation assessment, checking blood glucose, performing a validated stroke severity scale assessment and accurate, focused history regarding the time of symptom onset or last known well or at baseline. The National Institutes of Health Stroke Scale (NIHSS) is a standardized method for quantifiable assessment of stroke symptoms. It is the preferred scoring system, and scores range from 0 to 42. A patient with a higher score on this scale is more likely to be considered disabled; however, the definition of "disabling" depends on age, occupation, underlying life-limiting comorbidities, advance directives.
The crucial step in the evaluation of stroke patients is to obtain brain imaging to ascertain the type and characteristics of the stroke. In this regard, non-contrast CT of the head is the imaging modality of choice. Ischemic changes may classify as acute, subacute, and chronic, depending on the time in which they present after the onset of stroke. CT scan can also rule out intracranial hemorrhage.[18] If an intracranial hemorrhage is present, aneurysmal rupture should be investigated given its association with arterial vasospasm resulting in stroke.[3] Anterior cerebral artery strokes could be missed on imaging studies depending on their location or size. One case series found that 37.5% (6 of 16) of ACA infarcts evaluated by CT were identifiable only after using contrast injection or angiography. If the area of hypodensity is small and localized over a sulcus, the infarct could be overlooked.[1] [13] Noncontrast head CT should be quickly followed by CT angiography of the head and neck to expedite identification of intracranial large vessel occlusion.
The finding of a hyperdense lesion in the ACA on CT scan aid in the diagnosis of stroke in its acute phase, particularly when it may be otherwise difficult to establish. The frequency of this sign in ACA infarcts is similar to that in the territories of the middle cerebral artery and the posterior circulation.[19]
As in strokes involving other areas of the brain, magnetic resonance imaging is also of critical value in the diagnosis of ACA strokes. MRI with diffusion-weight imaging is a highly useful modality, which facilitates the demarcation of ischemic boundaries in the territory of the ACA.[3] [18] MR angiography can be a helpful adjunct in the evaluation of stroke mechanisms.[7] The goal of completing head CT or MRI should be 25 min or less within patient arrival.
The National Institutes of Neurological Disorders and Stroke (NINDS) established time frame goals in the evaluation of stroke patients: door to physician less than 10 min, door to stroke team less than 15 min, door to CT scan less than 25 min, door to drug less than 60 min.[20]
Along with accurate history and early imaging, laboratory studies including capillary blood glucose, complete blood count with platelets, chemistries, coagulation studies, hemoglobin A1c, lipid panel, and markers of hypercoagulability or inflammation can be useful in identifying the risk factors or establishing the etiology of stroke. The medication checklist is an integral part of the evaluation, specifically recent use of anticoagulants, as contraindications to thrombolytic therapy should undergo rapid assessment. Cardiac sources of embolism can be evaluated as part of the work up with EKG monitoring and echocardiogram.
Management
Pulse oximetry can guide the use of supplemental oxygen to maintain oxygen saturation greater than 94%. Hyperoxia should be avoided as may be detrimental in stroke. Hypertension is common in an acute ischemic stroke. A low BP is uncommon and may indicate symptoms exacerbation of a previous stroke due to poor perfusion. Blood pressure of 220/120 mmHg should receive treatment. There is a consensus approach of allowing permissive hypertension up to 220/120 mmHg for patients that are not candidates for thrombolysis.[21]
However, for a patient that is a potential candidate for alteplase, attempt to control BP should be made immediately as goal BP for initiation of IV alteplase is 185/110 mmHg. Usually, titratable short-acting intravenous hypotensive agents are recommended to avoid dropping the BP too much once the patient is at goal. Hypotensive agents that can be options include labetalol, nicardipine, clevidipine, hydralazine, enalaprilat.[21]
For the patients that present within the therapeutic window, the decision to treat with intravenous recombinant tissue plasminogen (less than 4.5 hours from symptom onset) or endovascular treatment with mechanical thrombectomy should be made. Initiation of IV alteplase treatment in the 3 to 4.5-hour window is the current recommendation for patients less than 80 years of age, no history of both diabetes mellitus and prior stroke, use of anticoagulants, and NIHSS score of less than 25. Only patients with disabling symptoms are considered eligible for thrombolytic treatment. Eligibility and absolute and relative contraindications should undergo rapid assessment. Randomized controlled trials have shown that intravenous administration of recombinant tissue plasminogen activator (alteplase) decrease functional disability with an absolute reduction risk of 7%-13% relative to placebo.[21]
Unfortunately, over half of patients arrive after this time window has closed and are not eligible for thrombolysis. Treatment delays may result from failure to ascribe a patients symptoms to stroke, and furthermore, the risk of harm increases with time elapsed from symptom onset.[21] This situation could be of particular concern in ACA strokes, given their sometimes atypical presentation.
Endovascular treatment with mechanical thrombectomy (MT) is another proven treatment modality in the management of patients with acute stroke suffering a large vessel occlusion, although treatment efficacy is highly time-dependent. The procedure is available in tertiary hospitals as requires stroke team with the expertise to use timely imaging and intervention. One study evaluating MT in ACA stroke patients found that while recanalization rates were high, the outcomes were otherwise unsatisfactory. The latter was attributed to larger infarct volumes and longer times to recanalization.[22] [23].
New guidelines recommend that in patients with acute ischemic stroke within 6 to 24 hours from last known well and who have large vessel occlusion in anterior circulation, obtaining CTP, DW-MRI, or MRI perfusion is recommended to aid in selection for mechanical thrombectomy. However, this is only with the strict application of imaging or other eligibility criteria from RCTs showing benefit are in selecting patients for MT. The DAWN trial used clinical imaging mismatch (imaging from CTP or DW-MRI and NIHSS scoring) as criteria to select patients with anterior circulation LVO for MT between 6 and 24 hours from last known well. The trial demonstrated an overall functional benefit at 90 days in the treatment group (mRS score 0 to 2, 49% versus 13%, adjusted difference 33%, 95% CI, 21 to 44; a probability of superiority greater than 0.999). The DEFUSE 3 trial used perfusion core mismatch and maximum core size as criteria in selecting the patient for MT with LVO in anterior circulation 6 to 16 hours from last time seen normal. This trial also showed outcome benefit at 90 days in the treated group (mRS score 0 to 2, 44.6% vs. 16.7%, RR 2.67, 95% CI, 1.60 to 4.48, p greater than 0.0001). DAWN and DEFUSE 3 are the only trials showing a benefit of mechanical thrombectomy greater than 6 hours from symptoms onset. Only criteria from these trials should be viable for patient selection who might benefit from MT.[21] One should be aware that most of the patients involved in DAWN and DEFUSE 3 trials had middle cerebral artery occlusions.
Beyond the acute management of stroke, the use of antihypertensives, dual antiplatelet therapy, anticoagulants, carotid endarterectomy should be used to prevent recurrent events. Antiplatelet therapy or anticoagulants are not recommended within 24h after alteplase administration. Aspirin is not a recommendation as a substitute for other interventions for acute stroke. Administration of glycoprotein IIb/IIIa receptor inhibitor is not recommended, and a recent Cochrane review showed that these agents correlated with a high risk of intracranial hemorrhage. Dual antiplatelet therapy (aspirin and clopidogrel) are recommended to start within 24 hours for 21 days in patients with minor stroke for early secondary stroke prevention. The CHANCE trial showed that the primary outcome of recurrent stroke at 90 days favored dual antiplatelet therapy over Aspirin alone (HR 0.68; 95% CI, 0.57 to 0.81, p<0.0001). Ticagrelor over aspirin in acute stroke treatment is not recommended. According to SOCRATES trial with the primary outcome of time to the composite endpoint of stroke, MI or death up to 90 days, ticagrelor was not found to be superior to aspirin (HR 0.89, 95% CI, 0.78-1.01; p=0.07). However, ticagrelor is a reasonable alternative in patients with contraindication to aspirin. The efficacy of tirofiban and eptifibatide is currently unknown.[21] [20]
Optimization of risk factors is essential for secondary prevention of stroke in order to improve outcomes from the principal event.[21]
References
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Chandra A, Li WA, Stone CR, Geng X, Ding Y. The cerebral circulation and cerebrovascular disease I: Anatomy. Brain Circ. 2017 Apr-Jun;3(2):45-56. [PMC free article] [PubMed]
Kumral E, Bayulkem G, Evyapan D, Yunten N. Spectrum of anterior cerebral artery territory infarction: clinical and MRI findings. Eur. J. Neurol. 2002 Nov;9(6):615-24. [PubMed]
Toyoda K. Anterior cerebral artery and Heubners artery territory infarction. Front Neurol Neurosci. 2012;30:120-2. [PubMed]
Krishnan M, Kumar S, Ali S, Iyer RS. Sudden bilateral anterior cerebral infarction: unusual stroke associated with unusual vascular anomalies. Postgrad Med J. 2013 Feb;89(1048):120-1. [PubMed]
Arboix A, García-Eroles L, Sellarés N, Raga A, Oliveres M, Massons J. Infarction in the territory of the anterior cerebral artery: clinical study of 51 patients. BMC Neurol. 2009 Jul 09;9:30. [PMC free article] [PubMed]
Kang SY, Kim JS. Anterior cerebral artery infarction: stroke mechanism and clinical-imaging study in 100 patients. Neurology. 2008 Jun 10;70(24 Pt 2):2386-93. [PubMed]
Hensler J, Jensen-Kondering U, Ulmer S, Jansen O. Spontaneous dissections of the anterior cerebral artery: a meta-analysis of the literature and three recent cases. Neuroradiology. 2016 Oct;58(10):997-1004. [PubMed]
Mohindra S, Kovai P, Chhabra R. Fatal Bilateral ACA Territory Infarcts after Pituitary Apoplexy: A Case Report and Literature Review. Skull Base. 2010 Jul;20(4):285-8. [PMC free article] [PubMed]
Kurre W, Vorlaender K, Aguilar-Pérez M, Schmid E, Bäzner H, Henkes H. Frequency and relevance of anterior cerebral artery embolism caused by mechanical thrombectomy of middle cerebral artery occlusion. AJNR Am J Neuroradiol. 2013 Aug;34(8):1606-11. [PubMed]
Nagaratnam N, Davies D, Chen E. Clinical effects of anterior cerebral artery infarction. J Stroke Cerebrovasc Dis. 1998 Nov-Dec;7(6):391-7. [PubMed]
Bogousslavsky J, Martin R, Moulin T. Homolateral ataxia and crural paresis: a syndrome of anterior cerebral artery territory infarction. J. Neurol. Neurosurg. Psychiatry. 1992 Dec;55(12):1146-9. [PMC free article] [PubMed]
Honig A, Eliahou R, Auriel E. Confined anterior cerebral artery infarction manifesting as isolated unilateral axial weakness. J. Neurol. Sci. 2017 Feb 15;373:18-20. [PubMed]
Kobayashi S, Maki T, Kunimoto M. Clinical symptoms of bilateral anterior cerebral artery territory infarction. J Clin Neurosci. 2011 Feb;18(2):218-22. [PubMed]
Edlow JA, Selim MH. Atypical presentations of acute cerebrovascular syndromes. Lancet Neurol. 2011 Jun;10(6):550-60. [PubMed]
Nishida Y, Irioka T, Sekiguchi T, Mizusawa H. Pure sensory infarct in the territories of anterior cerebral artery. Neurology. 2010 Jul 20;75(3):287. [PubMed]
Bejot Y, Caillier M, Osseby GV, Didi R, Ben Salem D, Moreau T, Giroud M. Involuntary masturbation and hemiballismus after bilateral anterior cerebral artery infarction. Clin Neurol Neurosurg. 2008 Feb;110(2):190-3. [PubMed]
Birenbaum D, Bancroft LW, Felsberg GJ. Imaging in acute stroke. West J Emerg Med. 2011 Feb;12(1):67-76. [PMC free article] [PubMed]
Jensen UR, Weiss M, Zimmermann P, Jansen O, Riedel C. The hyperdense anterior cerebral artery sign (HACAS) as a computed tomography marker for acute ischemia in the anterior cerebral artery territory. Cerebrovasc. Dis. 2010;29(1):62-7. [PubMed]
Jauch EC, Saver JL, Adams HP, Bruno A, Connors JJ, Demaerschalk BM, Khatri P, McMullan PW, Qureshi AI, Rosenfield K, Scott PA, Summers DR, Wang DZ, Wintermark M, Yonas H., American Heart Association Stroke Council. Council on Cardiovascular Nursing. Council on Peripheral Vascular Disease. Council on Clinical Cardiology. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013 Mar;44(3):870-947. [PubMed]
Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL., American Heart Association Stroke Council. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2018 Mar;49(3):e46-e110. [PubMed]
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Notes
== External links == |
Chronic periodontitis | Chronic periodontitis is one of the seven categories of periodontitis as defined by the American Academy of Periodontology 1999 classification system. Chronic periodontitis is a common disease of the oral cavity consisting of chronic inflammation of the periodontal tissues that is caused by the accumulation of profuse amounts of dental plaque. Periodontitis initially begins as gingivitis and can progress onto chronic and subsequent aggressive periodontitis according to the 1999 classification.
Diagnosing chronic periodontitis is important in its early stages to prevent severe and irreversible damage to the protective and supportive structures of the tooth. However, due to chronic periodontitis being a painless progressing disease, few patients will seek dental care in the early stages. Mild to moderate chronic periodontitis can be managed by proper mechanical removal of the biofilm and calculus subgingivally. Full and effective oral hygiene and regular 3 monthly periodontal checkups are important for maintaining the stability of the disease.
Chronic periodontitis is prevalent in adults and seniors worldwide. In the US around 35% of adults (30–90 years) are affected. The cumulative effects of alveolar bone loss, attachment loss and pocket formation is more apparent with an increase in age. Age is related to the incidence of periodontal destruction: "...in a well-maintained population who practises oral home care and has regular check-ups, the incidence of incipient periodontal destruction increases with age, the highest rate occurs between 50 and 60 years, and gingival recession is the predominant lesion before 40 years, while periodontal pocketing is the principal mode of destruction between 50 and 60 years of age."There are a variety of periodontal risk factors which can affect the prevalence, rate, extent and severity of the disease progression. Major risk factors include smoking, lack of oral hygiene with inadequate plaque biofilm control.
There is a slow to moderate rate of disease progression but the patient may have periods of rapid progression ("bursts of destruction"). Chronic periodontitis can be associated with local predisposing factors (e.g. tooth-related or iatrogenic factors). The disease may be modified by and be associated with systemic diseases (e.g. diabetes mellitus, HIV infection) It can also be modified by factors other than systemic disease such as smoking and emotional stress, anxiety and depression. Care should be taken however, when diagnosing a patient who smokes as smoking can alter some of the results of an examination. In smokers, the gingiva are pale and fibrous and tend to bleed less while being probed due to the effect of nicotine on the vasculature by vasoconstricting them. Thus, a lowered response is produced and this explains why incorrect data can be gained. There is also an increase in supragingival calculus alongside visible nicotine staining. The anterior dentition occasionally have recession and maxillary anterior and palatal surfaces are more adversely affected.
Pathophysiology
Chronic periodontitis is initiated by Gram-negative tooth-associated microbial biofilms that elicit a host response, which results in bone and soft tissue destruction. In response to endotoxin derived from periodontal pathogens, several osteoclast-related mediators target the destruction of alveolar bone and supporting connective tissue such as the periodontal ligament. Major drivers of this aggressive tissue destruction are matrix metalloproteinases (MMPs), cathepsins, and other osteoclast-derived enzymes.
Plaque hypothesis
At least two mechanisms of the microbiology of periodontitis have been described: the specific plaque hypothesis and the non-specific plaque hypothesis.
Consensus is that neither view is entirely correct, but via a middle path, that damage is due to a shift in the relative populations of more and less dangerous bacteria in the plaque. This is called the ecological plaque hypothesis.
The disease is associated with a variable microbial pattern.Anaerobic species of bacteria Porphyromonas gingivalis, Bacteroides forsythus, Treponema denticola, Prevotella intermedia, Fusobacterium nucleatum, Eubacterium sp. have all been implicated in chronic periodontitis.Microaerophile bacteria Actinomyces actinomycetemcomitans, Campylobacter rectus, and Eikenella corrodens also may play a role in chronic periodontitis.
Signs and symptoms
In the early stages, chronic periodontitis has few symptoms and in many individuals the disease has progressed significantly before they seek treatment.
Symptoms may include the following:
Redness or bleeding of gums while brushing teeth, using dental floss or biting into hard food (e.g. apples) (though this may occur even in gingivitis, where there is no attachment loss)
Gum swelling that reoccurs
Halitosis, or bad breath, and a persistent metallic taste in the mouth
Gingival recession, resulting in apparent lengthening of teeth. (This may also be caused by heavy-handed brushing or with a stiff tooth brush.)
Deep pockets between the teeth and the gums (pockets are sites where the attachment has been gradually destroyed by collagen-destroying enzymes, known as collagenases)
Loose teeth, in the later stages (though this may occur for other reasons as well)
Drifting of incisorsGingival inflammation and bone destruction are often painless. Patients sometimes assume that painless bleeding after teeth cleaning is insignificant, although this may be a symptom of progressing chronic periodontitis in that patient.
Subgingival calculus is a frequent finding as well as supragingival calculus due to the bacteria migrating apically and the combined effect of the host response system of the body.
Diagnosis
1999 classification
Chronic periodontitis is one of the seven destructive periodontal diseases as listed in the 1999 classification. Not every case of gingivitis will progress onto chronic periodontitis, but all chronic perodontitis results from gingivitis. Therefore it is important to control the first step; gingival inflammation.
A difficulty which arises with diagnosing chronic periodontitis patients is due to the slow and painless progression of the disease. The most effective and timely diagnosis would be during the mild to moderate stage. However, usually when presenting complaints do arise the effects of mobility and alveolar bone loss have become severe.
A full mouth examination and recording is required to document and track periodontal disease including:
Pocket Depth (PD)
Clinical Attachment Loss (CAL)
Bleeding On Probing (BOP)
Plaque index/score
Furcation involvement
Suppuration
Mobility
RadiographsMeasuring disease progression is carried out by measuring probing pocket depth (PPD) and bleeding indices using a periodontal probe. Pockets greater than 3mm in depth are considered to be unhealthy. True pocket formation of 4 mm or more are specifically related to chronic periodontitis. Bleeding on probing is considered to be a sign of active disease. Discharge of pus, involvement of the root furcation area and deeper pocketing may all indicate reduced prognosis for an individual tooth.
Evidence of alveolar bone loss is also required to differentiate between true bone loss and not attributions of gingival oedema. Usually, a horizontal pattern of bone loss would be found however, vertical (infrabony) bone loss may also be present on specific sites. A Basic Periodontal Examination (BPE) or Periodontal Screening and Recording (PSR) should give a score of 3 or 4. A correct diagnosis is vital to allow the formation of a specific treatment plan for the patient and to arrest the disease progression.
Chronic periodontitis can be further classified into:
Extent (can be either localised affecting < 30% of sites; or generalised if > 30% of sites are affected)
Severity (slight = 1–2 mm CAL; moderate = 3–4 mm CAL; severe ≥5 mm CAL)
2017 classification
Chronic periodontitis is not included within the newer 2017 World Workshop classification. The 2017 classification of Periodontal Diseases and Conditions includes:Periodontitis:
Necrotizing periodontal diseases
Periodontitis
Periodontitis as a manifestation of systemic diseaseTherefore, in accordance to the 2017 classification, a diagnosis would be achieved through the patient assessment individually on the basis of:
Type
Distribution: localised (up to 30% of teeth) or generalised (more than 30% of teeth) and the molar/incisor pattern
Stage and grading
Stages: I (early/mild) with <15% or <2mm interproximal bone loss, II (moderate) with coronal third of root bone loss, III (severe) with mid third of root bone loss, IV (very severe) with apical third of root bone loss
Grading: A (slow) with <0.5% bone loss/age, B (moderate) with 0.5-1.0% bone loss/age, C (rapid) with >1.0% bone loss/age
Status: stable, remission or unstable (see Table 1)
Risk factors, which include systemic diseases such as diabetes or extrinsic factors such as smoking.
Treatment
There is professional agreement among dentists that smoking cessation and good oral hygiene are key to effective treatment and positive outcomes for patients. Similarly, any plaque retentive factors which exist and are modifiable should be corrected, such as overhangs on restorations.
Treatment can involve both non-surgical and surgical therapies. The typical initial treatment known to be effective is scaling and root planing (SRP) to mechanically debride the depths of the periodontal pocket and disrupt the biofilm present. This is done using a powered ultrasonic or sonic scaler and/or unpowered hand instruments.
"In patients with chronic periodontitis, subgingival debridement (in conjunction with supragingival plaque control) is an effective treatment in reducing probing pocket depth and improving the clinical attachment level. In fact it is more effective than supragingival plaque control alone". It is important for patients to be reviewed within 8–12 weeks to assess the treatment response.
Full mouth disinfection protocols are favoured by some clinicians. There is no evidence that full mouth disinfection or full mouth scaling protocols improve the outcome when compared to standard mechanical scaling and root planing.
Open flap debridement
Open flap debridement is used by some practitioners particularly in deeper pocket areas. The advantages of this approach is better visualization of the root surface to be cleaned. This must be weighed against the risks of surgery. Open flap surgery is more effective than non-surgical periodontal therapy in deep pocketing : "Both scaling and root planing alone and scaling and root planing combined with flap procedure are effective methods for the treatment of chronic periodontitis in terms of attachment level gain and reduction in gingival inflammation. In the treatment of deep pockets open flap debridement results in greater PPD reduction and clinical attachment gain."
Guided tissue regeneration
Guided tissue regeneration (GTR) using PTFE membranes is favoured by some practitioners, despite its cost and complexity: "GTR has a greater effect on probing measures of periodontal treatment than open flap debridement, including improved attachment gain, reduced pocket depth, less increase in gingival recession and more gain in hard tissue probing at re-entry surgery. However there is marked variability between studies and the clinical relevance of these changes is unknown. As a result, it is difficult to draw general conclusions about the clinical benefit of GTR. Whilst there is evidence that GTR can demonstrate a significant improvement over conventional open flap surgery, the factors affecting outcomes are unclear from the literature and these might include study conduct issues such as bias. Therefore, patients and health professionals need to consider the predictability of the technique compared with other methods of treatment before making final decisions on use."
Enamel matrix derivative
Enamel matrix derivative (EMD) is favoured by some practitioners despite its high cost: "One year after its application, EMD significantly improved probing attachment levels (1.1 mm) and probing pocket depth reduction (0.9 mm) when compared to a placebo or control, however, the high degree of heterogeneity observed among trials suggests that results have to be interpreted with great caution. In addition, a sensitivity analysis indicated that the overall treatment effect might be overestimated. The actual clinical advantages of using EMD are unknown. With the exception of significantly more postoperative complications in the GTR group, there was no evidence of clinically important differences between GTR and EMD. Bone substitutes may be associated with less gingival recession than EMD."However, studies have shown that regardless of the conventional periodontal treatments, 20-30% of chronic periodontitis patients do not respond favorably to their treatment. There are many factors which account for these including: ineffective removal of calculus, defective restorations, impaired immune response as a result of a systemic condition, poor plaque control, smoking, etc.
Adjunctive systemic antibiotic treatment
Systemic antibiotics such as amoxicillin or metronidazole are sometimes used in addition to debridement based treatments.
"Systemic antimicrobials in conjunction with scaling and root planing (SRP), can offer an additional benefit over SRP alone in the treatment of periodontitis, in terms of clinical attachment loss (CAL) and probing pocket depth (PPD) change, and reduced risk of additional CAL loss. However, differences in study methodology and lack of data precluded an adequate and complete pooling of data for a more comprehensive analyses. It was difficult to establish definitive conclusions, although patients with deep pockets, progressive or active disease, or specific microbiological profile, can benefit more from this adjunctive therapy."There is currently low-quality evidence suggesting if adjunctive systemic antimicrobials are beneficial for the non-surgical treatment of periodontitis. It is not sure whether some antibiotics are better than others when used alongside scaling and root planning).
Locally delivered adjunctive antimicrobial treatment
Chemical antimicrobials may be used by the clinician to help reduce the bacterial load in the diseased pocket.
"Among the locally administered adjunctive antimicrobials, the most positive results occurred for tetracycline, minocycline, metronidazole, and chlorhexidine. Adjunctive local therapy generally reduced PD levels....Whether such improvements, even if statistically significant, are clinically meaningful remains a question."Minocycline is typically delivered via slim syringe applicators.
Chlorhexidine impregnated chips are also available.
Hydrogen peroxide is a naturally occurring antimicrobial that can be delivered directly to the gingival sulcus or periodontal pocket using a custom formed medical device called a Perio Tray. [Title = Custom Tray Application of Peroxide Gel as an Adjunct to Scaling and Root Planing in the Treatment of Periodontitis:
A Randomized, Controlled Three-Month Clinical Trial J Clin Dent 2012;23:48–56.]
Hydrogen peroxide gel was demonstrated to be effective in controlling the bacteria biofilm [Subgingival Delivery of Oral Debriding Agents: A Proof of Concept J Clin Dent 2011;22:149–158] The research shows that a direct application of hydrogen peroxide gel killed virtually all of the bacterial biofilm, was directly and mathematically delivered up to 9mm into periodontal pockets.
Modulating the host response
Sub-antimicrobial doses of doxycycline (SDD) have been used to alter host response to the periodontal pathogens. This is believed to disrupt the action of matrix metalloproteinases and thus minimise host mediated tissue destruction.
"The adjunctive use of SDD with SRP is statistically more effective than SRP alone in reducing PD and in achieving CAL gain."
Systemic Factors
Chronic periodontitis is an inflammatory immune response against the presence of bacteria present. Recent research has suggested that epithelial lining ulceration in chronic periodontal pockets are due to systemic bacterial dissemination and widespread bacterial inflammatory markers present in the host. Two of the most widely investigated systemic diseases associated with chronic periodontitis is diabetes mellitus and cardiovascular disease.
Diabetes Mellitus
Both type 1 and type 2 diabetes have shown a link with the treatment and progression of chronic periodontitis. Chronic periodontitis is more serve in patients that have diabetes than those without, confirming a significant association. With type 2 diabetes patients being shown to have 3.8 times more bone loss and 2.8 times more clinical attachment loss than non-diabetic individuals. With patients with poorly controlled diabetes having a higher risk of alveolar bone loss. Chronic periodontitis can also be a metabolic stressor influencing diabetes control, influencing insulin resistance or becoming a source of inflammatory marker secretion which may strengthen the amount of advanced glycation end product (AGE) mediated cytokine response. Monocytic hyperresponsiveness to bacterial antigen is a biological mechanism that links periodontal disease and diabetes. Increased production of proinflammatory cytokines and mediators cause tissue destruction, attachment loss as well as bone loss causing delayed wound healing.
Cardiovascular Disease
Chronic periodontitis is a marker for cardiovascular disease (CVD). Mechanisms associated with cardiovascular risk are that chronic periodontitis increases inflammatory mediator levels and this may contribute to the onset of CVD, while treatment of chronic periodontitis reduces systemic levels of inflammatory mediators. Certain bacteria found in the periodontal pockets have also been associated to cause atheromatous plaques. Treatment protocol for chronic periodontitis with CVD does not need to be modified as normal periodontal treatment techniques are seen to be effective in CVD patients with additional supportive therapy.
Costs of treatment
"Costs for tooth retention via supportive periodontal therapy are relatively low compared with alternatives (e.g. implants or bridgework) even in periodontally impaired teeth.". However, health outcomes of periodontal therapy are not directly comparable with those from implants or bridgework.
Research
Management
For adults without severe periodontitis and who get routine dental care, regular scale and polish treatment does not make any difference to gingivitis, probing depths or other oral health-related problems. It seems that there is also no difference in plaque levels.Lasers are increasingly being used in treatments for chronic periodontitis. However, there is some controversy over their use:
"No consistent evidence supports the efficacy of laser treatment as an adjunct to non-surgical periodontal treatment in adults with chronic periodontitis."
Tentative links to other conditions
There is little evidence linking progression of periodontal disease to low birth weight or preterm birth:
"In these women with periodontitis and within this studys limitations, disease progression was not associated with an increased risk for delivering a pre-term or a low birthweight infant."There is recently emerged evidence linking chronic periodontitis with head and neck squamous cell carcinoma: "Patients with periodontitis were more likely to have poorly differentiated oral cavity SCC than those without periodontitis (32.8% versus 11.5%; P = 0.038)".
References
External links
British Society for Periodontology
American Society of Periodontology
https://web.archive.org/web/20090720042329/http://www.uic.edu/classes/peri/peri323/syallbus/class/charac1.htm |
Ichthyosis prematurity syndrome | Ichthyosis prematurity syndrome (IPS) is a dermatological disease with known genetic causes. This syndrome is a rare subcategory of autosomal recessive congenital ichthyosis (ARCI). It is associated with complications in the mid-trimester of a pregnancy leading to premature births. Although most prevalent in individuals of Scandinavian origin, there have also been scattered cases in people of Japanese, Italian and Indian ethnicity. This disorder is also referred to as ichthyosis congenital type IV.
Signs and symptoms
The symptoms associated with the disorder are often confused for other dermatological disorders. The symptoms below are ones specifically associated with IPS.
Premature birth
Pregnancies that have a foetus affected with this syndrome are complicated because of polyhydramnion. Complications arise because of opaque amnionic fluid resulting from the shedding of skin. As a result, ultrasounds are difficult to conduct. Triggered by the harsh environment in the uterus, delivery results around 30– 34 weeks of gestation (pregnancy) and the baby is born in prematurely.
Thick caseous layer of skin
A white layer of thick scaly substance covers the surface of the skin of the infant. This is characterized by aggregating membranes in the upper layer of skin on epidermal cells.
Desquamating skin
Red endemic skin as well as spongy and desquamating (peeling) skin are consistent with this syndrome.
Respiratory problems
After premature delivery, the baby often has neonatal asphyxia from breathing amnionic debris mainly composed of shedding skin cells. Neonatal refers to the very young infant and amniotic fluid refers to the liquid environment the baby is bathed in inside the uterus.
Eosinophilia
Eosinophils are a kind of a white blood cell which help protect the body from certain infections and involved in allergic responses. Eosionphelia is an abnormal increase of eosinophils in tissue, blood or both and is present in individuals born with this syndrome.
Genetics
Mode of inheritance
This rare syndrome is associated with an autosomal recessive mode of inheritance. The parents are classified as heterozygote carriers of the disease and the chance that the offspring will be affected is 25%. Both parents need to have the mutant allele in order to pass on the disease to their offspring and the offspring need to inherit both mutant alleles in order to express the disorder.
Genetic cause
IPS is caused by a number of mutations at different loci of the FATP4 gene. One nonsense mutation and a number of missense mutation in the FATP4 (SLC27A4) gene which codes for the fatty acid transport protein 4 are associated with IPS. Splice site mutations have also been linked to IPS. When the splice site between exons and introns is mutated, it leads to a deletion or duplication event which would change the stability or soundness of the protein the RNA is coding for.
When a mutation is present in the gene coding for this protein, the protein product is not stable or able to perform its role. As a result, the pathway it is involved in is compromised and a diseased phenotype is often noted. In this particular case the fatty acid transport protein 4 is deformed due to the presence of mutations in the FATP4 gene and an interference occurs in the lipid metabolic pathway in the skin that this protein is involved with.This results in the abnormal formation of epidermal skin cells and a compromised formation and maintenance of an epidermal barrier. These underlying genetic causes explain the symptoms of the flaky, dry, cutaneous skin phenotype expressed.IPS genes segregate independently of the already known general ARCI locus. As a result, IPS has been identified to have its own gene locus making it easier to diagnose.
Diagnosis
Diagnosis can be made at birth by identifying the symptoms of the child. Ultrastructural diagnosis where tissues are analyzed is using electron microscopy is also conducted. A specimen of skin is obtained via a skin biopsy and analyzed to see any tell tale characteristics. Genetic testing can also be done to identify the mutation on the FATP4 gene associated with fatty acid synthesis. Genetic consultation through a genetic counsellor is done to determine whether the individual has this syndrome and reduces the chances of misdiagnoses with other cutaneous diseases.
Treatment
The infant is intubated post delivery to stabilize the respiratory problems experienced. Often the skin condition becomes less severe resolving itself to flaky dry skin as the individual grows. No intervention is usually required and the condition becomes less severe as the patient grows. The dry skin symptoms can be managed with topical ointments or creams and the individual remains otherwise healthy.
Prognosis
There are no life-threatening complications after the perinatal period (around the time of birth) and the skin conditions persist but to a lesser degree of severity. Individuals have a favourable prognosis as symptoms can be managed and past the infancy stage are not life-threatening. The red skin edema improves after a three-week period but the ichthyosis scaling persists. Asthma has been recorded in some cases later on in the individuals life and sign of atopic dermatitis persist, follicular hyperkeratosis and small amounts of scaling at the scalp that goes on into adulthood but otherwise the individual continues a healthy life.
Epidemiology
Frequencies of this disease are the greatest in Norway with a few Finnish cases have also having been noted to date. Some cases have been found in other ethnicities such as in people of Indian or Japanese descent as well as a north Italian family. These cases are scattered and there are potentially more under reported cases as this disease is often under diagnosed for other cutaneous diseases. It is most prevalent in a defined region in the middle of Norway and Sweden with a heterozygote carrier frequency of 1 in 50.
References
== External links == |
Nevus of Ito | Nevus of Ito (also known as "Nevus fuscoceruleus acromiodeltoideus") is a skin condition with similar features to the Nevus of Ota, but occurring in a different distribution.: 700
See also
Skin lesion
References
== External links == |
Far East scarlet-like fever | Far East scarlet-like fever is an infectious disease caused by the gram negative bacillus Yersinia pseudotuberculosis. In Japan it is called Izumi fever.
Signs and symptoms
These include
red skin rash usually of the face, elbows, and knees
skin desquamation
exanthema
red tongue
toxic shock syndromeOther features include mesenteric lymphadenitis and arthritis. Kidney failure rarely occurs.
Relapses occur in up to 50% of patients.
Cause
The cause of this disease is Yersinia pseudotuberculosis serotype O1. 95% are subtype O1b.
Yersinia pseudotuberculosis has been divided into 6 genetic groups: group 1 has only been isolated from the Far East.
Pathophysiology
The clinical features of this disease appear to be due—at least in part—to the production of a superantigen—YpM (Yersinia pseudotuberculosis-derived mitogen). This is present in almost all strains from the Far East but only 20% of European isolates. The antigen was discovered in 1993 and is encoded by a 456-base gene. The protein has 151 amino acids, with a signal sequence of 20 amino acids. The mitogenic antigens are scattered across the protein but two cysteine residues (residues 32 and 129) which form a disulfide bridge are critical.
The G+C content of this gene is 35%—lower than the genomic average (47%) suggesting that this gene has been acquired from some other organism. The organism from which this gene originated has not yet been identified. This gene seems likely to have been introduced into the genome by a bacteriophage, given the nearby presence of a phage integration site, but the mechanism of entry into the genome is not currently known.
Diagnosis
Differential diagnosis
The main differential diagnosis is scarlet fever.
History
The first outbreak of this disease was reported from the Pacific coastal areas (Primorsky Krai) of Russia in the 1950s.
== References == |
Adenomyomatosis | Adenomyomatosis is a benign condition characterized by hyperplastic changes of unknown cause involving the wall of the gallbladder. Adenomyomatosis is caused by an overgrowth of the mucosa, thickening of the muscular wall, and formation of intramural diverticula or sinus tracts termed Rokitansky–Aschoff sinuses, also called entrapped epithelial crypts.
Signs and symptoms
Pathophysiology
Rokitansky–Aschoff sinuses
Rokitansky–Aschoff sinuses are pseudodiverticula or pockets in the wall of the gallbladder. They may be microscopic or macroscopic. Histologically, they are outpouchings of gallbladder mucosa into the gallbladder muscle layer and subserosal tissue as a result of hyperplasia and herniation of epithelial cells through the fibromuscular layer of the gallbladder wall.Rokitansky–Aschoff sinuses are not of themselves considered abnormal but they can be associated with cholecystitis.They form as a result of increased pressure in the gallbladder and recurrent damage to the wall of the gallbladder.
Associations
Black pigment gallstones can form in Rokitansky–Aschoff sinuses of the gallbladder after the fourth to fifth decades of life in absence of the typical risk factors for bilirubin supersaturation of bile. Hence, they are associated with gallstones (cholelithiasis). Cases of gall bladder cancer have also been reported to arise from Rokitansky–Aschoff sinuses.
Diagnosis
Abdominal ultrasound has low accuracy in differentiating gall bladder adenomyomatosis from cancer and is operator dependent. However, it is used as the exam of the first-line due to its wide availability. Ultrasound findings may show thickened gall bladder wall, tiny anechoic spaces (Rokitansky–Aschoff sinuses or RAS), and twinkling artifact (or comet-tail reverberation). Comet tail reverberation, which is due to reflections from cholesterol crystals, is a highly specific sign for adenomyomatosis.On CT scan, it may show rosary sign, showing mucosal epithelium with intramural diverticula.Magnetic resonance imaging also plays an important role in the diagnosis of Rokitansky–Aschoff sinuses. In fat-suppression MRI, RAS present with small, rounded, high signal intensity foci, called “pearl necklace sign”.
Eponym
Rokitansky–Aschoff sinuses are named after Carl Freiherr von Rokitansky (1804–1878), a pathologist in Vienna, Austria and Ludwig Aschoff (1866–1942), a pathologist in Bonn, Germany.
See also
Cholecystectomy
Strawberry gallbladder
Diverticulum
Hyperplasia
Gallbladder
References
External links
00859 at CHORUS |
Orthokeratosis | Orthokeratosis is hyperkeratosis without parakeratosis. No nucleus is seen in the cells. There is also formation of an anuclear keratin layer, as in the normal epidermis.
== References == |
Borderline tuberculoid leprosy | Borderline tuberculoid leprosy is a cutaneous condition similar to tuberculoid leprosy except the skin lesions are smaller and more numerous.: 345
See also
Leprosy
Skin lesion
References
== External links == |
Pityriasis rotunda | Pityriasis rotunda is a disorder of keratisation of the skin that manifests as a perfectly circular, scaly patches on the torso and proximal portions of the extremities. It may be associated with diseases like hepatocellular carcinoma in racially predisposed groups.
See also
Skin lesion
List of cutaneous conditions
References
== External links == |
Congenital bilateral perisylvian syndrome | Congenital bilateral perisylvian syndrome (CBPS) is a rare neurological disease characterized by paralysis of certain facial muscles and epileptic seizures.
Signs and symptoms
Signs and symptoms of CBPS typically appear in infancy or at birth, but can appear later in childhood. These include facial diplegia (paralysis on both sides), facial muscle spasms, pseudobulbar palsy, dysarthria (difficulty speaking), difficulty chewing, dysphagia (difficulty swallowing), epilepsy, and intellectual disability. Epileptic seizures in individuals with CBPS are different between individuals and can vary between episodes.
Pathophysiology
Though the underlying cause of CBPS is unknown, it is thought to arise from improper migration of neuroblasts (neuronal stem cells) to the cerebral cortex in the embryonic brain. This causes the layers of the cerebral cortex to not form properly, and too many small folds (gyri) to form on the surface of the brain. This condition is called bilateral perisylvian polymicrogyria. The sulci, deep grooves on the brain, may also not form correctly. Cranial nerves are affected and cause muscle paralysis and spasms in the face and throat.
Diagnosis
Several disorders may appear similar to CBPS and need to be distinguished in the process of diagnosing CBPS. These include pachygyria, double cortex syndrome, and lissencephaly, all of which are classified along with CBPS as neuronal migration disorders. Diagnostic tests for CBPS include electroencephalograms, CT scanning, and magnetic resonance imaging.
Treatment
CBPS is commonly treated with anticonvulsant therapy to reduce seizures. Therapies include anticonvulsant drugs, adrenocorticotropic hormone therapy, and surgical therapy, including focal corticectomy and callosotomy. Special education, speech therapy, and physical therapy are also used to help children with intellectual disability due to CBPS.
Epidemiology
Males and females have an equal chance of having CBPS.
== References == |
Solar erythema | Solar erythema is a skin condition characterized by redness of the skin following exposure to ultraviolet light, not to be confused with sunburn.: 27
See also
Skin lesion
== References == |
Acute posterior multifocal placoid pigment epitheliopathy | Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is an acquired inflammatory uveitis that belongs to the heterogenous group of white dot syndromes in which light-coloured (yellowish-white) lesions begin to form in the macular area of the retina. Early in the course of the disease, the lesions cause acute and marked vision loss (if it interferes with the optic nerve) that ranges from mild to severe but is usually transient in nature. APMPPE is classified as an inflammatory disorder that is usually bilateral and acute in onset but self-limiting. The lesions leave behind some pigmentation, but visual acuity eventually improves even without any treatment (providing scarring doesnt interfere with the optic nerve).
It occurs more commonly in females and is more likely to affect persons between 20 and 30 years of age, but has been seen in people aged 16 to 40. It is known to occur after or concurrently with a systemic infection (but not always), showing that it is related generally to an altered immune system. Recurrent episodes can happen, but are extremely rare.
Signs and symptoms
The onset of ocular symptoms are usually preceded by episode of viral or flu-like symptoms such as fever, cough or sore throat (however this is not always the case). Patients can typically present erythema nodosum, livido reticularus, bilateral uveitis, and sudden onset of marked visual loss associated with the appearance of multiple lesions in the retina. These lesions may be colored from grey-white to cream-shaded yellow.
Other symptoms include scotomata and photopsia. In weeks to a month times the lesions begin to clear and disappear (with prednisone) leaving behind areas of retinal pigment epithelial atrophy and diffuse fine pigmentation (scarring). Rarely choroidal neovascularization occur as a late onset complication.
Cause
Since The cause of the inflammation remains unknown, with various theories of it occurring as an autoimmune response to a mild infection, or the possibility of it being viral because of the preceding flu-like illness that generally accompanies it. It is usually associated with HLA-B7 and HLA-DR2.
The underlying etiology of APMPPE continues to cause debate. The term Pigment Epitheliopathy was chosen by Gass to reflect what he thought was the tissue most significantly affected. Van Buskirk et al., and Deutman et al. proposed choriocapillaris ischemia as the more likely primary etiology. Indocyanine green angiography (ICGA), and OCT angiography (OCTA) studies have provided support for choriocapillaris involvement.
However, a novel hypothesis has recently been proposed implicating a direct neurotropic infection as a possible underlying cause given the dynamic changes observed along the neuronal pathway of the retina
Diagnosis
Diagnosis is usually made on clinical appearance alone on fundoscopy and/or retinal imaging. Supplementary tests such as Optical coherence tomography(OCT) and fundus fluorescein angiography/Indocyanine angiography together with OCT-Angiography are commonly performed to help aid diagnosis and monitoring.
Treatment
Owing to the self-limiting nature of the disease, treatment is generally not required. In cases where lesions appear to be interfering with the optic nerve, methyl prednisone is prescribed.
Prognosis
Vision improves in almost all cases. In rare cases, a patient may suffer permanent visual loss associated with lesions on their optic nerve.
Rarely, coexisting vasculitis may cause neurological complications. These occurrences can start with mild headaches that steadily worsen in pain and onset, and can include attacks of dysesthesia. This type of deterioration happens usually if the lesions involve the fovea.
See also
White dot syndromes
Uveitis
References
== External links == |
Cryptophthalmos | Cryptophthalmos is a rare congenital anomaly in which the skin is continuous over the eyeball with absence of eyelids. It is classified into three types: complete, incomplete and abortive. Failure of eyelid separation can be associated with maldevelopment of the underlying cornea and microphthalmia. Cryptophthalmos usually occurs on both sides and occurs in association with multiple other malformations collectively referred to as Fraser syndrome.
References
== External links == |
Septicemic plague | Septicemic plague is one of the three forms of plague, and is caused by Yersinia pestis, a gram-negative species of bacterium. Septicemic plague is a systemic disease involving infection of the blood, and is most commonly spread by bites from infected fleas. Septicemic plague can cause disseminated intravascular coagulation, and is almost always fatal when untreated. The other varieties of the plague are bubonic plague and pneumonic plague.
Signs and symptoms
The usual symptoms are:
Abdominal pain
Bleeding under skin due to blood clotting problems
Bleeding from mouth, nose or rectum
Gastrointestinal symptoms, including nausea, vomiting, which can be with blood, and diarrhea
Fever
Chills
Low blood pressure
Organ failure
Shock
Death of tissue (gangrene) in extremities, mostly fingers, nose, and toes
Difficulty breathingThese symptoms are common to many human illnesses, and are not considered, in and of themselves, to signify infection with any form of plague.It is important to note that septicemic plague may be asymptomatic, and may cause death absent of any symptoms.
Cause
Transmission
Human Yersinia infections most commonly result from the bite of an infected flea or occasionally an infected mammal, but like most bacterial systemic diseases, the disease may be transmitted through an opening in the skin or by inhaling infectious droplets of moisture from sneezes or coughs. In both cases septicemic plague need not be the result, and in particular, not the initial result, but it occasionally happens that bubonic plague for example leads to infection of the blood, and septicemic plague results. If the bacteria happen to enter the bloodstream rather than the lymph or lungs, they multiply in the blood, causing bacteremia and severe sepsis. In septicemic plague, bacterial endotoxins cause disseminated intravascular coagulation (DIC), where tiny blood clots form throughout the body, commonly resulting in localised ischemic necrosis, tissue death from lack of circulation and perfusion.DIC results in depletion of the bodys clotting resources, so that it can no longer control bleeding. Consequently, the unclotted blood bleeds into the skin and other organs, leading to red or black patchy rash and to hematemesis (vomiting blood) or hemoptysis (coughing up blood). The rash may cause bumps on the skin that look somewhat like insect bites, usually red, sometimes white in the center.Septicemic plague is caused by horizontal and direct transmission. Horizontal transmission is the transmitting of a disease from one individual to another regardless of blood relation. Direct transmission occurs from close physical contact with individuals, through common air usage, from direct bite from a flea or an infected rodent. Most common rodents may carry the bacteria and so may Leporidae such as rabbits:
Significant carriers of the bacteria in the United States include:
- Rats
- Prairie dogs
- Squirrels
- Chipmunks
- Rabbits
- Fleas
The bacteria are cosmopolitan, mainly in rodents in all continents except Australia and Antarctica. The greatest frequency of human plague infections occurs in Africa. The bacteria most commonly appear in rural areas and wherever there is poor sanitation, overcrowding, and high rodent populations in urban areas. Outdoor activities such as hiking, camping, or hunting where plague-infected animals may be found, increase the risk of contracting septicemic plague, and so do certain occupations such as veterinary or other animal-related work.
Diagnosis
A doctor or veterinarian will perform a physical exam which includes asking about the medical history and possible sources of exposure. The following possible test could include:
Blood samples (detecting antibodies)
Culture samples of body fluids (check for the bacteria Yersinia pestis)
Kidney and liver testing
Checking lymphatic system for signs of infection
Examining body fluids for abnormal signs
Checking for swelling
Checking for signs of dehydration
Checking for fever
Checking for lung infection
Prevention
The following steps and precautions should be used to avoid infection of the septicemic plague:
Caregivers of infected patients should wear masks, gloves, goggles and gowns
Take antibiotics if close contact with infected patient has occurred
Use insecticides throughout house
Avoid contact with dead rodents or sick cats
Set traps if mice or rats are present around the house
Do not allow family pets to roam in areas where plague is common
Flea control and treatment for animals (especially rodents)
Treatment
Starting antibiotics early is a first step in treating septicemic plague in humans. One of the following antibiotics may be used:
Streptomycin
Gentamicin
Tetracycline or Doxycycline
Chloramphenicol
CiprofloxacinLymph nodes may require draining and the patient will need close monitoring.In animals, antibiotics such as tetracycline or doxycycline can be used. Intravenous drip may be used to assist in dehydration scenarios. Flea treatment can also be used. In some cases euthanasia may be the best option for treatment and to prevent further spreading.
Prognosis
Untreated septicemic plague is almost always fatal. Early treatment with antibiotics reduces the mortality rate to between 4 and 15 percent. Death is almost inevitable if treatment is delayed more than about 24 hours, and some people may even die on the same day they present with the disease.
Epidemiology
In 2015, Taylor Gaes, a 16-year-old in Larimer County in northern Colorado, contracted septicemic plague and subsequently died after being bitten by a flea that had bitten a rodent on his familys rural property. Only three people in Colorado had contracted the bacteria in the previous thirty years.
History
Septicemic plague was the least common of the three plague varieties that occurred during the Black Death from 1348 to 1350 (the other two being bubonic plague and pneumonic plague). Like the others, septicemic plague spread from the East through trade routes on the Black Sea and down to the Mediterranean Sea.Major port cities and trade centers such as Venice and Florence were hit the hardest. The massive loss of working population in Europe following the Black Death, resulting in increased economic bargaining power of the serf labour force, was a major precipitating factor for the Peasants Revolt of 1381.
Other animals
Septicemic plague is a zoonosis, a disease that generally is acquired by humans from animals, such as rodents and carnivores. Goats, sheep and camels also may carry the bacteria. Cats rarely develop clinical signs but can be infected. Areas west of the Great Plains of North America are one region where plague-infected animals commonly occur. Plague-infested animals are found in many other countries as well, especially in developing countries where health controls are not effective.
Animals that commonly carry plague bacteria are largely rodents and Leporidae, but carnivores sometimes also become infected by their prey. Prey animals are not immune to the disease, and outbreaks of various strains of plague, such as sylvatic plague, have on occasion devastated populations of black-tailed prairie dogs and black-footed ferrets.Plague has been active in black-tailed prairie dog populations since the 1960s. In the United States outbreaks only occur in the western States and they are devastating, with mortality rates near 100% because the animals have no immunity to the plague. Survivors are the ones that happened not to become infected and colonies that recover from a plague outbreak remain at risk.Because black-footed ferrets prey on black-tailed prairie dogs, wild ferret populations also fall victim to sylvatic plague. An outbreak can kill nearly 100% of ferrets in a population, and surviving ferrets commonly face starvation because the prairie dogs are their main prey. Spray-and-vaccinate campaigns have aimed at preventing the spread of the plague among these animals.Similar septicemic problems occurs in many countries across the world, especially in developing countries where spending on health systems is very low and health controls are not effective.
== References == |
Heat syncope | Heat syncope is fainting or dizziness as a result of overheating (syncope is the medical term for fainting). It is a type of heat illness. The basic symptom of heat syncope is fainting, with or without mental confusion. Heat syncope is caused by peripheral vessel dilation, resulting in diminished blood flow to the brain and dehydration.
Signs and symptoms
Faintness, dizziness, headache, increased pulse, restlessness, nausea, vomiting, pale/clammy skin, and brief loss of consciousness.
Causes
Heat syncope occurs in a warm environment when blood pressure is lowered as the body dilates (widens) arterioles (small blood vessels) in the skin to radiate heat. This condition occurs within five days of heat acclimatization, before the blood volume expands. The result is less blood to the brain, causing light-headedness and fainting when a person stands up quickly or stands for a long period of time. Those who perform strenuous work outside in warm climates are at particular risk.
Diagnosis
The diagnosis of heat syncope is done during a physical examination. During the physical exam the practitioner will test the blood pressure of the patient, and the pulse. If the patient is experiencing heat syncope the blood pressure will be low, and the pulse will be elevated. Observation of excess sweating will also be a key sign. Finally, the practitioner will ask questions figuring out the history of the patients symptoms. If the patient developed symptoms while engaging in physical activity and high temperatures it will then be a true case of heat syncope.
Prevention
Physical activity in extremely hot weather should be avoided. If a person starts to experience over heating, and symptoms of heat syncope, they should move or be moved to a shaded or cool area. It is also recommended to avoid alcoholic beverages in hot weather, because they cause dehydration which may worsen symptoms. Finally, drinking plenty of water with electrolytes is imperative when engaging in physical activity in hot weather.
Treatment
The basic treatment for heat syncope is like that for other types of fainting: the patient is positioned in a seating or supine position with legs raised. Water containing salt, or another drink containing electrolytes, is administered slowly, and the patient is moved to a cooler area, such as the shade.
The affected person should rest and recover, because heat syncope can lead to heat stroke or heat exhaustion.
References
== External links == |
IgA pemphigus | IgA pemphigus is a subtype of pemphigus with two distinct forms:
Subcorneal pustular dermatosis (also known as Sneddon–Wilkinson disease and pustulosis subcornealis) is skin condition that is a rare, chronic, recurrent, pustular eruption characterized histopathologically by subcorneal pustules that contain abundant neutrophils.: 203 This is distinct from and not to be confused with subcorneal pustular dermatosis type of IgA pemphigus. Sneddons syndrome, also known as Ehrmann-Sneddon syndrome, is also a different syndrome.
Intraepidermal neutrophilic IgA dermatosis is characterized histologically by intraepidermal bullae with neutrophils, some eosinophils, and acantholysis.: 465
History
Early descriptions were made by Darrell Wilkinson, a British dermatologist.
See also
Pemphigus
List of cutaneous conditions
List of conditions caused by problems with junctional proteins
List of immunofluorescence findings for autoimmune bullous conditions
References
== External links == |
Angiolymphoid hyperplasia with eosinophilia | Angiolymphoid hyperplasia with eosinophilia (also known as: "Epithelioid hemangioma," "Histiocytoid hemangioma," "Inflammatory angiomatous nodule," "Intravenous atypical vascular proliferation," "Papular angioplasia," "Inflammatory arteriovenous hemangioma," and "Pseudopyogenic granuloma") usually presents with pink to red-brown, dome-shaped, dermal papules or nodules of the head or neck, especially about the ears and on the scalp.It, or a similar lesion, has been suggested as a feature of IgG4-related skin disease, which is the name used for skin manifestations of IgG4-related disease.
See also
List of cutaneous conditions
References
== External links == |
Cerebro-costo-mandibular syndrome | Cerebro-costo-mandibular syndrome is a very rare genetic disorder which is characterized by jaw/chin, palate and rib abnormalities.
Signs and symptoms
The following list comprises the most common symptoms people with this disorder exhibit:
Severe micrognathia
Thorax in the shape of a bell
Cleft palate
Neonatal respiratory difficulties
Rib gapsCommon (but not the most) symptoms include:
External auditory canal atresia
Hearing loss
Failure to thrive
Glossoptosis
Intellectual disabilities
Fetal growth delays
Kyphosis
Short height
TracheomalaciaNot common but also not rare symptoms include:
Fifth finger clinodactyly
Cerebral calcification
Hydranencephaly
Meningocele
Microcephaly
Polycystic kidney dysplasia
Myelomeningocele
Porencephalic cyst
Short, hard palate
Spina bifida
Ventricular septal defect
Webbed neck
Causes
This disorder is caused by autosomal dominant mutations in the SNRPB gene, in chromosome 20.
Epidemiology
Only 110 cases have been described in medical literature.
== References == |
Paralytic shellfish poisoning | Paralytic shellfish poisoning (PSP) is one of the four recognized syndromes of shellfish poisoning, which share some common features and are primarily associated with bivalve mollusks (such as mussels, clams, oysters and scallops). These shellfish are filter feeders and accumulate neurotoxins, chiefly saxitoxin, produced by microscopic algae, such as dinoflagellates, diatoms, and cyanobacteria. Dinoflagellates of the genus Alexandrium are the most numerous and widespread saxitoxin producers and are responsible for PSP blooms in subarctic, temperate, and tropical locations. The majority of toxic blooms have been caused by the morphospecies Alexandrium catenella, Alexandrium tamarense, Gonyaulax catenella and Alexandrium fundyense, which together comprise the A. tamarense species complex. In Asia, PSP is mostly associated with the occurrence of the species Pyrodinium bahamense.Some pufferfish, including the chamaeleon puffer, also contain saxitoxin, making their consumption hazardous.
PSP and cyanobacteria
Saxitoxin can be produced in both eukaryotic dinoflagellates as well as prokaryotic cyanobacteria (usually referred to as blue-green algae). The biosynthesis pathway of this toxin within cyanobacteria is well defined, while the pathway within dinoflagellates is mostly unknown.
Within cyanobacteria the saxitoxin pathway is complex with many steps, enzymes and chemical reactions. Using radioisotope tracing experiments scientists have determined how the initial reagent of the pathway, L-arginine (via acetyl-CoA), turns into this toxin. L-arginine goes through a rare reaction known as Claisen condensation forming four intermediates before turning into the final product of saxitoxin.Cyanobacteria is general responsible for the accumulation of PSP toxins, mainly being saxitoxin, within freshwater marine life. Studies have been completed showing that the Australian freshwater mussel Alathyria condola are highly susceptible to neurotoxin accumulation. This specific shellfish has shown upwards of 80 ug of neurotoxin accumulation for every 100g of the mussel after a 2-3 day of exposure to the cyanobacteria A. circinalis , which is significant enough to cause health risks for humans.
Pathophysiology
The toxins responsible for most shellfish poisonings are water insoluble, heat and acid-stable, and ordinary cooking methods do not eliminate the toxins. The principal toxin responsible for PSP is saxitoxin. Some shellfish can store this toxin for several weeks after a harmful algal bloom passes, but others, such as butter clams, are known to store the toxin for up to two years. Additional toxins are found, such as neosaxitoxin and gonyautoxins I to IV. All of them act primarily on the nervous system.
PSP and its associated toxin can cause paralysis in extreme cases by targeting the sodium ion channels. Saxitoxin is able to bind to the receptor site of a cellular membrane near the sodium ion channel, blocking the entrance and not allowing potassium or sodium to pass into the cell. This blockage restricts the transmission of signals between neurons potentially resulting in paralysis.PSP can be fatal in extreme cases, particularly in immunocompromised individuals. Children are more susceptible. PSP affects those who come into contact with the affected shellfish by ingestion. Symptoms can appear ten to 30 minutes after ingestion, and include nausea, vomiting, diarrhea, abdominal pain, tingling or burning lips, gums, tongue, face, neck, arms, legs, and toes. Shortness of breath, dry mouth, a choking feeling, confused or slurred speech, and loss of coordination are also possible.
PSP in wild marine mammals
PSP has been implicated as a possible cause of sea otter mortality and morbidity in Alaska, as one of its primary prey items, the butter clam (Saxidomus gigantea) bioaccumulates saxitoxin as a chemical defense mechanism. In addition, ingestion of saxitoxin-containing mackerel has been implicated in the death of humpback whales.Additional cases where PSP was suspected as the cause of death in Mediterranean monk seals (Monachus monachus) in the Mediterranean Sea have been questioned due to lack of additional testing to rule out other causes of mortality.
Detection and treatment
In Vivo, in Vitro, analytical techniques and immunoassays can all be used in order to determine whether saxitoxin is present within shellfish or has been ingested by humans. The most common In Vivo method used is that of mouse bioassays, which provides quantitative and qualitative data regarding the relative toxicity of a suspected PSP infection. An in Vitro method of detection commonly used is that of receptor binding assays which provides similar data to that of mouse bioassays. Analytical techniques that can be used for PSP detection include High performance liquid chromatography (HPLC) and other forms of chromatography.These detection methods can be used on shellfish in order to determine the concentration of saxitoxin within the organism. Concentrations of saxitoxin greater than or equal to 80 ug per 100g of flesh within a shellfish are determined to be unsafe for human consumption.In terms of treatment there is no current antidote for the PSP disease that is able to combat the saxitoxin molecule. Most patients are able to recover without treatment, however biomedical devices such as mechanical respirators as well as oxygen supports can help treat any respiratory paralysis symptoms until the toxin passes through the patients body
See also
Amnesic shellfish poisoning
Diarrheal shellfish poisoning
Neurotoxic shellfish poisoning
Harmful algal blooms (see "toxins")
Ciguatera
Cyanotoxin
Dinoflagellate ecology and physiology (see "neurotoxins", "red tide", and "phosphate")
Red tide crisis in Chiloé
References
External links
Toxicity, Shellfish |
Barrel chest | Barrel chest generally refers to a broad, deep chest found on a patient. A barrel chested person will usually have a naturally large ribcage, very round (i.e., vertically cylindrical) torso, large lung capacity, and can potentially have great upper body strength. It can sometimes be found alongside acromegaly (an enlargement of the acra resulting from excess levels of human growth hormone (HGH) in the body). It is most commonly related to osteoarthritis as individuals age. Arthritis can stiffen the chest causing the ribs to become fixed in their most expanded position, giving the appearance of a barrel chest.Barrel chest refers to an increase in the anterior posterior diameter of the chest wall resembling the shape of a barrel, most often associated with emphysema. There are two main causes of the barrel chest phenomenon in emphysema:
Increased compliance of the lungs leads to the accumulation of air pockets inside the thoracic cavity.
Increased compliance of the lungs increases the intrathoracic pressure. This increase in pressure allows the chest wall to naturally expand outward.Barrel chest occurs naturally in native people who live at altitudes of over 5500 m, e.g. the Himalayas or the Andes. These natives also have polycythemia and other accommodations for high altitude life.
See also
Barrel
Pectus carinatum
Respiratory examination
== References == |
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy | Nasu–Hakola disease also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy is a rare disease characterised by early-onset dementia and multifocal bone cysts. It is caused by autosomal recessive loss of function mutations in either the TREM2 or TYROBP gene that are found most frequently in the Finnish and Japanese populations.
Signs and symptoms
Four stages are recognised in this condition. The first (latent stage) show no symptoms or signs. This stage typically lasts up to the early 20s. This is followed by the osseous stage. This is characterised by recurrent bone pain usually affecting the long bones of the limbs. This is usually followed by pathological fractures of these bones. The third stage (early neurological) is marked by the onset of symptoms typical of a frontal lobe syndrome (euphoria, lack of concentration, loss of judgment and social inhibitions) with memory loss. Epilepsy may occur. This stage usually has its onset in the late 20s and early 30s. The final stage is characterised by severe dementia and paralysis. Death usually occurs in the late 40s or early 50s.
Genetics
This condition has been associated with mutations in the TYRO protein tyrosine kinase binding protein (TYROBP) gene and in the triggering receptor expressed on myeloid cells 2 (TREM2) gene. TYROBP is located on the long arm of chromosome 19 (19q13.12) and TREM2 is located on short arm of chromosome 6 (6p21.1).
Pathopysiology
This is not understood but appears to involve the microglia.
Diagnosis
This syndrome may be suspected on clinical grounds. The diagnosis is established by sequencing the TYROBP and TREM2 genes.
Differential diagnosis
Frontotemporal dementia
Investigations
X rays show the presence of bone cysts and osteoporosis. CT or MRI of the brain show loss of tissue in the frontotemporal lobes of the brain. Calcification of the basal ganglia is common. EEG is typically normal initially but diffuse slowing and irritative activity later.
Treatment
There is no specific treatment for this condition. Management is supportive.
Epidemiology
This condition is considered to be rare, with ~200 cases described in the literature. The estimated population prevalence is 2.0 x 10−6 in Finns.
History
This condition was first described in 1973.
== References == |
Absent pulmonary valve syndrome | Absent pulmonary valve syndrome is a congenital heart defect that occurs when the flaps of the pulmonary valve do not develop or are severely underdeveloped (hypoplasia) resulting in aneurysms (dilation) of the pulmonary arteries and softening of the trachea and bronchi (tracheobronchomalacia). Usually, APVS occurs together with other congenital heart defects, most commonly ventricular septal defect and right ventricular outflow tract obstruction. It is sometimes considered a variant of Tetralogy of Fallot.
== References == |
Anomalous pulmonary venous connection | Anomalous pulmonary venous connection (or anomalous pulmonary venous drainage or anomalous pulmonary venous return) is a congenital defect of the pulmonary veins.
Total anomalous pulmonary venous connection
Total anomalous pulmonary venous connection, also known as total anomalous pulmonary venous return, is a rare cyanotic congenital heart defect in which all four pulmonary veins are malpositioned and make anomalous connections to the systemic venous circulation. (Normally, pulmonary veins return oxygenated blood from the lungs to the left atrium where it can then be pumped to the rest of the body). A patent foramen ovale, patent ductus arteriosus or an atrial septal defect must be present, or else the condition is fatal due to a lack of systemic blood flow.In some cases, it can be detected prenatally.There are four variants: Supracardiac (50%): blood drains to one of the innominate veins (brachiocephalic veins) or the superior vena cava; Cardiac (20%), where blood drains into coronary sinus or directly into right atrium; Infradiaphragmatic (20%), where blood drains into portal or hepatic veins; and a mixed (10%) variant.TAPVC can occur with obstruction, which occurs when the anomalous vein enters a vessel at an acute angle and can cause pulmonary venous hypertension and cyanosis because blood cannot enter the new vein as easily.
Signs and symptoms
right ventricular heave
Loud S1
fixed split S2
S3 gallop
systolic ejection murmur at left upper sternal border
cardiomegaly
right axis deviation on ECG
Snowman sign or figure of 8 configuration on chest radiograph
right ventricular hypertrophy
cyanosis, tachypnea, dyspnea since the overloaded pulmonary circuit can cause pulmonary edema
Cottage-loaf sign, that is, chest X-ray appearance similar to a cottage loaf, also known as the snow man sign or figure of 8 sign.
Treatment
In TAPVC without obstruction, surgical redirection can be performed within the first month of life. The operation is performed under general anesthesia. The four pulmonary veins are reconnected to the left atrium, and any associated heart defects such as atrial septal defect, ventricular septal defect, patent foramen ovale, and/or patent ductus arteriosus are surgically closed. With obstruction, surgery should be undertaken emergently. PGE1 should be given because a patent ductus arteriosus allows oxygenated blood to go from the circulation of the right heart to the systemic circulation.
Partial anomalous pulmonary venous connection
A Partial anomalous pulmonary venous connection (or Partial anomalous pulmonary venous drainage or Partial anomalous pulmonary venous return) is a congenital defect where the left atrium is the point of return for the blood from some (but not all) of the pulmonary veins.It is less severe than total anomalous pulmonary venous connection which is a life-threatening anomaly requiring emergent surgical correction, usually diagnosed in the first few days of life. Partial anomalous venous connection may be diagnosed at any time from birth to old age. The severity of symptoms, and thus the likelihood of diagnosis, varies significantly depending on the amount of blood flow through the anomalous connections. In less severe cases, with smaller amounts of blood flow, diagnosis may be delayed until adulthood, when it can be confused with other causes of pulmonary hypertension. There is also evidence that a significant number of mild cases are never diagnosed, or diagnosed incidentally. It is associated with other vascular anomalies, and some genetic syndromes such as Turner syndrome.
Diagnosis
It can be diagnosed with CT scan, angiography, transesophageal echocardiography, or cardiac MRI. Unfortunately, less invasive and expensive testing, such as transthoracic echocardiography and CT scanning are generally less sensitive.
Treatment
It is sometimes treated with surgery, which involves rerouting blood from the right atrium into the left atrium with a patch or use of the Warden procedure. However, interest is increasing in catheter-based interventional approaches, as well as medical therapy for less severe cases.
References
== External links == |
Hoarse voice | A hoarse voice, also known as dysphonia or hoarseness, is when the voice involuntarily sounds breathy, raspy, or strained, or is softer in volume or lower in pitch. A hoarse voice, can be associated with a feeling of unease or scratchiness in the throat. Hoarseness is often a symptom of problems in the vocal folds of the larynx. It may be caused by laryngitis, which in turn may be caused by an upper respiratory infection, a cold, or allergies. Cheering at sporting events, speaking loudly in noisy situations, talking for too long without resting ones voice, singing loudly, or speaking with a voice thats too high or too low can also cause temporary hoarseness. A number of other causes for losing ones voice exist, and treatment is generally by resting the voice and treating the underlying cause. If the cause is misuse or overuse of the voice, drinking plenty of water may alleviate the problems.It appears to occur more commonly in females and the elderly. Furthermore, certain occupational groups, such as teachers and singers, are at an increased risk.Long-term hoarseness, or hoarseness that persists over three weeks, especially when not associated with a cold or flu should be assessed by a medical doctor. It is also recommended to see a doctor if hoarseness is associated with coughing up blood, difficulties swallowing, a lump in the neck, pain when speaking or swallowing, difficulty breathing, or complete loss of voice for more than a few days. For voice to be classified as "dysphonic", abnormalities must be present in one or more vocal parameters: pitch, loudness, quality, or variability. Perceptually, dysphonia can be characterised by hoarse, breathy, harsh, or rough vocal qualities, but some kind of phonation remains.Dysphonia can be categorized into two broad main types: organic and functional, and classification is based on the underlying pathology. While the causes of dysphonia can be divided into five basic categories, all of them result in an interruption of the ability of the vocal folds to vibrate normally during exhalation, which affects the voice. The assessment and diagnosis of dysphonia is done by a multidisciplinary team, and involves the use of a variety of subjective and objective measures, which look at both the quality of the voice as well as the physical state of the larynx. Multiple treatments have been developed to address organic and functional causes of dysphonia. Dysphonia can be targeted through direct therapy, indirect therapy, medical treatments, and surgery. Functional dysphonias may be treated through direct and indirect voice therapies, whereas surgeries are recommended for chronic, organic dysphonias.
Types
Voice disorders can be divided into 2 broad categories: organic and functional. The distinction between these broad classes stems from their cause, whereby organic dysphonia results from some sort of physiological change in one of the subsystems of speech (for voice, usually respiration, laryngeal anatomy, and/or other parts of the vocal tract are affected). Conversely, functional dysphonia refers to hoarseness resulting from vocal use (i.e. overuse/abuse). Furthermore, according to ASHA, organic dysphonia can be subdivided into structural and neurogenic; neurogenic dysphonia is defined as impaired functioning of the vocal structure due to a neurological problem (in the central nervous system or peripheral nervous system); in contrast, structural dysphonia is defined as impaired functioning of the vocal mechanism that is caused by some sort of physical change (e.g. a lesion on the vocal folds). Notably, an additional subcategory of functional dysphonia recognized by professionals is psychogenic dysphonia, which can be defined as a type of voice disorder that has no known cause and can be presumed to be a product of some sort of psychological stressors in ones environment. It is important to note that these types are not mutually exclusive and much overlap occurs. For example, Muscle Tension Dysphonia (MTD) has been found to be a result of many different causes including the following: MTD in the presence of an organic pathology (i.e. organic type), MTD stemming from vocal use (i.e. functional type), and MTD as a result of personality and/or psychological factors (i.e. psychogenic type).
Causes
The most common causes of hoarseness is laryngitis (acute 42.1%; chronic 9.7%) and functional dysphonia (30%). Hoarseness can also be caused by laryngeal tumours (benign 10.7 - 31%; malignant 2.2 - 3.0%). Causes that are overall less common include neurogenic conditions (2.8 - 8.0%), psychogenic conditions (2.0 - 2.2%), and aging (2%).A variety of different causes, which result in abnormal vibrations of the vocal folds, can cause dysphonia. These causes can range from vocal abuse and misuse to systemic diseases. Causes of dysphonia can be divided into five basic categories, although overlap may occur between categories. (Note that this list is not exhaustive):
Employment
It has been suggested that certain occupational groups may be at increased risk of developing dysphonia due to the excessive or intense vocal demands of their work. Research on this topic has primarily focused on teachers and singers, although some studies have examined other groups of heavy voice users (e.g. actors, cheerleaders, aerobic instructors, etc.). At present, it is known that teachers and singers are likely to report dysphonia. Moreover, physical education teachers, teachers in noisy environments, and those who habitually use a loud speaking voice are at increased risk. The term clergymans throat or dysphonia clericorum was previously used for painful dysphonia associated with public speaking, particularly among preachers. However, the exact prevalence rates for occupational voice users are unclear, as individual studies have varied widely in the methodologies used to obtain data (e.g. employing different operational definitions for "singer").
Mechanism
Located in the anterior portion of the neck is the larynx (also known as the voice box), a structure made up of several supporting cartilages and ligaments, which houses the vocal folds. In normal voice production, exhaled air moves out of the lungs and passes upward through the vocal tract. At the level of the larynx, the exhaled air causes the vocal folds to move toward the midline of the tract (a process called adduction). The adducted vocal folds do not close completely but instead remain partially open. The narrow opening between the folds is referred to as the glottis. As air moves through the glottis, it causes a distortion of the air particles which sets the vocal folds into vibratory motion. It is this vibratory motion that produces phonation or voice. In dysphonia, there is an impairment in the ability to produce an appropriate level of phonation. More specifically, it results from an impairment in vocal fold vibration or the nerve supply of the larynx.
Diagnosis
The assessment and diagnosis of a dysphonic voice is completed by a multidisciplinary team, such as an otolaryngologist (ear, nose and throat doctor) and Speech-Language Pathologist, involving the use of both objective and subjective measures to evaluate the quality of the voice as well as the condition of the vocal fold tissue and vibration patterns.
Definition
Dysphonia is a broad clinical term which refers to abnormal functioning of the voice. More specifically, a voice can be classified as "dysphonic" when there are abnormalities or impairments in one or more of the following parameters of voice: pitch, loudness, quality, and variability. For example, abnormal pitch can be characterized by a voice that is too high or low whereas abnormal loudness can be characterized by a voice that is too quiet or loud. Similarly, a voice that has frequent, inappropriate breaks characterizes abnormal quality while a voice that is monotone (i.e., very flat) or inappropriately fluctuates characterizes abnormal variability. While hoarseness is used interchangeably with the term dysphonia, it is important to note that the two are not synonymous. Hoarseness is merely a subjective term to explain the perceptual quality (or sound) of a dysphonic voice. While hoarseness is a common symptom (or complaint) of dysphonia, there are several other signs and symptoms that can be present such as: breathiness, roughness, and dryness. Furthermore, a voice can be classified as dysphonic when it poses problems in the functional or occupational needs of the individual or is inappropriate for their age or sex.
Auditory-perceptual measures
Auditory-perceptual measures are the most commonly used tool by clinicians to evaluate the voice quality due to its quick and non-invasive nature. Additionally, these measures have been proven to be reliable in a clinical setting. Ratings are used to evaluate the quality of a patients voice for a variety of voice features, including overall severity, roughness, breathiness, strain, loudness and pitch. These evaluations are done during spontaneous speech, sentence or passage reading or sustained vowel productions. The GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) and the CAPE-V (Consensus Auditory Perceptual Evaluation—Voice) are two formal voice rating scales commonly used for this purpose.
Vocal fold imaging
Vocal fold imaging techniques are used by clinicians to examine the vocal folds and allows them to detect vocal pathology and assess the quality of the vocal fold vibrations. Laryngeal stroboscopy is the primary clinical tool used for this purpose. Laryngeal stroboscopy uses a synchronized flashing light passed through either a rigid or flexible laryngoscope to provide an image of the vocal fold motion; the image is created by averaging over several vibratory cycles and is thus not provided in real-time. As this technique relies on periodic vocal fold vibration, it cannot be used in patients with moderate to severe dysphonia. High speed digital imaging of the vocal folds (videokymography), another imaging technique, is not subject to the same limitations as laryngeal stroboscopy. A rigid endoscope is used to take images at a rate of 8000 frames per second, and the image is displayed in real time. As well, this technique allows imaging of aperiodic vibrations and can thus be used with patients presenting with all severities of dysphonia.
Acoustic measures
Acoustic measures can be used to provide objective measures of vocal function. Signal processing algorithms are applied to voice recordings made during sustained phonation or during spontaneous speech. The acoustic parameters which can then be examined include fundamental frequency, signal amplitude, jitter, shimmer, and noise-to-harmonic ratios. However, due to limitations imposed by the algorithms employed, these measures cannot be used with patients who exhibit severe dysphonia.
Aerodynamic measures
Aerodynamic measures of voice include measures of air volume, air flow and sub glottal air pressure. The normal aerodynamic parameters of voice vary considerably among individuals, which leads to a large overlapping range of values between dysphonic and non-dysphonic patients. This limits the use of these measures as a diagnostic tool. Nonetheless, they are useful when used in adjunct with other voice assessment measures, or as a tool for monitoring therapeutic effects over time.
Prevention
Given that certain occupations are more at risk for developing dysphonia (e.g. teachers) research into prevention studies have been conducted. Research into the effectiveness of prevention strategies for dysphonia have yet to produce definitive results, however, research is still ongoing. Primarily, there are two types of vocal training recognized by professionals to help with prevention: direct and indirect. Direct prevention describes efforts to reduce conditions that may serve to increase vocal strain (such as patient education, relaxation strategies, etc.), while indirect prevention strategies refer to changes in the underlying physiological mechanism for voice production (e.g., adjustments to the manner in which vocal fold adduction occurs, respiratory training, shifting postural habits, etc.).
Treatment
Although there is no universal classification of voice problems, voice disorders can be separated into certain categories: organic (structural or neurogenic), functional, neurological (psychogenic) or iatrogenic, for example. Depending on the diagnosis and severity of the voice problem, and depending on the category that the voice disorder falls into, there are various treatment methods that can be suggested to the patient. The professional has to keep in mind there is not one universal treatment, but rather the clinical approach must find what the optimal effective course of action for that particular patient is.There are three main type of treatments: medical treatments, voice therapy and surgical treatments. When necessary, certain voice disorders use a combination of treatment approaches. A medical treatment involves the use of botulinum toxin (botox) or anti-reflux medicines, for example. Botox is a key treatment for voice disorders such as Spasmodic Dysphonia. Voice therapy is mainly used with patients who have an underlying cause of voice misuse or abuse. Laryngologists also recommend this type of treatment to patients who have an organic voice disorder - such as vocal fold nodules, cysts or polyps as well as to treat functional dysphonia. Certain surgical treatments can be implemented as well - phono microsurgery (removal of vocal fold lesions performed with a microscope), laryngeal framework surgery (the manipulation of the voice box), as well as injection augmentation (injection of substance to vocal folds to improve closure). Surgical treatments may be recommended for patients having an organic dysphonia.A combination of both an indirect treatment method (an approach used to change external factors affecting the vocal folds) and a direct treatment method (an approach used where the mechanisms functioning during the use of the vocal folds, such as phonation or respiration, are the main focus) may be used to treat dysphonia.
Direct therapies
Direct therapies address the physical aspects of vocal production. Techniques work to either modify vocal fold contact, manage breathing patterns, and/or change the tension at level of the larynx. Notable techniques include, but are not limited to, the yawn-sigh method, optimal pitch, laryngeal manipulation, humming, the accent method, and the Lee Silverman Voice Treatment. An example of a direct therapy is circumlaryngeal manual therapy, which has been used to reduce tension and massage hyoid-laryngeal muscles. This area is often tense from chronic elevation of the larynx. Pressure is applied to these areas as the patient hums or sustains a vowel. Traditional voice therapy is often used to treat muscular tension dysphonia.
Indirect therapies
Indirect therapies take into account external factors that may influence vocal production. This incorporates maintenance of vocal hygiene practices, as well as the prevention of harmful vocal behaviours. Vocal hygiene includes adequate hydration of the vocal folds, monitoring the amount of voice use and rest, avoidance of vocal abuse (e.g., shouting, clearing of the throat), and taking into consideration lifestyle choices that may affect vocal health (e.g., smoking, sleeping habits). Vocal warm-ups and cool-downs may be employed to improve muscle tension and decrease risk of injury before strenuous vocal activities. It should be taken into account that vocal hygiene practices alone are minimally effective in treating dysphonia, and thus should be paired with other therapies.
Medication and surgery
Medical and surgical treatments have been recommended to treat organic dysphonias. An effective treatment for spasmodic dysphonia (hoarseness resulting from periodic breaks in phonation due to hyperadduction of the vocal folds) is botulinum toxin injection. The toxin acts by blocking acetylcholine release at the thyro-arytenoid muscle. Although the use of botulinum toxin injections is considered relatively safe, patients responses to treatment differ in the initial stages; some have reported experiencing swallowing problems and breathy voice quality as a side-effect to the injections. Breathiness may last for a longer period of time for males than females.Surgeries involve myoectomies of the laryngeal muscles to reduce voice breaks, and laryngoplasties, in which laryngeal cartilage is altered to reduce tension.
Epidemiology
Dysphonia is a general term for voice impairment that is sometimes used synonymously with the perceptual voice quality of hoarseness. It is the reason for 1% of all visits to primary care providers. The lifetime risk of hoarse voice complaints among primary care patients is 30%. Since hoarseness is a general symptom, it is associated with a number of laryngeal diagnoses.There is an interplay of sex and age differences associated with dysphonia. The point prevalence of dysphonia in adults under the age of 65 is 6.6%. Dysphonia is more common in adult females than males, possibly due to sex-related anatomical differences of the vocal mechanism. In childhood, however, dysphonia is more often found in boys than girls. As there are no anatomical differences in larynges of boys and girls prior to puberty, it has been proposed that the higher rate of voice impairment found in boys arises from louder social activities, personality factors, or more frequent inappropriate vocal use. The most common laryngeal diagnosis among children is vocal fold nodules, a condition known to be associated with vocally damaging behaviours. However, a causal relationship has not yet been definitively proven. The overall prevalence of dysphonia in children ranges from 3.9% - 23.4%, most commonly affecting children between the ages of 8 - 14. Among the elderly, dysphonia is associated with both naturally occurring anatomical and physiological changes as well as higher rates of pathological conditions. The point prevalence of dysphonia among the elderly is 29%. Findings regarding the prevalence of geriatric dysphonia in the general population are very variable, ranging from 4 - 29.1%. This variability is likely due to different methodology used in obtaining information from participants. The most common laryngeal diagnoses among the elderly are polyps, laryngopharyngeal reflux, muscle tension dysphonia, vocal fold paresis or paralysis, vocal fold mass, glottic insufficiency, malignant lesions, and neurologic conditions affecting the larynx.
References
External links
ASHA: Voice Disorders
ASHA: Clinical Topics - Voice Disorders Overview |
Walker–Warburg syndrome | Walker–Warburg syndrome (WWS), also called Warburg syndrome, Chemke syndrome, HARD syndrome (Hydrocephalus, Agyria and Retinal Dysplasia), Pagon syndrome, cerebroocular dysgenesis (COD) or cerebroocular dysplasia-muscular dystrophy syndrome (COD-MD), is a rare form of autosomal recessive congenital muscular dystrophy. It is associated with brain (lissencephaly, hydrocephalus, cerebellar malformations) and eye abnormalities. This condition has a worldwide distribution. The overall incidence is unknown but a survey in North-eastern Italy has reported an incidence rate of 1.2 per 100,000 live births. It is the most severe form of congenital muscular dystrophy with most children dying before the age of three years.
Presentation
The clinical manifestations present at birth are generalized hypotonia, muscle weakness, developmental delay with mental retardation and occasional seizures. The congenital muscular dystrophy is characterized by hypoglycosylation of α-dystroglycan.
Those born with the disease also experience severe ocular and brain defects. Half of all children with WWS are born with encephalocele, which is a gap in the skull that will not seal. The meninges of the brain protrude through this gap due to the neural tube failing to close during development. A malformation of the a babys cerebellum is often a sign of this disease. Common ocular issues associated with WWS are abnormally small eyes and retinal abnormalities cause by an underdeveloped light-sensitive area in the back of the eye.
Genetics
Several genes have been implicated in the etiology of Walker–Warburg syndrome, and others are as yet unknown. Several mutations were found in the protein O-Mannosyltransferase POMT1 and POMT2 genes, and one mutation was found in each of the fukutin and fukutin-related protein genes. Another gene that has been linked to this condition is Beta-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2).
Diagnosis
Laboratory investigations usually show elevated creatine kinase, myopathic/dystrophic muscle pathology and altered α-dystroglycan. Antenatal diagnosis is possible in families with known mutations. Prenatal ultrasound may be helpful for diagnosis in families where the molecular defect is unknown.
Prognosis
No specific treatment is available. Management is only supportive and preventive.
Those who are diagnosed with the disease often die within the first few months of life. Almost all children with the disease die by the age of three.
Eponym
WWS is named for Arthur Earl Walker and Mette Warburg (1926-2015), a Danish ophthalmologist. Its alternative names include Chemke’s syndrome and Pagon’s syndrome, named after Juan M. Chemke and Roberta A. Pagon.
References
Further reading
HARD syndrome; Walker–Warburg syndrome; Chemke syndrome; COD (cerebroocular dysgenesis) at NIHs Office of Rare Diseases
== External links == |
Autoimmune enteropathy | Autoimmune enteropathy (AIE) is a rare disorder of the immune system that affects infants, young children and (rarely) adults causing severe diarrhea, vomiting, and other morbidities of the digestive tract. AIE causes malabsorption of food, vitamins, and minerals often necessitating replacement fluids and total parenteral nutrition. Some disorders, such as IPEX syndrome, include autoimmune enteropathy as well as autoimmune "pathies" of the skin, thyroid, other glands, or kidneys.
Symptoms
The main symptoms of AIE include:
Diarrhea (frequent loss of fluids)
Intestinal inflammation
Vomiting
Intestinal bleeding
Difficulty or inability to gain weight
Rapid weight loss
Decreased urine output from dehydration
Diagnosis
There is a diagnostic test for AIE that looks for an antibody against the enterocyte. The diagnostic test contains the Western Blot which can identify the antibody IgG or IgA and with the immunohistochemistry can localize these antibodies. Endoscopy with biopsies of the colon, small colon, stomach, and other locations may be helpful in diagnosing. This test is done to look at the stomach and small intestines and to see what cells are infiltrating the digestive tract. There are also documented cases of autoimmune enteropathy where the auto-antibodies were undetectable and the diagnosis was made on the basis of clinical presentation and response to treatment.
Types
There are 3 types of autoimmune enteropathy:Type 1: IPEX syndrome: Immune dysregulation, Polyendocrinopathy, Enteropathy, X – linked
syndrome, which is caused by a mutation in the FOXP3 gene. This can only affect boys.
Type 2: IPEX-like, which manifests similarly to IPEX syndrome but without recognizable mutations in the FOXP3 gene. This can affect both genders and includes a variety of manifestations of varying severity.
Type 3: Autoimmune manifestations primarily limited to the GI tract. This can affect both genders and may also be considered IPEX-like.
There is considerable overlap in these disorders, and it is often unclear how to properly distinguish between them as the responsible genes are generally poorly understood at this time.
Treatment
Medical therapy is commonly used, most typically with corticosteroids (budesonide and prednisone). However, some patients are refractory to corticosteroids, and in these patients immunosuppressive therapy with azathioprine, cyclophosphamide, tacrolimus, cyclosporine and infliximab has been described.
An intravenous nutrition such as total parenteral nutrition and/or a special diet may be necessary. Hematopoietic stem cell transplantation may be curative.
References
Further reading
Montalto, Massimo; DOnofrio, Ferruccio; Santoro, Luca; Gallo, Antonella; Gasbarrini, Antonio; Gasbarrini, Giovanni (January 2009). "Autoimmune enteropathy in children and adults". Scandinavian Journal of Gastroenterology. 44 (9): 1029–1036. doi:10.1080/00365520902783691. PMID 19255930. S2CID 33004674.
"Autoimmune Enteropathy". Cincinnati Childrens. |
Anisometropia | Anisometropia refers to a condition when two eyes have unequal refractive power. Generally, a difference in power of one diopter (1D) or more is the accepted threshold to label the condition anisometropia. Patients can tolerate 3 D of anisometropia before it becomes clinically symptomatic with headaches, asthenopia, double vision and photophobia.In certain types of anisometropia, the visual cortex of the brain will not process images from both eyes together (binocular summation), and will instead suppress the central vision of one of the eyes. If this occurs often enough during the first 10 years of life while the visual cortex is developing, it can result in amblyopia, a condition where even when correcting the refractive error properly, the persons vision in the affected eye is still not correctable to 20/20.
The name is from four Greek components: an- "not," iso- "same," metr- "measure," ops "eye."
Antimetropia is a rare sub-type of anisometropia, in which one eye is myopic (nearsighted) and the other eye is hyperopic (farsighted). Around 0.1% of the population may be antimetropic.
Causes
Anisometropia is caused by common refractive errors, such as astigmatism, far-sightedness, and myopia, in one eye.Anisometropia is likely the result of both genetic and environmental influences.Some studies suggest, in older adults, developing asymmetric cataracts may cause worsen anisometropia. However, anisometropia is associated with age regardless of cataract development: a rapid decrease in anisometropia during the first years of life, an increase during the transition to adulthood, relatively unchanging levels during adulthood but significant increases in older age.
Diagnosis
Anisometropia causes some people to have mild vision problems, or occasionally more serious symptoms like alternating vision or frequent squinting. However, since most people do not show any clear symptoms, the condition usually is found during a routine eye exam.For early detection in preverbal children, photoscreening can be used. In this brief vision test specialized cameras detect each eyes light reflexes, which the equipments software or a test administrator then interprets. If photoscreening indicates the presence of risk factors, an ophthalmologist can then diagnose the condition after a complete eye exam, including dilating the pupils and measuring the focusing power of each eye.
Treatment
Spectacle correction
For those with large degrees of anisometropia, the wearing of standard spectacles may cause the person to experience a difference in image magnification between the two eyes (aniseikonia) which could also prevent the development of good binocular vision. This can make it very difficult to wear glasses without symptoms such as headaches and eyestrain. However, the earlier the condition is treated, the easier it is to adjust to glasses.
It is possible for spectacle lenses to be made which can adjust the image sizes presented to the eye to be approximately equal. These are called iseikonic lenses. In practice though, this is rarely ever done.
The formula for iseikonic lenses (without cylinder) is:
Magnification
=
1
(
1
−
(
t
n
)
P
)
⋅
1
(
1
−
h
F
)
{\displaystyle {\textrm {Magnification}}={\frac {1}{(1-({\frac {t}{n}})P)}}\cdot {\frac {1}{(1-hF)}}}
where: t = center thickness (in metres);n = refractive index;P = front base curve (in 1/metres);h = vertex distance (in metres);F = back vertex power (in 1/metres), (essentially, the prescription for the lens, quoted in diopters).
If the difference between the eyes is up to 3 diopters, iseikonic lenses can compensate. At a difference of 3 diopters the lenses would however be very visibly different — one lens would need to be at least 3 mm thicker and have a base curve increased by 7.5 spheres.
Example
Consider a pair of spectacles to correct for myopia with a prescription of −1.00 m−1 in one eye and −4.00 m−1 in the other. Suppose that for both eyes the other parameters are identical, namely t = 1 mm = 0.001 m, n = 1.6, P = 5 m−1, and h = 15 mm = 0.015 m.
Then for the first eye
Magnification
=
1
(
1
−
(
0.001
/
1.6
)
×
5
)
⋅
1
(
1
−
0.015
×
−
1
)
=
1.0031
×
0.9852
=
0.9883
=
98.83
%
{\displaystyle {\textrm {Magnification}}={\frac {1}{(1-(0.001/1.6)\times 5)}}\cdot {\frac {1}{(1-0.015\times -1)}}=1.0031\times 0.9852=0.9883=98.83\,\%}
,
while for the second eye
Magnification
=
1
(
1
−
(
0.001
/
1.6
)
×
5
)
⋅
1
(
1
−
0.015
×
−
4
)
=
1.0031
×
0.9434
=
0.9464
=
94.64
%
{\displaystyle {\textrm {Magnification}}={\frac {1}{(1-(0.001/1.6)\times 5)}}\cdot {\frac {1}{(1-0.015\times -4)}}=1.0031\times 0.9434=0.9464=94.64\,\%}
.
Thus, in the first eye the size of the image formed on the retina will be 1.17% smaller than without spectacles (although it will be sharp, rather than blurry), whilst in the second eye the image formed on the retina will be 5.36% smaller.
As alluded to above, one method of producing more iseikonic lenses would be to adjust the thickness and base curve of the second lens. For instance, theoretically it could be set to t = 5 mm = 0.005 m and P = 14.5 m−1, with all other parameters unchanged. Then for the second eye the magnification would become
Magnification
=
1
(
1
−
(
0.005
/
1.6
)
×
14.5
)
⋅
1
(
1
−
0.015
×
−
4
)
=
1.0475
×
0.9434
=
0.9882
=
98.82
%
{\displaystyle {\textrm {Magnification}}={\frac {1}{(1-(0.005/1.6)\times 14.5)}}\cdot {\frac {1}{(1-0.015\times -4)}}=1.0475\times 0.9434=0.9882=98.82\,\%}
,
which is much closer to that of the first eye.
In this example the first eye, with a −1.00 diopter prescription, is the stronger eye, needing only slight correction to sharpen the image formed, and hence a thin spectacle lens. The second eye, with a −4.00 diopter prescription, is the weaker eye, needing moderate correction to sharpen the image formed, and hence a moderately thick spectacle lens — if the aniseikonia is ignored. In order to avoid the aniseikonia (so that both magnifications will be practically the same, while retaining image sharpness in both eyes), the spectacle lens used for the second eye will have to be made even thicker.
Contact lenses
The usual recommendation for those needing iseikonic correction is to wear contact lenses. The effect of vertex distance is removed and the effect of center thickness is also almost removed, meaning there is minimal and likely unnoticeable image size difference. This is a good solution for those who can tolerate contact lenses.
Refractive surgery
Refractive surgery causes only minimal size differences, similar to contact lenses. In a study performed on 53 children who had amblyopia due to anisometropia, surgical correction of the anisometropia followed by strabismus surgery if required led to improved visual acuity and even to stereopsis in many of the children (see: Refractive surgery).
Epidemiology
A determination of the prevalence of anisometropia has several difficulties. First of all, the measurement of refractive error may vary from one measurement to the next. Secondly, different criteria have been employed to define anisometropia, and the boundary between anisometropia and isometropia depend on their definition.Several studies have found that anisometropia occurs more frequently and tends to be more severe for persons with high ametropia, and that this is particularly true for myopes. Anisometropia follows a U-shape distribution according to age: it is frequent in infants aged only a few weeks, is more rare in young children, comparatively more frequent in teenagers and young adults, and more prevalent after presbyopia sets in, progressively increasing into old age.One study estimated that 6% of those between the ages of 6 and 18 have anisometropia.Notwithstanding research performed on the biomechanical, structural and optical characteristics of anisometropic eyes, the underlying reasons for anisometropia are still poorly understood.Anisometropic persons who have strabismus are mostly far-sighted, and almost all of these have (or have had) esotropia. However, there are indications that anisometropia influences the long-term outcome of a surgical correction of an inward squint, and vice versa. More specifically, for patients with esotropia who undergo strabismus surgery, anisometropia may be one of the risk factors for developing consecutive exotropia and poor binocular function may be a risk factor for anisometropia to develop or increase.
References
== External links == |
Nutcracker esophagus | Nutcracker esophagus, Jackhammer esophagus, or hypercontractile peristalsis, is a disorder of the movement of the esophagus characterized by contractions in the smooth muscle of the esophagus in a normal sequence but at an excessive amplitude or duration. Nutcracker esophagus is one of several motility disorders of the esophagus, including achalasia and diffuse esophageal spasm. It causes difficulty swallowing, or dysphagia, to both solid and liquid foods, and can cause significant chest pain; it may also be asymptomatic. Nutcracker esophagus can affect people of any age but is more common in the sixth and seventh decades of life.
The diagnosis is made by an esophageal motility study (esophageal manometry), which evaluates the pressure of the esophagus at various points along its length. The term "nutcracker esophagus" comes from the finding of increased pressures during peristalsis, with a diagnosis made when pressures exceed 180 mmHg; this has been likened to the pressure of a mechanical nutcracker. The disorder does not progress, and is not associated with any complications; as a result, treatment of nutcracker esophagus targets control of symptoms only.
Signs and symptoms
Nutcracker esophagus is characterized as a motility disorder of the esophagus, meaning that it is caused by abnormal movement, or peristalsis of the esophagus. People with motility disorders present with two main symptoms: chest pain or difficulty with swallowing. Chest pain is the more common. The chest pain is very severe and intense, and mimics cardiac chest pain. It may spread into the arm and back. The symptoms of nutcracker esophagus are intermittent, and may occur with or without food. Rarely, patients can present with a sudden obstruction of the esophagus after eating food (termed a food bolus obstruction, or the steakhouse syndrome) requiring urgent treatment. The disorder does not progress to produce worsening symptoms or complications, unlike other motility disorders (such as achalasia) or anatomical abnormalities of the esophagus (such as peptic strictures or esophageal cancer). Many patients with nutcracker esophagus do not have any symptoms at all, as esophageal manometry studies done on patients without symptoms may show the same motility findings as nutcracker esophagus. Nutcracker esophagus may also be associated with metabolic syndrome. The incidence of nutcracker esophagus in all patients is uncertain.
Pathophysiology
Pathology specimens of the esophagus in patients with nutcracker esophagus show no significant abnormality, unlike patients with achalasia, where destruction of the Auerbachs plexus is seen. The pathophysiology of nutcracker esophagus may be related to abnormalities in neurotransmitters or other mediators in the distal esophagus. Abnormalities in nitric oxide levels, which have been seen in achalasia, are postulated as the primary abnormality. As GERD is associated with nutcracker esophagus, the alterations in nitric oxide and other released chemicals may be in response to reflux.
Diagnosis
In patients who have dysphagia, testing may first be done to exclude an anatomical cause of dysphagia, such as distortion of the anatomy of the esophagus. This usually includes visualization of the esophagus with an endoscope, and can also include barium swallow X-rays of the esophagus. Endoscopy is typically normal in patients with nutcracker esophagus; however, abnormalities associated with gastroesophageal reflux disease, or GERD, which associates with nutcracker esophagus, may be seen. Barium swallow in nutcracker esophagus is also typically normal, but may provide a definitive diagnosis if contrast is given in tablet or granule form. Studies on endoscopic ultrasound show slight trends toward thickening of the muscularis propria of the esophagus in nutcracker esophagus, but this is not useful in making the diagnosis.
Esophageal motility studies
The diagnosis of nutcracker esophagus is typically made with an esophageal motility study, which shows characteristic features of the disorder. Esophageal motility studies involve pressure measurements of the esophagus after a patient takes a wet (fluid-containing) or dry (solid-containing) swallow. Measurements are usually taken at various points in the esophagus.Nutcracker esophagus is characterized by a number of criteria described in the literature. The most commonly used criteria are the Castell criteria, named after American gastroenterologist D.O. Castell. The Castell criteria include one major criterion: a mean peristaltic amplitude in the distal esophagus of more than 180 mm Hg. The minor criterion is the presence of repetitive contractions (meaning two or more) that are greater than six seconds in duration. Castell also noted that the lower esophageal sphincter relaxes normally in nutcracker esophagus, but has an elevated pressure of greater than 40 mm Hg at baseline.Three other criteria for the definition of the nutcracker esophagus have been defined. The Gothenburg criterion consists of the presence of peristaltic contractions, with an amplitude of 180 mm Hg at any place in the esophagus. The Richter criterion involves the presence of peristaltic contractions with an amplitude of greater than 180 mm Hg from an average of measurements taken 3 and 8 cm above the lower esophageal sphincter. It has been incorporated into a number of clinical guidelines for the evaluation of dysphagia. The Achem criteria are more stringent, and are an extension of the study of 93 patients used by Richter and Castell in the development of their criteria, and require amplitudes of greater than 199 mm Hg at 3 cm above the lower esophageal sphincter (LES), greater than 172 mm Hg at 8 cm above the LES, or greater than 102 mm Hg at 13 cm above the LES.
Treatment
People are usually reassured that the disease is unlikely to worsen. However, the symptoms of chest pain and trouble swallowing may be severe enough to require treatment with medications, and rarely, surgery.
The initial step of treatment focuses on reducing risk factors. While weight reduction may be useful in reducing symptoms, the role of acid suppression therapy to reduce esophageal reflux is still uncertain. Very cold and very hot beverages may trigger esophageal spasms.
Medications
Medications for nutcracker esophagus includes the use of calcium-channel blockers, which relax the lower esophageal sphincter (LES) and palliate the dysphagia symptoms. Diltiazem, a calcium-channel blocker, has been used in randomized control studies with good effect. Nitrate medications, including isosorbide dinitrate, given before meals, may also help relax the LES and improve symptoms. The inexpensive generic combination of belladonna and phenobarbital (Donnatal and other brands) may be taken three times daily as a tablet to prevent attacks or, for patients with only occasional episodes, as an elixir at the onset of symptoms. Phosphodiesterase inhibitors, such as sildenafil, can be given to reduce symptoms, particularly pain, but small trials have not been able to demonstrate clinical improvement.
Procedures
Endoscopic therapy with botulinum toxin can also be used to improve dysphagia which stabilizes unintentional weight loss, but the effect has limited effect on other symptoms, including pain, while also being a temporary treatment lasting a few weeks. Finally, pneumatic dilatation of the esophagus, which is an endoscopic technique where a high-pressure balloon is used to stretch the muscles of the LES, can be performed to improve symptoms, but again no clinical improvement is seen in regards to motility.In people who have no response to medical or endoscopic therapy, surgery can be performed. A Heller myotomy involves an incision to disrupt the LES and the myenteric plexus that innervates it. The Heller myotomy is used as a final treatment option in patients who do not respond to other therapies.
Prognosis
Nutcracker esophagus is a benign, nonprogressive condition, meaning it is not associated with significant complications.
See also
Esophageal spasm
References
== External links == |
Noonan syndrome | Noonan syndrome (NS) is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. Facial features include widely spaced eyes, light-colored eyes, low-set ears, a short neck, and a small lower jaw. Heart problems may include pulmonary valve stenosis. The breast bone may either protrude or be sunken, while the spine may be abnormally curved. Intelligence in the syndrome is often normal. Complications of NS can include leukemia.A number of genetic mutations can result in Noonan syndrome. The condition may be inherited from a persons parents as an autosomal dominant condition or occur as a new mutation. Noonan syndrome is a type of RASopathy, the underlying mechanism for which involves overactivation within the RAS/MAPK cell signaling pathway. The diagnosis may be suspected based on symptoms, medical imaging, and blood tests. Confirmation may be achieved with genetic testing.No cure for NS is known. Treatment is based on the symptoms and underlying problems, and extra support in school may be required. Growth hormone therapy during childhood can increase an affected persons final height. Long-term outcomes typically depend on the severity of heart problems.An estimated 1 in 1000 people are mildly affected by NS, while about 1 in 2,000 have a more severe form of the condition. Males appear to be affected more often than females. The condition was first described in 1883 and was named after American pediatric cardiologist Jacqueline Noonan, who described further cases in 1963.
Signs and symptoms
The most common signs leading to the diagnosis of Noonan syndrome are unique facial characteristics and musculoskeletal features. The facial characteristics are most prominent in infancy, becoming less apparent with age in many people with Noonan syndrome.
Head
Some of the characteristic features of Noonan syndrome include a large head with excess skin on the back of the neck, low hairline at the nape of the neck, high hairline at the front of the head, triangular face shape, broad forehead, and a short, webbed neck.
In the eyes, hypertelorism (widely set eyes) is a defining characteristic, present in 95% of people with Noonan syndrome. This may be accompanied by epicanthal folds (extra fold of skin at the inner corner of the eye), ptosis (drooping of the eyelids), proptosis (bulging eyes), strabismus (inward or outward turning of the eyes), nystagmus (jerking movement of the eyes) and refractive visual errors.
The nose may be small, wide, and upturned.
The development of the ears and auditory system may be affected in people with Noonans syndrome. This can result in low-set ears (in over 90%), backward-rotated ears (over 90%), thick helix (outer rim) of ear (over 90%), incomplete folding of ears, chronic otitis media (ear infections), and hearing loss.
Development of the mouth may also be affected in Noonan syndrome. This can result in deeply grooved philtrum (top lip line) (over 90%), micrognathia (undersized lower jaw), high arched palate, articulation difficulties (teeth dont line up) which can lead to dental problems. Similar to the muscular manifestations above, in the mouth, poor tongue control may be observed.
Skin
Skin signs and symptoms in Noonan syndrome include lymphedema (lymph swelling of the extremities), keloid formation, excessive scar formation, hyperkeratosis (overdevelopment of outer skin layer), pigmented nevi (darkly pigmented skin spots), and connective tissue disease.
Musculoskeletal
Abnormalities in the limbs and extremities may occur in Noonan syndrome. This may manifest as bluntly ended fingers, extra padding on fingers and toes, edema of the back of hands and tops of feet, and cubitus valgus (wide carrying angle of the elbows).
For short stature, growth hormone is sometimes combined with IGF-1 (or as an alternative, IGF-1 as a stand-alone) can be used to achieve an increased height/final height quicker. The final adult height of individuals with Noonan syndrome is about 161–167 cm in males and 150–155 cm in females, which approaches the lower limit of normal.Spinal abnormalities may be present up to 30% of the time and this may require surgery to correct in over 60% of these cases. Other musculoskeletal manifestations in Noonan syndrome are associated with undifferentiated connective-tissue disorders which can be associated with joint contractures (tightness) or joint hypermobility (looseness). Additional factors may present in the form of winging of the scapula, scoliosis, breast bone prominence (pectus carinatum), breast bone depression (pectus excavatum). Muscle abnormalities may present as hypotonia (low muscle tone), which may lead to lordosis (increased hollow in the back) due to poor abdominal muscle tone.
Heart
Noonan syndrome is the second most common syndromic cause of congenital heart disease. This includes pulmonary valvular stenosis (50–60%), atrial septal defects (10–25%), ventricular septal defects (5–20%) and hypertrophic cardiomyopathy (12–35%).
Lungs
Restrictive lung function has been reported in some people.
Gastrointestinal
A number of diverse gastrointestinal (GI) symptoms have been associated with Noonan syndrome. These include swallowing difficulties, low gut motility, gastroparesis (delayed gastric emptying), intestinal malrotation, and frequent or forceful vomiting. These digestive issues may lead to decreased appetite, failure to thrive from infancy to puberty (75%), and occasionally the need for a feeding tube.
Genitourinary system
In some males with Noonan syndrome, testicles do not descend (cryptorchidism).
Circulation
Lymphatic anomalies including Posterior cervical hygroma (webbed neck) and Lymphedema may present in people with Noonan syndrome.
A number of bleeding disorders have been associated with Noonan syndrome, these include platelet dysfunction, Blood clotting disorders, partial deficiency of factor VIII:C, partial deficiency of factor XI:C, partial deficiency of factor XII:C, and an imbalance of plasminogen activator inhibitor type-1 (PAI-1) and tissue plasminogen activator (t-PA) activity. It has been associated with Von Willebrand disease, Amegakaryocytic thrombocytopenia (low platelet count), prolonged activated partial thromboplastin time, combined coagulation defects. When present, these Noonan-syndrome accompanying disorders can be associated with a predisposition to bruise easily, or hemorrhage.
Neurological
Occasionally, Chiari malformation (type 1), may occur, which can lead to hydrocephalus. Seizures have also been reported.
Causes
Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with autosomal dominant inheritance and variable expression. Mutations in the Ras/mitogen activated protein kinase signaling pathways are known to be responsible for about 70% of NS cases.Persons with NS have up to a 50% chance of transmitting it to their offspring. The fact that an affected parent is not always identified for children with NS suggests several possibilities:
Manifestations could be so subtle as to go unrecognized (variable expressivity)
NS is heterogeneous, comprising more than one similar condition of differing causes, and some of these may not be inherited.
A high proportion of cases may represent new, sporadic mutations.Heterozygous mutations in NRAS, HRAS, BRAF, SHOC2, MAP2K1, MAP2K2, and CBL have also been associated with a smaller percentage of NS and related phenotypes.A condition known as "neurofibromatosis–Noonan syndrome" is associated with neurofibromin.
Diagnosis
NS can be confirmed genetically by the presence of any of the known mutations listed above. However, despite identification of 14 causative genes, the absence of a known mutation will not exclude the diagnosis, as more, as-yet-undiscovered genes can cause NS. Thus, the diagnosis of NS is still based on clinical features. In other words, it is made when a physician feels that a person has enough of the features to warrant the label. The principal values of making a genetic diagnosis are that it guides additional medical and developmental evaluations, it excludes other possible explanations for the features, and it allows more accurate recurrence risk estimates. With more genotype-phenotype correlation studies being performed, a positive genetic diagnosis will help the clinician to be aware of possible anomalies specific to that certain gene mutation. For example, an increase in hypertrophic cardiomyopathy is seen in people with a mutation of KRAS and an increased risk of juvenile myelomonocytic leukemia exists for a mutation of PTPN11. In the future, studies may lead to a targeted management of NS symptoms that depends on what genetic mutation a person has.
Before birth
Prenatal features that might lead physicians to consider a diagnosis of Noonan syndrome include cystic hygroma, increased nuchal translucency, pleural effusion, and edema.
Differential diagnosis
While Turner syndrome has similarities with renal anomalies and developmental delay, Turner syndrome is only found in females and often expresses differently. In Turner syndrome, there is a lower incidence of developmental delays, left-sided heart defects are constant and the occurrence of renal abnormalities is much lower.Other RASopathies
Watson syndrome - Watson Syndrome has a number of similar characteristics with Noonans Syndrome such as short stature, pulmonary valve stenosis, variable intellectual development, and skin pigment changes.
Cardiofaciocutaneous (CFC) syndrome - CFC syndrome is very similar to Noonans Syndrome due to similar cardiac and lymphatic features. However, In CFC syndrome intellectual disability and gastrointestinal problems are often more severe and pronounced.
Costello syndrome - Like CFC syndrome, Costello syndrome has overlapping features with Noonans Syndrome. However, the conditions can be distinguished by their genetic cause.
Neurofibromatosis 1 (NF1)
Williams syndrome
Management
The treatment varies depending on complications but tend to be quite standard, reflecting the treatment of the general population. Management guidelines, divided by systems, including general, developmental, dental, growth and feeding, cardiovascular, audiological, haematological, renal and skeletal, that account for actions to be taken at diagnosis, after diagnosis and if symptomatic, have been published by an American consortium.Specifically, treatment of cardiovascular complications resemble that of the general population and treatment of bleeding diathesis is guided by the specific factor deficiency or platelet aggregation.
Neuropsychological testing is recommended to find strengths and challenges to tailor support needed for school and career.
Educational customization such as an individualized education program plan is sometimes needed for school-aged children.
Speech therapy if speech and articulation issues present
Physical therapy and occupational therapy for gross- and fine-motor delays
Hypotonia and motor difficulties often impact handwriting. Accommodations for lessening handwriting demands will improve performance and save long-term hand function.
Periodic follow up and lifelong monitoring of abnormalities found in any system, especially the cardiovascular system, is recommended.
Anesthesia risk
Although a few people with Noonan syndrome have been reported to develop malignant hyperthermia, the gene mutation of diseases known to be associated with malignant hyperthermia is different from that of Noonan syndrome.
Prognosis
The lifespan of people with Noonans syndrome can be similar to the general population, however, Noonan syndrome can be associated with several health conditions that can contribute to mortality. The greatest contributor to mortality in individuals with Noonan syndrome is complications of cardiovascular disease. Prognosis is therefore largely dependent on the presence or absence of cardiac disease, as well as the type and severity of the disease (if disease is present). Most notably, Noonan syndrome with hypertrophic cardiomyopathy is associated with increased mortality.
History
Jacqueline Noonan was practicing as a pediatric cardiologist at the University of Iowa when she noticed that children with a rare type of heart defect, valvular pulmonary stenosis, often had a characteristic physical appearance, with short stature, webbed neck, wide spaced eyes, and low-set ears. Both boys and girls were affected. These characteristics were sometimes seen running in families but were not associated with gross chromosomal abnormalities. She studied 833 people with Noonan syndrome at the congenital heart disease clinic, looking for other congenital abnormalities, and, in 1963, presented a paper: "Associated non-cardiac malformations in children with congenital heart disease". This described 9 children who in addition to congenital heart disease had characteristic facial features, chest deformities and short stature.
Dr. John Opitz, a former student of Dr. Noonans, first began to call the condition "Noonan syndrome" when he saw children who looked like those whom Dr. Noonan had described. Dr. Noonan produced a paper titled "Hypertelorism with Turner Phenotype" in 1968 where she studied 19 patients who displayed symptoms indicative of Noonans Syndrome. In 1971, at the Symposium of Cardiovascular defects, the name Noonan syndrome became officially recognized.
References
== External links == |
Majeed syndrome | Majeed syndrome is an inherited skin disorder characterized by chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia and a neutrophilic dermatosis.
It is classified as an autoinflammatory bone disorder.
The condition is found in people with two defective copies (autosomal recessive inheritance) of the LPIN2 gene. LPIN2 encodes lipin-2 which is involved in lipid metabolism.
The pathogenesis of this mutation with the clinical manifestations has not been elucidated.
Treatments
Treatments for this disorder are often based on what symptoms are present in the patient. Most commonly prescribed treatments include nonsteroidal anti-inflammatory drugs (NSAIDs), as well as physical therapy in order to prevent from muscle atrophy in patients. Red blood transfusions could also be done for patients with severe congenital dyserythrypoietic anemia (CDA).
See also
TNF receptor associated periodic syndrome
List of cutaneous conditions
References
External links
Orphanet syndrome Majeed syndrome |
Intraocular hemorrhage | Intraocular hemorrhage is bleeding (hemorrhage) inside the eye (oculus in Latin) . It may be the result of physical trauma (direct injury to the eye) or other diseases, injuries or disorders (such as diabetes, hypertension, or shaken baby syndrome). Severe bleeding may cause high pressures inside the eye, leading to blindness.
Types
The types of ocular hemorrhages are classified based on where the bleeding is occurring:
Subconjunctival hemorrhage (bleeding just underneath the conjunctiva)
Intraocular hemorrhages:
Hyphema (in the anterior chamber)
In the posterior segment of eyeball:
Vitreous hemorrhage (into the vitreous)
Subretinal hemorrhage (under the retina)
Submacular hemorrhage (under the macula)
Causes
Different causes may cause bleeding in different locations.
Tersons syndrome (as a result of subarachnoid hemorrhage)
Hemophilia (a severe bleeding disorder, usually hereditary)
Anticoagulants and thrombolysis (medication to reduce blood clotting tendency or to disperse blood clots, respectively)The major causes of bleeding are injury diabetes mellitus hypertension.
Diagnosis
Intraocular hemorrhage is typically diagnosed with slit lamp examination.
Treatment
References
== External links == |
Variant angina | Variant angina, also known as Prinzmetal angina, vasospastic angina, angina inversa, coronary vessel spasm, or coronary artery vasospasm, is a syndrome typically consisting of angina (cardiac chest pain). Variant angina differs from stable angina in that it commonly occurs in individuals who are at rest or even asleep, whereas stable angina is generally triggered by exertion or intense exercise. Variant angina is caused by vasospasm, a narrowing of the coronary arteries due to contraction of the hearts smooth muscle tissue in the vessel walls. In comparison, stable angina is caused by the permanent occlusion of these vessels by atherosclerosis, which is the buildup of fatty plaque and hardening of the arteries.
Signs and symptoms
In contrast to those with angina secondary to atherosclerosis, people with variant angina are generally younger and have fewer risk factors for coronary artery disease with the exception of smoking, which is a common and significant risk factor for both types of angina. Affected people usually have repeated episodes of unexplained (e.g., in the absence of exertion and occurring at sleep or in the early morning hours) chest pain, tightness in throat, chest pressure, light-headedness, excessive sweating, and/or reduced exercise tolerance that, unlike atherosclerosis-related angina, typically does not progress to myocardial infarction (heart attack). Unlike cases of atherosclerosis-related stable angina, these symptoms are often unrelated to exertion and occur in night or early morning hours. However, individuals with atherosclerosis-related unstable angina may similarly exhibit night to early morning hour symptoms that are unrelated to exertion.Cardiac examination of individuals with variant angina is usually normal in the absence of current symptoms. Two-thirds of these individuals do have concurrent atherosclerosis of a major coronary artery, but this is often mild or not in proportion to the degree of their symptoms. Persons who have atherosclerosis-based occlusion that is ≥70% in a single coronary artery or that involves multiple coronary arteries are predisposed to develop a variant angina form that has a poorer prognosis than most other forms of this disorder. In these individuals but also in a small percentage of individuals without appreciable atherosclerosis of their coronary arteries, attacks of coronary artery spasm can have far more serious presentations such as fainting, shock, and cardiac arrest. Typically, these presentations reflect the development of a heart attack and/or a potentially lethal heart arrhythmia; they require immediate medical intervention as well as consideration for the presence of, and specific treatment regimens for, their disorder.Variant angina should be suspected by a cardiologist when a) an individuals symptoms occur at rest or during sleep; b) an individuals symptoms occur in clusters; c) an individual with a history of angina does not develop angina during treadmill stress testing (variant angina is exercise tolerant); d) an individual with a history of angina shows no evidence of other forms of cardiac disease; and/or e) an individual without features of coronary artery atherosclerotic heart disease has a history of unexplained fainting.Complaints of chest pain should be immediately checked for an abnormal electrocardiogram (ECG). ECG changes compatible but not indicative of variant angina include elevations rather than depressions of the ST segment or an elevated ST segment plus a widening of the R wave to create a single, broad QRS complex peak termed the "monophasic curve". Associated with these ECG changes, there may be small elevations in the blood levels of cardiac damage marker enzymes, especially during long attacks. Some individuals with otherwise typical variant angina may show depressions, rather than elevations in the ST segments of their ECGs during angina pain; they may also show new U waves on ECGs during angina attacks.A significant percentage of those with variant angina have symptom-free episodes of coronary artery spasm. These episodes may be far more frequent than expected, cause myocardial ischemia (i.e. insufficient blood flow to portions of the heart), and be accompanied by potentially serious abnormalities in the rhythm of heart beats, i.e. arrythmias. The only evidence of the presence of totally asymptomatic variant angina would be detection of diagnostic changes on fortuitously conducted ECGs.
Risk factors
The intake of certain agents have been reported to trigger an attack of variant angina. These agents include:
recreational agents (e.g. nicotine in tobacco and other forms, alcoholic beverages, marijuana, cocaine);
catecholamine-like stimulants (e.g. epinephrine, dopamine, various amphetamines);
the uterus-contracting drug, ergonovine;
parasympathomimetic drugs (e.g. acetylcholine, methacholine);
anti-migraine drugs (e.g. various triptans);
chemotherapeutic drugs (e.g. 5-fluorouracil, capecitabine);
high consumption of energy drinks have been associated with variant angina.In addition, hyperventilation and virtually any stressful emotional or physical (e.g. cold exposure) event that is suspected of causing significant rises in the blood levels of catecholamines may trigger variant angina.
Mechanism
The mechanism that causes such intense vasospasm, as to cause a clinically significant narrowing of the coronary arteries is so far unknown, but there are three relevant hypotheses:
Enhanced contractility of coronary vascular smooth muscle due to reduced nitric oxide bioavailability caused by a defect in the endothelial nitric oxide synthetase enzyme which leads to endothelial function abnormalities.Acetylcholine is normally released by the parasympathetic nervous system (PSNS) at rest, and causes dilation of the coronary arteries. While acetylcholine induces vasoconstriction of vascular smooth muscle cells through a direct mechanism, acetylcholine also stimulates endothelial cells to produce nitric oxide (NO). NO then diffuses out of the endothelial cells, stimulating relaxation of the nearby smooth muscle cells. In healthy arterial walls, the overall indirect relaxation induced by acetylcholine (via nitric oxide) is of greater effect than any contraction that is induced.
When the endothelium is dysfunctional, stimulation with acetylcholine will fail to produce, or produce very little, nitric oxide. Thus, acetylcholine released by the PSNS at rest will simply cause contraction of the vascular smooth muscle.
Thromboxane A2, serotonin, histamine, and endothelin are vasoconstrictor which activated platelets release and/or cause to be released. Abnormal platelet activation (e.g. by lipoprotein(a) interference with fibrinolysis by competing with plasminogen to thereby impair fibrinolysis and promote platelet activation) results in the release of these mediators and coronary vasospasm.
Increased alpha-adrenergic receptor activity in epicardial coronary arteries or the excessive release of the "flight or fight" catecholamines (e.g. norepinephrine) that activate these receptors may lead to coronary vasospasm.Other factors thought to be associated with the development of variant angina include: intrinsic hypercontractility of coronary artery smooth muscle; existence of significant atherosclerotic coronary artery disease; and reduced activity of the parasympathetic nervous system (which normally functions to dilate blood vessels).
Diagnosis
Although variant angina has been documented in between 2% to 10% of angina patients, it can be overlooked by cardiologists who stop further evaluations after ruling out typical angina. Individuals who develop cardiac chest pain are generally treated empirically as an "acute coronary syndrome", and are immediately tested for elevations in their blood levels of enzymes such as creatine kinase isoenzymes or troponin that are markers for cardiac damage. They are also tested by ECG which may suggest variant angina if it shows elevations in the ST segment or an elevated ST segment plus a widening of the R wave during symptoms that are triggered by a provocative agent (e.g. ergonovine or acetylcholine). The electrocardiogram may show depressions rather than elevations in ST segments but in all diagnosable cases clinical symptoms should be promptly relieved and ECG changes should be promptly reversed by rapidly acting sublingual or intravenous nitroglycerin. However, the gold standard for diagnosing variant angina is to visualize coronary arteries by angiography before and after injection of a provocative agent such as ergonovine, methylergonovine or acetylcholine to precipitate an attack of vasospasm. A positive test to these inducing agents is defined as a ≥90% (some experts require lesser, e.g. ≥70%) constriction of involved arteries. Typically, these constrictions are fully reversed by rapidly acting nitroglycerin.Individuals with variant angina may have many undocumented episodes of symptom-free coronary artery spasm that are associated with poor blood flow to portions of the heart and subsequent irregular and potentially serious heart arrhythmias. Accordingly, individuals with variant angina should be intermittently evaluated for this using long-term ambulatory cardiac monitoring.
Prevention
Numerous methods are recommended to avoid attacks of variant angina. Affected individuals should not smoke tobacco products. Smoke cessation significantly reduces the incidence of patient-reported variant angina attacks. They should also avoid any trigger known to them to trigger these attacks such as emotional distress, hyperventilation, unnecessary exposure to cold, and early morning exertion. And, they should avoid any of the recreational and therapeutic drugs listed in the above signs and symptoms and risk factors sections as well as blockers of beta receptors such as propranolol which may theoretically worsen vasospasm by inhibiting beta-2 adrenergic receptors vasodilation effect mediated by these receptors naturally occurring stimulator i.e. epinephrine. In addition, aspirin should be used with caution and at low doses since at high doses it inhibits the production of the naturally occurring vasodilator, prostacyclin.
Treatment
Acute attacks
During acute attacks, individuals typically respond well to fast-acting sublingual, intravenous, or spray nitroglycerin formulations. The onset of symptom relief in response to intravenous administration, which is used in more severe attacks of angina, occurs almost immediately while sublingual formulations of it act within 1–5 minutes. Spray formulations also require ~1–5 minutes to act.
Maintenance
As maintenance therapy, sublingual nitroglycerin tablets can be taken 3-5 min before conducting activity that causes angina by the small percentage of patients who experience angina infrequently and only when doing such activity. For most affected individuals, antianginals are used as maintenance therapy to avoid attacks of variant angina. Calcium channel blockers of the dihydropyridine class (e.g. nifedipine, amlodipine) or non-dihydropyridine class (e.g. verapamil, diltiazem) are regarded as first-line drugs to avoid angina attacks. Long-acting nitroglycerins such as isosorbide dinitrate or intermittent use of short-acting nitroglycerin (to treat acute symptoms) may be added to the calcium channel blocker regimen in individuals responding sub-optimally to the channel blockers. However, individuals commonly develop tolerance, i.e. resistance, to the efficacy of continuously used long-acting nitroglycerin formulations. One strategy to avoid this development is to schedule nitroglycerin-free periods of between 12 and 14 hours between doses of long-acting nitroglycerin formulations. Individuals whose symptoms are poorly controlled by a calcium blocker may benefit from addition of a long-acting nitroglycerin and/or a second calcium channel blocker of a different class than the blocker already in use. Nevertheless, about 20% of individuals fail to respond adequately to the two-drug calcium blocker plus long-acting nitroglycerin regimen. If these individuals have significant permanent occlusion of their coronary arteries, they may benefit by stenting their occluded arteries. However, coronary stenting is contraindicated in drug- refractory individuals who do not have significant organic occlusion of their coronary arteries. For the latter individuals, other, less fully investigated drugs may provide symptom relief. Statins, e.g. fluvastatin, while not evaluated in large-scale double-blind studies, are reportedly helpful in reducing variant angina attacks and should be considered in patients when calcium channel blockers and nitroglycerin fail to achieve good results. There is also interest in using rho-kinase inhibitors, such as fasudil (available in Japan and China but not the USA), and blocker of alpha-1 adrenergic receptors such as prazosin (which when activated cause vasodilation) but studies are needed to support their clinical utility in variant angina.
Emergency
Individuals with certain severe complications of variant angina require immediate therapy. Individuals presenting with potentially lethal irregularities in the rhythm of their heart beating or a history of episodic fainting spells due to such arrhythmias require implantation of an internal defibrillator and/or cardiac pacemaker to stop such arrhythmias and restore normal heart beating. Other rare but severe complications of variant angina viz., myocardial infarction, severe congestive heart failure, and cardiogenic shock require the same immediate medical interventions that are used for other causes of these extremis conditions. In all of these emergency cases, percutaneous coronary intervention to stent areas where coronary arteries evidence spasm is only useful in individuals who have concomitant coronary atherosclerosis on coronary angiogram.
Prognosis
Most individuals with variant angina have a favorable prognosis provided they are maintained on calcium channel blockers and/or long-acting nitrates; five-year survival rates in this group are estimated as over 90%. The Japanese Coronary Spasm Association established a clinical risk scoring system to predict outcomes for variant angina. Seven major factors (i.e. history of out of hospital cardiac arrest [score = 4]; smoking, angina at rest, physically obstructive coronary artery disease, and spasm in multiple coronary arteries [score = 2]; and presence of ST segment elevations on ECG and history of using beta blockers [score = 1]) where assigned the indicated scores. Individuals with scores of 0 to 2, 3 to 5, and ≥6 experienced an incidence of a major cardiovascular event in 2.5, 7.0, and 13.0% of cases.
History
Dr. William Heberden is credited with being the first to describe in a 1768 publication the occurrence of chest pain attacks (i.e. angina pectoris) that appeared due to pathologically occluded coronary arteries. These attacks were triggered by exercise or other forms of exertion and relieved by rest and nitroglycerin. In 1959, Dr. Myron Prinzmetal described a type of angina that differed from the classic cases of Heberden angina in that it commonly occurred in the absence of exercise or exertion. Indeed, it often woke patients from their normal sleep. This variant angina differed from the classical angina described by Dr. Heberden in that it appeared due to episodic vasospasm of coronary arteries that were typically not occluded by pathological processes such as atherosclerosis, emboli, or spontaneous dissection (i.e. tears in the walls of coronary arteries). Variant angina had been described twice in the 1930s by other authors and was referred to as cardiac syndrome X (CSX) by Kemp in 1973, in reference to patients with exercise-induced angina who nonetheless had normal coronary angiograms. CSX is now termed microvascular angina, i.e. angina caused by disease of the hearts small arteries.Some key features of variant angina are chest pain that is concurrently associated with elevations in the ST segment on electrocardiography recordings, that often occurs during the late evening or early morning hours in individuals who are at rest, doing non-strenuous activities, or asleep, and that is not associated with permanent occlusions of their coronary vessels. The disorder seems to occur more often in women than men, has a particularly high incidence in Japanese males as well as females, and affects individuals who may smoke tobacco products but exhibit few other cardiovascular risk factors. However, individuals exhibiting angina symptoms that are associated with depressions in their electrocardiogram ST segments, that are triggered by exertion, and/or who have atherosclerotic coronary artery disease are still considered to have variant angina if their symptoms are caused by coronary artery spasms. Finally, rare cases may exhibit symptom-free coronary artery spasm that is nonetheless associated with cardiac muscle ischemia (i.e. restricted blood flow and poor oxygenation) along with concurrent ischemic electrocardiographic changes. The term vasospastic angina is sometimes used to include all of these atypical cases with the more typical cases of variant angina. Here, variant angina is taken to include typical and atypical cases.
For a portion of patients, variant angina may be a manifestation of a more generalized episodic smooth muscle-contractile disorder such as migraine, Raynauds phenomenon, or aspirin-induced asthma. Variant angina is also the major complication of eosinophilic coronary periarteritis, an extremely rare disorder caused by extensive eosinophilic infiltration of the adventitia and periadventitia, i.e. the soft tissues, surrounding the coronary arteries. Variant angina also differs from the Kounis syndrome (also termed allergic acute coronary syndrome) in which coronary artery constriction and symptoms are caused by allergic or strong immune reactions to a drug or other substance. Treatment of the Kounis syndrome very much differs from that for variant angina.
See also
Angina pectoris: the most common form of coronary artery spasm; it is due to atherosclerosis.
Kounis syndrome: coronary artery spasm due to an allergic reaction.
Eosinophilic coronary periarteritis: a very rare form of coronary artery spasm; it is due to non-allergic infiltration of coronary arteries by eosinophils.
References
External links
Crea, F; Lanza, GA (11 Nov 2003). "Vasospastic Angina". e-Journal of Cardiology Practice. 2 (9). |
Antithrombin III deficiency | Antithrombin III deficiency (abbreviated ATIII deficiency) is a deficiency of antithrombin III. This deficiency may be inherited or acquired. It is a rare hereditary disorder that generally comes to light when a patient suffers recurrent venous thrombosis and pulmonary embolism, and repetitive intrauterine fetal death (IUFD). Hereditary antithrombin deficiency results in a state of increased coagulation which may lead to venous thrombosis. Inheritance is usually autosomal dominant, though a few recessive cases have been noted. The disorder was first described by Egeberg in 1965. The causes of acquired antithrombin deficiency are easier to find than the hereditary deficiency.The prevalence of antithrombin deficiency is estimated at ~0.02 to 0.2% of the general population, and 1-5% of patients with venous thromboembolism. There is an elevated risk of thrombosis, whereby 50% patients with AT deficiency were found to have venous thromboembolism by age 50.
Cause
Diagnosis
A clinical suspicion for antithrombin deficiency can be made in patients with: 1. recurrent venous thromboembolic disease, 2. childhood thrombosis, 3. thrombosis in pregnancy. Testing for antithrombin activity can confirm deficiency if the levels are less than 70%. Deficiency can result from genetic predisposition or from acquired causes such as: acute thrombosis, disseminated intravascular coagulopathy, liver disease, nephrotic syndrome, asparaginase deficiency, oral contraception/estrogens. Genetic testing for abnormalities of the SERPINC1 gene can be done to evaluate further.
Management
In patients with antithrombin deficiency, they may develop resistance to unfractionated heparin, especially with continuous infusions. If large quantities of unfractionated heparin are required e.g. greater than 35000 units per day, this would point towards resistance. Antithrombin concentrates have been used, though with risk of bleeding at large doses of unfractionated heparin. Low molecular weight heparin at full weight based dosing is effective; however, measurements of peak anti-Xa levels may not reflect anticoagulant effect. Vitamin K antagonists, and direct oral anticoagulants, including anti-Xa inhibitors and thrombin inhibitors have also been used, though data is limited.
See also
Antithrombin
References
== External links == |
Hemoglobinemia | Hemoglobinemia (or haemoglobinaemia) is a medical condition in which there is an excess of hemoglobin in the blood plasma. This is an effect of intravascular hemolysis, in which hemoglobin separates from red blood cells, a form of anemia.
Hemoglobinemia can be caused by intrinsic or extrinsic factors. When hemoglobinemia is internally caused, it is a result of recessive genetic defects that cause the red blood cells to lyse, letting the hemoglobin spill out of the cell into the blood plasma.
In intravascular hemolysis, hemoglobin is released and binds with haptoglobin. This causes haptoglobin levels to decrease.
Once haptoglobin is saturated, free hemoglobin readily distributes to tissues where it might be exposed to oxidative conditions. In such conditions, heme can be released from ferric hemoglobin. The free heme can then accelerate tissue damage by promoting peroxidative reactions and activation of inflammatory cascades. Hemopexin (Hx) is another plasma glycoprotein able to bind heme with high affinity. Hx sequesters heme in an inert, non-toxic form and transports it to the liver for catabolism and excretion. As long as both haptoglobin and hemopexin are saturated, the remaining free hemoglobins are filtered in the kidney and some of them will be reabsorbed by way of proximal tubules.
In externally caused hemoglobinemia, an outside attacker acts as an antibody against the red blood cells. This can cause the cells to be destroyed and their hemoglobin released. In extravascular hemolysis, red blood cells are phagocytized by macrophages in the spleen and liver.Abnormal value of hemoglobin does not necessarily indicate a medical problem needing treatment. Diet, activity level, medications, a womens menstrual cycle, and other considerations can affect the results. Additionally to these, one may have higher than normal hemoglobin if he/she lives in a high altitude area.
Causes
There are other causes besides what happens within the body in the blood cells. Other factors that can cause an excess amount of hemoglobin are:
Smoking (which may result in low blood oxygen levels)
Higher altitudes where your red blood cell production naturally increases to compensate for the lower oxygen supply thereSpecific disorders or other factors that may cause a high hemoglobin count include:
Lung disease
Heart disease
COPD (chronic obstructive pulmonary disease)
Dehydration
Emphysema
Heart failure
Kidney cancer
Liver cancer
Other types of heart disease
Other types of lung disease
Polycythemia vera, a disorder in which your body makes too many red blood cells. It can cause headaches, fatigue, and shortness of breath.
Diagnosis
Normal hemoglobin levels
Normal hemoglobin levels correlate with the persons age and sex. Levels can vary between different testing systems and under their doctors consultation. A hemoglobin test measures the amount of hemoglobin in your blood. If a hemoglobin tests shows that a persons levels are below normal, it means they have a low red blood cell count, which is known as anemia. If the test shows higher levels than normal, it means they have hemoglobinemia.The normal range for hemoglobin is:
For men, 13.5 to 17.5 grams per deciliter. 13.5 and 18 g/dl are the lower and upper limits of the acceptable range.
For women, 12.0 to 15.5 grams per deciliter 12 and 16 g/dl are the lower and upper limits of the acceptable range.
Treatment
High hemoglobin levels are a rare occurrence but is usually treated as a symptom for an underlying disease. Consulting a doctor is the best treatment, so they can diagnose your illness and give a recommended treatment plan to lower hemoglobin levels back to normal.
See also
Coagulation
Blood diseases
Methemoglobinemia, an abnormal amount of methemoglobin which is carrying oxygen but unable to release it effectively to body tissues, is produced.
References
"Hemolytic Anemia". University of Virginia Health System. Retrieved 2009-05-01. |
Vaginal adenosis | Vaginal adenosis is a benign abnormality in the vagina, commonly thought to be caused by intrauterine and neonatal exposure of diethylstilbestrol and other progestogens and nonsteroidal estrogens, however it has also been observed in otherwise healthy women and has been considered at times idiopathic or congenital. Postpubertal lesions have also been observed to grow de novo. It has a rather common incidence, of about 10% of adult women.
Causes
Vaginal adenosis is characterised by the presence of metaplastic cervical or endometrial epithelium within the vaginal wall, considered as derived from Müllerian epithelium islets in later life. In women who were exposed to certain chemicals, vaginal adenosis may arise in up to 90%. Since these contraceptives were discontinued, incidence has dropped dramatically. Risk is however still present in subsequent generations due to recent exposure.It is thought steroid hormones play a stimulatory growth in adenosis formation. Vaginal adenosis is also often observed in adenocarcinoma patients.
Diagnosis
Colposcopically, it presents itself similarly to columnar epithelium on the cervix, assisted with lugols solution application for diagnosis. It can be discovered as nodules or cysts on the vaginal tube, with biopsy needed for further diagnosis. As seen cytologically, epithelial and stromal cells in vaginal adenosis show characteristic fusion through the basal lamina or with stromal fibroblasts. Adenosal cells can be distinguished as mucinous, tuboendometrial, and embryonic. Its mucinous cells resemble the normal cervical lining, while its tuboendometrial cells resemble the lining of normal fallopian tubes or endometrium.It is sometimes considered a precancerous lesion, given clear-cell adenocarcinoma patients present these lesions in close proximity to atypical tuboendometrial glands, and microglandular hyperplasia has been seen to arise from these lesions.
References
Further reading
OBrien, P. C.; Noller, K. L.; Robboy, S. J.; Barnes, A. B.; Kaufman, R. H.; Tilley, B. C.; Townsend, D. E. (March 1979). "Vaginal epithelial changes in young women enrolled in the National Cooperative Diethylstilbestrol Adenosis (DESAD) project". Obstetrics & Gynecology. 53 (3): 300–308. PMID 424101.
Laronda, Monica M.; Unno, Kenji; Butler, Lindsey M.; Kurita, Takeshi (2012). "The development of cervical and vaginal adenosis as a result of diethylstilbestrol exposure in utero". Differentiation. 84 (3): 252–260. doi:10.1016/j.diff.2012.05.004. ISSN 0301-4681. PMC 3443265. PMID 22682699. PMID 22682699.
Ganesan, R.; Ferryman, S. R.; Waddell, C. A. (1999). "Vaginal adenosis in a patient on Tamoxifen therapy: a case report". Cytopathology. 10 (2): 127–130. doi:10.1046/j.1365-2303.1999.00162.x. ISSN 0956-5507. PMID 10211619. S2CID 33999959.
Laronda, M. M.; Unno, K.; Ishi, K.; Serna, V. A.; Butler, L. M; Mills, A. A.; Orvis, G. D.; Behringer, R. R.; Deng, C.; Sinha, S.; Kurita, T. (2013). "Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1-mediated cell fate decision in the Müllerian duct epithelium". Developmental Biology 381(1): 5-16. doi: 10.1016/j.ydbio.2013.06.024. PMID 23830984. |
Cerebral softening | Cerebral softening, also known as encephalomalacia, is a localized softening of the substance of the brain, due to bleeding or inflammation. Three varieties, distinguished by their color and representing different stages of the disease progress, are known respectively as red, yellow, and white softening.
Causes
Stroke
Ischemia: A decreased or restriction of circulating blood flow to a region of the brain which deprives neurons of the necessary substrates (primarily glucose); represents 80% of all strokes. A thrombus or embolus plugs an artery so there is a reduction or cessation of blood flow. This hypoxia or anoxia leads to neuronal injury, which is known as a stroke. The death of neurons leads to a so-called softening of the cerebrum in the affected area.Hemorrhage: Intracerebral hemorrhage occurs in deep penetrating vessels and disrupts the connecting pathways, causing a localized pressure injury and in turn injury to brain tissue in the affected area. Hemorrhaging can occur in instances of embolic ischemia, in which the previously obstructed region spontaneously restores blood flow. This is known as a hemorrhagic infarction and a resulting red infarct occurs, which points to a type of cerebral softening known as red softening.
Circle of Willis
In a study on the circle of Willis and its relation to cerebral vascular disorders, a comparison on various anomalies between normal brains (those without the condition of cerebral softening) and brains with cerebral softening were looked at to observe trends in the differences of the anatomical structure of the circle of Willis. Statistically significant results were found in the percentage of normal brains that had a normal circle of Willis and those that had cerebral softening and had a normal circle of Willis. The results yielded 52% of normal brains having a normal circle of Willis, while only 33% of brains with cerebral softening had a normal circle of Willis. There were also a higher number of string-like vessels in brains with cerebral softening (42%), than there were in normal brains (27%). These results point to an assumption of a higher incidence rate of anomalies in brains with cerebral softening versus those that do not have cerebral softening.
Types of softening
Red softening
Red softening is one of the three types of cerebral softening. As its name suggests, certain regions of cerebral softening result in a red color. This is due to a hemorrhagic infarct, in which blood flow is restored to an area of the brain that was previously restricted by an embolism. This is termed a "red infarct" or also known as red softening.Upon autopsy of several subjects, Dr. Cornelio Fazio found that the most common areas of this type of softening occurred where there was a hemorrhage of the middle cerebral artery or the superior or deep branches to it. The subjects softened area was not always near the arteries but where the capillaries perfused the brain tissue. The symptoms were similar to that of a stroke.
White softening
White softening is another form of cerebral softening. This type of softening occurs in areas that continue to be poorly perfused, with little to no blood flow. These are known as "pale" or "anemic infarcts" and are areas that contain dead neuronal tissue, which result in a softening of the cerebrum.
Yellow softening
Yellow softening is the third type of cerebral softening. As its name implies, the affected softened areas of the brain have a yellow appearance. This yellow appearance is due to atherosclerotic plaque build-up in interior brain arteries coupled with yellow lymph around the choroid plexus, which occurs in specific instances of brain trauma.
Stages
Early life
Newborn cerebral softening has traditionally been attributed to trauma at birth and its effect on brain tissue into adulthood. However, more recent research shows that cerebral softening in newborns and the degeneration of white matter is caused by asphyxia and/or later infection. There is no causal evidence to support the hypothesis that problems in labor contribute to the development of softening in infant white matter. Also, further evidence shows a possible connection between low sugar and high protein levels in cerebral spinal fluid that can contribute to disease or virus susceptibility leading to cerebral softening.
Later life
Cases of cerebral softening in infancy versus in adulthood are much more severe due to an infants inability to sufficiently recover brain tissue loss or compensate the loss with other parts of the brain. Adults can more easily compensate and correct for the loss of tissue use and therefore the mortality likelihood in an adult with cerebral softening is less than in an infant.
Documented cases
In this late 19th-century case study, a 10-year-old boy was found to have cerebral softening in specific parts of the brain, limiting specific sensory function. The identifiable softening enabled researchers to detect and partition cerebral areas related to different sensory perceptions.Another case in the late 19th century showed that cerebral softening, when caused by hemorrhaging, can affect various neural pathways leading to convulsions, spasms, coma and death.A third case in 1898 followed the ten-day decline of a 66-year-old woman with cerebral softening. She had yellow softening which led to symptoms that started slowly with transient facial paralysis on the right side of the face. The limbs later became cold and the right side of the body transiently progressed between semi-paralysis and tetanus. Her heart rate and respiration rate became slow by days three and four. Later she developed a yellow jaundiced appearance in the sclera and skin that the doctor proposed as paroxysmal hemoglobinuria upon autopsy. On the last days, the paralysis became more frequent, respiration rose and she developed tachycardia. She died on the evening of the tenth day. The autopsy revealed that the top of the brain down to the lateral ventricle were healthy, but below that there was a 2.5 × 2 × 1 inch area on the left side of the brain that was softened and yellow. The choroid plexus was also matted and surrounded by vessels filled with yellow lymph. The floor of the left lateral ventricle, thalamus, and corpus striatum were softened to the point of unrecognition. These physical abnormalities match the symptoms mentioned and are a prime example of yellow cerebral softening.In 1858 doctor Thomas Inman described four of thirty discovered cases with cerebral softening. Each case was similar to the previous article. There was some atheroma in the internal brain arteries that led to the cerebral softening of the left side of the brain around the left lateral ventricle, thalamus and corpus striatum. There were similar right sided numbness in some patients, coldness of the extremities, and impairments in vision. In some cases, the lungs and the pleura were stuck together as well as the intestines to the peritoneal wall. This again matches yellow cerebral softening.
== References == |
Nezelof syndrome | Nezelof syndrome is an autosomal recessive congenital immunodeficiency condition due to underdevelopment of the thymus. The defect is a type of purine nucleoside phosphorylase deficiency with inactive phosphorylase, this results in an accumulation of deoxy-GTP which inhibits ribonucleotide reductase. Ribonucleotide reductase catalyzes the formation of deoxyribonucleotides from ribonucleotides, thus, DNA replication is inhibited.
Symptoms and signs
This condition causes severe infections. it is characterized by elevated immunoglobulins that function poorly.
Other symptoms are:
Bronchiectasis
Hepatosplenomegaly
Pyoderma
Emphysema
Diarrhea
Cause
Genetically speaking, Nezelof syndrome is autosomal recessive. the condition is thought to be a variation of severe combined immunodeficiency (SCID). However, the precise cause of Nezelof syndrome remains uncertain
Mechanism
In the mechanism of this condition, one first finds that the normal function of the thymus has it being important in T-cell development and release into the bodys blood circulation Hassals corpuscles absence in thymus(atrophy) has an effect on T-cells.
Diagnosis
The diagnosis of Nezelof syndrome will indicate a deficiency of T-cells, additionally in ascertaining the condition the following is done:
Blood test (B-cells will be normal)
X-ray of thymus (atrophy present)
Differential diagnosis
The differential diagnosis for this condition consists of acquired immune deficiency syndrome and severe combined immunodeficiency syndrome
Treatment
In terms of treatment for individuals with Nezelof syndrome, which was first characterized in 1964, includes the following(how effective bone marrow transplant is uncertain) :
Antimicrobial therapy
IV immunoglobulin
Bone marrow transplantation
Thymus transplantation
Thymus factors
See also
List of radiographic findings associated with cutaneous conditions
References
Further reading
Lavini, Corrado; Moran, Cesar A.; Uliano, Morandi; Schoenhuber, Rudolf (2009-05-08). Thymus Gland Pathology: Clinical, Diagnostic and Therapeutic Features. Springer Science & Business Media. ISBN 9788847008281.
External links
PubMed |
Targetoid hemosiderotic hemangioma | Targetoid hemosiderotic hemangioma, also known as a hobnail hemangioma is a skin condition characterized by a central brown or purplish papule that is surrounded by an ecchymotic halo.It may appear similar to melanoma.It was first described by Santa Cruz and Aronberg in 1988.
See also
Skin lesion
List of cutaneous conditions
== References == |
Exostosis | An exostosis, also known as bone spur, is the formation of new bone on the surface of a bone. Exostoses can cause chronic pain ranging from mild to debilitatingly severe, depending on the shape, size, and location of the lesion. It is most commonly found in places like the ribs, where small bone growths form, but sometimes larger growths can grow on places like the ankles, knees, shoulders, elbows and hips. Very rarely are they on the skull.
Exostoses are sometimes shaped like spurs, such as calcaneal spurs.
Osteomyelitis, a bone infection, may leave the adjacent bone with exostosis formation. Charcot foot, the neuropathic breakdown of the feet seen primarily in diabetics, can also leave bone spurs that may then become symptomatic.
They normally form on the bones of joints, and can grow upwards. For example, if an extra bone formed on the ankle, it might grow up to the shin.
When used in the phrases "cartilaginous exostosis" or "osteocartilaginous exostosis", the term is considered synonymous with osteochondroma. Some sources consider the two terms to mean the same thing even without qualifiers, but this interpretation is not universal.
Osteophytes
Osteophytes are bone spurs that develop on the margins of joints secondary to external stimuli such as osteoarthritis. However, these are not always distinguished from exostoses in any definite way.
Fossil record
Evidence for exostosis found in the fossil record is studied by paleopathologists, specialists in ancient disease and injury. Exostosis has been reported in dinosaur fossils from several species, including Acrocanthosaurus atokensis, Albertosaurus sarcophagus, Allosaurus fragilis, Gorgosaurus libratus, and Poekilopleuron bucklandii.
Hereditary multiple exostoses
Hereditary multiple exostoses (HME), also called hereditary multiple osteochondromas (HMO), is a condition that is estimated to affect 1 in 50,000 individuals. Multiple benign or noncancerous bone tumors develop in the affected individuals. The number and location vary among affected patients. Most people seem unaffected at birth; however, by the age of 12 years, they develop multiple exostoses. Affected individuals commonly complain of palpable and recognizable lumps (exostoses) at about the knees and in the forearms. The condition characteristically occurs bilaterally. It may lead to mild degrees of growth retardation and limb asymmetry. Genu valgum (commonly known as "knock-knees"), ankle valgus, and bowing and shortening of one or both of the forearm bones are common manifestations.
Types
Buccal exostosis
Footballers ankle (exotosis of the ankle bone)
Hereditary multiple exostoses (HME)
Subungual exostosis
Surfers ear (exostosis of the ear canal)
Torus mandibularis
Torus palatinus
Calcaneal spur (heel spur)
See also
Ganglion cyst
List of radiographic findings associated with cutaneous conditions
Osteoma
Osteosclerosis
Pachyosteosclerosis
Pachyostosis
References
External links
The Ear and Balance Center, The Sonos Group
MHE Research Foundation (Multiple Hereditary Exostoses) |
MORM syndrome | MORM syndrome is an autosomal recessive congenital disorder characterized by mental retardation, truncal obesity, retinal dystrophy, and micropenis". The disorder shares similar characteristics with Bardet–Biedl syndrome and Cohen syndrome, both of which are autosomal recessive genetic disorders. MORM syndrome can be distinguished from the above disorders because symptoms appear at a young age. The disorder is not dependent on sex of the offspring, both male and female offspring are equally likely to inherit the disorder.
The syndrome is caused by a mutation in the INPP5E gene which can be located on chromosome 9 in humans. Further mapping resulted in the identification of a MORM syndrome locus on chromosome 9q34.3 between the genetic markers D9S158 and D9S905.
Presentation
For individuals with MORM syndrome, symptoms do not appear until about one year of age. From conception to birth, individuals with MORM syndrome appear asymptotic, with no abnormal characteristics. Vision is negatively affected within the first year of life, particularly night vision. Individuals with MORM syndrome experience decreased visual acuity, meaning their ability to see distinct sharp lines decreases. Vision quality continues to deteriorate until age three. Any further reduction in vision acuity is not observed until the individual is between the ages thirty to forty. Delayed sentence processing and intellectual disability is associated with individuals with MORM syndrome, primarily observed at age four. Individuals continue to develop and grow until they are five to twelve years old. During this age bracket, truncal obesity can develop, characterized by the buildup of fat around ones trunk or torso as opposed to the persons extremities. Males enter puberty at around age twelve and develop normally, except for their penis, which will remain at the prepubescent size, resulting in a micropenis. Both the life span and fertility of individuals with MORM syndrome is unclear .
Genetic
MORM syndrome is associated with the gene INPP5E. INPP5E is a gene whose function is not well understood. It is hypothesized to play a role in primary cilia stability. A homozygous mutation in the INPP5E gene, on chromosome 9q34, is the cause for MORM syndrome. The mutation causes a homozygous transition in the last exon of the INPP5E gene. This transition results in the DNA bases changing from a cytosine residue to a thymine residue.
The resulting protein will then have an altered amino acid sequence. In unaffected individuals this specific codon (region of DNA bases) is supposed to code for the amino acid glutamine. In cases of MORM syndrome this codon codes for a termination sequence, which prematurely stops the production of the protein. In unaffected individuals the protein is evenly disbursed throughout the cilia axoneme, which stabilizes the cilia, which are antenna like structures which protrude from the extracellular surface of the cell. They play an important role in extracellular signalling/communication between cells and their environment. When the INPP5E gene is mutated, the protein is damaged and is unable to spread out along the cilia axoneme or interact with other stabilizing proteins. This inability to stabilize ones cilia axoneme results in MORM syndrome. The exact mechanism as to how the mutation in the INPP5E gene causes cilia instability is still not well understood.
Diagnosis
MORM syndrome is a genetic disorder obtained through inheritance. The main method for testing individuals showing symptoms of MORM syndrome is sequence analysis of the entire coding region. When performing a sequence analysis of the entire coding region the gene INPP5E is targeted. Sequence analysis is the biotechnological process in which the structure and sequence of DNA, RNA, or protein sequence is determined through the use of technology. This sequence can be analyzed to determine mutations or abnormalities in that particular region. When testing for MORM syndrome, sequence analysis of the region of the genome which contains the gene INPP5E is targeted and examined to look for mutations.
Management
References
== External links == |
Thyrotoxic myopathy | Thyrotoxic myopathy (TM) is a neuromuscular disorder that develops due to the overproduction of the thyroid hormone thyroxine. Also known as hyperthyroid myopathy, TM is one of many myopathies that lead to muscle weakness and muscle tissue breakdown. Evidence indicates the onset may be caused by hyperthyroidism. There are two known causes of hyperthyroidism that lead to development thyrotoxic myopathy including a multinodular goiter and Graves disease. Physical symptoms of TM may include muscle weakness, the breakdown of muscle tissue, fatigue, and heat intolerance. Physical acts such as lifting objects and climbing stairs may become increasingly difficult. If untreated, TM can be an extremely debilitating disorder that can, in extreme rare cases, lead to death. If diagnosed and treated properly the effects can be controlled and in most cases reversed leaving no lasting effects.
Symptoms and signs
Physical symptoms may include:
Muscle weakness
Degeneration of muscle tissue
Fatigue
Heat intolerance
Chronic TM
Symptoms of chronic TM arise slowly. Patients usually cite decreased exercise tolerance, increased fatigue, and difficulty completing certain tasks after six months of onset. If chronic TM goes untreated worse symptoms may develop including difficulty swallowing and respiratory distress. These occurrences are rare since diagnosis of chronic TM usually occurs during the early stages of onset, before these symptoms develop.
Acute TM
Acute TM is rarer than chronic TM and symptoms appear within days of onset. Acute TM degrades muscle fibers rapidly. Due to the rapid degradation of muscle fibers patients usually cite severe muscle cramps and muscle pain. Some acute TM patients may present symptoms of blurred vision and bulging eyes due to eye muscle degradation and inflammation, but documented cases are rare. Acute TM patients usually have very weak respiratory muscles and often severe respiratory failure occurs.
Cause
TM is directly related to thyroxine toxicity. It is believed this disorder is a direct result of hyperthyroidism, specifically hyperthyroidism caused by Graves disease or a multinodular goiter. Both cause the thyroid gland to overproduce thyroxine. A multinodular goiter is a condition where the thyroid develops nodules. Overproduction of thyroxine is due to the enlargement of the thyroid gland. Graves disease is an autoimmune condition where the immune system chronically stimulates the TSH receptor in the thyroid and induces overproduction of the thyroxine hormone.
Pathophysiology
Excess thyroxine is believed to bring about the onset of thyrotoxic myopathy and eventually cause the degradation of muscle tissue. Thyroxine is a hormone produced in the thyroid gland that regulates the growth metabolism of the nervous system and regulates basal metabolic rate of many cell types. Scientists agree thyroxine brings about the degradation of muscle fibers specifically at the motor end plates of neuromuscular junctions. There is debate as to whether thyroxine degrades the motor end plates from the muscular side, from the nervous system side, or a combination.To understand how high levels of thyroxine can be toxic and lead to thyrotoxic myopathy physiologically, consider basic neuromuscular junction function. Under normal circumstances, muscle contraction occurs when electrical impulses travel down descending axons from the brain or spinal cord towards the neuromuscular junction. The axon terminal depolarizes and releases Acetylcholine (ACh), a neurotransmitter, which in turn stimulates the motor end plate (MEP) of the muscle fiber the nerve is innervating. When the MEP depolarizes the muscle fiber releases calcium initiating the process of muscle contraction.With the onset of TM due to thyroxine toxicity, there is evidence to suggest that structural changes in MEPs could lead to muscle fiber degradation, weakness, and fatigue. Research indicates that decreased levels of Acetylcholinesterase AChE, an enzyme that breaks down ACh, was observed within the neuromuscular junction. This decrease in AChE blocks degradation of ACh causing ACh to increasingly stimulate the MEP of the muscle fiber. Over stimulation of MEP could cause more muscle contractions which eventually evoke muscle fiber fatigue, weakness, and finally degradation, which are characteristic symptoms of TM. It is believed this decrease in AChE and MEP structural changes could be the result of over stimulation of thyroxin blocking the axoplasmic flow of trophic factors down the axon terminal especially considering thyroxines role in nervous system growth and metabolism regulation.
Other research indicates muscle fiber fatigue, weakness, and degradation associated with TM is the direct action thyroxine has on the muscle fibers themselves. Research suggests thyroxine directly causes a decrease in protein kinase affinity to cAMP within muscle fibers This causes an increase in cAMP within the muscle fibers since protein kinases are not inactivating cAMP. Increased levels of cAMP within the muscle fibers cause increased release of Ca2+ from the muscle fibers sarcoplasmic reticulum which eventually leads to more muscle contractions. Like the nervous system proposal increased muscle contractions eventually evoke muscle fiber fatigue, weakness, and finally degradation, which are characteristic symptoms of TM. There is evidence to support both theories; it has been suggested that toxic levels of thyroxine may ultimately attack muscle fibers directly and indirectly by the motor neurons that innervate the affected muscle fibers.
Diagnosis
Thyrotoxic myopathy is usually diagnosed by a neurologist who has extensive experience diagnosing neuromuscular disorders. There are many types of neuromuscular disorders that present similar physical symptoms. Extensive clinical tests are performed first to determine if there is a neuromuscular disorder and then to determine which disorder it is. Electromyography is used to diagnose myopathies by comparing muscle contraction responses to electrical stimulus. For TM results may indicate normal responses or myopathic responses depending on how the disorder has progressed. Early detection may indicate normal contractual responses while highly progressed TM may show a significant decrease in contraction response.Blood tests are then conducted to determine the specific myopathy. For TM, blood tests reveal increased thyroxine levels. Increased thyroxine levels accompanied with decreased neuromuscular responses together provide best evidence for TM diagnosis. Creatine phosphokinase levels are also examined during the blood tests. Normal or increased levels may be observed with TM depending on the severity of TMs progression. Normal levels indicate possible early stages of progression while increased levels may indicate later stages of thyrotoxic myopathy. Muscle biopsies may also be taken and examined to determine TMs progression with respect to physical degradation. Like measured creatine phosphokinase levels results from the muscle biopsy characteristic of TM typically show normal to severe fiber degradation with respective indications to the severity of progression.
Treatment
Treatment for TM is typically done with the collaboration of many medical specialists. Usually a neuromuscular specialist, an endocrinologist, a surgeon, and an ophthalmologist will combine their efforts to successfully treat patients with TM. If a patient develops significant to severe muscle degradation as a result of TM, a physical therapist may be consulted for rehabilitation. Since excess thyroxine leads to onset of TM, the overall goal of treatment is to reduce the overproduction of thyroxine from the thyroid gland and restore normal thyroid homeostasis. This can be accomplished three ways including using medication, radiation, and surgery.The first choice involves using medications to alleviate the symptoms and reverse the damage by blocking the production of thyroxine from the thyroid gland. Beta-blockers are used to alleviate the symptoms associated with TM. But beta-blockers do not reduce the damage done by excess thyroxine. Medications such as propylthiouracil and methimazole are administered to block the release of thyroxine from the thyroid and to block the damage thyroxine inflicts on muscle fiber tissue.One treatment option is the use of radioactive iodine which directly destroys the overactive thyroid gland. The thyroid gland naturally uses iodine to produce thyroxine and other hormones. It cannot distinguish between normal iodine and the radioactive version. Administering the radioactive isotope causes the thyroid to take in the lethal iodine and quickly radiation destroys it. Typically overproduction of thyroxine using radio-iodine is blocked with one dose. The drawback to this treatment is the thyroid gland is completely destroyed and patients often develop hypothyroidism. Some do so only a few months after treatment while others may not be affected for 20–30 years. Hypothyroidism patients must begin a lifelong regimen of thyroid replacement hormones. While the onset of hypothyroidism is most common with radio-iodine treatment, the condition has been observed in patients treated with medication series and surgery.The last option for TM treatment includes surgical removal of portions of the thyroid which can also be performed to restore thyroid homeostasis. This treatment option usually is done when overproduction of TM is caused by multinodular goiters. Since these goiters enlarge the thyroid and can cause the patient to become physically disfigured surgical treatment can alleviate both the aesthetic and physiological effects simultaneously.
Prognosis
TM, with proper diagnosis and effective treatment, can be beaten. Patients who are diagnosed have a normal life expectancy and can ultimately lead healthy lives if proper treatment is administered. Typically, once the over-production of thyroxine is corrected and thyroid function adequately reaches a level of homeostasis, patients begin to regain muscle strength in two to four months. Depending on the severity of the TM progression symptoms may take up to a year to completely reverse the damage done by TM. Untreated TM can eventually cause severe respiratory distress or arrest possible leading to death, yet this is very rarely seen.
Epidemiology
The onset of TM requires toxic levels of the thyroxine hormone due to overproduction by the thyroid gland. Documented cases have only been diagnosed in conjunction with patients with hyperthyroidism. While hyperthyroidism is more common in women, the development of TM was more common among men with hyperthyroidism. Case studies of patients with diagnosed hyperthyroidism showed that only about half of them complained of symptoms characteristic of TM. Further examination as described above indicated that about 75% of the studied patients showed signs of muscle fiber degeneration. This indicates that either at the time of study some patients were in early stages of TM or the symptoms were insignificant patients.
References
== External links == |
First arch syndrome | First arch syndromes are congenital defects caused by a failure of neural crest cells to migrate into the first pharyngeal arch. They can produce facial anomalies. Examples of first arch syndromes include Treacher Collins syndrome and Pierre Robin syndrome.
== References == |
Jamaican vomiting sickness | Jamaican vomiting sickness, also known as toxic hypoglycemic syndrome (THS), acute ackee fruit intoxication, or ackee poisoning, is an acute illness caused by the toxins hypoglycin A and hypoglycin B, which are present in fruit of the ackee tree. While in the fully ripened arils, hypoglycin A is at levels of less than 0.1 ppm, in unripe arils it can be over 1000 ppm and can cause vomiting and even death. Some countries in the Caribbean and Western Africa experience frequent cases.
Presentation
Abdominal discomfort begins two to six hours after eating unripe ackee fruit, followed by sudden onset vomiting. In severe cases, profound dehydration, seizures, coma, and death may ensue. Children and those who are malnourished are more susceptible to the disease.
Pathophysiology
When ingested, hypoglycin A is metabolized to produce methylenecyclopropylacetic acid (MCPA). MCPA acts to inhibit the beta-oxidation of fatty acids in two ways. First, it interferes with the transport of long-chain fatty acids into the mitochondria. Also, it inhibits acyl-CoA dehydrogenases, so that only unsaturated fatty acids can be fully oxidized. Fatty acids accumulate in the liver in a microvesicular pattern that can be seen on biopsy. In the absence of fatty acid metabolism, the body becomes dependent on glucose and glycogen for energy. Octreotide can be used to reduce the secretion of insulin by the pancreas, thereby preventing severe hypoglycemia.Inhibition of beta-oxidation of fatty acids, however, also depletes a necessary cofactor for gluconeogenesis. Once the liver glycogen stores are depleted, the body cannot synthesize glucose, and severe hypoglycemia results.Initial symptoms appear after about four hours, and deaths have been reported from 12 to 48 hours following consumption. Supportive care involves carefully metered IV glucose infusion and fluid/eletrolyte replacement; Mortality was 80% before glucose infusion was introduced in 1954. A similar outbreak of lethal hypoglycemic encephalopathy has been linked to the consumption of lychee fruit in Muzaffarpur, India. Urinalysis of children affected by the disease has shown all affected have elevated levels of hypoglycin suggesting the same underlying pathophysiology as Jamaican vomiting sickness.
Diagnosis
In popular culture
The disease appears in the ER episode "Great Expectations", where the symptoms are recognised by Dr Mallucci who, it is later revealed, attended medical school in Grenada.
== References == |
Bertolottis syndrome | Bertolottis syndrome is a commonly missed cause of back pain which occurs due to lumbosacral transitional vertebrae (LSTV). It is a congenital condition but is not usually symptomatic until ones later twenties or early thirties. However, there are a few cases of Bertolottis that become symptomatic at a much earlier age.
It is named for Mario Bertolotti, an Italian physician who first described it in 1917.
Presentation
A chronic, persistent low back pain along with buttock pain is the most important presentation. Radicular pain is observed.
Pathophysiology
Bertolottis syndrome is characterized by sacralization of the lowest lumbar vertebral body and lumbarization of the uppermost sacral segment. It involves a total or partial unilateral or bilateral fusion of the transverse process of the lowest lumbar vertebra to the sacrum, leading to the formation of a transitional 5th lumbar vertebra. Of importance is that this syndrome will result in a pain generating 4th lumbar disc resulting in a "sciatic" type of a pain correlating to the 5th lumbar nerve root. Usually the transitional vertebra will have a "spatulated" transverse process on one side resulting in articulation or partial articulation with the sacrum or at time the ilium and in some cases with both. This results in limited / altered motion at the lumbo-sacral articulation. This loss of motion will then be compensated for at segments superior to the transitional vertebra resulting in accelerated degeneration and strain through the L4 disc level which can become symptomatic and inflame the adjacent L5 nerve root resulting in "sciatic" or radicular pain patterns. Scoliosis is frequently found to be associated.
Diagnosis
The diagnosis depends on appropriate patient history backed by imaging studies like X ray and MRI. Lumbosacral spine radiographs help in the identification of the skeletal abnormality. MRI helps in confirmation.
Treatment
Non surgical treatments include steroid injections in the lower back or radiofrequency sensory ablation. Physical therapy interventions are also helpful in early cases and are focused around mobilization, neural stretching, and core strengthening exercises. Surgical intervention is usually a last resort if all conservative methods fail. It can be treated surgically with posterolateral fusion or resection of the transitional articulation.
References
Further reading
Paraskevas, Georgios; Tzaveas, Alexandros; Koutras, Georgios; Natsis, Konstantinos (2009). "Lumbosacral transitional vertebra causing Bertolottis syndrome: A case report and review of the literature". Cases Journal. 2: 8320. doi:10.4076/1757-1626-2-8320. PMC 2740102. PMID 19830065.
== External links == |
Subsets and Splits