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Abdominal pregnancy | An abdominal pregnancy is a rare type of ectopic pregnancy where the embryo or fetus is growing and developing outside the womb in the abdomen, but not in the Fallopian tube (usual location), ovary or broad ligament.Because tubal, ovarian and broad ligament pregnancies are as difficult to diagnose and treat as abdominal pregnancies, their exclusion from the most common definition of abdominal pregnancy has been debated.Others—in the minority—are of the view that abdominal pregnancy should be defined by a placenta implanted into the peritoneum.
Signs and symptoms
Symptoms may include abdominal pain or vaginal bleeding during pregnancy. As this is nonspecific in areas where ultrasound is not available the diagnosis was often only discovered during surgery to investigate the abnormal symptoms. They are typically diagnosed later in the developing world than the developed. In about half of cases from a center in the developing world the diagnosis was initially missed.It is a dangerous condition as there can be bleeding into the abdomen that results in low blood pressure and can be fatal. Other causes of death in women with an abdominal pregnancy include anemia, pulmonary embolus, coagulopathy, and infection.
Risk factors
Risk factors are similar to tubal pregnancy with sexually transmitted disease playing a major role; however about half of those with ectopic pregnancy have no known risk factors (which include damage to the Fallopian tubes from previous surgery or from previous ectopic pregnancy, and tobacco smoking).
Mechanism
Implantation sites can be anywhere in the abdomen but can include the peritoneum outside of the uterus, the rectouterine pouch (culdesac of Douglas), omentum, bowel and its mesentery, mesosalpinx, and the peritoneum of the pelvic wall and the abdominal wall. The growing placenta may be attached to several organs including tube and ovary. Rare other sites have been the liver and spleen, giving rise to a hepatic pregnancy or splenic pregnancy, respectively. Even an early diaphragmatic pregnancy has been described in a patient where an embryo began growing on the underside of the diaphragm.
Primary versus secondary implantation
A primary abdominal pregnancy refers to a pregnancy that first implanted directly in the peritoneum, save for the tubes and ovaries; such pregnancies are very rare, only 24 cases having been reported by 2007. Typically an abdominal pregnancy is a secondary implantation which means that it originated from a tubal (less common an ovarian) pregnancy and re-implanted. Other mechanisms for secondary abdominal pregnancy include uterine rupture, rupture of a uterine rudimentary horn and fimbrial abortion.
Diagnosis
Suspicion of an abdominal pregnancy is raised when the fetal anatomy can be easily felt, or the lie is abnormal, the cervix is displaced, or there is failed induction of labor. X-rays can be used to aid diagnosis. Sonography can demonstrate that the pregnancy is outside an empty uterus, there is reduced to no amniotic fluid between the placenta and the fetus, no uterine wall surrounding the fetus, fetal parts are close to the abdominal wall, the fetus has an abnormal lie, the placenta looks abnormal and there is free fluid in the abdomen. MRI has also been used with success to diagnose abdominal pregnancy and plan for surgery. Elevated alpha-fetoprotein levels are another clue of the presence of an abdominal pregnancy.
Ultrasound
Most cases can be diagnosed by ultrasound. The diagnosis however may be missed with ultrasound depending on the operators skill.
Criteria
To diagnose the rare primary abdominal pregnancy, Studdifords criteria need to be fulfilled: tubes and ovaries should be normal, there is no abnormal connection (fistula) between the uterus and the abdominal cavity, and the pregnancy is related solely to the peritoneal surface without signs that there was a tubal pregnancy first. Studdifords criteria were refined in 1968 by Friedrich and Rankin to include microscopic findings.
Differential diagnosis
Depending on gestational age the differential diagnoses for abdominal pregnancy include miscarriage, intrauterine fetal death, placental abruption, an acute abdomen with an intrauterine pregnancy and a fibroid uterus with an intrauterine pregnancy .
Treatment
Ideally the management of abdominal pregnancy should be done by a team that has medical personnel from multiple specialties. Potential treatments consist of surgery with termination of the pregnancy (removal of the fetus) via laparoscopy or laparotomy, use of methotrexate, embolization, and combinations of these. Sapuri and Klufio indicate that conservative treatment is also possible if the following criteria are met: 1. there are no major congenital malformations; 2. the fetus is alive; 3. there is continuous hospitalization in a well-equipped and well-staffed maternity unit which has immediate blood transfusion facilities; 4. there is careful monitoring of maternal and fetal well-being; and 5. placental implantation is in the lower abdomen away from the liver and spleen. The choice is largely dictated by the clinical situation. Generally, treatment is indicated when the diagnosis is made; however, the situation of the advanced abdominal pregnancy is more complicated.
Advanced abdominal pregnancy
Advanced abdominal pregnancy refers to situations where the pregnancy continues past 20 weeks of gestation (versus early abdominal pregnancy < 20 weeks). In those situations, live births have been reported in the lay press where the babies are not uncommonly referred to as Miracle babies. A patient may carry a dead fetus but will not go into labor. Over time, the fetus calcifies and becomes a lithopedion.It is generally recommended to perform a laparotomy when the diagnosis of an abdominal pregnancy is made. However, if the baby is alive and medical support systems are in place, careful watching could be considered to bring the baby to viability. Women with an abdominal pregnancy will not go into labor. Delivery in a case of an advanced abdominal pregnancy will have to be via laparotomy. The survival of the baby is reduced and high perinatal mortality rates between 40% and 95% have been reported.Babies of abdominal pregnancies are prone to birth defects due to compression in the absence of the uterine wall and the often reduced amount of amniotic fluid surrounding the unborn baby. The rate of malformations and deformations is estimated to be about 21%; typical deformations are facial and cranial asymmetries and joint abnormalities and the most common malformations are limb defects and central nervous malformations.Once the baby has been delivered placental management becomes an issue. In normal deliveries the contraction of uterus provides a powerful mechanism to control blood loss, however, in an abdominal pregnancy the placenta is located over tissue that cannot contract and attempts of its removal may lead to life-threatening blood loss. Thus blood transfusion is frequent in the management of patients with this kind of pregnancy, with others even using tranexamic acid and recombinant factor VIIa, which both minimize blood loss.Generally, unless the placenta can be easily tied off or removed, it may be preferable to leave it in place and allow for a natural regression. This process may take several months and can be monitored by clinical examination, checking human chorionic gonadotropin levels and by ultrasound scanning (in particular using doppler ultrasonography. Use of methotrexate to accelerate placental regression is controversial as the large amount of necrotic tissue is a potential site for infection, mifepristone has also be used to promote placental regression. Placental vessels have also been blocked by angiographic embolization. Complications of leaving the placenta can include residual bleeding, infection, bowel obstruction, pre-eclampsia (which may all necessitate further surgery) and failure to breast feed due to placental hormones.Outcome with abdominal pregnancy can be good for the baby and mother, Lampe described an abdominal pregnancy baby and her mother who were well more than 22 years after surgery.
Epidemiology
About 1.4% of ectopic pregnancies are abdominal, or about 1 out of every 8,000 pregnancies. A report from Nigeria places the frequency in that country at 34 per 100,000 deliveries and a report from Zimbabwe, 11 per 100,000 deliveries. The maternal mortality rate is estimated to be about 5 per 1,000 cases, about seven times the rate for ectopics in general, and about 90 times the rate for a "normal" delivery (1987 US data).
History
Al-Zahrawi (936–1013) is credited with first recognizing abdominal pregnancy which was apparently unknown to Greek and Roman physicians and was not mentioned in the writings of Hippocrates; Jacopo Berengario da Carpi (1460–1530) the Italian physician is credited with the first detailed anatomical description of abdominal pregnancy.
Natural experiment
Because pregnancy is outside the uterus, abdominal pregnancy serves as a model of human male pregnancy or for females who lack a uterus, although such pregnancy would be dangerous. Abdominal pregnancy has served to further clarify the disease pre-eclampsia which was previously thought (1980s) to require a uterus for it to occur, however pre-eclampsias occurrence in abdominal pregnancy (with the conceptus outside the uterus) helped throw light on pre-eclampsias etiology. Cases of combined simultaneous abdominal and intrauterine pregnancy have been reported.
References
== External links == |
Catastrophic antiphospholipid syndrome | Catastrophic antiphospholipid syndrome (CAPS), also known as Ashersons syndrome, is a rare autoimmune disease in which widespread, intravascular clotting causes multi-organ failure. The syndrome is caused by antiphospholipid antibodies that target a group of proteins in the body that are associated with phospholipids. These antibodies activate endothelial cells, platelets, and immune cells, ultimately causing a large inflammatory immune response and widespread clotting. CAPS was first described by Ronald Asherson in 1992. The syndrome exhibits thrombotic microangiopathy, multiple organ thromboses, and in some cases tissue necrosis and is considered an extreme or catastrophic variant of the antiphospholipid syndrome.
CAPS has a mortality rate of about 50%. With the establishment of a CAPS-Registry more has been learned about this syndrome, but its cause remains unknown. Infection, trauma, medication, and/or surgery can be identified in about half the cases as a "trigger". It is thought that cytokines are activated leading to a cytokine storm with the potentially fatal consequences of organ failure. A low platelet count is a common finding.
Presentation
Clinically, the syndrome affects at least three organs and may affect many organ systems. The syndrome usually occurs with small vessel thromboses affecting organ systems such as the gastrointestinal tract and manifestations of the acute respiratory distress syndrome (ARDS), a type of systemic inflammatory response syndrome (SIRS). Peripheral thrombosis may be encountered affecting veins and arteries. Intra-abdominal thrombosis may lead to pain. A thrombotic storm may also occur due to the following precipitating events: alterations in coagulation and fibrinolysis, which induce high mortality rates, and infections amongst pediatric patients where IgM and IgG anti-β2-GPI antibodies induce an endothelial signal, leading to a procoagulant state. It is also hypothesized that thrombotic storms occur due to prothrombotic genetic risk factors, which trigger a sped-up form of thrombosis after its first occurrence, rather than being caused solely by environmental factors. Cardiovascular, nervous, kidney, and lung system complications are common. More specifically with the heart, Ashersons syndrome can lead to complications such as mitral valve regurgitation (MVR) in which the mitral valve does not shut properly allowing backflow of blood into the heart as well as angina (chest pain) and myocardial infarction (heart attack). Furthermore, complications in the kidneys may occur, including low urine production and high blood pressure, while complications with the lungs can result in rapid breathing (hyperventilation) and low oxygen levels (hypoxemia). The affected individual may exhibit skin purpura and necrosis. Cerebral manifestations may lead to encephalopathy and seizures. Myocardial infarctions may occur. Strokes may occur due to the arterial clotting involvement. Death may result from multiple organ failure.
Furthermore, the syndrome has been shown to manifest multi-organ failures and miscarriages in the context of pregnancies. 54% of pregnant mothers with the disease experienced fetal loss, and around 50% of pregnant mothers died from complications associated with the syndrome.
Diagnosis
Two specific types of blood tests are used to aid in the diagnosis of Ashersons Syndrome. A coagulation blood test is used to measure and determine the bloods ability to clot and how fast it takes to clot, indicating the presence of lupus anticoagulant in the blood. An Enzyme-Linked ImmunoSorbent Assay (ELISA) test is done to detect anticardiolipin antibodies presence in the blood. Individuals with CAPS often exhibit a positive test to antilipid antibodies, typically IgG. Patients with high aPL(positive antiphospholipid antibodies) must have microthrombosis in multiple organs to definitively be diagnosed with CAPS— a high antilipid antibody count is not sufficient enough for diagnosis. To be diagnosed with CAPS, a patient must have three or more new organ thromboses developing within less than a week, and a biopsy must be later performed testing for microthrombosis in order to accurately diagnose the patient with ‘definite CAPS’. If the patient has two or less new organ thromboses within a week but a biopsy still indicates the presence of microthrombosis, the patient is not considered to have CAPS. Positive test are often repeated due to the fact that antilipid antibodies can be present in the body for short stints due to infection or drug use. Along with that, individuals may or may not have a history of lupus or another connective tissue disease. Association with another disease such as lupus is called a secondary APS unless it includes the defining criteria for CAPS.
Treatment
Treatments may involve the following steps:
Prevention includes the use of antibiotics for infection and parenteral anticoagulation for susceptible patients.
Specific therapy includes the use of intravenous heparin and corticosteroids, and possibly plasma exchanges, intravenous immunoglobulin.
As a disease associated with high morbidity and mortality, CAPS requires an aggressive multidisciplinary treatment strategy. The following treatments have been used in various combinations: anticoagulation, glucocorticoids, plasma exchange, cyclophosphamide, intravenous immunoglobulins, and anti-platelet agents.
Additional steps may have to be taken to manage circulatory problems, kidney failure, and respiratory distress.
Recent investigational treatment therapies include high doses of Rituxan (Rituximab) and eculizumab, which are both humanized monoclonal antibodies that target B cell malignancies and prevent C5 complement cleavage, respectively.
References
== External links == |
Foreign body | A foreign body (FB) is any object originating outside the body of an organism. In machinery, it can mean any unwanted intruding object.
Most references to foreign bodies involve propulsion through natural orifices into hollow organs.
Foreign bodies can be inert or irritating. If they irritate they will cause inflammation and scarring. They can bring infection into the body or acquire infectious agents and protect them from the bodys immune defenses. They can obstruct passageways either by their size or by the scarring they cause. Some can be toxic or generate toxic chemicals from reactions with chemicals produced by the body, as is the case with many examples of ingested metal objects.
With sufficient force (as in firing of bullets), a foreign body can become lodged into nearly any tissue.
Gastrointestinal tract
One of the most common locations for a foreign body is the alimentary tract.
It is possible for foreign bodies to enter the tract from the mouth or rectum.
Both children and adults experience problems caused by foreign objects becoming lodged within their bodies. Young children, in particular, are naturally curious and may intentionally put shiny objects, such as coins or button batteries, into their mouths. They also like to insert objects into their ear canals and nostrils. The severity of a foreign body can range from unconcerning to a life-threatening emergency. For example, a coin causes local pressure on the tissue but generally is not a medical emergency to remove. A button battery, which can be a very similar size to a coin, generates hydroxide ions at the anode and causes a chemical burn in two hours. An ingested button battery that is stuck in the esophagus is a medical emergency. In 2009, Avolio Luigi and Martucciello Giuseppe showed that although ingested nonmagnetic foreign bodies are likely to be passed spontaneously without consequence, ingested magnets (magnetic toys) may attract each other through childrens intestinal walls and cause severe damage, such as pressure necrosis, perforation, intestinal fistulas, volvulus, and obstruction.
Pancreas
Sometimes foreign bodies can pass spontaneously through the gastrointestinal tract and perforate or penetrate the wall of stomach and duodenum and migrate into pancreas. The laparoscopic approach before open surgery could be performed safely for the removal of foreign bodies embedded in the pancreas.
Airways
It is possible for a foreign body to enter the airways and cause choking. A choking case can require the fast usage of basic anti-choking techniques to clear the airway.
In one study, peanuts were the most common obstruction. In addition to peanuts, hot dogs, grapes, and latex balloons are also serious choking hazards in children that can result in death. A latex balloon will conform to the shape of the trachea, blocking the airway and making it difficult to expel with basic anti-choking techniques.
Eyes
Airborne particles can lodge in the eyes of people at any age. These foreign bodies often result in allergies which are either temporary or even turn into a chronic allergy. This is especially evident in the case of dust particles.
It is also possible for larger objects to lodge in the eye. The most common cause of intraocular foreign bodies is hammering. Corneal foreign bodies are often encountered due to occupational exposure and can be prevented by instituting safety eye-wear at work place.Foreign bodies in the eye affect about 2 per 1,000 people per year.
Skin
Splinters are common foreign bodies in skin. Staphylococcus aureus infection often causes boils to form around them.Tetanus prophylaxis may be appropriate.
Peritoneum
Foreign bodies in the peritoneum can include retained surgical instruments after abdominal surgery. Rarely, an intrauterine device can perforate the uterine wall and enter the peritoneum.
Foreign bodies in the peritoneum eventually become contained in a foreign body granuloma. In the extremely rare case of retained ectopic pregnancy, this forms a lithopedion.
Other
Foreign bodies can also become lodged in other locations:
anus or rectum
blood vessels or thoracic system
ears
nose
teeth and periodontium
urethra
vagina
Other animals
Foreign bodies are common in animals, especially young dogs and cats. Dogs will readily eat toys, bones, and any object that either has food on it or retains the odor of food. Unlike humans, dogs are susceptible to gastrointestinal obstruction due to their ability to swallow relatively large objects and pass them through the esophagus. Foreign bodies most commonly become lodged in the stomach because of the inability to pass through the pyloric sphincter into the jejunum. Symptoms of gastrointestinal obstruction include vomiting, abdominal pain often characterized by aggression, acute infection, and depression due to dehydration. Treatment of a foreign body is determined by its severity. The amount of time a foreign body is present, location of the object, degree of obstruction, previous health status of the animal and the type of material from which the foreign body is made can all determine the severity of the condition. Peritonitis results if either the stomach or intestine has ruptured. Foreign bodies in the stomach can sometimes be removed by endoscopic retrieval or if necessary by gastrotomy. Very often, a simple instrument to remove foreign bodies without operation endoscopy is the Hartmann Alligator Forceps. The instrument is manufactured from 8 cm to 1 m length. Foreign bodies in the jejunum are removed by enterotomy.
Certain foreign bodies in animals are especially problematic. Bones or objects with sharp edges may cause tearing of the wall of the esophagus, stomach, or small intestine and lead to peritonitis. Pennies swallowed in large numbers may cause zinc poisoning, which in dogs leads to severe gastroenteritis and hemolytic anemia. Linear foreign bodies can especially be dangerous. A linear foreign body is usually a length of string or yarn with a larger object or clump of material at either end. One end is usually lodged in the stomach or proximal small intestine and the other end continues to travel through the intestines. The material becomes tightly stretched and the intestines may "accordion up" on themselves or be lacerated by it. This is especially common in cats who may enjoy playing with a ball of string or yarn. Sometimes the linear foreign body anchors in the mouth by catching under the tongue. Pantyhose is a common linear foreign body in dogs.
References
External links
Ingested Magnets. The New England Journal of Medicine.
The Susy Safe Project. A Surveillance System on Suffocation Injuries due to Foreign Bodies in European Children. |
Leukodystrophy | Leukodystrophies are a group of usually inherited disorders characterized by degeneration of the white matter in the brain. The word leukodystrophy comes from the Greek roots leuko, "white", dys, "abnormal" and troph, "growth". The leukodystrophies are caused by imperfect growth or development of the myelin sheath, the fatty insulating covering around nerve fibers. Leukodystrophies may be classified as hypomyelinating or demyelinating diseases, depending on whether the damage is present before birth or occurs after. Other demyelinating diseases are usually not congenital and have a toxic or autoimmune cause.When damage occurs to white matter, immune responses can lead to inflammation in the central nervous system (CNS), along with loss of myelin. The degeneration of white matter can be seen in an MRI scan and used to diagnose leukodystrophy. Leukodystrophy is characterized by specific symptoms including decreased motor function, muscle rigidity, and eventual degeneration of sight and hearing. While the disease is fatal, the age of onset is a key factor, as infants have a typical life expectancy of 2–8 years, while adults typically live more than a decade after onset. Treatment options are limited, although hematopoietic stem cell transplantations using bone marrow or cord blood seem to help in certain types while further research is being done.
The combined incidence of the leukodystrophies is estimated at 1 in 7,600. The majority of types involve the inheritance of an X-linked recessive, or X-linked dominant trait, while others, although involving a defective gene, are the result of spontaneous mutation rather than genetic inheritance.
Symptoms and signs
Some specific symptoms vary from one type of leukodystrophy to the next, but the vast majority of symptoms are shared as the causes for the disease generally have the same effects. Symptoms are dependent on the age of onset, which is predominantly in infancy and early childhood, although the exact time of onset may be difficult to determine. Hyperirritability and hypersensitivity to the environment are common, as well as some tell-tale physical signs including muscle rigidity and a backwards-bent head. Botox therapy is often used to treat patients with spasticity. Juvenile and adult onsets display similar symptoms including a decrease or loss in hearing and vision. While children do experience optic and auditory degeneration, the course of the disease is usually too rapid, causing death relatively quickly, whereas adults may live with these conditions for many years. In children, spastic activity often precedes progressive ataxia and rapid cognitive deterioration which has been described as mental retardation. Epilepsy is commonplace for patients of all ages. More progressed patients show weakness in deglutition, leading to spastic coughing fits due to inhaled saliva. Classic symptomatic progression of juvenile X-linked adrenoleukodystrophy is shown in the 1992 film, Lorenzos Oil.Course and timetable are dependent on the age of onset with infants showing a lifespan of 2–8 years, juveniles 2–10 years and adults typically 10+ years. Adults typically see an extended period of stability followed by a decline to a vegetative state and death. While treatments do exist, most are in the experimental phase and can only promise a halt in the progression of symptoms, although some gene therapies have shown some symptomatic improvement. The debilitating course of the disease has led to numerous philosophical and ethical arguments over experimental clinical trials, patients rights and physician-assisted suicide.
Causes
While the more specific underlying causes of leukodystrophy are dependent upon the type, there are, however, common pathophysiological patterns that can be seen amongst all types. First and foremost, leukodystrophy is a neurodegenerative disease that is always the result of both impairment and maintenance of myelin sheaths surrounding neuronal axons in the central nervous system as the result of a genetic mutation. Myelin is a fatty white substance that acts as an electrical insulator and coats axons in order to speed up impulses (i.e., action potentials) traveling down the axon. Thus, the natural result of a loss of this substance is decreased efficiency in impulse propagation. As myelin is produced by oligodendrocytes (a type of glial cell) in the central nervous system, an easy place to look for the cause is a mutation or malfunctioning of these cells and in other glial cells.
Genetic influence
Leukodystrophy is most often an inherited disease that is usually the result of an autosomal recessive inheritance pattern, although dominant inheritance patterns are not unheard of, as in the case of adult-onset leukodystrophy. This means that the affected allele is carried on an autosomal, or non-sex, chromosome and is masked by the dominant, unaffected phenotype. In other words, for an individual to inherit the leukodystrophy phenotype, he or she must carry two of the recessive, mutant alleles. Krabbe disease and metachromatic leukodystrophy (MLD) are two of such type. MLD is found on human chromosome 22 at position q13.31. Another type of inherited leukodystrophy is X-linked adrenoleukodystrophy (X-ALD). As its name implies, this type of leukodystrophy is the result of a mutation found on the X-chromosome. It is also carried in a recessive pattern. The X chromosome is a sex chromosome, and since women have two "chances" of acquiring a normal X chromosome (one maternal, one paternal), and males only one (one maternal), this disease is more likely to be seen in men than in women. The mutation resulting in adult-onset leukodystrophy is mapped at 5q23.
Pathophysiology
Although there are nearly forty different types of leukodystrophies, many are lacking in formal and comprehensive research. Most of the research so far has been done on five types: (1) metachromatic leukodystrophy (MLD), (2) Krabbe disease, (3) X-Linked adrenoleukodystrophy (ALD), (4) Canavan disease, and (5) Alexander disease. Each type of leukodystrophy has a unique pathophysiology, but all five of these in some way affect a subset of glial cells, therefore disrupting myelin production and maintenance, and usually involve a mutation involving genes that code for enzymes necessary for the catabolism of very long chain fatty acids (VLCFAs) that are toxic to the myelin-producing cells of the central nervous system.
Metachromatic leukodystrophy
Metachromatic leukodystrophy is the result of genetic defects in the enzymes associated with the cellular compartment the lysosome. MLD is one of two leukodystophies that are also a lysosomal storage disorder. MLD is inherited in an autosomal recessive way and is the result of mutations in three different ARSA alleles that encode the enzyme arylsulfatase A (ASA or sometimes ARSA), also called sulfatide sulfatase. ASA is responsible for the breakdown of sulfatides, sphingolipids present in neuronal membranes as well as in myelin. When there is a mutation in the gene that encodes ASA, the result is it decreases production, which subsequently leads to diminished degradation of sulfatides, thus causing them to accumulate. This accumulation of sulfatides is poisonous to oligodendrocytes, the myelin-producing cells of the CNS, effectively leading to a disturbance in myelin structure followed by demyelination. The pattern of inheritance of the three different alleles affects what type of MLD a person develops. Two null alleles are responsible for the infantile version, and do not allow for any production of ASA. A heterozygous individual (one null allele, one non-null allele) develops the juvenile form and sees some production of ASA, while an individual with two non-null alleles (but still mutated) develops the adult form.
Krabbe disease
Like MLD, Krabbe disease is another type of leukodystrophy with autosomal recessive inheritance that is the result of a lysosomal storage disorder. It is due to a deletion in exon 16 of the GALC gene that causes a frameshift mutation leading to a premature stop codon. The GALC gene, found on chromosome 14 at position 31 (14q31), codes for the enzyme beta-galactocerebrosidase (GALC). GALC is a lysosomal enzyme responsible for the catabolism of galactolipids, especially psychosine, that are heavily distributed throughout the brain. A deficiency in GALC thus causes a buildup of these fatty acids known as globoid macrophages that destroy oligodendrocytes, thereby inhibiting myelin formation.Because of the presence of globoid cells clustered near white matter, Krabbe disease often goes by the name globoid cell leukodystrophy. Furthermore, new research has shown that Krabbe disease and globoid cell leukodystrophy may be distinct disease entities due to the secretion of inflammatory mediators by natural killer cells in some cases. This research has shown that Natural Killer cells have receptors (TDAG8) for certain glycosphingolipids that build up in an individual with leukodystrophy, again due to insufficient GALC levels, and when bound, target the Natural Killer cells for destruction thereby preventing their cytotoxic effects. These sphingolipids have been identified as galactosyl sphingosine and glycosyl sphingosine and are not present in unaffected individuals.
Canavan disease
Canavan disease is a lesser-studied type of leukodystrophy that, like MLD and Krabbe disease, is also passed on in an autosomal recessive inheritance pattern. It is due to a mutation in the ASPA gene that encodes aspartoacylase, an enzyme needed to metabolize N-acetyl-L-aspartate (NAA). The mutation causes a deficiency of aspartoacyclase. NAA is involved in the formation of lipids, and if it is not broken down by aspartoacylase, excess levels of it build up causing demyelination.
X-linked adrenoleukodystrophy
In X-linked adrenoleukodystrophy (X-ALD), a mutation occurs in the peroxisomal ATP-binding cassette (ABC transporter). This leads to cerebral inflammatory demyelination caused by the myelin destabilization that occurs in these patients. The inflammatory demyelination begins in the corpus callosum and it slowly progresses outwards towards both hemispheres. In X-ALD patients, abnormally high levels of very long chain fatty acid (VLCFA) accumulate in various body tissues and fluids. This increased concentration then incorporates into various complex lipids where they are not normally found. This has been found to be directly involved in the cerebral inflammation. The accumulated and embedded VLCFA in the complex lipids could lead to the destabilization of myelin sheath and eventually to demyelination.
Alexander disease
Alexander disease is unique from the leukodystrophies mentioned above in that it is the result of spontaneous mutation, that is it is not inherited. This means that the mutation found in the affected individual is not found in either of his or her parents. It is due to the accumulation of Glial fibrillary acidic protein (GFAP) as the result of a mutation in the GFAP gene; which, rather than being found in association with lysosomes or peroxisomes, is an intermediate filament linked to the nuclear envelope. Intermediate filaments are proteins responsible for the makeup of the cellular cytoskeleton, and thus this type of mutation is involved in malfunctioning structural development of the cells. In fact, cytoskeletal and transporter molecule defects have been observed in the astrocytes (type of glial cell) of affected individuals. These astrocytes have an unhealthily large amount of GFAP that affects astrocyte formation and function.
Diagnosis
The degeneration of white matter, which shows the degeneration of myelin, can be seen in a basic MRI and used to diagnose leukodystrophies of all types. T-1 and T-2 weighted FLAIR images are the most useful. FLAIR stands for fluid-attenuated inversion recovery. Electrophysiological and other kinds of laboratory testing can also be done. In particular, nerve conduction velocity is looked at to distinguish between leukodystrophy and other demyelinating diseases, as well as to distinguish between individual leukodystrophies. For example, individuals with X-ALD have normal conduction velocities, while those with Krabbe disease or metachromatic leukodystrophy have abnormalities in their conduction velocities. Next generation multigene sequencing panels for undifferentiated leukodystrophy can now be offered for rapid molecular diagnosis after appropriate genetic counselling.
Types
Specific types of leukodystrophies include the following with their respective ICD-10 codes when available:
(E71.3) Adrenomyeloneuropathy
(E75.2) Alexander disease
(E75.5) Cerebrotendineous xanthomatosis
Hereditary CNS demyelinating disease
(E75.2) Krabbe disease
(E75.2) Metachromatic leukodystrophy
(E75.2) Pelizaeus–Merzbacher disease
(E75.2) Canavan disease
(E75.2) Hypomyelinating leukodystrophy type 7 (4H syndrome)
(G93.49) Leukoencephalopathy with vanishing white matter
(E71.3) Adrenoleukodystrophy
(G60.1) Refsum disease
Treatment
With many different types of leukodystrophies and causes, treatment therapies vary for each type. Many studies and clinical trials are in progress to find treatment and therapies for each of the different leukodystrophies. Stem cell transplants and gene therapy appear to be the most promising in treating all leukodystrophies providing it is done as early as possible.
For hypomyelinating leukodystrophies, therapeutic research into cell-based therapies appears promising. Oligodendrocyte precursor cells and neural stem cells have been transplanted successfully and have shown to be healthy a year later. Fractional anisotropy and radial diffusivity maps showed possible myelination in the region of the transplant. Induced pluripotent stem cells, oligodendrocyte precursor cells, gene correction, and transplantation to promote the maturation, survival, and myelination of oligodendrocytes seem to be the primary routes for possible treatments.For three types of leukodystrophies (X-linked adrenoleukodystrophy (X-ALD), metachromatic leukodystrophy (MLD) and Krabbe Disease (globoid cell leukodystrophy - GLD), gene therapy using autologous hematopoietic stem cells to transfer the disease gene with lentiviral vectors have shown to be successful and are currently being used in clinical trials for X-ALD and MLD. The progression of X-ALD has shown to be disrupted with hematopoietic stem cell gene therapy but the exact reason why demyelination stops and the amount of stem cells needed is unclear. While there is an accumulation of very long chain fatty acids in the brain, it does not seem to be the reason behind the disease as gene therapy does not correct it.For those leukodystrophies that result from a deficiency of lysozyme enzymes, such as Krabbe disease, enzyme replacement therapy seems hopeful. However, enzyme delivery proves difficult, because the blood-brain barrier severely limits what can pass into the central nervous system. Current gene therapy research for metachromatic leukodystrophy has been reviewed with an emphasis on ex vivo transplantation of genetically modified hematopoietic stem cells.
Epidemiology
Currently, no research has shown a higher prevalence of most leukodystrophy types in any one place around the world. There is, however, a higher prevalence of the Canavan disease in the Jewish population. 1 in 40 individuals of Ashkenazi Jewish descent are carriers of Canavan disease. This estimates to roughly 2.5%. Additionally, due to an autosomal recessive inheritance patterns, there is no significant difference found between affected males and affected females for most types of leukodystrophy including, but not limited to, metachromatic leukodystrophy, Krabbe disease, Canavan disease, and Alexander disease. The one exception to this is any type of leukodystrophy carried on a sex chromosome, such as X-linked adrenoleukodystrophy, which is carried on the X-chromosome. Because of the inheritance pattern of X-linked diseases, males are more often affected by this type of leukodystrophy, although female carriers are often symptomatic, though not as severely so as males.
Research
The National Institute of Neurological Disorders and Stroke (NINDS, under the U.S. National Institutes of Health) supports research on genetic disorders, including the leukodystrophies. NINDS also supports researchers who are working with the Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) which promotes advances in the diagnosis and treatment of leukodystrophies.The European Leukodystrophy Association also supports research into leukodystrophy. As of 2020, more than 387 research projects have been funded. Each year, ELA invites the international scientific community to submit research projects in the field of genetic leukodystrophies, the cerebral white matter in premature infants, and of myelin repair.
Society
The United Leukodystrophy Foundation (ULF), incorporated in 1982, is a non-profit, voluntary health organization dedicated to funding cutting-edge research and to providing patients and their families with disease information and medical referrals.Cure MLD is a global network of patient advocates and nonprofits dedicated to helping families impacted by metachromatic leukodystrophy (MLD).The MLD Foundation was co-founded by Dean and Teryn Suhr in 2001 after the diagnosis in 1995 of two of their daughters with MLD. MLD Foundation serves families and works with researchers, clinicians, regulators, payors, and policy-makers around the world on MLD, leukodystrophy, lysosomal, and rare disease issues.The Leukodystrophy Alliance works to promote awareness and quality of care for those with leukodystrophy.Jill Kelly and her husband, NFL quarterback Jim Kelly, founded Hunters Hope Foundation to fund research after their son Hunter (1997-2005) was diagnosed with infantile Krabbe leukodystrophy.Matthew and Michael Clark of Hull, UK had the condition. Both died, in 2013 and 2016 respectively. Their story was the subject of the Channel 4 documentary The Curious Case of the Clark Brothers.Augusto and Michaela Odone founded The Myelin Project after their son, Lorenzo was diagnosed with Adrenoleukodystrophy (ALD). The 1992 film, Lorenzos Oil is a true story about a boy with Adrenoleukodystrophy (ALD).
See also
Leukoencephalopathy
References
== External links == |
Rapidly progressive glomerulonephritis | Rapidly progressive glomerulonephritis (RPGN) is a syndrome of the kidney that is characterized by a rapid loss of kidney function, (usually a 50% decline in the glomerular filtration rate (GFR) within 3 months) with glomerular crescent formation seen in at least 50% or 75% of glomeruli seen on kidney biopsies. If left untreated, it rapidly progresses into acute kidney failure and death within months. In 50% of cases, RPGN is associated with an underlying disease such as Goodpasture syndrome, systemic lupus erythematosus or granulomatosis with polyangiitis; the remaining cases are idiopathic. Regardless of the underlying cause, RPGN involves severe injury to the kidneys glomeruli, with many of the glomeruli containing characteristic glomerular crescents (crescent-shaped scars).
Signs and symptoms
Most types of RPGN are characterized by severe and rapid loss of kidney function with marked hematuria; red blood cell casts in the urine; and proteinuria sometimes exceeding three grams in twenty-four hours, a range associated with nephrotic syndrome. Some patients also experience hypertension and edema. Severe disease is characterized by pronounced oliguria or anuria, which portends a poor prognosis.
Pathophysiology
It is thought that antineutrophil cytoplasmic antibodies (ANCA) interact with antigens in the cytoplasm of neutrophils to cause an early degranulation, triggering the release of lytic enzymes at the site of injury and leading to the formation of glomerular crescents that consist primarily of parietal epithelial cells from Bowmans capsule and in some cases podocytes.
Diagnosis
Serum analysis often aids in the diagnosis of a specific underlying disease. The presence of anti-glomerular basement membrane (GBM) antibodies suggests type I RPGN; antinuclear antibodies (ANA) may support a diagnosis of systemic lupus erythematosus and type II RPGN; and type III and idiopathic RPGN are frequently associated with anti-neutrophil cytoplasmic antibodies (ANCA)-positive serum.Impaired kidney function in an individual who has had the condition for fewer than three months is characteristic of RPGN. An ultrasonographic examination of the abdomen should be obtained. Although the presence of sediment in the urine on examination can indicate proliferative glomerulonephritis, many cases of rapidly progressive glomerulonephritis need a renal biopsy to make a diagnosis.
Classification
RPGN can be classified into three types, based upon the immunofluorescence patterns:
Type I
Accounting for approximately 20% of RPGN, type I RPGN, also called anti-GBM glomerulonephritis, is characterized by the presence of autoantibodies directed against type IV collagen (specifically, the noncollagenous region of its α3 chain) in the glomerular basement membrane (GBM). Some cases are associated with antibodies directed against the basement membrane of lung alveoli, producing Goodpasture syndrome. The majority of type I disease, however, features anti-GBM antibodies alone; these cases are considered idiopathic.
Type II
Characterized by deposition of immune complexes in glomerular tissues, type II RPGN accounts for 25% of cases. Any immune complex disease—including systemic lupus erythematosus, acute proliferative glomerulonephritis, Henoch–Schönlein purpura, and IgA nephropathy—that involves the glomerulus may progress to RPGN if severe enough.
Type III
Also known as pauci-immune RPGN, type III RPGN accounts for 55% of RPGN and features neither immune complex deposition nor anti-GBM antibodies. Instead, the glomeruli are damaged in an undefined manner, perhaps through the activation of neutrophils in response to ANCA. Type III RPGN may be isolated to the glomerulus (primary, or idiopathic) or associated with a systemic disease (secondary). In most cases of the latter, the systemic disease is an ANCA-associated vasculitis such as granulomatosis with polyangiitis, microscopic polyangiitis or eosinophilic granulomatosis with polyangiitis.
Treatment
Therapy consists of a combination of rituximab, corticosteroids, and cyclophosphamide, with a substitution of azathioprine for cyclophosphamide after a ninety-day initial period being another option. When remission is achieved, immunosuppressants are still used, usually corticosteroids with azathioprine or rituximab infusions.
Epidemiology
The incidence rate of rapidly progressive glomerulonephritis is approximately 3.9 individuals per million.
References
Further reading
Greenhall, George H. B.; Salama, Alan D. (2015-02-19). "What is new in the management of rapidly progressive glomerulonephritis?". Clinical Kidney Journal. 8 (2): 143–50. doi:10.1093/ckj/sfv008. ISSN 2048-8505. PMC 4370308. PMID 25815169.
== External links == |
Acrania | Acrania is a rare congenital disorder that occurs in the human fetus in which the flat bones in the cranial vault are either completely or partially absent. The cerebral hemispheres develop completely but abnormally. The condition is frequently, though not always, associated with anencephaly. The fetus is said to have acrania if it meets the following criteria: the fetus should have a perfectly normal facial bone, a normal cervical column but without the fetal skull and a volume of brain tissue equivalent to at least one-third of the normal brain size.
Causes
Genetics
There are no known family ties in acrania and recurrence rates are extremely low. Not much is known about the exact mechanism involved in acrania. It is hypothesized that, like other developmental malformations, there are multiple origins for acrania.Recent work has identified mutations in the hedgehog acyltransferase (HHAT) gene that have caused acrania along with holoprosencephaly and agnathia. The mutation in HHAT which causes this disease is a loss-of-function mutation. Before this discovery in 2010, HHAT was known to play a role in the sonic hedgehog pathway. When HHAT contains a loss-of-function mutation, less HHAT protein is produced. HHAT is necessary for the production of Hedgehog (Hh) proteins post-transcriptionally. As HHAT production decreases, production of long-range Hh proteins decreases proportionally. Decreases in Hh| production disturb the production of extracellular signal-regulated kinases, bone morphogenetic proteins, and fibroblast growth factors, all of which play important roles in craniofacial patterning. Disruption of these pathways leads to abnormal bone and cartilage formation causing acrania and multiple other craniofacial patterning problems.
Genetic counseling
Little genetic counseling can be offered for acrania because the genetic origins are not fully understood. In order to make genetic counseling for families easier this disease is often differentially diagnosed with other diseases that can occur at the same time such as anencephaly and acalvaria, though these diseases may not always occur simultaneously. Recurrence rates are extremely low, so genetic counseling is not always necessary.
Amniotic band syndrome
During amniotic band syndrome (ABS), fibrous bands may entrap various parts of the developing fetus causing malformations. When these fibrous bands form around the developing skull, the bones will not form properly. ABS occurring in the developing brain neural tissue is one cause of acrania. When ABS is the cause of acrania the fibrous bands cannot be detected through ultrasound.
Mechanism
During the fourth week of human development the neuropore in a normally developing fetus closes. When this process is either interrupted or never initiated, acrania occurs. The desmocranium becomes a membranous coverage instead of forming the epidermis of the scalp. Whether from being blocked by amniotic bands or by just not initiating, the migration of mesenchyme under the ectoderm does not occur. Because this migration does not occur, the skull, and all involved muscles, are never formed. Without the presence of the neurocranium, the brain fails to separate into two separate lobes. The hindbrain proceeds to develop normally, allowing for the child to be carried to term, but the diencephalon and ocular lobe remain small and underdeveloped.
Ectodermal mesenchyme
Mesenchyme is formed in the developing embryo and will eventually become cartilage and bone. When ectodermal mesenchyme fails to migrate into the head region of the embryo, the skull will not be able to form. What exactly causes the failure of mesenchymal migration is unknown.
Diagnosis
Acrania can be diagnosed early in pregnancy through an ultrasound. This abnormality appears during the beginning or end of the fourth week of the fetuss development. An absence of the skull is needed in order to make a diagnosis. A presence of brain tissue will confirm the diagnosis of acrania and differentiate it from other developmental problems such as anencephaly.
Prognosis
Anencephaly is a fatal condition. Infants with anencephaly are stillborn in about 75 percent of cases. Newborns who survive die within several hours, days, or weeks. This disease is rare, occurring in 1 in 20,000 live births. In order to better manage an acrania diagnosis, early detection is of extreme importance. Families may choose either to terminate the pregnancy, or to carry the fetus to term, depending on the laws where they live. Acrania may cause a fetus to spontaneously abort before reaching term.
References
External links
Acalvaria (Acrania) at NIHs Office of Rare Diseases |
Disorganized schizophrenia | Disorganized schizophrenia, or hebephrenia, was a subtype of schizophrenia prior to 2013. Subtypes of schizophrenia were no longer recognized as separate conditions in the DSM 5, published in 2013. The disorder is no longer listed in the 11th revision of the International Classification of Diseases (ICD-11).
Disorganized schizophrenia was classified within ICD-10 the existing classification, in practice, until January 1, 2022, as a mental and behavioural disorder, because the classification was thought to be an extreme expression of the disorganization syndrome that has been hypothesized to be one aspect of a three-factor model of symptoms in schizophrenia, the other factors being reality distortion (involving delusions and hallucinations) and psychomotor poverty (lack of speech, lack of spontaneous movement and various aspects of blunting of emotion).
Presentation
The condition is also known as hebephrenia, named after the Greek term for "adolescence" – ἥβη (hḗbē) – and possibly the ancient-Greek goddess of youth, Hebe, daughter of Hera. The term refers to the ostensibly more prominent appearance of the disorder in persons around puberty.The prominent characteristics of this form are disorganized behavior and speech (see formal thought disorder), including loosened associations and schizophasia ("word salad"), and flat or inappropriate affect. In addition, psychiatrists must rule out any possible sign of catatonic schizophrenia.
The most prominent features of disorganized schizophrenia are not delusions and hallucinations, as in paranoid schizophrenia, although fragmentary delusions (unsystemized and often hypochondriacal) and hallucinations may be present. A person with disorganized schizophrenia may also experience behavioral disorganization, which may impair his or her ability to carry out daily activities such as showering or eating.The emotional responses of such people often seem strange or inappropriate. Inappropriate facial responses may be common, and behavior is sometimes described as "silly", such as inappropriate laughter. Sometimes, there is a complete lack of emotion, including anhedonia (lack of pleasure), and avolition (lack of motivation). Some of these features are also present in other types of schizophrenia, but they are most prominent in disorganized schizophrenia.
Treatment
This form of schizophrenia is typically associated with early onset (often between the ages of 15 and 25 years) and is thought to have a poor prognosis because of the rapid development of negative symptoms and decline in social functioning.Use of electroconvulsive therapy has been proposed; however, the effectiveness after treatment is in question.
See also
Catatonia
Communication deviance
Paranoid schizophrenia
References
== External links == |
Postural orthostatic tachycardia syndrome | Postural orthostatic tachycardia syndrome (POTS) is a condition characterized by an abnormally large increase in heart rate upon standing. Symptoms may include lightheadedness, brain fog, blurred vision, weakness, fatigue, headaches, heart palpitations, exercise intolerance, nausea, diminished concentration, tremulousness (shaking), syncope (fainting), coldness or pain in the extremities, chest pain and shortness of breath. Other conditions associated with POTS include Ehlers–Danlos syndrome, mast cell activation syndrome, irritable bowel syndrome, insomnia, chronic headaches, chronic fatigue syndrome, and fibromyalgia. POTS symptoms may be treated with lifestyle changes such as increasing fluid and salt intake, wearing compression stockings, gentler and slow postural changes, avoiding prolonged bedrest, medication and physical therapy.
The causes of POTS are varied. POTS may develop after a viral infection, surgery, trauma or pregnancy. It has been shown to emerge in previously healthy patients after COVID-19. Risk factors include a family history of the condition. A POTS diagnosis in adults is characterized by an increased heart rate of 30 beats per minute within ten minutes of standing up, while accompanied by symptoms. This increased heart rate should occur in the absence of orthostatic hypotension (>20 mm Hg drop in systolic blood pressure) to be considered POTS. A spinal fluid leak (called spontaneous intracranial hypotension) may have the same signs and symptoms as POTS and should be excluded. Prolonged bedrest may lead to multiple symptoms, including blood volume loss and postural tachycardia. Other conditions which can cause similar symptoms, such as dehydration, orthostatic hypotension, heart problems, adrenal insufficiency, epilepsy, and Parkinsons disease, must not be present.Treatment may include avoiding factors that bring on symptoms, increasing dietary salt and water, small and frequent meals, avoidance of immobilization, wearing compression stockings, and taking medications. Medications used may include beta blockers, pyridostigmine, midodrine or fludrocortisone. More than 50% of patients whose condition was triggered by a viral infection get better within five years. About 80% of patients have symptomatic improvement with treatment, while 25 percent of patients are so disabled they are unable to work. Retrospective studies has shown that five years after diagnosis, 19% of patients had a full resolution of symptoms.It is estimated that 500,000 people in the United States have POTS. The average age for POTS onset is 20 years old, and it occurs about five times more frequently in females than in males.
Signs and symptoms
In adults, the primary manifestation is an increase in heart rate of more than 30 beats per minute within ten minutes of standing up. The resulting heart rate is typically more than 120 beats per minute. For people between ages 12 and 19, the minimum increase for a POTS diagnosis is 40 beats per minute. POTS is often accompanied by common features of orthostatic intolerance—in which symptoms that develop while upright are relieved by reclining. These orthostatic symptoms include palpitations, light-headedness, chest discomfort, shortness of breath, nausea, weakness or "heaviness" in the lower legs, blurred vision, and cognitive difficulties. Symptoms may be exacerbated with prolonged sitting, prolonged standing, alcohol, heat, exercise, or eating a large meal.Up to one-third of POTS patients experience fainting for many reasons, including but not limited to standing, physical exertion, or heat exposure. POTS patients may also experience orthostatic headaches. Some POTS patients may develop blood pooling in the extremities, characterized by a reddish-purple color of the legs and/or hands upon standing. 48% of people with POTS report chronic fatigue and 32% report sleep disturbances. Other POTS patients only exhibit the cardinal symptom of orthostatic tachycardia. Additional signs and symptoms are varied, and may include excessive sweating, lack of sweating, heat intolerance, digestive issues such as nausea, indigestion, constipation, and diarrhea, post-exertional malaise, coat-hanger pain, brain fog, and syncope or presyncope.
Brain fog
One of the most disabling and prevalent symptoms in POTS is "brain fog", a term used by patients to describe the cognitive difficulties they experience. In one survey of 138 POTS patients, brain fog was defined as "forgetful" (91%), "difficulty thinking" (89%), and "difficulty focusing" (88%). Other common description was "Difficulty processing what others say" (80%), Confusion (71%), Lost (64%), and "Thoughts moving too quickly" (40%). The same survey described the most common triggers of brain fog to be fatigue (91%), lack of sleep (90%), prolonged standing (87%) and dehydration (86%).Neuropsychological testing has shown that a POTS patient has reduced attention (Ruff 2&7 speed and WAIS-III digits forward), short-term memory (WAIS-III digits back), cognitive processing speed (Symbol digits modalities test) and executive function (Stroop word color and trails B).A potential cause for brain fog is a decrease in cerebral blood flow (CBF), especially in upright position.There may be a loss of neurovascular coupling and reduced functional hyperemia in response to cognitive challenge under orthostatic stress – perhaps related to a loss of autoregulatory buffering of beat-by-beat fluctuations in arterial blood flow.
Causes
The symptoms of POTS can be caused by several distinct pathophysiological mechanisms. These mechanisms are poorly understood, and can overlap, with many patients showing features of multiple POTS types. Many people with POTS exhibit low blood volume (hypovolemia), which can decrease the rate of blood flow to the heart. To compensate for low blood volume, the heart increases its cardiac output by beating faster, leading to the symptoms of presyncope and reflex tachycardia.In the 30% to 60% of cases classified as hyperadrenergic POTS, norepinephrine levels are elevated on standing, often due to hypovolemia or partial autonomic neuropathy. A smaller minority of people with POTS have (typically very high) standing norepinephrine levels that are elevated even in the absence of hypovolemia and autonomic neuropathy; this is classified as central hyperadrenergic POTS. The high norepinephrine levels contribute to symptoms of tachycardia. Another subtype, neuropathic POTS, is associated with denervation of sympathetic nerves in the lower limbs. In this subtype, it is thought that impaired constriction of the blood vessels causes blood to pool in the veins of the lower limbs. Heart rate increases to compensate for this blood pooling.In up to 50% of cases, there was an onset of symptoms following a viral illness. It may also be linked to vaccination, physical trauma, concussion, pregnancy, or surgery. It is believed that these events could act as a trigger for an autoimmune response that result in POTS.POTS is more common in females than males. It has also been shown to be linked in patients with acute stressors such as pregnancy, recent surgery, or recent trauma. POTS also has been linked to patients with a history of autoimmune diseases, irritable bowel syndrome, anemia, hyperthyroidism, fibromyalgia, diabetes, amyloidosis, sarcoidosis, systemic lupus erythematosus, and cancer. Genetics likely plays a role, with one study finding that one in eight POTS patients reported a history of orthostatic intolerance in their family.
Autoimmunity
There is an increasing number of studies indicating that POTS is an autoimmune disease. A high number of patients has elevated levels of autoantibodies against the adrenergic alpha 1 receptor and against the muscarinic acetylcholine M4 receptor.Elevations of autoantibodies targeting adrenergic α1 receptor has been associated with symptoms severity in patients with POTS.More recently, autoantibodies against other targets have been identified in small cohorts of POTS patients. Signs of innate immune system activation with elaboration of pro-inflammatory cytokines has also been reported in a cohort of POTS patients.
Secondary POTS
If POTS is caused by another condition, it may be classified as secondary POTS. Chronic diabetes mellitus is one common cause. POTS can also be secondary to gastrointestinal disorders that are associated with low fluid intake due to nausea or fluid loss through diarrhea, leading to hypovolemia. Systemic lupus erythematosus and other autoimmune diseases have also been linked to POTS.There is a subset of patients who present with both POTS and mast cell activation syndrome (MCAS), and it is not yet clear whether MCAS is a secondary cause of POTS or simply comorbid, however, treating MCAS for these patients can significantly improve POTS symptoms.POTS can also co-occur in all types of Ehlers–Danlos syndrome (EDS), a hereditary connective tissue disorder marked by loose hypermobile joints prone to subluxations and dislocations, skin that exhibits moderate or greater laxity, easy bruising, and many other symptoms. A trifecta of POTS, EDS, and Mast Cell Activation Syndrome (MCAS) is becoming increasingly more common, with a genetic marker common among all three conditions. POTS is also often accompanied by vasovagal syncope, with a 25% overlap being reported. There are some overlaps between POTS and chronic fatigue syndrome, with evidence of POTS in 10–20% of CFS cases. Fatigue and reduced exercise tolerance are prominent symptoms of both conditions, and dysautonomia may underlie both conditions.POTS can sometimes be a paraneoplastic syndrome associated with cancer.There are case reports of people developing POTS and other forms of dysautonomia post-COVID. There is no good large-scale empirical evidence yet to prove a connection, so for now the evidence is preliminary.
Diagnosis
POTS is most commonly diagnosed by a cardiologist (41%), cardiac electrophysiologist (15%), or Neurologist (19%). The average number of physicians seen before receiving diagnosis is seven, and the average delay before diagnosis is 4.7 years.
Diagnostic criteria
A POTS diagnosis requires the following characteristics:
For patients age 20 or older, increase in heart rate ≥30 bpm within ten minutes of upright posture (tilt table test or standing) from a supine position
For patients age 12–19, heart rate increase must be >40 bpm
Associated with related symptoms that are worse with upright posture and that improve with recumbence
Chronic symptoms that have lasted for longer than six months
In the absence of other disorders, medications, or functional states that are known to predispose to orthostatic tachycardia
Orthostatic intolerance
An increase in heart rate upon moving to an upright posture is known as orthostatic (upright) tachycardia (fast heart rate). It occurs without any coinciding drop in blood pressure, as that would indicate orthostatic hypotension. Certain medications to treat POTS may cause orthostatic hypotension. It is accompanied by other features of orthostatic intolerance—symptoms that develop in an upright position and are relieved by reclining. These orthostatic symptoms include palpitations, light-headedness, chest discomfort, shortness of breath, nausea, weakness or "heaviness" in the lower legs, blurred vision, and cognitive difficulties.
Differential diagnoses
A variety of autonomic tests are employed to exclude autonomic disorders that could underlie symptoms, while endocrine testing is used to exclude hyperthyroidism and rarer endocrine conditions. Electrocardiography is normally performed on all patients to exclude other possible causes of tachycardia. In cases where a particular associated condition or complicating factor are suspected, other non-autonomic tests may be used: echocardiography to exclude mitral valve prolapse, and thermal threshold tests for small-fiber neuropathy.Testing the cardiovascular response to prolonged head-up tilting, exercise, eating, and heat stress may help determine the best strategy for managing symptoms. POTS has also been divided into several types (see § Causes), which may benefit from distinct treatments. People with neuropathic POTS show a loss of sweating in the feet during sweat tests, as well as impaired norepinephrine release in the leg, but not arm. This is believed to reflect peripheral sympathetic denervation in the lower limbs. People with hyperadrenergic POTS show a marked increase of blood pressure and norepinephrine levels when standing, and are more likely to have from prominent palpitations, anxiety, and tachycardia.People with POTS can be misdiagnosed with inappropriate sinus tachycardia (IST) as they present similarly. One distinguishing feature is those with POTS rarely exhibit >100 bpm while in a supine position, while patients with IST often have a resting heart rate >100 bpm. Additionally patients with POTS display a more pronounced change in heart rate in response to postural change.
Treatment
POTS treatment involves using multiple methods in combination to counteract cardiovascular dysfunction, address symptoms, and simultaneously address any associated disorders. For most patients, water intake should be increased, especially after waking, in order to expand blood volume (reducing hypovolemia). Eight to ten cups of water daily are recommended. Increasing salt intake, by adding salt to food, taking salt tablets, or drinking sports drinks and other electrolyte solutions is an effective way to raise blood pressure by helping the body retain water. Different physicians recommend different amounts of sodium to their patients. Combining these techniques with gradual physical training enhances their effect. In some cases, when increasing oral fluids and salt intake is not enough, intravenous saline or the drug desmopressin is used to help increase fluid retention.Large meals worsen symptoms for some people. These people may benefit from eating small meals frequently throughout the day instead. Alcohol and food high in carbohydrates can also exacerbate symptoms of orthostatic hypotension. Excessive consumption of caffeine beverages should be avoided, because they can promote urine production (leading to fluid loss) and consequently hypovolemia. Exposure to extreme heat may also aggravate symptoms.
Prolonged physical inactivity can worsen the symptoms of POTS. Techniques that increase a persons capacity for exercise, such as endurance training or graded exercise therapy, can relieve symptoms for some patients. Aerobic exercise performed for 20 minutes a day, three times a week, is sometimes recommended for patients who can tolerate it. Exercise may have the immediate effect of worsening tachycardia, especially after a meal or on a hot day. In these cases, it may be easier to exercise in a semi-reclined position, such as riding a recumbent bicycle, rowing, or swimming.When changing to an upright posture, finishing a meal, or concluding exercise, a sustained hand grip can briefly raise the blood pressure, possibly reducing symptoms. Compression garments can also be of benefit by constricting blood pressures with external body pressure.
Medication
If nonpharmacological methods are ineffective, medication may be necessary. Medications used may include beta blockers, pyridostigmine, midodrine, or fludrocortisone. As of 2013, no medication has been approved by the U.S. Food and Drug Administration to treat POTS, but a variety are used off-label. Their efficacy has not yet been examined in long-term randomized controlled trials.Fludrocortisone may be used to enhance sodium retention and blood volume, which may be beneficial not only by augmenting sympathetically mediated vasoconstriction, but also because a large subset of POTS patients appear to have low absolute blood volume.While people with POTS typically have normal or even elevated arterial blood pressure, the neuropathic form of POTS is presumed to constitute a selective sympathetic venous denervation. In these patients the selective Alpha-1 adrenergic receptor agonist midodrine may increase venous return, enhance stroke volume, and improve symptoms. Midodrine should only be taken during the daylight hours as it may promote supine hypertension.Sinus node blocker Ivabradine can successfully restrain heart rate in POTS without affecting blood pressure, demonstrated in approximately 60% of people with POTS treated in an open-label trial of ivabradine experienced symptom improvement.Pyridostigmine has been reported to restrain heart rate and improve chronic symptoms in approximately half of people.The selective alpha-1 agonist phenylephrine has been used successfully to enhance venous return and stroke volume in some people with POTS. However, this medication may be hampered by poor oral bioavailability.
Prognosis
POTS has a favorable prognosis when managed appropriately. Symptoms improve within five years of diagnosis for many patients, and 60% return to their original level of functioning. Approximately 90% of people with POTS respond to a combination of pharmacological and physical treatments. Those who develop POTS in their early to mid teens during a period of rapid growth will most likely see complete symptom resolution in two to five years. Outcomes are more guarded for adults newly diagnosed with POTS. Some people do not recover, and a few even worsen with time. The hyperadrenergic type of POTS typically requires continuous therapy. If POTS is caused by another condition, outcomes depend on the prognosis of the underlying disorder.
Epidemiology
The prevalence of POTS is unknown. One study estimated a minimal rate of 170 POTS cases per 100,000 individuals, but the true prevalence is likely higher due to underdiagnosis. Another study estimated that there are at least 500,000 cases in the United States. POTS is more common in women than men, with a female-to-male ratio of 4:1. Most people with POTS are aged between 20 and 40, with an average onset of 21. Diagnoses of POTS beyond age 40 are rare, perhaps because symptoms improve with age.
Co-morbidities
Conditions that are commonly reported with POTS include:
Migraine headaches (11–40%)
Ehlers–Danlos syndrome (20–25%)
Fibromyalgia (11–20%)
Irritable bowel syndrome (7–30%)
Chronic fatigue syndrome (7–21%)
Mast cell activation disorder (6–9%)
History
In 1871, physician Jacob Mendes Da Costa described a condition that resembled the modern concept of POTS. He named it irritable heart syndrome. Cardiologist Thomas Lewis expanded on the description, coining the term soldiers heart because it was often found among military personnel. The condition came to be known as Da Costas syndrome, which is now recognized as several distinct disorders, including POTS.Postural tachycardia syndrome was coined in 1982 in a description of a patient who had postural tachycardia, but not orthostatic hypotension. Ronald Schondorf and Phillip A. Low of the Mayo Clinic first used the name postural orthostatic tachycardia syndrome, POTS, in 1993.
Notable cases
British politician Nicola Blackwood revealed in March 2015 that she had been diagnosed with Ehlers–Danlos syndrome in 2013 and that she had later been diagnosed with POTS. She was appointed Parliamentary Under-Secretary of State for Life Science by Prime Minister Theresa May in 2019 and given a life peerage that enabled her to take a seat in Parliament. As a junior minister, it is her responsibility to answer questions in parliament on the subjects of Health and departmental business. When answering these questions, it is customary for ministers to sit when listening to the question and then to rise to give an answer from the despatch box, thus standing up and sitting down numerous times in quick succession throughout a series of questions. On 17 June 2019, she fainted during one of these questioning sessions after standing up from a sitting position four times in the space of twelve minutes, and it was suggested that her POTS was a factor in her fainting. Asked about the incident, she stated: "I was frustrated and embarrassed my body gave up on me at work ... But I am grateful it gives me a chance to shine a light on a condition many others are also living with."
References
== Further reading == |
Papular xanthoma | Papular xanthoma is a cutaneous condition that is a rare form of non-X histiocytosis.: 718
See also
Non-X histiocytosis
List of cutaneous conditions
== References == |
Spanish flu (disambiguation) | Spanish flu or Spanish influenza, also known as purulent bronchitis, may refer to:
the 1918 flu pandemic where 500 million people worldwide were infected with H1N1 influenza A virus between 1918 and 1920, killing from 20 to 100 million people
the Influenza A virus subtype H1N1 which caused the influenza pandemic between 1918 and 1920, as well as the 2009 swine flu pandemic and 1977 Russian flu pandemic
See also
Flu (disambiguation)
Influenzavirus, the viruses that cause influenza disease
Influenza pandemic, "the influenza" global mass disease for a given year |
Eosinophilia–myalgia syndrome | Eosinophilia–myalgia syndrome is a rare, sometimes fatal neurological condition linked to the ingestion of the dietary supplement L-tryptophan. The risk of developing EMS increases with larger doses of tryptophan and increasing age. Some research suggests that certain genetic polymorphisms may be related to the development of EMS. The presence of eosinophilia is a core feature of EMS, along with unusually severe myalgia (muscle pain).
Signs and symptoms
The initial, acute phase of EMS, which last for three to six months, presents as trouble with breathing and muscle problems, including soreness and spasm, but which may also be intense. Muscle weakness is not a feature of this phase, but some people experience muscle stiffness. Additional features can include cough, fever, fatigue, joint pain, edema, and numbness or tingling, usually in the limbs, hands and feet.The chronic phase follows the acute phase. Eosinophilic fasciitis may develop, primarily in the limbs. CNS signs may appear, including numbness, increased sensation, muscle weakness, and sometimes cardiac or digestive dysfunction. Fatigue is present to some degree, while the muscle pain (which may be extremely intense) and dyspnea continue in this phase.
Causes
Subsequent epidemiological studies suggested that EMS was linked to specific batches of L-tryptophan supplied by a single large Japanese manufacturer, Showa Denko. It eventually became clear that recent batches of Showa Denkos L-tryptophan were contaminated by trace impurities, which were subsequently thought to be responsible for the 1989 EMS outbreak. The L-tryptophan was produced by a bacterium grown in open vats in a Showa Denko fertilizer factory. While a total of 63 trace contaminants were eventually identified, only six of them could be associated with EMS. The compound EBT (1,1-ethylidene-bis-L-tryptophan, also known as "Peak E") was the only contaminant identifiable by initial analysis, but further analysis revealed PAA (3-(phenylamino)-L-alanine, also known as "UV-5"), and peak 200 (2[3-indolyl-methyl]-L-tryptophan). Two of the remaining uncharacterized peaks associated with EMS were later determined to be 3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo-[2,3-b]-indole-2-carboxylic acid (peak C) and 2-(2-hydroxy indoline)-tryptophan (peak FF). These were characterized using accurate mass LC–MS, LC–MS/MS and multistage mass spectrometry (MSn). The last of the six contaminants (peak AAA/"UV-28", being "the contaminant most significantly associated with EMS" has been characterized as two related chain-isomers; peak AAA1 ((S)-2-amino-3-(2-((S,E)-7-methylnon-1-en-1-yl)-1H-indol-3-yl)propanoic acid, a condensation product between L-tryptophan and 7-methylnonanoic acid) and peak AAA2 ((S)-2-amino-3-(2-((E)-dec-1-en-1-yl)-1H-indol-3-yl)propanoic acid, a condensate between L-tryptophan and decanoic acid). No consistent relationship has ever been firmly established between any specific trace impurity or impurities identified in these batches and the effects of EMS. While EBT in particular has been frequently implicated as the culprit, there is no statistically significant association between EBT levels and EMS. Of the 63 trace contaminants, only the two AAA compounds displayed a statistically significant association with cases of EMS (with a p-value of 0.0014).As most research has focused on attempts to associate individual contaminants with EMS, there is a comparative lack of detailed research on other possible causal or contributing factors. Tryptophan itself has been implicated as a potentially major contributory factor in EMS. While critics of this theory have argued that this hypothesis fails to explain the near-absent reports of EMS prior to and following the EMS outbreak, this fails to take into account the sudden rapid increase in tryptophans usage immediately prior to the 1989 outbreak, and ignores the strong influence of the EMS outbreaks legacy and the extended FDA ban on later usage of tryptophan. Crucially, this also ignores the existence of a number of cases of EMS that developed both prior to and after the primary epidemic, including at least one case where the tryptophan was tested and found to lack the contaminants found in the contaminated lots of Showa Denkos tryptophan, as well as cases with other supplements inducing EMS, and even a case of EMS induced by excessive dietary L-tryptophan intake via overconsumption of cashew nuts. A major Canadian analysis located a number of patients that met the CDC criteria for EMS but had never been exposed to tryptophan, which "brings causal interpretations of earlier studies into question". Other studies have highlighted numerous major flaws in many of the epidemiological studies on the association of tryptophan with EMS, which cast serious doubt on the validity of their results. As the FDA concluded, "other brands of L-tryptophan, or L-tryptophan itself, regardless of the levels or presence of impurities, could not be eliminated as causal or contributing to the development of EMS". Even animal studies have suggested that tryptophan itself "when ingested by susceptible individuals either alone or in combination with some other component in the product, results in the pathological features in EMS".At the time of the outbreak, Showa Denko had recently made alterations to its manufacturing procedures that were thought to be linked to the possible origin of the contaminants detected in the affected lots of tryptophan. A key change was the reduction of the amount of activated charcoal used to purify each batch from >20 kg to 10 kg. A portion of the contaminated batches had also bypassed another filtration step that used reverse-osmosis to remove certain impurities. Additionally, the bacterial culture used to synthesize tryptophan was a strain of Bacillus amyloliquefaciens that had been genetically engineered to increase tryptophan production. Although the prior four generations of the genetically engineered strain had been used without incident, the fifth generation used for the contaminated batches was thought to be a possible source of the impurities that were detected. This has been misused to argue that the genetic engineering itself was the primary cause of the contamination, a stance that was heavily criticized for overlooking the other known non-GMO causes of contamination, as well as for its use by anti-GMO activists as a way to threaten the development of biotechnology with false information. The reduction in the amount of activated carbon used and the introduction of the fifth generation Bacillus amyloliquefaciens strain were both associated with the development of EMS, but due to the high overlap of these changes, the precise independent contribution of each change could not be determined (although the bypass of the reverse-osmosis filtration for certain lots was determined to be not significantly associated with the contaminated lots of tryptophan). While Showa Denko claimed a purity of 99.6%, it was noted that "the quantities of the known EMS associated contaminants, EBT and PAA, were remarkably small, of the order of 0.01%, and could easily escape detection".
Regulatory response
The FDA loosened its restrictions on sales and marketing of tryptophan in February 2001, but continued to limit the importation of tryptophan not intended for an exempted use until 2005.
Diagnosis
Treatment
Treatment is withdrawal of products containing L-tryptophan and the administration of glucocorticoids. Most patients recover fully, remain stable, or show slow recovery, but the disease is fatal in up to 5% of patients.
History
The first case of eosinophilia–myalgia syndrome was reported to the Centers for Disease Control and Prevention (CDC) in November 1989, although some cases had occurred as early as 2–3 years before this. In total, more than 1,500 cases of EMS were reported to the CDC, as well as at least 37 EMS-associated deaths. After preliminary investigation revealed that the outbreak was linked to intake of tryptophan, the U.S. Food and Drug Administration (FDA) recalled tryptophan supplements in 1989 and banned most public sales in 1990, with other countries following suit. This FDA restriction was loosened in 2001, and fully lifted in 2005. Since the initial ban on L-tryptophan, a normal metabolite of the compound in mammals, 5-hydroxtryptophan (5-HTP) has become a popular replacement dietary supplement.
See also
Toxic oil syndrome
References
== External links == |
Orbital cellulitis | Orbital cellulitis is inflammation of eye tissues behind the orbital septum. It is most commonly caused by an acute spread of infection into the eye socket from either the adjacent sinuses or through the blood. It may also occur after trauma. When it affects the rear of the eye, it is known as retro-orbital cellulitis.
It should not be confused with periorbital cellulitis, which refers to cellulitis anterior to the septum.
Without proper treatment, orbital cellulitis may lead to serious consequences, including permanent loss of vision or even death.
Signs and symptoms
Orbital cellulitis commonly presents with painful eye movement, sudden vision loss, chemosis, bulging of the infected eye, and limited eye movement. Along with these symptoms, patients typically have redness and swelling of the eyelid, pain, discharge, inability to open the eye, occasional fever and lethargy.
Complications
Complications include hearing loss, blood infection, meningitis, cavernous sinus thrombosis, cerebral abscess, and blindness. It is possible that children experience more severe complications due to their immature immune system and because they have thinner orbital bones, which makes the infection easier to spread.
Causes
Orbital cellulitis occurs commonly from bacterial infection spread via the paranasal sinuses, usually from a previous sinus infection. Other ways in which orbital cellulitis may occur are from blood stream infections or from eyelid skin infections. Upper respiratory infection, sinus infection, trauma to the eye, ocular or periocular infection, and systemic infection all increase ones risk of orbital cellulitis.
Staphylococcus aureus, Haemophilus influenzae B, Moraxella catarrhalis, Streptococcus pneumoniae, and beta-hemolytic streptococci are bacteria that can be responsible for orbital cellulitis.
Staphylococcus aureus is a gram-positive bacterium, which is the most common cause of staphylococcal infections. Staphylococcus aureus infection can spread from the skin to the orbit. This organism is able to produce toxins which promotes its virulence, leading to the inflammatory response seen in orbital cellulitis. Staphylococcus infections are identified by a cluster arrangement on gram stain. Staphylococcus aureus forms large yellow colonies when cultured (which is distinct from other Staph infections such as Staphylococcus epidermidis, which forms white colonies).
Streptococcus pneumoniae is also a gram-positive bacterium responsible for orbital cellulitis due to its ability to infect the sinuses. Streptococcal bacteria can invade surrounding tissues, causing the inflammatory response seen in orbital cellulitis (similar to Staphyloccoccus aureus). Streptococcal infections are identified on culture by their formation of pairs or chains. Streptococcus pneumoniae produce green (alpha) hemolysis, or partial reduction of red blood cell hemoglobin.
Risk Factors
Risk factors for the development of orbital cellulitis include, but are not limited to:
Recent upper respiratory illness
Sinus infection
Younger age
Retained foreign bodies within the orbit
Trauma
Immunosuppression
Systemic infection
Dental infection
Diagnosis
Early diagnosis of orbital cellulitis is urgent, and it involves a complete and thorough physical examination. Common presenting signs include: a protruding eye (proptosis), eyelid edema (swelling), eye pain, vision loss, inability to move the eye completely (ophthalmoplegia), and fever. It is important to correlate physical findings with patient history and reported symptoms.CT scan and MRI of the orbits are two imaging modalities that are commonly used to aid in the diagnosis and monitoring of orbital cellulitis, as they can provide detailed images that can show the extent of inflammation along with possible abscess location, size, and involvement of surrounding structures. Ultrasound has also been used as an imaging modality in the past, but it cannot provide the same level of detail as CT or MRI.Blood cultures, electrolytes, and a complete blood count (CBC) with differential showing elevated white blood cell count is a useful laboratory test that may aid in diagnosis.
Differential Diagnosis
A variety of pathologies and diseases can present similarly to orbital cellulitis, including:
Inflammatory causes (thyroid eye disease, idiopathic orbital inflammatory syndrome, sarcoidosis, granulomatosis with polyangiitis)
Infectious causes (subperiosteal abscess)
Neoplastic, benign and malignant (dermoid cyst, capillary hemangioma, rhabdomyosarcoma, optic nerve glioma, lymphangioma, neurofibroma, leukemia)
Trauma (orbital fracture, retrobulbar hemorrhage, orbital foreign body, carotid cavernous fistula)
Malformation (congenital, vascular)
Treatment
Immediate treatment is very important, and it typically involves intravenous (IV) antibiotics in the hospital and frequent observation (every 4–6 hours). Several lab tests should be ordered, including a complete blood count, differential, and blood culture.
Antibiotic therapy – Since orbital cellulitis is commonly caused by Staphylococcus and Streptococcus species, both penicillins and cephalosporins are typically the best choices for IV antibiotics. However, due to the increasing rise of MRSA (methicillin-resistant Staphylococcus aureus) orbital cellulitis can also be treated with Vancomycin, Clindamycin, or Doxycycline. If improvement is noted after 48 hours of IV antibiotics, healthcare professionals can then consider switching a patient to oral antibiotics (which must be used for 2–3 weeks).
Surgical intervention – An abscess can threaten the vision or neurological status of a patient with orbital cellulitis, therefore sometimes surgical intervention is necessary. Surgery typically requires drainage of the sinuses and if a subperiosteal abscess is present in the medial orbit, drainage can be performed endoscopically. Post-operatively, patients must follow up regularly with their surgeon and remain under close observation.
Corticosteroids - Complications of orbital cellulitis may arise as a result of swelling from the infection. Because the orbit is a small space, increasing the pressure inside can harm the eye. Steroids are drugs that are used to reduce swelling caused by various illnesses, but they can also weaken the immune systems ability to fight the infection. There is inadequate evidence to draw judgments about the use of steroids in the treatment of orbital cellulitis. More research is needed to inform decision making.
Prognosis
Although orbital cellulitis is considered an ophthalmic emergency, the prognosis is good if prompt medical treatment is received.
Death and blindness rates without treatment
Bacterial infections of the orbit have long been associated with a risk of devastating outcomes and intracranial spread.
The natural course of the disease, as documented by Gamble (1933), in the pre-antibiotic era,
resulted in death in 17% of patients and permanent blindness in 20%.
Epidemiology
Orbital cellulitis is an uncommon medical condition, with the reported rates being much higher among the pediatric population compared to the adult population. One study reported that children are approximately 16 times more likely to suffer from orbital cellulitis compared to adults. It is twice as common among male children compared to female children. Some studies reported that orbital cellulitis follows a seasonal pattern, with the highest rates occurring during the fall and winter, which coincides with the higher rates of sinus infection during the colder months.
References
Noel LP, Clarke WN, MacDonald N (1990). "Clinical management of orbital cellulitis in children". Canadian Journal of Ophthalmology. 25 (1): 11–16. PMID 2328431.
Shapiro E, Wald E, Brozanski B (1982). "Periorbital cellulitis and paranasal sinusitis: a reappraisal". Pediatric Infectious Disease. 1 (2): 91–94. doi:10.1097/00006454-198203000-00005. PMID 7177909. S2CID 24237202.
External links
MedlinePlus.
Death Rates for Orbital Cellulitis
Pub Med Health - Orbital Cellulitis |
Myelophthisic anemia | Myelophthisic anemia (or myelophthisis) is a severe type of anemia found in some people with diseases that affect the bone marrow. Myelophthisis refers to the displacement of hemopoietic bone-marrow tissue by fibrosis, tumors, or granulomas. The word comes from the roots myelo-, which refers to bone marrow, and phthysis, shrinkage or atrophy.
Causes
Myelophthisis can occur in the setting of chronic myeloproliferative disease (e.g. myelofibrosis), leukemia, lymphoma, and metastatic carcinoma or myeloma. It is common in people who have chronic idiopathic myelofibrosis. It has been linked to small-cell lung cancer, breast cancer or prostate cancer that metastasizes to the bone marrow.Currently, the most common cause is displacement of bone marrow by metastatic cancer (extramedullary hematopoiesis tends to be modest). Other causes include myeloproliferative disorders (especially late-stage or spent polycythemia vera), granulomatous diseases, and (lipid) storage diseases. Myelofibrosis can occur in all of these.
Factors that may contribute to decreased RBC production include a decreased quantity of functioning hematopoietic tissue, disordered metabolism related to the underlying disorder, and, in some cases, erythrophagocytosis.
Pathophysiology
Some cases of myelophthisis are thought to be related to the release of cytokines that simulate fibroblastic proliferation and fibrosis in the marrow.
Diagnosis
The first test for diagnosis myelophthisis involves looking at a small sample of blood under a microscope. Myelophthisis is suggested by the presence of red blood cells that contain nuclei or are teardrop-shaped (dacryocytes), or immature granulocyte precursor cells which indicates leukoerythroblastosis is occurring because the displaced hematopoietic cells begin to undergo extramedullary hematopoiesis. These immature granulocytes are seen in peripheral blood smears. Diagnosis is confirmed when a bone marrow biopsy demonstrates significant replacement of the normal bone marrow compartment by fibrosis, malignancy or other infiltrative process. The presence of immature blood cell precursors helps distinguish another cause of pancytopenia, aplastic anemia, from myelophthisic anemia because in aplastic anemia the hematopoietic cells are damaged and immature blood cells are not seen in the peripheral blood.
There may be evidence of extramedullary hematopoiesis (marrow elements can be found in the spleen, liver).
Treatment
Treatment of this disorder involves treatment of the underlying cancer.
See also
List of circulatory system conditions
List of hematologic conditions
References
External links
Myelophthisic Anemia at eMedicine |
Adult attention deficit hyperactivity disorder | Adult attention deficit hyperactivity disorder is the neurological condition of attention deficit hyperactivity disorder (ADHD) in adults. About one-third to two-thirds of children with symptoms from early childhood continue to demonstrate ADHD symptoms throughout life.: 44 Three types of ADHD are identified in the DSM-5 as:
Predominantly Inattentive Type (ADHD-PI or ADHD-I)
Predominantly Hyperactive or Hyperactive-Impulsive Type (ADHD-PH or ADHD-HI)
Combined Type (ADHD-C)In later life, the hyperactive/impulsive subtype manifests less frequently.: 44 The hyperactivity symptoms tend to turn more into "inner restlessness", starting in adolescence and carrying on in adulthood.Adult ADHD is typically marked by inattention and hyperfocus, hyperactivity (often internalised as restlessness), emotional dysregulation, and excessive mind wandering. Specifically, adults with ADHD present with persistent difficulties in following directions, remembering information, concentrating, organizing tasks, completing work within specified time frames and appearing timely in appointments. These difficulties affect several different areas of an ADHD adults life, causing emotional, social, vocational, marital, legal, financial and/or academic problems.Diagnosis follows one or several psychiatric assessment which may include examination of personal history, observational evidence from family members or friends, academic reports, often going back to school years, as well as evaluation to diagnose additional possible conditions which often coexist with ADHD, called comorbidities or comorbid disorders.
The condition often runs in families, and while its exact causes are not fully known, genetic or environmental factors are understood to play a part. ADHD often - but not always - is a childhood-onset condition. Children under treatment will migrate to adult health services if necessary as they transit into adulthood, however diagnosis of adults involves full examination of their history.
Treatment of ADHD is usually based on a combination of behavioral interventions and medication. Stimulant medication is the first line treatment for ADHD in adults, particularly amphetamines. Non-stimulant medications, such as atomoxetine, or Viloxazine, are also recommended for some ADHD adults. Psychotherapy such as cognitive behavioural therapy is helpful, particularly in combination with medication. Similarly, exercise, sufficient sleep and nutritious food are also known to have a positive effect. Within school and work, reasonable accommodations may be put in place, such as by structuring work tasks, and setting up clear rules and limits for tasks.
Classification
The DSM-5, or Diagnostic and Statistical Manual of Mental Disorders, 2013 edition, defines three types of ADHD:
a Predominantly Inattentive presentation
a Predominantly Hyperactive-Impulsive presentation
a Combined Type, that displays symptoms from both presentationTo meet the diagnostic criteria of ADHD, an individual must display:
at least six inattentive-type symptoms for the inattentive type
at least six hyperactive-type symptoms for the hyperactive-impulsive type
all of the above to have the combined typeThe symptoms (see below) were required to have been present since before the individual was seven years old, and must have interfered with at least two spheres of his or her functioning (at home and at school or work, for example) over the last six months. The DSM-IV criteria for ADHD were, however, tailored towards the type of symptoms that children would show, and might therefore have underestimated the prevalence of ADHD in adults. In 2013, the newer DSM-5 reviewed some of these criteria, with more lenient requirements for the diagnosis, especially in adults, and the age limit for symptoms first arising raised to twelve years.
Signs and symptoms
ADHD is a chronic condition, beginning in early childhood that can persist throughout a persons lifetime. It is estimated that 33–66% of children with ADHD will continue to have significant ADHD-related symptoms persisting into adulthood, resulting in a significant impact on education, employment, and interpersonal relationships.Individuals with ADHD exhibit deficiencies in self-regulation and self-motivation which in turn foster problematic characteristics such as distractibility, procrastination, and disorganization. They are often perceived by others as chaotic, with a tendency to need high stimulation to be less distracted and function effectively. The learning potential and overall intelligence of an adult with ADHD, however, is no different from the potential and intelligence of adults who do not have the disorder.Whereas teachers and caregivers responsible for children are often attuned to the symptoms of ADHD, employers and others who interact with adults are less likely to regard such behaviors as a symptom. In part, this is because symptoms do change with maturity; adults who have ADHD are less likely to exhibit obvious hyperactive behaviors. Instead, they may report constant mental activity and inner restlessness as their hyperactivity internalizes.Symptoms of ADHD (see table below) can vary widely between individuals and throughout the lifetime of an individual. As the neurobiology of ADHD is becoming increasingly understood, it is becoming evident that difficulties exhibited by individuals with ADHD are due to problems with the parts of the brain responsible for executive functions (see below: Pathophysiology). These result in problems with sustaining attention, planning, organization, prioritization, time management, impulse control, and decision making.The difficulties generated by these deficiencies can range from moderate to extreme, resulting in the inability to effectively structure their lives, plan daily tasks, or think of and act accordingly even when aware of potential consequences. These can lead to poor performance in school and work and can be followed by underachievement in these areas. In young adults, poor driving records with traffic violations may surface.As problems accumulate, a negativistic self-view becomes established and a vicious circle of failure is set up. Up to 80% of adults may have some form of psychiatric comorbidity, such as depression or anxiety. Many with ADHD also have associated learning disabilities, such as dyslexia, which contributes to their difficulties.Studies on adults with ADHD have shown that, more often than not, they experience self-stigma and depression in childhood, commonly resulting from feeling neglected and different from their peers. These problems may play a role in the high levels of depression, substance abuse, and relationship problems that affect adults with ADHD later in life.
Pathophysiology
Over the last 30 years, research into ADHD has greatly increased. There is no single, unified theory that explains the cause of ADHD. Genetic factors are presumed important, and it has been suggested that environmental factors may affect how symptoms manifest.It is becoming increasingly accepted that individuals with ADHD have difficulty with "executive functioning". In higher organisms, such as humans, these functions are thought to reside in the frontal lobes. They enable recall of tasks that need accomplishing, organization to accomplish these tasks, assessment of consequences of actions, prioritization of thoughts and actions, keeping track of time, awareness of interactions with surroundings, the ability to focus despite competing stimuli, and adaptation to changing situations.Several lines of research based on structural and/or functional imaging techniques, stimulant drugs, psychological interventions have identified alterations in the dopaminergic and adrenergic pathways of individuals with ADHD. In particular, areas of the prefrontal cortex appear to be the most affected. Dopamine and norepinephrine are neurotransmitters which play an important role in brain function. The uptake transporters for dopamine and norepinephrine are overly active and clear these neurotransmitters from the synapse a lot faster than in other individuals. This is thought to increase processing latency and salience, and diminish working memory.
Adult ADHD in Men
Studies have shown that adult men with ADHD-type symptoms have issues with interpersonal and romantic relationships. Adult men with ADHD have reported, in a study done by Canu in 2007, to have more romantic partners than their counterparts. They are commonly rated as less desirable to women than people without ADHD-type symptoms. Stimulant medication does not appear to affect the rating given by women. Ratings of self worth also appear to be lower in adult men who are diagnosed with ADHD (Canu, 2007). Canus study looked at adult men with ADHD and found that they did not have higher levels of rejection sensitivity. This may be due to the possibility that individuals with ADHD may not recognize their own impairment of judgement and will overestimate their ability to interact with others to the point that they may not be aware of how poorly a social interaction may go. This may result in lower reports of rejection sensitivity.Other results of adult ADHD are higher reported incidences of traffic citations, missed workdays, and accidents. According to Fritz in a 2016 study, adult men with ADHD may be able to focus better on mental tasks after completing some type of physical exertion. This may help individuals that suffer with adult ADHD. Mood improvements were shown to be statistically significant for a short while but quickly the mood would return to pre-exertion levels.
Diagnosis
While there is no single medical, physical, or genetic test for ADHD, an evaluation can be provided by a qualified mental health care professional or physician who gathers information from multiple sources. These can include ADHD symptom checklists, standardized behavior rating scales, a detailed history of past and current functions including the persons history of childhood behavior and school experiences, and information obtained from family members, friends, or significant others. The evaluations also seek to rule out other conditions or differential diagnoses such as depression, anxiety, or substance use disorders. Other diseases such as hyperthyroidism may exhibit symptoms similar to those of ADHD, and it is imperative to rule these out as well. Autism is sometimes mistaken for ADHD, due to impairments in executive functioning found in some people with autism. However, autism also typically involves difficulties in social interaction, restricted and repetitive patterns of behavior and interests, and problems with sensory processing, including hypersensitivity. Along with this, the quality of diagnosing an adult with ADHD can often be skewed being that the majority of adults with ADHD also have other complications, ranging from anxiety and depression to substance abuse.Formal tests and assessment instruments such as IQ tests, standardized achievement tests, or neuropsychological tests typically are not helpful for identifying people with ADHD. Furthermore, no currently available physiological or medical measure is definitive diagnostically. However, psycho-educational, such as the Continuous Performance Test (CPT), and medical tests are helpful in ruling in or out other conditions (e.g. learning disabilities, allergies) that may be associated with ADHD-like behaviors.The use of neuroimaging is also steadily increasing to help in an ADHD diagnosis. Some of these include:
single-photon emission computed tomography (SPECT)
positron emission tomography (PET)
functional magnetic resonance imaging (fMRI)United States medical and mental health professionals follow the Diagnostic and Statistical Manual of Mental Disorders (DSM) of the American Psychiatric Association; the International Classification of Diseases (ICD) published by the World Health Organisation (WHO) is often used by health professionals elsewhere.
Until recently ADHD in adults was considered as a continuation of child-onset ADHD. It is now established, however, that also an adult-onset version exists. In a large longitudinal study from 2015 it was found that 28 of the 31 persons who had an ADHD-diagnosis at the age of 38 never had received an ADHD-diagnosis when tested at the ages of 11, 13 and 15.
Treatment
As a first step, adults with ADHD should receive psychoeducation about ADHD, so they understand the diagnosis. This is vital to ensure that adults with ADHD can make informed decisions about their treatment, and has other benefits such as improved relationships with others. Treatment often begins with medication selected to address the symptoms of ADHD, along with any comorbid conditions that may be present. Medication alone, while sometimes effective in correcting the physiological symptoms of ADHD, will not address the paucity of skills which many adults will have acquired because of their ADHD (e.g., one might regain ability to focus with medication, but skills such as organizing, prioritizing and effectively communicating have taken others time to cultivate). Suggested treatment for adult ADHD is to include a combined approach of psychosocial interventions (behavioural or cognitive), medication, vocational interventions, and regular follow-up support.
Medications
Medications to help treat ADHD include psychostimulants and non-stimulants. Guidelines and availability of the different options available for medication may vary depending on what country the person lives in.
Stimulants
Stimulants have moderate-to-high effects, which have higher average effects than non-stimulant medications. For adults, amphetamines in particular are the most efficacious medications and they (along with methylphenidate) have the least adverse effects. While there is some debate about whether to treat ADHD adults with substance use disorder (SUD) with stimulants, the 2019 Updated European Consensus Statement on diagnosis and treatment of adult ADHD notes that "in SUD patients, treatment of ADHD [with stimulants] can be useful to reduce ADHD symptoms without worsening the SUD, and should not be avoided".Amphetamine and its derivatives, prototype stimulants, are available in immediate and long-acting formulations. Amphetamines act by multiple mechanisms including reuptake inhibition, displacement of transmitters from vesicles, reversal of uptake transporters and reversible MAO inhibition. Thus amphetamines actively increases the release of these neurotransmitters into the synaptic cleft. In the short term, methylphenidate, a benzylpiperidine and phenethylamine derivative stimulant medication, is well tolerated. As of a 2008 review, long-term studies had not been conducted in adults, although no serious side effects had been reported to regulatory authorities.In the UK, clinical guidelines recommend that psychostimulants are used as a first-line treatment. For people who cannot be treated with stimulants due to a substance use disorder or other contraindications, atomoxetine is the suggested first line treatment in the UK. In Canada, clinical guidelines suggest that first line treatment be methylphenidate or lisdexamfetamine. Non-stimulant medications are generally second-line treatments in Canada.
Non-stimulant medications
The non-stimulant atomoxetine (Strattera), may be an effective treatment for adult ADHD. Although atomoxetine has a half life similar to stimulants it exhibits delayed onset of therapeutic effects similar to antidepressants. Unlike stimulants which are generally controlled substances, atomoxetine lacks addictive potential. It is particularly effective for those with the predominantly inattentive concentration type of attention deficit due to being primarily a norepinephrine reuptake inhibitor. It is often prescribed in adults who cannot tolerate the side effects of amphetamines or methylphenidate. It is also approved for ADHD by the US Food and Drug Administration. A rare but potentially severe side effect includes liver damage and increased suicidal ideation.Viloxazine is a selective norepinephrine reuptake inhibitor that was FDA-approved to treat ADHD in children, adolescents, and adults.Bupropion and desipramine are two antidepressants that have demonstrated some evidence of effectiveness in the management of ADHD particularly when there is comorbid major depression, although antidepressants have lower treatment effect sizes.
Psychotherapy
Psychotherapy, including behavioral therapy, can help an adult with ADHD monitor their own behaviour and provide skills for improving organization and efficiency in daily tasks. Research has shown that, alongside medication, psychological interventions in adults can be effective in reducing symptomatic deficiencies. Cognitive behavioral therapy in particular can provide benefits, especially alongside medication, in the treatment of adult ADHD.
Epidemiology
In North America and Europe, it is estimated that three to five percent of adults have ADHD. Of those adults with ADHD, an estimated 10% of those have received a formal diagnosis. It has been estimated that 5% of the global population has ADHD (including cases not yet diagnosed). In the context of the World Health Organization World Mental Health Survey Initiative, researchers screened more than 11,000 people aged 18 to 44 years in ten countries in the Americas, Europe and the Middle East. On this basis they estimated the adult ADHD proportion of the population to average 3.5 percent with a range of 1.2 to 7.3 percent, with a significantly lower prevalence in low-income countries (1.9%) compared to high-income countries (4.2%). The researchers concluded that adult ADHD often co-occurs with other disorders, and that it is associated with considerable role disability. Although they found that few adults are treated for ADHD itself, in many instances treatment is given for the co-occurring disorders.
History
Early work on disorders of attention was conducted by Alexander Crichton in 1798 writing about "mental restlessness". The underlying condition came to be recognized from the early 1900s by Sir George Still. Efficacy of medications on symptoms was discovered during the 1930s and research continued throughout the twentieth century. ADHD in adults began to be studied from the early 1970s and research has increased as worldwide interest in the condition has grown.In the 1970s researchers began to realize that the condition now known as ADHD did not always disappear in adolescence, as was once thought. The expansion of the definition for ADHD beyond only being a condition experienced by children was mainly accomplished by refocusing the diagnosis on inattention instead of hyperactivity. At about the same time, some of the symptoms were also noted in many parents of the children under treatment.
Society and culture
ADHD in adults, as with children, is recognized as an impairment that may constitute a disability under U.S. federal disability nondiscrimination laws, including such laws as the Rehabilitation Act of 1973 and the Americans With Disabilities Act (ADA, 2008 revision), if the disorder substantially limits one or more of an individuals major life activities. For adults whose ADHD does constitute a disability, workplaces have a duty to provide reasonable accommodations, and educational institutions have a duty to provide appropriate academic adjustments or modifications, to help the individual work more efficiently and productively.In a 2004 study it was estimated that the yearly income discrepancy for adults with ADHD was $10,791 less per year than high school graduate counterparts and $4,334 lower for college graduate counterparts. The study estimates a total loss in productivity in the United States of over US$77 billion.
Controversy
ADHD controversies include concerns about its existence as a disorder, its causes, the methods by which ADHD is diagnosed and treated including the use of stimulant medications in children, possible overdiagnosis, misdiagnosis as ADHD leading to undertreatment of the real underlying disease, alleged hegemonic practices of the American Psychiatric Association and negative stereotypes of children diagnosed with ADHD. These controversies have surrounded the subject since at least the 1970s.
References
Further reading
External links
"Publications About ADHD". National Institute for Mental Health. Rockville, Maryland. Archived from the original on 2017-01-18. Retrieved 2015-04-13. |
Wandering spleen | Wandering spleen (or pelvic spleen) is a rare medical disease caused by the loss or weakening of the ligaments that help to hold the spleen stationary.
Symptoms and signs
Although symptoms include an enlargement in the size of the spleen, or a change from the spleens original position to another location, usually in either other parts of the abdomen or into the pelvis. This ability to move to other locations is commonly attributed to the spleens pedicle being abnormally long.Physical factors may cause ischuria, constipation, as well as numerous spleen-related diseases such as hypersplenism, thrombocytopenia, and lymphoma. Blocking of the arteries and torsion (twisting that interrupts the blood supply to that organ) in the spleen can also result in abdominal pain or swelling. However, lack of visible symptoms — except in incidents of abdominal pain — makes the disease difficult for doctors to diagnose, though medical imaging techniques such as medical ultrasonography, magnetic resonance imaging, or computed tomography can be used to confirm its occurrence. Characteristics of the disorder include the loss, weakening, or malformation of the ligaments that help to keep the spleen located in the upper left part of the abdomen.
Cause
Though not a genetic disease, wandering spleen is often found at birth. It can occur in adults as the result of injuries and other similar conditions that cause the ligaments to weaken, such as connective tissue disease or pregnancy. Wandering spleen (splenoptosis) predisposes the spleen to complications such as torsion, splenic infarction, pancreatic necrosis and rarely pseudocyst formation.
Diagnosis
Treatment
The usual treatment is splenopexy, fixation of the spleen, but if there is no blood flow after unwinding the spleen through detorsion then splenectomy must be performed. Although there have been few reported cases of treatment through laparoscopic surgery due to the rarity of the disease, it has been proven to be an effective surgical technique.
Prevalence
Wandering spleen is most commonly diagnosed in young children as well as women between the ages of 20 and 40. Even so, the disease is very rare and fewer than 500 occurrences of the disease have been reported as of 2005, of which around 148 (including both children and adult cases) were documented to have been from between 1960 and 1992. Less than 0.5% of all splenectomies, surgical removal of the spleen, are performed due to having this disorder.
In 1992, the youngest case of the literature of torsion of wandering spleen at two days of birth was reported in Lebanon, by Dr Edouard Sayad.
Media
Susan Mayer, in season 2 of the television show Desperate Housewives, had an operation to fix her wandering spleen.
References
== External links == |
Epidemic typhus | Epidemic typhus, also known as louse-borne typhus, is a form of typhus so named because the disease often causes epidemics following wars and natural disasters where civil life is disrupted. Epidemic typhus is spread to people through contact with infected body lice, in contrast to endemic typhus which is usually transmitted by fleas.Though typhus has been responsible for millions of deaths throughout history, it is still considered a rare disease that occurs mainly in populations that suffer unhygienic extreme overcrowding. Typhus is most rare in industrialized countries. It occurs primarily in the colder, mountainous regions of central and east Africa, as well as Central and South America. The causative organism is Rickettsia prowazekii, transmitted by the human body louse (Pediculus humanus corporis). Untreated typhus cases have a fatality rate of approximately 40%.Epidemic typhus should not be confused with Murine typhus, which is more endemic to the United States, particularly Southern California and Texas. This form of typhus has similar symptoms, but is caused by Rickettsia typhi. It is carried primarily in rat feces and fleas, as well as other rodents. It is not as deadly as louse-born typhus. It occurs only during the summer and fall, when rodents are active among humans.
Signs and symptoms
Symptoms of this disease typically begin within 2 weeks of contact with the causative organism. Signs/Symptoms may include:
Fever
Chills
Headache
Confusion
Cough
Rapid Breathing
Body/Muscle Aches
Rash
Nausea
VomitingAfter 5–6 days, a macular skin eruption develops: first on the upper trunk and spreading to the rest of the body (rarely to the face, palms, or soles of the feet, however).Brill–Zinsser disease, first described by Nathan Brill in 1913 at Mount Sinai Hospital in New York City, is a mild form of epidemic typhus that recurs in someone after a long period of latency (similar to the relationship between chickenpox and shingles). This recurrence often arises in times of relative immunosuppression, which is often in the context of a person suffering malnutrition or other illnesses. In combination with poor sanitation and hygiene in times of social chaos and upheaval, which enable a greater density of lice, this reactivation is why typhus generates epidemics in such conditions.
Complications
Complications are as follows
Myocarditis
Endocarditis
Mycotic aneurysm
Pneumonia
Pancreatitis
Kidney or bladder infections
Acute renal failure
Meningitis
Encephalitis
Myelitis
Septic shock
Transmission
Feeding on a human who carries the bacterium infects the louse. R. prowazekii grows in the louses gut and is excreted in its feces. The louse transmits the disease by biting an uninfected human, who scratches the louse bite (which itches) and rubs the feces into the wound. The incubation period is one to two weeks. R. prowazekii can remain viable and virulent in the dried louse feces for many days. Typhus will eventually kill the louse, though the disease will remain viable for many weeks in the dead louse.Epidemic typhus has historically occurred during times of war and deprivation. For example, typhus killed millions of prisoners in German Nazi concentration camps during World War II. The unhygenic conditions in camps such as Auschwitz, Theresienstadt, and Bergen-Belsen allowed diseases such as typhus to flourish. Situations in the twenty-first century with potential for a typhus epidemic would include refugee camps during a major famine or natural disaster. In the periods between outbreaks, when human to human transmission occurs less often, the flying squirrel serves as a zoonotic reservoir for the Rickettsia prowazekii bacterium.
In 1916, Henrique da Rocha Lima proved that the bacterium Rickettsia prowazekii was the agent responsible for typhus; he named it after H. T. Ricketts and Stanislaus von Prowazek, two zoologists who had died from typhus while investigating epidemics. Once these crucial facts were recognized, Rudolf Weigl in 1930 was able to fashion a practical and effective vaccine production method. He ground up the insides of infected lice that had been drinking blood. It was, however, very dangerous to produce, and carried a high likelihood of infection to those who were working on it.
A safer mass-production-ready method using egg yolks was developed by Herald R. Cox in 1938. This vaccine was widely available and used extensively by 1943.
Diagnosis
IFA, ELISA or PCR positive after 10 days.
Treatment
The infection is treated with antibiotics. Intravenous fluids and oxygen may be needed to stabilize the patient. There is a significant disparity between the untreated mortality and treated mortality rates: 10-60% untreated versus close to 0% treated with antibiotics within 8 days of initial infection. Tetracycline, chloramphenicol, and doxycycline are commonly used. Infection can also be prevented by vaccination.Some of the simplest methods of prevention and treatment focus on preventing infestation of body lice. Completely changing the clothing, washing the infested clothing in hot water, and in some cases also treating recently used bedsheets all help to prevent typhus by removing potentially infected lice. Clothes left unworn and unwashed for 7 days also result in the death of both lice and their eggs, as they have no access to a human host. Another form of lice prevention requires dusting infested clothing with a powder consisting of 10% DDT, 1% malathion, or 1% permethrin, which kill lice and their eggs.Other preventive measures for individuals are to avoid unhygienic, extremely overcrowded areas where the causative organisms can jump from person to person. In addition, they are warned to keep a distance from larger rodents that carry lice, such as rats, squirrels, or opossums.
History
History of outbreaks
Before 19th century
During the second year of the Peloponnesian War (430 BC), the city-state of Athens in ancient Greece had an epidemic, known as the Plague of Athens, which killed, among others, Pericles and his two elder sons. The plague returned twice more, in 429 BC and in the winter of 427/6 BC. Epidemic typhus is proposed as a strong candidate for the cause of this disease outbreak, supported by both medical and scholarly opinions.
The first description of typhus was probably given in 1083 at La Cava abbey near Salerno, Italy. In 1546, Girolamo Fracastoro, a Florentine physician, described typhus in his famous treatise on viruses and contagion, De Contagione et Contagiosis Morbis.Typhus was carried to mainland Europe by soldiers who had been fighting on Cyprus. The first reliable description of the disease appears during the siege of the Emirate of Granada by the Catholic Monarchs in 1489 during the Granada War. These accounts include descriptions of fever and red spots over arms, back and chest, progressing to delirium, gangrenous sores, and the stench of rotting flesh. During the siege, the Catholics lost 3,000 men to enemy action, but an additional 17,000 died of typhus.Typhus was also common in prisons (and in crowded conditions where lice spread easily), where it was known as Gaol fever or Jail fever. Gaol fever often occurs when prisoners are frequently huddled together in dark, filthy rooms. Imprisonment until the next term of court was often equivalent to a death sentence. Typhus was so infectious that prisoners brought before the court sometimes infected the court itself. Following the Black Assize of Oxford 1577, over 300 died from epidemic typhus, including Speaker Robert Bell, Lord Chief Baron of the Exchequer. The outbreak that followed, between 1577 and 1579, killed about 10% of the English population.During the Lent assize held at Taunton (1730), typhus caused the death of the Lord Chief Baron of the Exchequer, the High Sheriff of Somerset, the sergeant, and hundreds of other persons. During a time when there were 241 capital offences, more prisoners died from gaol fever than were put to death by all the public executioners in the realm. In 1759 an English authority estimated that each year a quarter of the prisoners had died from gaol fever. In London, typhus frequently broke out among the ill-kept prisoners of Newgate Gaol and moved into the general city population.
19th century
Epidemics occurred in the British Isles and throughout Europe, for instance, during the English Civil War, the Thirty Years War, and the Napoleonic Wars. Many historians believe that the typhus outbreak among Napoleons troops is the real reason why he stalled his military campaign into Russia, rather than starvation or the cold. A major epidemic occurred in Ireland between 1816 and 1819, and again in the late 1830s. Another major typhus epidemic occurred during the Great Irish Famine between 1846 and 1849. The Irish typhus spread to England, where it was sometimes called "Irish fever" and was noted for its virulence. It killed people of all social classes since lice were endemic and inescapable, but it hit particularly hard in the lower or "unwashed" social strata. It was carried to North America by the many Irish refugees who fled the famine. In Canada, the 1847 North American typhus epidemic killed more than 20,000 people, mainly Irish immigrants in fever sheds and other forms of quarantine, who had contracted the disease aboard coffin ships. As many as 900,000 deaths have been attributed to the typhus fever during the Crimean War in 1853–1856, and 270,000 to the 1868 Finnish typhus epidemic.In the United States, a typhus epidemic struck Philadelphia in 1837. The son of Franklin Pierce died in 1843 of a typhus epidemic in Concord, New Hampshire. Several epidemics occurred in Baltimore, Memphis, and Washington, D.C. between 1865 and 1873. Typhus fever was also a significant killer during the American Civil War, although typhoid fever was the more prevalent cause of US Civil War "camp fever." Typhoid is a completely different disease from typhus. Typically more men died on both sides of disease than wounds.Rudolph Carl Virchow, a physician, anthropologist, and historian attempted to control an outbreak of typhus in Upper Silesia and wrote a 190-page report about it. He concluded that the solution to the outbreak did not lie in individual treatment or by providing small changes in housing, food or clothing, but rather in widespread structural changes to directly address the issue of poverty. Virchows experience in Upper Silesia led to his observation that "Medicine is a social science". His report led to changes in German public health policy.
20th century
Typhus was endemic in Poland and several neighboring countries prior to World War I (1914–1918). During and shortly after the war, epidemic typhus caused up to three million deaths in Russia, and several million citizens also died in Poland and Romania. Since 1914, many troops, prisoners and even doctors were infected, and at least 150,000 died from typhus in Serbia, 50,000 of whom were prisoners. Delousing stations were established for troops on the Western Front, but the disease ravaged the armies of the Eastern Front. Fatalities were generally between 10 and 40 percent of those infected, and the disease was a major cause of death for those nursing the sick. During World War I and the Russian Civil War between the White and Red, the typhus epidemic caused 2–3 million deaths out of 20–30 million cases in Russia between 1918 and 1922.
Typhus caused hundreds of thousands of deaths during World War II. It struck the German Army during Operation Barbarossa, the invasion of Russia, in 1941. In 1942 and 1943 typhus hit French North Africa, Egypt and Iran particularly hard. Typhus epidemics killed inmates in the Nazi concentration camps and death camps such as Auschwitz, Dachau, Theresienstadt, and Bergen-Belsen. Footage shot at Bergen-Belsen concentration camp shows the mass graves for typhus victims. Anne Frank, at age 15, and her sister Margot both died of typhus in the camps. Even larger epidemics in the post-war chaos of Europe were averted only by the widespread use of the newly discovered DDT to kill lice on the millions of refugees and displaced persons.Following the development of a vaccine during World War II, Western Europe and North America have been able to prevent epidemics. These have usually occurred in Eastern Europe, the Middle East, and parts of Africa, particularly Ethiopia. Naval Medical Research Unit Five worked there with the government on research to attempt to eradicate the disease.In one of its first major outbreaks since World War II, epidemic typhus reemerged in 1995 in a jail in NGozi, Burundi. This outbreak followed the start of the Burundian Civil War in 1993, which caused the displacement of 760,000 people. Refugee camps were crowded and unsanitary, and often far from towns and medical services.
21st century
A 2005 study found seroprevalence of R. prowazekii antibodies in homeless populations in two shelters in Marseille, France. The study noted the "hallmarks of epidemic typhus and relapsing fever".
History of vaccines
Major developments for typhus vaccines started during World War I, as typhus caused high mortality, and threatened the health and readiness for soldiers on the battlefield. Vaccines for typhus, like other vaccines of the time, were classified as either living or killed vaccines. Live vaccines were typically an injection of live agent, and killed vaccines are live cultures of an agent that are chemically inactivated prior to use.Attempts to create a living vaccine of classical, louse-borne, typhus were attempted by French researchers but these proved unsuccessful. Researchers turned to murine typhus to develop a live vaccine. At the time, murine vaccine was viewed as a less severe alternative to classical typhus. Four versions of a live vaccine cultivated from murine typhus were tested, on a large scale, in 1934.While the French were making advancements with live vaccines, other European countries were working to develop killed vaccines. During World War II, there were three kinds of potentially useful killed vaccines. All three killed vaccines relied on the cultivation of Rickettsia prowazekii, the organism responsible for typhus. The first attempt at a killed vaccine was developed by Germany, using the Rickettsia prowazekii found in louse feces. The vaccine was tested extensively in Poland between the two world wars and used by the Germans for their troops during their attacks on the Soviet Union.A second method of growing Rickettsia prowazekii was discovered using the yolk sac of chick embryos. Germans tried several times to use this technique of growing Rickettsia prowazekii but no effort was pushed very far.The last technique was an extended development of the previously known method of growing murine typhus in rodents. It was discovered that rabbits could be infected, by a similar process, and contract classical typhus instead of murine typhus. Again, while proven to produce suitable Rickettsia prowazekii for vaccine development, this method was not used to produce wartime vaccines.During WWII, the two major vaccines available were the killed vaccine grown in lice and the live vaccine from France. Neither was used much during the war. The killed, louse-grown vaccine was difficult to manufacture in large enough quantities, and the French vaccine was not believed to be safe enough for use.The Germans worked to develop their own live vaccine from the urine of typhus victims. While developing a live vaccine, Germany used live Rickettsia prowazekii to test multiple possible vaccines capabilities. They gave live Rickettsia prowazekii to concentration camp prisoners, using them as a control group for the vaccine tests.The use of DDT as an effective means of killing lice, the main carrier of typhus, was discovered in Naples.
Society and culture
Biological weapon
Typhus was one of more than a dozen agents that the United States researched as potential biological weapons before President Richard Nixon suspended all non-defensive aspects of the U.S. biological weapons program in 1969.
Poverty and displacement
The CDC lists the following areas as active foci of human epidemic typhus: Andean regions of South America, some parts of Africa; on the other hand, the CDC only recognizes an active enzootic cycle in the United States involving flying squirrels (CDC). Though epidemic typhus is commonly thought to be restricted to areas of the developing world, serological examination of homeless persons in Houston found evidence for exposure to the bacterial pathogens that cause epidemic typhus and murine typhus. A study involving 930 homeless people in Marseille, France, found high rates of seroprevalence to R. prowazekii and a high prevalence of louse-borne infections in the homeless.Typhus has been increasingly discovered in homeless populations in developed nations. Typhus among homeless populations is especially prevalent as these populations tend to migrate across states and countries, spreading the risk of infection with their movement. The same risk applies to refugees, who travel across country lines, often living in close proximity and unable to maintain necessary hygienic standards to avoid being at risk for catching lice possibly infected with typhus.Because the typhus-infected lice live in clothing, the prevalence of typhus is also affected by weather, humidity, poverty and lack of hygiene. Lice, and therefore typhus, are more prevalent during colder months, especially winter and early spring. In these seasons, people tend to wear multiple layers of clothing, giving lice more places to go unnoticed by their hosts. This is particularly a problem for poverty-stricken populations as they often do not have multiple sets of clothing, preventing them from practicing good hygiene habits that could prevent louse infestation.Due to fear of an outbreak of epidemic typhus, the US Government put a typhus quarantine in place in 1917 across the entirety of the US-Mexican border. Sanitation plants were constructed that required immigrants to be thoroughly inspected and bathed before crossing the border. Those who routinely crossed back and forth across the border for work were required to go through the sanitation process weekly, updating their quarantine card with the date of the next weeks sanitation. These sanitation border stations remained active over the next two decades, regardless of the disappearance of the typhus threat. This fear of typhus and resulting quarantine and sanitation protocols dramatically hardened the border between the US and Mexico, fostering scientific and popular prejudices against Mexicans. This ultimately intensified racial tensions and fueled efforts to ban immigrants to the US from the Southern Hemisphere because the immigrants were associated with the disease.
Literature
(1847) In Jane Eyre by Charlotte Brontë, an outbreak of typhus occurs in Janes school Lowood, highlighting the unsanitary conditions the girls live in.
(1862) In Fathers and Sons by Ivan Turgenev, Evgeny Bazarov dissects a local peasant and dies after contracting typhus.
(1886) In the short story "Excellent People" by Anton Chekhov, typhus kills a Russian provincial.
(1886) In The Strange Adventures of Captain Dangerous by George Augustus Henry Sala: "We Convicts were all had to the Grate, for the Knight and Alderman would not venture further in, for fear of the Gaol Fever;"
(1890) In How the Other Half Lives by Jacob Riis, the effects of typhus fever and smallpox on "Jewtown" are described.
(1935) Hans Zinssers Rats, Lice and History, although a touch outdated on the science, contains many useful cross-references to classical and historical impact of typhus.
(1940) in The Don Flows Home to the Sea by Mikhail Sholokhov, numerous characters contract typhus during the Russian Civil War.
(1946) In Viktor Frankls Mans Search for Meaning, Frankl, a Nazi concentration camp prisoner and trained psychiatrist, treats fellow prisoners for delirium due to typhus, while being occascionally affected with the disease himself.
(1955) In Vladimir Nabokovs Lolita, Humbert Humberts childhood sweetheart, Annabel Leigh, dies of typhus.
(1956) In Doctor Zhivago by Boris Pasternak, the main character contracts epidemic typhus in the winter following the Russian Revolution, while living in Moscow.
(1964) In Nacht (novel) by Edgar Hilsenrath, characters imprisoned in a ghetto in Transnistria during World War II are portrayed infected with and dying of epidemic typhus.
(1978) In Patrick OBrians novel Desolation Island, an outbreak of "gaol-fever" strikes the crew while sailing aboard the Leopard.
(1980–1991) In Maus by Art Spiegelman, Vladek Spiegelman contracts typhus during his imprisonment at the Dachau concentration camp.
(1982) There is a typhus epidemic in Chile graphically described in The House of the Spirits by Isabel Allende
(1996) In Andrea Barretts novella Ship Fever, the characters struggle with a typhus outbreak at the Canadian Grosse Isle Quarantine Station during 1847.
(2001) Lynn and Gilbert Morris novel Where Two Seas Met portrays an outbreak of typhus on the island of Bequia in the Grenadines, in 1869.
(2004) In Neal Stephensons The System Of The World, a fictionalized Sir Isaac Newton dies of "gaol fever" before being resurrected by Daniel Waterhouse.
See also
Globalization and disease
List of epidemics
Weil-Felix test
References
55. ↑ Alice S. Chapman (2006). "Cluster of Sylvatic Epidemic Typhus Cases Associated with Flying Squirrels, 2004 - 2006" MedscapeCME Epidemic Typhus Associated with Flying Squirrels -- United States |
Progressive nodular histiocytosis | Progressive nodular histiocytosis is a cutaneous condition clinically characterized by the development of two types of skin lesions: superficial papules and deeper larger subcutaneous nodules.: 718
See also
Non-X histiocytosis
== References == |
Juvenile hyaline fibromatosis | Juvenile hyaline fibromatosis (also known as "Fibromatosis hyalinica multiplex juvenilis," "Murray–Puretic–Drescher syndrome") is a very rare, autosomal recessive disease due to mutations in capillary morphogenesis protein-2 (CMG-2 gene). It occurs from early childhood to adulthood, and presents as slow-growing, pearly white or skin-colored dermal or subcutaneous papules or nodules on the face, scalp, and back, which may be confused clinically with neurofibromatosis. The World Health Organization, 2020, reclassified the papules and nodules that occur in juvenile hyaline firbromatosis as one of the specific benign types of tumors in the category of fibroblastic and myofibroblastic tumors.
Presentation
This condition is characterised by abnormal growth of hyalinized fibrous tissue with cutaneous, mucosal, osteoarticular and systemic involvement.
Clinical features include extreme pain at minimal handling in a newborn, gingival hypertrophy, subcutaneous nodules, painful joint stiffness and contractures, muscle weakness and hypotonia.
Genetics
This condition is due to mutations in the anthrax toxin receptor-2 (ANTXR2) gene. This gene is also known as capillary morphogenesis protein-2.
This gene is located on the long arm of chromosome 4 (4q21.21).
Management
There is no presently known curative treatment for this condition.Management is supportive
Prognosis
This is very poor with a median age at death of 15 months.
Epidemiology
84 cases have been reported as of 2018.
See also
List of cutaneous conditions
References
== External links == |
Camurati–Engelmann disease | Camurati–Engelmann disease (CED) is a very rare autosomal dominant genetic disorder that causes characteristic anomalies in the skeleton. It is also known as progressive diaphyseal dysplasia. It is a form of dysplasia. Patients typically have heavily thickened bones, especially along the shafts of the long bones (called diaphyseal dysplasia). The skull bones may be thickened so that the passages through the skull that carry nerves and blood vessels become narrowed, possibly leading to sensory deficits, blindness, or deafness.
This disease often appears in childhood and is considered to be inherited, however many patients have no previous history of CED within their family. The disease is slowly progressive and, while there is no cure, there is treatment.
It is named for M. Camurati and G. Engelmann.
Signs and symptoms
Patients with CED complain of chronic bone pain in the legs or arms, muscle weakness (myopathy) and experience a waddling gait. Other clinical problems associated with the disease include increased fatigue, weakness, muscle spasms, headache, difficulty gaining weight, and delay in puberty. Some patients have an abnormal or absent tibia, may present with a flat foot, or scoliosis.This disease may also cause bones to become abnormally hardened which is referred to as sclerosis. This hardening may affect the bones at the base of the skull or those in the hands, feet, or jaw. This causes ongoing pain and aching within the body parts that are affected. The pain has been described as either a hot electric stabbing pain, an ever-increasing pressure sensation around the bones (especially before electrical storms) or as a constant ache that radiates through several long bones at once. Pain may also occur in the hips, wrists, knees and other joints as they essentially just lock-up (often becoming very stiff, immobile and sore), mostly when walking up or down staircases, writing for extended periods of time, or during the colder months of the year. Those with the disease tend to have a very characteristic walk medically diagnosed as a waddling gait. This is observed by the broad-based gait with a duck-like waddle to the swing phase, the pelvis drops to the side of the leg being raised, notable forward curvature of the lumbar spine and a marked body swing.The pain is especially severe during a flare-up, these can be unpredictable, exhausting and last anywhere from a few hours to several weeks. This is a common occurrence for several CED patients, often causing myopathy and extensive sleep deprivation from the chronic, severe and disabling pain. Patients may even require the use of a wheelchair (or additional carers help with getting dressed, showering, mobility/shopping, preparing meals or lifting heavy items) especially when bedridden or housebound for days or weeks at a time. Flare-ups may be attributed to, or exacerbated by growth spurts, stress, exhaustion, exercise, standing or walking for too long, illness, infection, being accidentally knocked/hurt or injured, after surgery/anaesthetics, cold weather, electrical storms, and sudden changes in barometric pressure.CED may also affect internal organs, the liver and spleen, which may become enlarged. A loss of vision and/or hearing can occur if bones are adversely affected by the hardening in the skull. Hence proactive specialist check-ups, X-rays, diagnostic tests/scans, and regular blood tests are recommended on an annual basis to monitor the CED bony growth and secondary medical issues that may arise from this condition.
Cause
Camurati-Engelmann disease is caused by autosomal dominant mutations in the gene TGFB1, localized at chromosome 19q13.
Diagnosis
Classification
There are two forms:
Type 1 is associated with TGFB1
Type 2 is not associated with TGFB1Type 1 Camurati-Engelmann Disease is associated with an error occurring in the TGFB1 protein. Affected individuals shared a haplotype between D19S881 to D19S606. TGFB1 protein is encoded by the TGF-B1 gene, which occurs on chromosome 19q13.1-13.3. This protein is responsible for a multitude of functions, one of which includes regulating the function of osteoblasts and osteoclasts, which decreases bone resorption and increases bone formation. These functions can be affected by a series of mutations that occur on exon 4, near the carboxyl terminus of the latency associated peptide, or LAP. TGFB1 is expressed as a latent form, a mature form and a B1-LAP. Mutations to R218H affect the association of the B1-LAP and the mature form of TGFB1 by conformational changes to B1-LAP. These mutations can lead to a buildup of mature TGFB1, which accumulates in the mutant R218H fibroblasts. Fibroblasts are a type of cell that creates collagen and the extracellular matrix. This suggests that R218H mutation causes a disassociation between mature-TGFB1 and B1-LAP. Mutations at the LLL12-13ins and Y81H regions decrease the secretion of TGFB1, which leads to intracellular buildup of TGFB1.Type 2 Camurati-Engelmann Disease is still speculative, with no distinct evidence to credit its existence. There are many similarities between Type 2 CED and hyperostosis generalisata with striations of the bones (HGS), with some speculating they are two phenotypic variations of the same disease.
Treatment
Camurati–Engelmann disease is somewhat treatable. Glucocorticosteroids, which are anti-inflammatory and immunosuppressive agents, are used in some cases. This form of medication helps in bone strength, however can have multiple side effects. In several reports, successful treatment with glucocoricosteroids was described, as certain side effects can benefit a person with CED. This drug helps with pain and fatigue as well as some correction of radiographic abnormalities.Alternative treatments such as massage, relaxation techniques (meditation, essential oils, spa baths, music therapy, etc.), gentle stretching, and especially heat therapy have been successfully used to an extent in conjunction with pain medications. A majority of CED patients require some form of analgesics, muscle relaxant, and/or sleep inducing medication to manage the pain, specifically if experiencing frequent or severe flare-ups (e.g. during winter).
Notable persons
John Belluso, writer for the CBS television show Ghost Whisperer, used a wheel chair from the age of 13 because of the Camurati–Engelmann syndrome. He died on February 10, 2006, at the age of 36 in New York City.
References
Further reading
Camurati-Engelmann disease on Genetic Home Reference
GeneReviews/NCBI/NIH/UW entry on Camurati-Engelmann Disease
Wallace, Stephanie E.; Wilcox, William R. (1 January 1993). Camurati-Engelmann Disease. GeneReviews. University of Washington, Seattle. PMID 20301335.
== External links == |
Alternating hemiplegia | Alternating hemiplegia (also known as crossed hemiplegia) is a form of hemiplegia that has an ipsilateral cranial nerve palsies and contralateral hemiplegia or hemiparesis of extremities of the body. The disorder is characterized by recurrent episodes of paralysis on one side of the body. There are multiple forms of alternating hemiplegia, Webers syndrome, middle alternating hemiplegia, and inferior alternating hemiplegia. This type of syndrome can result from a unilateral lesion in the brainstem affecting both upper motor neurons and lower motor neurons. The muscles that would receive signals from these damaged upper motor neurons result in spastic paralysis. With a lesion in the brainstem, this affects the majority of limb and trunk muscles on the contralateral side due to the upper motor neurons decussation after the brainstem. The cranial nerves and cranial nerve nuclei are also located in the brainstem making them susceptible to damage from a brainstem lesion. Cranial nerves III (Oculomotor), VI (Abducens), and XII (Hypoglossal) are most often associated with this syndrome given their close proximity with the pyramidal tract, the location which upper motor neurons are in on their way to the spinal cord. Damages to these structures produce the ipsilateral presentation of paralysis or palsy due to the lack of cranial nerve decussation (aside from the trochlear nerve) before innervating their target muscles. The paralysis may be brief or it may last for several days, many times the episodes will resolve after sleep. Some common symptoms of alternating hemiplegia are mental impairment, gait and balance difficulties, excessive sweating and changes in body temperature.
Symptoms and signs
Superior alternating hemiplegia
Superior alternating hemiplegia (also known as Weber syndrome) has a few distinct symptoms: contralateral hemiparesis of limb and facial muscle accompanied by weakness in one or more muscles that control eye movement on the same side. Another symptom that appears is the loss of eye movement due to damage to the oculomotor nerve fibers. The upper and lower extremities have increased weakness.
Middle alternating hemiplegia
Middle alternating hemiplegia (also known as Foville Syndrome) typically constitutes weakness of the extremities accompanied by paralysis of the extraocular muscle specifically lateral rectus, on the opposite side of the affected extremities, which indicates a lesion in the caudal and medial pons involving the abducens nerve root (controls movement of the eye) and corticospinal fibers (carries motor commands from the brain to the spinal cord).
Inferior alternating hemiplegia
Inferior alternating hemiplegia (also known as medial medullary syndrome) typically involves a "weakness of the extremities accompanied by paralysis of muscles on the ipsilateral side of the tongue (seen as a deviation of the tongue on that side on protrusion). These symptoms indicate a lesion in the medulla involving the corticospinal fibers in the pyramid and the exiting hypoglossal nerve roots.
Causes
Note that this description is focused on alternating hemiplegia of childhood. Similar syndromes may develop following a brainstem infarction.
The cause of alternating hemiplegia of childhood is the mutation of ATP1A3 gene. In a study of fifteen female and nine male patients with alternating hemiplegia, a mutation in ATP1A3 gene was present. Three patients showed heterozygous de-novo missense mutation. Six patients were found with de-novo missense mutation and one patient was identified with de-novo splice site mutation. De novo mutation is a mutation that occurs in the germ cell of one parent. Neither parent has the mutation, but it is passed to the child through the sperm or egg.
Diagnosis
There is no diagnostic test for alternating hemiplegia, which makes it very difficult to diagnose. Also, because alternating hemiplegia is extremely rare, it is frequently missed and the patient is often misdiagnosed. Proper diagnosis, however, is critical for early treatment of the disorder. There are many criteria that can help in the proper general diagnosis of alternating hemiplegia.
Criteria for diagnosis
First, the symptoms must be observed before the patient is 18 months of age. Second, there must be frequent episodes of hemiplegia, involving either side of the body. Third, other paroxysmal disorders including tonic attacks, dystonia, nystagmus, strabismus, dyspnoea, and other uncontrollable disorders are noticed to occur. Although common, the paroxysmal disorders involving the eye, nystagmus and strabismus, may not be apparent in older children and may not have been remembered in childhood so a lack of these symptoms does not rule out alternating hemiplegia. Fourth, all symptoms clear up directly after falling asleep and usually come back after waking during an attack. This occurrence is very indicative of alternating hemiplegia and as such those who display this are usually diagnosed with probable alternating hemiplegia. Fifth, indications of developmental delays, learning disability, or neurological irregularities are present. These issues may not be obvious in very young patients; however, it appears in almost all older patients.: 777 The final criteria before a diagnosis of alternating hemiplegia can be made is that all of these symptoms must not be due to another disorder. If the symptoms can be attributed to another disease or disorder, then a definitive diagnosis is difficult to make.: 778
Diagnosis of Webers syndrome
Webers syndrome is the only form of alternating hemiplegia that is somewhat easy to diagnose beyond the general criteria. Although Webers syndrome is rare, a child born with the disorder typically has a port-wine stain on the face around the eye. While the port-wine stain does not necessarily mean the child has Webers syndrome, if the port-wine stain involves the ophthalmic division of the trigeminal nerve than the likelihood of it being webers syndrome greatly increases. If a port-wine stain around the eye is found, the patient should be screened for intracranial leptomeningeal angiomatosis. Magnetic resonance imaging (MRI) can be used to determine the presence and severity while computed cranial tomography can be used to determine the effect. MRI is the preferred diagnostic test on children presenting with port-wine stain. Other imaging techniques can be used in addition to further determine the severity of the disorder. The initial diagnosis is made based on the presence of neurologic and ophthalmic disease but the disease progresses differently in each patient so after initial diagnosis the patient should be monitored frequently in order to handle further complications resulting from the syndrome.
Treatment
Medical treatment of hemiplegia can be separate into several different categories:: 779
prophylactic treatment by avoiding triggers and long-term drug treatment
acute management of the episodes
management of the epilepsy
sleep as a management technique.Seizure trigger include exposure to cold, emotional stress, fatigue, bathing, hyperthermia/hypothermia, and upper respiratory infection. A drug called flunarizine, which is a calcium channel blocker can help to reduce the severity and the length of attacks of the paralysis.
Flunarizine
Many children affected by alternating hemiplegia also have epilepsy. Seizures may occur during an attack but more often occur between attacks. Anti-epilepsy drugs are given to prevent or lessen the seizures, but the drugs often dont work and have severe side effects that require the patient to discontinue use. Flunarizine, which blocks calcium channels, is an antiepilepsy drugs used in 50% of patients, and has been shown to shorten the duration of attacks as well as reducing the severity of the attacks. While Flunarizine does not stop the attacks, it is most common drug prescribed to treat those with alternating hemiplegia.: 779
Sleep and diet
Sleep is also used as a management technique. An early indication of an episode is tiredness so medication such as melatonin or Buccal midazolam can be administered to induce sleep and avoid the episode.
People with alternating hemiplegia are often underweight and with the help of dietitians, a meal plan should be developed for times of attack when consumption of food may be difficult.: 779–780
See also
Hemiplegia
Alternating hemiplegia of childhood
Webers syndrome
Medial medullary syndrome
Familial hemiplegic migraine
Brain stem stroke syndrome
References
External links
alternatinghemiplegia at NINDS |
Mastocytoma | A mastocytoma or mast cell tumor is a type of round-cell tumor consisting of mast cells. It is found in humans and many animal species; it also can refer to an accumulation or nodule of mast cells that resembles a tumor.
Mast cells originate from the bone marrow and are normally found throughout the connective tissue of the body as normal components of the immune system. As they release histamine, they are associated with allergic reactions. Mast cells also respond to tissue trauma. Mast cell granules contain histamine, heparin, platelet-activating factor, and other substances. Disseminated mastocytosis is rarely seen in young dogs and cats, while mast cell tumors are usually skin tumors in older dogs and cats. Although not always malignant, they do have the potential to be. Up to 25 percent of skin tumors in dogs are mast cell tumors, with a similar number in cats.
Signs and symptoms
Humans
When mastocytomas affect humans, they are typically found in skin. They usually occur as a single lesion on the trunk or wrist. Although it is rare, mastocytomas are sometimes found in the lung. It can also affect children.
Other animals
Mast cell tumors are known among veterinary oncologists as the great pretenders because their appearance can be varied, from a wart-like nodule to a soft subcutaneous lump (similar on palpation to a benign lipoma) to an ulcerated skin mass. Most mast cell tumors are small, raised lumps on the skin. They may be hairless, ulcerated, or itchy. They are usually solitary, but in about six percent of cases, there are multiple mast cell tumors (especially in Boxers and Pugs).Manipulation of the tumor may result in redness and swelling from release of mast cell granules, also known as Dariers sign, and prolonged local hemorrhage. In rare cases, a highly malignant tumor is present, and signs may include loss of appetite, vomiting, diarrhea, and anemia. The presence of these signs usually indicates mastocytosis, which is the spread of mast cells throughout the body. Release of a large amount of histamine at one time can result in ulceration of the stomach and duodenum (present in up to 25 percent of cases) or disseminated intravascular coagulation. When metastasis does occur, it is usually to the liver, spleen, lymph nodes and bone marrow.
Diagnosis
A needle aspiration biopsy of the tumor will typically show a large number of mast cells. This is sufficient to make the diagnosis of a mast cell tumor, although poorly differentiated mast cells may have few granules and thus are difficult to identify. The granules of the mast cell stain blue to dark purple with a Romanowsky stain, and the cells are medium-sized. However, a surgical biopsy is required to find the grade of the tumor. The grade depends on how well the mast cells are differentiated, mitotic activity, location within the skin, invasiveness, and the presence of inflammation or necrosis.
Grade I – well differentiated and mature cells with a low potential for metastasis
Grade II – intermediately differentiated cells with potential for local invasion and moderate metastatic behavior
Grade III – undifferentiated, immature cells with a high potential for metastasisHowever, there is a significant amount of discordance between veterinary pathologists in assigning grades to mast cell tumors due to imprecise criteria.The disease is also staged according to the WHO system:
Stage I - a single skin tumor with no spread to lymph nodes
Stage II - a single skin tumor with spread to lymph nodes in the surrounding area
Stage III - multiple skin tumors or a large tumor invading deep to the skin with or without lymph node involvement
Stage IV – a tumor with metastasis to the spleen, liver, or bone marrow, or with the presence of mast cells in the bloodX-rays, ultrasound, or lymph node, bone marrow, or organ biopsies may be necessary to stage the disease.
Treatment and prognosis
Removal of the mast cell tumor through surgery is the treatment of choice. Antihistamines, such as diphenhydramine, are given prior to surgery to protect against the effects of histamine released from the tumor. Wide margins (two to three centimeters) are required because of the tendency for the tumor cells to be spread out around the tumor. If complete removal is not possible due to the size or location, additional treatment, such as radiation therapy or chemotherapy, may be necessary. Prednisone is often used to shrink the remaining tumor portion. H2 blockers, such as cimetidine, protect against stomach damage from histamine. Vinblastine and lomustine are common chemotherapy agents used to treat mast cell tumors.Toceranib and masitinib, examples of receptor tyrosine kinase inhibitors, are used in the treatment of canine mast cell tumors. Both were recently approved by the U.S. Food and Drug Administration (FDA) as dog-specific anticancer drugs.Grade I or II mast cell tumors that can be completely removed have a good prognosis. One study showed about 23 percent of incompletely removed grade II tumors recurred locally. Any mast cell tumor found in the gastrointestinal tract, paw, or on the muzzle has a guarded prognosis. Previous beliefs that tumors in the groin or perineum carried a worse prognosis have been discounted. Tumors that have spread to the lymph nodes or other parts of the body have a poor prognosis. Any dog showing symptoms of mastocytosis or with a grade III tumor has a poor prognosis. Dogs of the Boxer breed have a better than average prognosis because of the relatively benign behavior of their mast cell tumors. Multiple tumors that are treated similarly to solitary tumors do not seem to have a worse prognosis.Mast cell tumors do not necessarily follow the histological prognosis. Further prognostic information can be provided by AgNOR stain of histological or cytological specimen. Even then, there is a risk of unpredictable behavior.
Other animals
Mast cell tumors are an uncommon occurrence in horses. They usually occur as benign, solitary masses on the skin of the head, neck, trunk, and legs. Mineralization of the tumor is common. In pigs and cattle, mast cell tumors are rare. They tend to be solitary and benign in pigs and multiple and malignant in cattle. Mast cell tumors are found in the skin of cattle most commonly, but these may be metastases from tumors of the viscera. Other sites in cattle include the spleen, muscle, gastrointestinal tract, omentum, and uterus.
Dogs
Mast cell tumors mainly occur in older adult dogs, but have been known to occur on rare occasions in puppies. The following breeds are commonly affected by mast cell tumors:
Boxer
Staffordshire bull terrier
Bulldog
Basset hound
Weimaraner
Boston terrier
Great Dane
Golden retriever
Labrador retriever
Beagle
German shorthaired pointer
Scottish terrier
Pug
Shar pei
Rhodesian ridgeback
Cats
Two types of mast cell tumors have been identified in cats, a mast cell type similar to dogs and a histiocytic type that appears as subcutaneous nodules and may resolve spontaneously. Young Siamese cats are at an increased risk for the histiocytic type, although the mast cell type is the most common in all cats and is considered to be benign when confined to the skin.Mast cell tumors of the skin are usually located on the head or trunk. Gastrointestinal and splenic involvement is more common in cats than in dogs; 50 percent of cases in dogs primarily involved the spleen or intestines. Gastrointestinal mast cell tumors are most commonly found in the muscularis layer of the small intestine, but can also be found in the large intestine. It is the third most common intestinal tumor in cats, after lymphoma and adenocarcinoma.Diagnosis and treatment are similar to that of the dog. Cases involving difficult to remove or multiple tumors have responded well to strontium-90 radiotherapy as an alternative to surgery. The prognosis for solitary skin tumors is good, but guarded for tumors in other organs. Histological grading of tumors has little bearing on prognosis.
References
External links
Mast Cell Tumors from The Pet Health Library
Mast Cell Tumors in Dogs from Pet Cancer Center
Mast Cell Tumors in Cats from Pet Cancer Center |
Elastosis perforans serpiginosa | Elastosis perforans serpiginosa is a unique perforating disorder characterized by transepidermal elimination of elastic fibers and distinctive clinical lesions, which are serpiginous in distribution and can be associated with specific diseases.
See also
List of cutaneous conditions
Poikiloderma vasculare atrophicans
References
== External links == |
Permanent junctional reciprocating tachycardia | Permanent junctional reciprocating tachycardia (PJRT) is a rare cardiac arrhythmia. It is a supraventricular tachycardia, and a cause of atrioventricular reentrant tachycardia (AVRT). PJRT can cause chronic tachycardia that, untreated, leads to cardiomyopathy. The cause is an accessory pathway in the heart which conducts from the ventricles back to the atria. Unlike the accessory pathway in a more common cause of AVRT, Wolff–Parkinson–White syndrome, the accessory pathway in PJRT conducts slowly. This means that the associated tachycardia may be subclinical and only diagnosed at a late stage, after significant damage to the heart has been caused from prolonged and recurrent episodes of AVRT.
Symptoms
Palpitations during exercise or stress may be the presenting symptom. Because the initial symptoms are often mild, there may be significant myocardial damage at the time of diagnosis. It is therefore possible for these patients to present with the symptoms of heart failure, such as shortness of breath, fatigue and oedema (fluid retention).
Cause
In-between episodes there is normal electrical conduction in the heart. During an episode of AVRT caused by PJRT, the accessory pathway conducts electrical activity from the ventricles directly back to the atria at the end of systole, which triggers the atria to contract, and the current to pass back to the ventricles again via the atrioventricular node (AV node); see diagram.
Diagnosis
There may be no signs outside of an episode. An electrocardiogram (ECG) undertaken during an episode of AVRT demonstrates typical features of retrograde (inverted) p-waves in the inferior leads II, III, aVF, and V4–V6 with a long RP′ interval. The P:QRS ratio would be 1:1 and they would be narrow complexes.
Treatment
Termination of an episode of AVRT in PJRT can be achieved with vagal manouvres, antiarrhythmic medications or DC cardioversion. Long-term management is best achieved with catheter ablation.
Prognosis
Without treatment, the prevalence of tachycardia-induced cardiomyopathy has been reported to be between 20% and 50%, however most patients who undergo ablation have significant improvement in their cardiac function
== References == |
Glutamate flavoring | Glutamate flavoring is the generic name for flavor-enhancing compounds based on glutamic acid and its salts (glutamates). These compounds provide an umami (savory) taste to food.
Glutamic acid and glutamates are natural constituents of many fermented or aged foods, including soy sauce, fermented bean paste, and cheese. They can also be found in hydrolyzed proteins such as yeast extract. The sodium salt of glutamic acid, monosodium glutamate (MSG), is manufactured on a large scale and widely used in the food industry.
Glutamic acid versus glutamates
When glutamic acid or any of its salts are dissolved in water, they form a solution of separate negative ions, called glutamates, and positive ions like H3O+ or Na+. The result is actually a chemical equilibrium among several ionized forms, including zwitterions, that depends on the pH (acidity) of the solution. Within the common pH range of foods, the prevailing ion can be described as −OOC-C(NH+3)-(CH2)2-COO−, which has an electric charge of −1.
Only the glutamate ion is responsible for the umami flavor, so the effect does not depend significantly on the starting compound. However, some crystalline salts such as monosodium glutamate dissolve much better and faster than crystalline glutamic acid. This has proven to be an important factor in the implementation of substances as flavor enhancers.
Discovery
Although they occur naturally in many foods, glutamic acid and other amino acid flavor contributions were not scientifically identified until early in the twentieth century. In 1866, the German chemist Karl Heinrich Ritthausen discovered and identified the compound. In 1907, Japanese researcher Kikunae Ikeda of the Tokyo Imperial University identified brown crystals left behind after the evaporation of a large amount of kombu broth as glutamic acid. These crystals, when tasted, reproduced the ineffable but undeniable flavor detected in many foods, especially seaweed. Professor Ikeda coined the term umami for this flavor. He then patented a method of mass-producing the crystalline salt of glutamic acid known as monosodium glutamate.
Isomers
Further research into the compound has found that only the L-glutamate enantiomer has flavor-enhancing properties. Manufactured monosodium glutamate consists to over 99.6% of the naturally predominant L-glutamate form, which is a higher proportion of L-glutamate than can be found in the free glutamate ions of fermented naturally occurring foods. Fermented products such as soy sauce, steak sauce, and Worcestershire sauce have levels of glutamate similar to those in foods with added monosodium glutamate. However, 5% or more of the glutamate may be the D-enantiomer. Nonfermented naturally occurring foods have lower relative levels of D-glutamate than fermented products do.
Taste perception
Glutamic acid stimulates specific receptors located in taste buds such as the amino acid receptor T1R1/T1R3 or other glutamate receptors like the metabotropic receptors (mGluR4 and mGluR1), which induce the flavor known as umami. This is classified as one of the five basic tastes (the word "umami" is a loanword from Japanese; it is also referred to as "savory" or "meaty").
The flavoring effect of glutamate comes from its free form, in which it is not bound to other amino acids in protein. Nonetheless, glutamate by itself does not elicit an intense umami taste. The mixing of glutamate with nucleotides inosine-5-monophosphate (IMP) or guanosine-5-monophosphate (GMP) enhances the taste of umami; T1R1 and T1R3 respond primarily to mixtures of glutamate and nucleotides. While research has shown that this synergism occurs in some animal species with other amino acids, studies of human taste receptors show that the same reaction only occurs between glutamate and the selected nucleotides. Moreover, sodium in monosodium glutamate may activate glutamate to produce a stronger umami taste.Two hypotheses for the explanation of umami taste transduction have been introduced: the first posits that the umami taste is transduced by an N-methyl-D-aspartate (NMDA) type glutamate ion channel receptor; the second posits that the taste is transduced by a metabotropic type glutamate receptor (taste-mGluR4). The metabotropic glutamate receptors such as mGluR4 and mGluR1 can be easily activated at glutamate concentration levels found in food.
Sources
Natural occurrence
Glutamate is ubiquitous in biological life. It is found naturally in all living cells, primarily in the bound form as a constituent of proteins. Only a fraction of the glutamate in foods is in its "free" form, and only free glutamate produces an umami flavor in foods. The savory flavor of tomatoes, fermented soy products, yeast extracts, certain sharp cheeses, and fermented or hydrolyzed protein products (such as soy sauce and fermented bean paste) is partially due to the presence of free glutamate ions.
Asia
Japanese cuisine originally used broth made from kombu (kelp) to produce the umami taste in soups. Manufacturers, such as Ajinomoto, use selected strains of Corynebacterium glutamicum bacteria in a nutrient-rich medium. The bacteria are selected for their ability to excrete glutamic acid, which is then separated from the nutrient medium and processed into its sodium salt, monosodium glutamate.
Rome
In the Roman Empire glutamic acid was found in a sauce called garum, made from fermenting fish in saltwater. The flavor enhancing properties of glutamic acid allowed Romans to reduce the use of expensive salt.
Concentration in foods
The following table illustrates the glutamate content of some selected common foods. Free glutamate is the form directly tasted and absorbed whereas glutamate bound in protein is not available until further breakdown by digestion or cooking. In general, vegetables contain more free glutamate but less protein-bound glutamate.
Hydrolyzed protein
Hydrolyzed proteins, or protein hydrolysates, are acid- or enzymatically treated proteins from certain foods. One example is yeast extract. Hydrolyzed protein contains free amino acids, such as glutamate, at levels of 5% to 20%. Hydrolyzed protein is used in the same manner as monosodium glutamate in many foods, such as canned vegetables, soups, and processed meats.
Safety as a flavor enhancer
Studies
Monosodium glutamate (MSG) is regarded as safe for consumption. An association between MSG consumption and a constellation of symptoms has not been demonstrated under rigorously controlled conditions. Techniques used to adequately control for experimental bias include a placebo-controlled double-blinded experimental design and the use of capsules to deliver the compound to mask the strong and unique after-taste of glutamates. Even though there are also reports of MSG sensitivity among a subset of the population, this has not been demonstrated in placebo‐controlled trials.
Controversy
Origin
The controversy surrounding the safety of MSG started on 4 April 1968, when Dr. Robert Ho Man Kwok wrote a correspondence letter to the New England Journal of Medicine, coining the term "Chinese restaurant syndrome". In his letter, Kwok suggested several possible causes before he nominated MSG for his symptoms. This letter was initially met with insider satirical responses, often using race as prop for humorous effect, within the medical community. Some claimed that during the discursive uptake in media, the conversations were recontextualized as legitimate while the supposed race-based motivations of the humor were not parsed.In January 2018, Dr. Howard Steel came forth claiming that it was actually a prank submission by him under a pseudonym. However, it turned out that there was a Dr. Robert Ho Man Kwok who worked at the National Biomedical Research Foundation, both names Steel claimed to have invented. Kwoks children, his colleague at the research foundation, and the son of his boss there confirmed that Dr. Robert Ho Man Kwok, who had died in 2014, wrote this letter. After hearing about Kwoks family, Steels daughter Anna came to believe that the admission that the letter was a prank was itself one of the last pranks by her late father.The claims of Chinese restaurant syndrome have the same symptoms as hypernatremia, so it may actually be salt poisoning.
Reactions
Some authors and activists have attributed the negative perceptions around MSG to xenophobic or racist biases towards East Asians and East Asian cuisine, criticising the classification of alleged MSG-related symptoms as "Chinese Restaurant Syndrome".In 2020, Ajinomoto, the leading manufacturer of MSG, launched the #RedefineCRS campaign to combat what it said was the myth that MSG is harmful to peoples health. Following the #RedefineCRS campaign, Merriam-Webster announced it will be "reviewing" the term, which was added to the dictionary in 1993.
Regulations
Regulation timeline
In 1959, the U.S. Food and Drug Administration (FDA) classified monosodium glutamate as generally recognized as safe (GRAS). This action stemmed from the 1958 Food Additives Amendment to the Federal Food, Drug, and Cosmetic Act that required premarket approval for new food additives and led the FDA to promulgate regulations listing substances, such as monosodium glutamate, which have a history of safe use or are otherwise GRAS.Since 1970, FDA has sponsored extensive reviews on the safety of monosodium glutamate, other glutamates, and hydrolyzed proteins, as part of an ongoing review of safety data on GRAS substances used in processed foods. One such review was by the Federation of American Societies for Experimental Biology (FASEB) Select Committee on GRAS Substances. In 1980, the committee concluded that monosodium glutamate was safe at current levels of use but recommended additional evaluation to determine monosodium glutamates safety at significantly higher levels of consumption. Additional reports attempted to look at this.In 1986, FDAs Advisory Committee on Hypersensitivity to Food Constituents concluded that monosodium glutamate poses no threat to the general public but that reactions of brief duration might occur in some people. Other reports have given the following findings:
The 1987 Joint Expert Committee on Food Additives of the United Nations Food and Agriculture Organization and the World Health Organization placed monosodium glutamate in the safest category of food ingredients.
A 1991 report by the European Communitys (EC) Scientific Committee for Foods reaffirmed monosodium glutamates safety and classified its "acceptable daily intake" as "not specified", the most favorable designation for a food ingredient. In addition, the EC Committee said, "Infants, including prematures, have been shown to metabolize glutamate as efficiently as adults and therefore do not display any special susceptibility to elevated oral intakes of glutamate." Legislation in effect since June 2013 classifies glutamic acid and glutamates as salt substitutes, seasonings, and condiments with a maximum level of consumption of 10g/kg expressed as glutamic acid.
European Union
Following the compulsory EU-food labeling law the use of glutamic acid and its salts has to be declared, and the name or E number of the salt has to be listed. Glutamic acid and its salts as food additives have the following E numbers: glutamic acid: E620, monosodium glutamate: E621, monopotassium glutamate: E622, calcium diglutamate: E623, monoammonium glutamate: E624, and magnesium diglutamate: E625. In the European Union, these substances are regarded as "flavor enhancers" and are not allowed to be added to milk, emulsified fat and oil, pasta, cocoa/chocolate products and fruit juice. The EU has not yet published an official NOAEL (no observable adverse effect level) for glutamate, but a 2006 consensus statement of a group of German experts drawing from animal studies was that a daily intake of glutamic acid of 6 grams per kilogram of body weight (6 g/kg/day) is safe. From human studies, the experts noted that doses as high as 147g/day produced no adverse effects in males when given for 30 days; in a 70 kg (150 lb) male, this amount corresponds to 2.1 g per kg of body weight.
United States
In 1959, the Food and Drug Administration classified MSG as a "generally recognized as safe" (GRAS) food ingredient under the Federal Food, Drug, and Cosmetic Act. In 1986, FDAs Advisory Committee on Hypersensitivity to Food Constituents also found that MSG was generally safe, but that short-term reactions may occur in some people. To further investigate this matter, in 1992 the FDA contracted the Federation of American Societies for Experimental Biology (FASEB) to produce a detailed report, which was published in 1995. The FASEB report reaffirmed the safety of MSG when it is consumed at usual levels by the general population, and found no evidence of any connection between MSG and any serious long-term reactions.Under 2003 U.S. Food and Drug Administration regulations, when monosodium glutamate is added to a food, it must be identified as "monosodium glutamate" in the labels ingredient list. Because glutamate is commonly found in food, primarily from protein sources, the FDA does not require foods and ingredients that contain glutamate as an inherent component to list it on the label. Examples include tomatoes, cheeses, meats, hydrolyzed protein products such as soy sauce, and autolyzed yeast extracts. These ingredients are to be declared on the label by their common or usual names. The term natural flavor is now used by the food industry when using glutamic acid. Because of lack of regulation, it is impossible to determine what percentage of natural flavor is actually glutamic acid.
The food additives disodium inosinate and disodium guanylate are usually used in synergy with monosodium glutamate-containing ingredients, and provide a likely indicator of the addition of glutamate to a product.
As of 2002 the National Academy of Sciences Committee on Dietary Reference Intakes had not set a NOAEL or LOAEL for glutamate.
Australia and New Zealand
Standard 1.2.4 of the Australia New Zealand Food Standards Code requires the presence of monosodium glutamate as a food additive to be labeled. The label must bear the food additive class name (such as "flavor enhancer"), followed by either the name of the food additive (such as "MSG") or its International Numbering System (INS) number (e.g., "621").
Canada
The Canada Food Inspection Agency considers claims of "no MSG" or "MSG free" to be misleading and deceptive when other sources of free glutamates are present.
Ingredients
Forms of glutamic acid that can be added to food include:
Monosodium glutamate
Glutamic acid (E620), glutamate (E620)
Monopotassium glutamate (E622)
Calcium glutamate (E623)
Monoammonium glutamate (E624)
Magnesium glutamate (E625)
Sodium glutamate (E621)The following are also rich sources of glutamic acid, and may be added for umami flavor:
Hydrolyzed vegetable protein
Autolyzed yeast, yeast extract, yeast food, and nutritional yeast
Cheese products, e.g. parmesan (1200 mg / 100 g)
Various savory fermented seasonings, including soy sauce and worcestershire sauce
(See § Sources for more examples.)
See also
Notes
References
External links
"The Long Fuse". This American Life (Radio broadcast). Episode 668. February 15, 2019. Public Radio Exchange (PRX). WBEZ. Retrieved February 21, 2019. See the segments "Prologue" and "Humor Is Not the Best Medicine" for the story behind "Chinese restaurant syndrome". |
Bifid rib | A bifid rib is a congenital abnormality of the rib cage and associated muscles and nerves which occurs in about 1.2% of humans. Bifid ribs occur in up to 8.4% of Samoans. The sternal end of the rib is cleaved into two. It is usually unilateral.
Bifid ribs are usually asymptomatic, and are often discovered incidentally by chest X-ray. Effects of this neuroskeletal anomaly can include respiratory difficulties, neurological difficulties, limitations, and limited energy from the stress of needing to compensate for the neurophysiological difficulties. An unstable bifid rib may lead to slipping rib syndrome.Another association is with odontogenic keratocysts of the jaw, which may behave aggressively and have a high propensity to recur when treated with simple enucleation and curettage. When seen together, the patient is likely to have nevoid basal-cell carcinoma syndrome (Gorlin-Goltz syndrome).
See also
List of radiographic findings associated with cutaneous conditions
== References == |
Familial partial lipodystrophy | Familial partial lipodystrophy, also known as Köbberling–Dunnigan syndrome, is a rare genetic metabolic condition characterized by the loss of subcutaneous fat.: 495 FPL also refers to a rare metabolic condition in which there is a loss of subcutaneous fat in the arms, legs and lower torso. The upper section of the body, face, neck, shoulders, back and trunk carry an excess amount of fat.
As the body is unable to store fat correctly this leads to fat around all the vital organs and in the blood (triglycerides). This results in heart problems, cirrhosis of the liver, lipoatrophic diabetes, and pancreatitis, along with various other complications.
Types
Presentation
Type 1 is believed to be underdiagnosed.
Genetics
A mutations in a number of genes have been associated with this condition. Mutations associated with FPL have been reported in LMNA (lamin A/C), PPARG (PPARγ), AKT2 (AKT serine/threonine kinase 2), PLIN1 (perilipin-1), and CIDEC (cell-death-inducing DFFA-like effector B).Six types (1-6) have been described. Types 1-5 are inherited in an autosomal dominant fashion.
Type 1 (Kobberling variety, FPL1) is very rare and has only been reported in women to date. Fat loss is confined to the limbs and mostly in the distal parts. Central obesity may be present. Complications include hypertension, insulin resistance and hypertriglyceridemia. The gene causing this condition is not yet known. This form was first described in 1975.
Type 2 (Dunnigan Variety, FPL2) is the most common form and is due to mutations in the LMNA gene. Over 500 cases have been reported to date. Development up to puberty is normal. Fat is then gradually lost in is the limbs and trunk. Fat may accumulate around the face and between the shoulder blades. Insulin resistance is common. Other conditions associated with this condition include acanthosis nigricans, fatty liver, hypertriglyceridemia and polycystic ovary syndrome in women. There is an increased risk of coronary heart disease. Cardiomyopathy and muscular dystrophy may occur rarely. Xanthoma and nail changes may occur.
Type 3 is due to mutations in the PPARG gene. It is rare with approximately 30 cases reported to date. It is similar to type 2 but tends to be milder.
Type 4 is due to mutations in the PLIN1 gene. It is rare with only a small number of cases reported. Fat loss tends to affect the lower limbs and buttocks. Insulin resistance and hypertriglyceridemia occur. Calf muscular hypertrophy may occur.
Type 5 is due to mutations in the AKT2 gene. It has been reported in four patients all members of the same family. Fat loss affects the upper and lower limbs. The patients also had hypertension, insulin resistance and hypertriglyceridemia.
Type 6 due to mutations in the CIDEC gene. It is inherited in an autosomal recessive fashion and has been reported in only one patient to date. Features included fat loss, severe insulin resistance, fatty liver, acanthosis nigricans and diabetes.
Another gene that has been associated with this condition is AGPAT2.
Diagnosis
Treatment
Prevalence
This not known with certainty but is estimated to be about one per million. It appears to be more common in females than males.
See also
Lipodystrophy
List of cutaneous conditions
References
== External links == |
Balo concentric sclerosis | Balós concentric sclerosis is a disease in which the white matter of the brain appears damaged in concentric layers, leaving the axis cylinder intact. It was described by József Mátyás Baló who initially named it "leuko-encephalitis periaxialis concentrica" from the previous definition, and it is currently considered one of the borderline forms of multiple sclerosis.
Balós concentric sclerosis is a demyelinating disease similar to standard multiple sclerosis, but with the particularity that the demyelinated tissues form concentric layers. Scientists used to believe that the prognosis was similar to Marburg multiple sclerosis, but now they know that patients can survive, or even have spontaneous remission and asymptomatic cases.The concentric ring appearance is not specific to Balós MS. Concentric lesions have also been reported in patients with neuromyelitis optica, standard MS, progressive multifocal leukoencephalopathy, cerebral autosomal dominant arteriopathy with subcortical infarcts, leukoencephalopathy, concomitant active hepatitis C and human herpes virus 6.
Pathophysiology
The lesions of the Balós sclerosis belong to the MS lesion pattern III (distal oligodendrogliopathy). Balo concentric sclerosis is now believed to be a variant of pattern III multiple sclerosis and probably due to metabolic problems.The Baló lesions show veins at their center, like those of MS, some suggestive of microhemorrhages or small ectatic venules. Unlike MS, no cortical gray matter lesions appear.
Theoretical models
According with Dr. Lucchinetti investigations, in Balós concentric sclerosis, the rings may be caused by a physiological hypoxia (similar to that caused by some toxins or viruses) in the lesion, which is in turn countered by expression of stress proteins at the border. This expression and counter-expression forms rings of preserved tissue within the lesion and rings of demyelinated tissue just beyond where the previous attack had induced the protective stress proteins. Hence, subsequent attacks form concentric rings.Some other researchers maintain that, as in pattern III MS, the mitochondrial respiratory chain complex IV activity is reduced and this could be the culprit of glutamate-mediated axonal injury.Ultimately, this expanding lesion causes the progressive picture typically seen. However, in some patients, the pathology underlying the disease appears to burn out and hence the disease may halt, hence the patients who spontaneously recover. The mechanisms triggering attacks and recovery remain uncertain.Nevertheless, this model is questioned by recent reports that found astrocyte damage, similar to the one found in aquaporin-seropositive neuromyelitis optica. Though no anti-NMO antibodies have been found, the damage is similar, pointing to problems in the water channel of the astrocytesIt presents three clinical subtypes: Monophasic, relapsing-remitting and primary rapidly progressive. Cerebrospinal fluid (CSF) is either normal or shows mild mononuclear inflammatory reaction. CSF-restricted oligoclonal bands are present only in a minority of cases
Other models
A mathematical model for concentric sclerosis has been proposed. Authors review the previous pathogenic theories, discuss the link between concentric sclerosis and Liesegangs periodic precipitation phenomenon and propose a new mechanism based on self-organization.
Clinical courses
It that the clinical course is primary progressive, but a relapsing-remitting course has been reported. It seems that the course gets better with prednisone therapy, although evidence of this is anecdotal and such conclusions are difficult to accept given that there are cases where patients spontaneously recover whether the patient was on steroid therapy or not.Baló lesions can disappear over time, but it has also been reported that the disease can convert to RRMSThe clinical course of Balo-like lesions also depends to the context in which they appear. Balo-like lesions have been reported in aquaporin-4 seropositive and seronegative NMOSD, and also in children, as part of an ADEM-like presentation
Diagnosis
Lesions under MRI are distinctive due to their natural concentric shape.Under a lumbar puncture CSF test, with Balós concentric sclerosis, as well as patients with pattern III lesions, were recently shown to be mostly negative for CSF-restricted oligoclonal bands. Also pattern III patients tend to be negative under the MRZ-reaction (measles, rubeola and zoster viruses)
Paediatric cases
Balós concentric sclerosis in children has been reported to behave different from adults
Lesions in autopsy and biopsy
A report comparing 1H-magnetic resonance spectroscopy, magnetization transfer and diffusion tensor imaging with histopathology in a patient with Balós concentric sclerosis, found that inflammation was traced by fractional anisotropy and increased lactate. In contrast, magnetization transfer ratio and the diffusion coefficient show a loss of tissue in the rings of the lesion.
Lesions under MRI
The features of the MRI and the characteristics of the lesion can be correlated when a biopsy has been taken, providing a way to standardize the future MRI diagnosisBalós concentric sclerosis lesions can be distinguished from normal lesions on MRI showing alternating hypointense and hyperintense layersBalós concentric lesions can be viewed using the myelin water imaging techniques. This is a special MRI sequence that shows the myelins percentage of water content.Pattern III lesions, including Baló lesions, have a specific initiation pattern under MRI (MRILIP) consisting in showing Gadolinium enhancement before FLAIR MRI appearance.Under 7-Tesla MRI Ball lesions show a center vein, like in MS.
Treatment
Treatment with corticosteroids is usual to relieve inflammation.
Epidemiology
The disease is more common in Chinese and Filipino populations (both Asiatic) than in caucasoids.Balo-like lesions have been reported to appear also in Tumefactive inflammatory leukoencephalopathy
Associations
A possible association with psoriasis and autoimmune thyroiditis has been reported
Pattern III (Baló-like) demyelinating spectrum
Baló-like lesions were classified as MS lesion pattern III in the MS spectrum. They have been reported alone, but also associated to standard multiple sclerosis, neuromyelitis optica, CADASIL and progressive multifocal leukoencephalopathyThere is an overlap between what is considered Baló concentric sclerosis and some atypical cases of multiple sclerosis. A special subtype of multiple sclerosis presents Baló-like lesions (pattern III lesions) creating an intersection between these two conditions.Some patients with BCS present oligoclonal bands while others do not. It has been proposed that BCS lesions may not denote a single disease, but a final pathway of various demyelinating diseases, reflecting the presence of intralesional hypoxia as recently proposedRecently it has been reported that pattern III lesions are responsive to Mitoxantrone. On the other hand, this pattern is the less responsive to plasmapheresisPattern III lesions can be diagnosed without a biopsy because these patients show a high reactivity to AQP1 (without antibody) and varicella zoster virus (VZV).
Origin of the lesions
Pattern III lesions were for sometime thought to be a MS nascent lesion, though it is not likely anymore. A strain of bacterium Clostridium perfringens has been found in Pattern III lesions. Tests in mice found that a toxin made by a rare strain of C. perfringens caused MS-like damage in the brain, and earlier work had identified this strain of C. perfringens in a human with MS. MS patients were found to be 10 times more immune-reactive to the epsilon toxin than healthy people.Later reports state that Balós patients showed loss of AQP1 and AQP4 in demyelinating lesions without binding auto-antibodies but with high reactivities to AQP1 peptides, which probably reflect astrocytic damage
History
Though the disease carries the name of József Baló, it was first described by Otto Marburg in 1906. Later, in 1928, József Baló studied the encephalitis periaxialis concentrica in a Hungarian patient, showing also demyelination of the peripheral nervous system.
See also
Multiple sclerosis
The Lesion Project
Tumefactive multiple sclerosis
References
Khonsari RH, Calvez V (September 2007). "Concentric demyelination by self-organization: a new hypothesis for Balós sclerosis". Nature Clinical Practice Neurology. 3 (9): E1. doi:10.1038/ncpneuro0619. PMID 17805242. S2CID 33938721.
== External links == |
Transverse myelitis | Transverse myelitis (TM) is a rare neurological condition wherein the spinal cord is inflamed. The adjective transverse implies that the spinal inflammation (myelitis) extends horizontally throughout the cross section of the spinal cord; the terms partial transverse myelitis and partial myelitis are sometimes used to specify inflammation that affects only part of the width of the spinal cord. TM is characterized by weakness and numbness of the limbs, deficits in sensation and motor skills, dysfunctional urethral and anal sphincter activities, and dysfunction of the autonomic nervous system that can lead to episodes of high blood pressure. Signs and symptoms vary according to the affected level of the spinal cord. The underlying cause of TM is unknown. The spinal cord inflammation seen in TM has been associated with various infections, immune system disorders, or damage to nerve fibers, by loss of myelin. As opposed to leukomyelitis which affects only the white matter, it affects the entire cross-section of the spinal cord. Decreased electrical conductivity in the nervous system can result.
Signs and symptoms
Symptoms include weakness and numbness of the limbs, deficits in sensation and motor skills, dysfunctional urethral and anal sphincter activities, and dysfunction of the autonomic nervous system that can lead to episodes of high blood pressure. Symptoms typically develop over the course of hours to a few weeks. Sensory symptoms of TM may include a sensation of pins and needles traveling up from the feet. The degree and type of sensory loss will depend upon the extent of the involvement of the various sensory tracts, but there is often a "sensory level" at the spinal ganglion of the segmental spinal nerve, below which sensation to pain or light touch is impaired. Motor weakness occurs due to involvement of the pyramidal tracts and mainly affects the muscles that flex the legs and extend the arms.Disturbances in sensory nerves and motor nerves and dysfunction of the autonomic nervous system at the level of the lesion or below, are noted. Therefore, the signs and symptoms depend on the area of the spine involved. Back pain can occur at the level of any inflamed segment of the spinal cord.If the upper cervical segment of the spinal cord is involved, all four limbs may be affected and there is risk of respiratory failure – the phrenic nerve which is formed by the cervical spinal nerves C3, C4, and C5 innervates the main muscle of respiration, the diaphragm.Lesions of the lower cervical region (C5–T1) will cause a combination of upper and lower motor neuron signs in the upper limbs, and exclusively upper motor neuron signs in the lower limbs. Cervical lesions account for about 20% of cases.A lesion of the thoracic segment (T1–12) will produce upper motor neuron signs in the lower limbs, presenting as a spastic paraparesis. This is the most common location of the lesion, and therefore most individuals will have weakness of the lower limbs.A lesion of the lumbar segment, the lower part of the spinal cord (L1–S5) often produces a combination of upper and lower motor neuron signs in the lower limbs. Lumbar lesions account for about 10% of cases.
Causes
TM is a heterogeneous condition, that is, there are several identified causes. Sometimes the term Transverse myelitis spectrum disorders is used. In 60% of patients the cause is idiopathic. In rare cases, it may be associated with meningococcal meningitisWhen it appears as a comorbid condition with neuromyelitis optica (NMO), it is considered to be caused by NMO-IgG autoimmunity, and when it appears in multiple sclerosis (MS) cases, it is considered to be produced by the same underlying condition that produces the MS plaques.Other causes of TM include infections, immune system disorders, and demyelinating diseases. Viral infections known to be associated with TM include HIV, herpes simplex, herpes zoster, cytomegalovirus, and Epstein-Barr. Flavivirus infections such as Zika virus and West Nile virus have also been associated. Viral association of transverse myelitis could result from the infection itself or from the response to it. Bacterial causes associated with TM include Mycoplasma pneumoniae, Bartonella henselae, and the types of Borrelia that cause Lyme disease. Lyme disease gives rise to neuroborreliosis which is seen in a small percentage (4 to 5 per cent) of acute transverse myelitis cases. The diarrhea-causing bacteria Campylobacter jejuni is also a reported cause of transverse myelitis.Other associated causes include the helminth infection schistosomiasis, spinal cord injuries, vascular disorders that impede the blood flow through vessels of the spinal cord, and paraneoplastic syndrome.
Pathophysiology
This progressive loss of the fatty myelin sheath surrounding the nerves in the affected spinal cord occurs for unclear reasons following infections or due to multiple sclerosis. Infections may cause TM through direct tissue damage or by immune-mediated infection-triggered tissue damage. The lesions present are usually inflammatory. Spinal cord involvement is usually central, uniform, and symmetric in comparison to multiple sclerosis which typically affects the cord in a patchy way and the lesions are usually peripheral. The lesions in acute TM are mostly limited to the spinal cord with no involvement of other structures in the central nervous system.
Longitudinally extensive transverse myelitis
A proposed special clinical presentation is the "longitudinally extensive transverse myelitis" (LETM), which is defined as a TM with a spinal cord lesion that extends over three or more vertebral segments. The causes of LETM are also heterogeneous and the presence of MOG auto-antibodies has been proposed as a diagnostic biomarker.
Diagnosis
Diagnostic criteria
In 2002, the Transverse Myelitis Consortium Working Group proposed the following diagnostic criteria for idiopathic acute transverse myelitis:
Investigations
Individuals who develop TM are typically transferred to a neurologist who can urgently investigate the patient in a hospital. If breathing is affected, particularly in upper spinal cord lesions, methods of artificial ventilation must be on hand before and during the transfer procedure. The patient should also be catheterized to test for and, if necessary, drain an over-distended bladder. A lumbar puncture can be performed after the MRI or at the time of CT myelography. Corticosteroids are often given in high doses when symptoms begin with the hope that the degree of inflammation and swelling of the spinal cord will be lessened, but whether this is truly effective is still debated.
Differential diagnosis
The differential diagnosis of acute TM includes demyelinating disorders, such as multiple sclerosis and neuromyelitis optica, infections, such as herpes zoster and herpes simplex virus, and other types of inflammatory disorders, such as systemic lupus erythematosus and neurosarcoidosis. It is important to also rule out an acute cause of compression on the spinal cord.
Treatment
If treated early, some people experience complete or near complete recovery. Treatment options also vary according to the underlying cause. One treatment option includes plasmapheresis. Recovery from TM is variable between individuals and also depends on the underlying cause. Some patients begin to recover between weeks 2 and 12 following onset and may continue to improve for up to two years. Other patients may never show signs of recovery.
Prognosis
The prognosis for TM depends on whether there is improvement in 3 to 6 months. Complete recovery is unlikely if no improvement occurs within this time. Incomplete recovery can still occur; however, aggressive physical therapy and rehabilitation will be very important. One-third of people with TM experience full recovery, one-third experience fair recovery but have significant neurological deficits, such as spastic gait. The final third experience no recovery at all.
Epidemiology
The incidence of TM is 4.6 per 1 million per year, affecting men and women equally. TM can occur at any age, but there are peaks around age 10, age 20, and after age 40.
History
The earliest reports describing the signs and symptoms of transverse myelitis were published in 1882 and 1910 by the English neurologist Henry Bastian.In 1928, Frank Ford noted that in mumps patients who developed acute myelitis, symptoms only emerged after the mumps infection and associated symptoms began to recede. In an article in The Lancet, Ford suggested that acute myelitis could be a post-infection syndrome in most cases (i.e. a result of the bodys immune response attacking and damaging the spinal cord) rather than an infectious disease where a virus or some other infectious agent caused paralysis. His suggestion was consistent with reports in 1922 and 1923 of rare instances in which patients developed "post-vaccinal encephalomyelitis" subsequent to receiving the rabies vaccine which then was made from brain tissue carrying the virus. The pathological examination of those who had died from the disease revealed inflammatory cells and demyelination as opposed to the vascular lesions predicted by Bastian.Fords theory of an allergic response being at the root of the disease was later shown to be only partially correct, as some infectious agents such as mycoplasma, measles and rubella were isolated from the spinal fluid of some infected patients, suggesting that direct infection could contribute to the manifestation of acute myelitis in certain cases.
In 1948, Dr. Suchett-Kaye described a patient with rapidly progressing impairment of lower extremity motor function that developed as a complication of pneumonia. In his description, he coined the term transverse myelitis to reflect the band-like thoracic area of altered sensation that patients reported. The term acute transverse myelopathy has since emerged as an acceptable synonym for transverse myelitis, and the two terms are currently used interchangeably in the literature.The definition of transverse myelitis has also evolved over time. Bastians initial description included few conclusive diagnostic criteria; by the 1980s, basic diagnostic criteria were established, including acutely developing paraparesis combined with bilateral spinal cord dysfunction over a period of <4 weeks and a well-defined upper sensory level, no evidence of spinal cord compression, and a stable, non-progressive course. Later definitions, were written in order to exclude patients with underlying systemic or neurological illnesses and to include only those who progressed to maximum deficit in fewer than 4 weeks.
Society and culture
In 2016, former Slipknot drummer Joey Jordison revealed that he had been hospitalised by the disease in 2013 and that this was the reason for his controversial firing. As the first celebrity to publicly speak about having transverse myelitis, this helped to raise public awareness of the disease. Jordison died in his sleep on July 26, 2021, however it is not known whether the disease had any connection to his death.
Etymology
The word is from Latin: myelitis transversa and the disorders name is derived from Greek myelós referring to the "spinal cord", and the suffix -itis, which denotes inflammation.
See also
Acute disseminated encephalomyelitis
References
Further reading
== External links == |
Dactyly | In biology, dactyly is the arrangement of digits (fingers and toes) on the hands, feet, or sometimes wings of a tetrapod animal. It comes from the Greek word δακτυλος (dáktylos) = "finger".
Sometimes the ending "-dactylia" is used. The derived adjectives end with "-dactyl" or "-dactylous".
As a normal feature
Pentadactyly
Pentadactyly (from Greek πέντε pénte "five") is the condition of having five digits on each limb. It is traditionally believed that all living tetrapods are descended from an ancestor with a pentadactyl limb, although many species have now lost or transformed some or all of their digits by the process of evolution. However, this viewpoint was challenged by Stephen Jay Gould in his 1991 essay "Eight (Or Fewer) Little Piggies", where he pointed out polydactyly in early tetrapods and described the specializations of digit reduction. Despite the individual variations listed below, the relationship is to the original five-digit model.
In reptiles, the limbs are pentadactylous.
Dogs and cats have tetradactylous paws but the dewclaw makes them pentadactyls.
Tetradactyly
Tetradactyly (from Greek τετρα tetra "four") is the condition of having four digits on a limb, as in many amphibians, birds, and theropod dinosaurs.
Tridactyly
Tridactyly (from Greek τρία tría "three") is the condition of having three digits on a limb, as in the rhinoceros and ancestors of the horse such as Protohippus and Hipparion. These all belong to the Perissodactyla. Some birds also have three toes, including emus, bustards, and quail.
Didactyly
Didactyly (from Greek δι- di- "two") or bidactyly is the condition of having two digits on each limb, as in the Hypertragulidae and two-toed sloth, Choloepus didactylus. In humans this name is used for an abnormality in which the middle digits are missing, leaving only the thumb and fifth finger, or big and little toes. Cloven-hoofed mammals (such as deer, sheep and cattle – Artiodactyla) have only two digits, as do ostriches.
Monodactyly
Monodactyly (from Greek μόνος monos- "one") is the condition of having a single digit on a limb, as in modern horses and other equidae (though one study suggests that the frog might be composed of remnants of digits II and IV, rendering horses as not truly monodactyl) as well as sthenurine kangaroos. Functional monodactyly, where the weight is supported on only one of multiple toes, can also occur, as in the theropod dinosaur Vespersaurus. The pterosaur Nyctosaurus retained only the wing finger on the forelimb, rendering it also partially monodactyl.
As a congenital defect
Among humans, the term "five-fingered hand" is sometimes used to mean the abnormality of having five fingers, none of which is a thumb.
Syndactyly
Syndactyly (from Greek συν- syn "together") is a condition where two or more digits are fused together. It occurs normally in some mammals, such as the siamang and most diprotodontid marsupials such as kangaroos. It occurs as an unusual condition in humans.
Polydactyly
Polydactyly (from Greek πολυ- poly- "many") is when a limb has more than the usual number of digits. This can be:
As a result of congenital abnormality in a normally pentadactyl animal. Polydactyly is very common among domestic cats. For more information, see polydactyly.
Polydactyly in early tetrapod aquatic animals, such as in Acanthostega gunnari (Jarvik 1952), one of an increasing number of genera of stem-tetrapods known from the Upper Devonian, which are providing insights into the appearance of tetrapods and the origin of limbs with digits. It also occurs secondarily in some later tetrapods, such as ichthyosaurs. The use of a term normally reserved for congenital defects reflects that it was regarded as an anomaly at the time, as it was believed that all modern tetrapods have either five digits or ancestors that did.
Oligodactyly
Oligodactyly (from Greek ὀλιγο- oligo- "few") is having too few digits when not caused by an amputation. It is sometimes incorrectly called hypodactyly or confused with aphalangia, the absence of the phalanx bone on one or (commonly) more digits. When all the digits on a hand or foot are absent, it is referred to as adactyly.
Ectrodactyly
Ectrodactyly, also known as split-hand malformation, is the congenital absence of one or more central digits of the hands and feet. Consequently, it is a form of oligodactyly. News anchor Bree Walker is probably the best-known person with this condition, which affects about one in 91,000 people. It is conspicuously more common in the Vadoma in Zimbabwe.
Clinodactyly
Clinodactyly is a medical term describing the curvature of a digit (a finger or toe) in the plane of the palm, most commonly the fifth finger (the "little finger") towards the adjacent fourth finger (the "ring finger"). It is a fairly common isolated anomaly which often goes unnoticed, but also occurs in combination with other abnormalities in certain genetic syndromes, such as Down syndrome, Turner syndrome and Cornelia de Lange syndrome.
In birds
Anisodactyly
Anisodactyly is the most common arrangement of digits in birds, with three toes forward and one back. This is common in songbirds and other perching birds, as well as hunting birds like eagles, hawks, and falcons. This arrangement of digits help with perching and/or climbing and clinging.
This occurs in Passeriformes, Columbiformes, Falconiformes, Accipitriformes, Galliformes and a vast majority of other birds.
Syndactyly
Syndactyly, as it occurs in birds, is like anisodactyly, except that the third and fourth toes (the outer and middle forward-pointing toes), or three toes, are fused together, as in the belted kingfisher (Megaceryle alcyon). This is characteristic of Coraciiformes (kingfishers, bee-eaters, rollers, and relatives).
Zygodactyly
Zygodactyly (from Greek ζυγος, even-numbered) is an arrangement of digits in birds and chameleons, with two toes facing forward (digits 2 and 3) and two back (digits 1 and 4). This arrangement is most common in arboreal species, particularly those that climb tree trunks or clamber through foliage. Zygodactyly occurs in the parrots, woodpeckers (including flickers), cuckoos (including roadrunners), and some owls. Zygodactyl tracks have been found dating to 120–110 million years ago (early Cretaceous), 50 million years before the first identified zygodactyl fossils. All Psittaciformes, Cuculiformes, the majority of Piciformes and the osprey are zygodactyl.
Heterodactyly
Heterodactyly is like zygodactyly, except that digits 3 and 4 point forward and digits 1 and 2 point back. This is found only in trogons, though the enantiornithean Dalingheornis might also have had this arrangement.
Pamprodactyly
Pamprodactyly is an arrangement in which all four toes point forward, outer toes (toe 1 and sometimes 4) often if not regularly reversible. It is a characteristic of swifts (Apodidae) and mousebirds (Coliiformes).
Chameleons
The feet of chameleons are organized into bundles of a group of two and a group of three digits which oppose one another to grasp branches in a pincer-like arrangement. This condition has been called zygodactyly or didactyly, but the specific arrangement in chameleons does not fit either definition. The feet of the front limbs in chameleons, for instance, are organized into a medial bundle of digits 1, 2 and 3, and a lateral bundle of digits 4 and 5, while the feet of the hind limbs are organized into a medial bundle of digits 1 and 2, and a lateral bundle of digits 3, 4 and 5. On the other hand, zygodactyly involves digits 1 and 4 opposing digits 2 and 3, which is an arrangement that chameleons do not exhibit in either front or hind limbs.
Aquatic tetrapods
In many secondarily aquatic vertebrates, the non-bony tissues of the forelimbs and/or hindlimbs are fused into a single flipper. Some remnant of each digit generally remains under the soft tissue of the flipper, though digit reduction gradually occurs such as in baleen whales (mysticeti). Marine mammals evolving flippers represents a classic example of convergent evolution, and by some analyses, parallel evolution.Full webbing of the digits in the manus and/or pes is present in a number of aquatic tetrapods. Such animals include marine mammals (cetaceans, sirenians, and pinnipeds), marine reptiles (modern sea turtles and extinct ichthyosaurs, mosasaurs, plesiosaurs, metriorhynchids), and flightless aquatic birds such as penguins. Hyperphalangy, or an increase in the number of phalanges beyond ancestral mammal and reptile conditions, is present in modern cetaceans and extinct marine reptiles.
Schizodactyly
Schizodactyly is a primate term for grasping and clinging with the second and third digit, instead of the thumb and second digit.
See also
Artiodactyl – even-toed ungulates, clade Cetartiodactyla
Perissodactyl – odd-toed ungulates
References
External links
Coates, Michael (25 April 2005). "Why do most species have five digits on their hands and feet?". Scientific American. Retrieved 2009-07-05. |
Multicystic dysplastic kidney | Multicystic dysplastic kidney (MCDK) is a condition that results from the malformation of the kidney during fetal development. The kidney consists of irregular cysts of varying sizes. Multicystic dysplastic kidney is a common type of renal cystic disease, and it is a cause of an abdominal mass in infants.
Signs and symptoms
When a diagnosis of multicystic kidney is made in utero by ultrasound, the disease is found to be bilateral in many cases. Those with bilateral disease often have other severe deformities or polysystemic malformation syndromes. In bilateral cases, the newborn has the classic characteristic of Potters syndrome.The bilateral condition is incompatible with survival, as the contralateral system frequently is abnormal as well. Contralateral ureteropelvic junction obstruction is found in 3% to 12% of infants with multicystic kidney and contralateral vesicoureteral reflux is seen even more often, in 18% to 43% of infants. Because the high incidence of reflux, voiding cystourethrography usually has been considered advisable in all newborns with a multicystic kidney.
Cause
The cause of multicystic dysplastic kidney can be attributed to genetics. Renal dysplasia can be a consequence of a genetic syndrome, which in turn may affect the digestive tract, nervous system, or other areas of the urinary tract. If the mother had been taking certain prescription drugs such as those for hypertension, this may be a precipitating factor as well.
Pathophysiology
The mechanism of multicystic dysplastic kidney is a result of an abnormal induction of metanephric mesenchyme. This could be a result of a formation difficulty of the mesonephric duct. Some mutations in genes associated with renal dysplasia (in syndromes) have been determined. The mutations in question occur at EYA1 or SIX1 genes (branchio-oto-renal syndrome). The PAX2 gene is also thought to play a role in MCDK.The contralateral kidney often undergoes hypertrophy. This is believed to be a compensatory mechanism to the non-functional MCDK. About 90% of patients with an MCDK will have contralateral hypertrophy into adulthood. The impact of contralateral hypertrophy on long-term renal outcomes is unknown.
Diagnosis
MCDK is usually diagnosed by ultrasound examination before birth. Mean age at the time of antenatal diagnosis is about 28 weeks A microscopic analysis of urine in individuals with probable multicystic dysplastic kidney should be done. One meta-analysis demonstrated that unilateral MCDK occurs more frequently in males and the greater percentage of MCKD occur on the left side of the body.
Treatment
MCDK is not treatable. However, the patient is observed periodically for the first few years during which ultrasounds are generally taken to ensure the healthy kidney is functioning properly and that the unhealthy kidney is not causing adverse effects. In severe cases MCDK can lead to neonatal fatality (in bilateral cases), however in unilateral cases the prognosis might be better (it would be dependent on associated anomalies).
Epidemiology
In regard to the epidemiology of multicystic dysplasia kidney, the incidence of MCDK is estimated to be 1 in every 4,000 live births, making it rare in terms of the general population.
References
Further reading
Al-Khaldi, N.; Watson, A. R.; Zuccollo, J.; Twining, P.; Rose, D. H. (1994). "Outcome of antenatally detected cystic dysplastic kidney disease". Archives of Disease in Childhood. 70 (6): 520–522. doi:10.1136/adc.70.6.520. PMC 1029874. PMID 8048824.
Van Eijk, L.; Cohen-Overbeek, T. E.; Den Hollander, N. S.; Nijman, J. M.; Wladimiroff, J. W. (2002). "Unilateral multicystic dysplastic kidney: A combined pre- and postnatal assessment". Ultrasound in Obstetrics and Gynecology. 19 (2): 180–183. doi:10.1046/j.0960-7692.2001.00497.x. PMID 11876812. S2CID 40854729.
== External links == |
Ranula | A ranula is a mucus extravasation cyst involving a sublingual gland and is a type of mucocele found on the floor of the mouth. Ranulae present as a swelling of connective tissue consisting of collected mucin from a ruptured salivary gland caused by local trauma. If small and asymptomatic further treatment may not be needed, otherwise minor oral surgery may be indicated.
Signs and symptoms
A ranula usually presents as a translucent, blue, dome-shaped, fluctuant swelling in the tissues of the floor of the mouth. If the lesion is deeper, then there is a greater thickness of tissue separating from the oral cavity and the blue translucent appearance may not be a feature. A ranula can develop into a large lesion many centimeters in diameter, with resultant elevation of the tongue and possibly interfering with swallowing (dysphagia). The swelling is not fixed, may not show blanching, and is non-painful unless it becomes secondarily infected. The usual location is lateral to the midline, which may be used to help distinguish it from a midline dermoid cyst. A cervical ranula presents as a swelling in the neck, with or without a swelling in the mouth. In common with other mucoceles, ranulae may rupture and then cause recurrent swelling. Ranulae may be asymptomatic, although they can fluctuate rapidly in size, shrinking and swelling, making them difficult to detect.
Complications
Infection
Repeated trauma
Bursting and reformation
Dysphagia (in the case of a large ranula)
Causes
Minor trauma to the floor of the mouth is thought to damage the delicate ducts that drain saliva from the sublingual gland into the oral cavity. The lesion is a mucous extravasation cyst (mucocele) of the floor of mouth, although a ranula is often larger than other mucoceles (mainly because the overlying mucosa is thicker). They can grow so large that they fill the mouth. The most usual source of the mucin spillage is the sublingual salivary gland, but ranulae may also arise from the submandibular duct or the minor salivary glands in the floor of the mouth. A cervical ranula occurs when the spilled mucin dissects its way through the mylohyoid muscle, which separates the sublingual space from the submandibular space, and creates a swelling in the neck. It may occur following rupture of a simple ranula. Rarely, ranulae may extend backwards into the parapharyngeal space.
Mechanism
The fluid within a ranula has the viscous, jellylike consistency of egg white.
Diagnosis
The histologic appearance is similar to mucoceles from other locations. The spilled mucin causes a granulation tissue to form, which usually contains foamy histiocytes. Ultrasound and magnetic resonance imaging may be useful to image the lesion. A small squamous cell carcinoma obstructing the Wharton duct may require clinical examination to be distinguished from a ranula.
Criteria
Mostly seen in young children and adolescents, both sexes are equally affected. Swelling in floor of mouth, which may be painful. Mostly unilateral, on one side of frenulum.
Shape is spherical
Size varies from 1 – 5 cm in diameter
Color is pale blue with characteristics semi transparent appearance.
Surface is smooth and mucous membrane is mobile over the swelling.
Tenderness is absent
Fluctuation test is positive
Transillumination test is positive
Cervical lymph nodes are not enlarged.
May or may not have prolongation in the neck.
Classification
A ranula is a type of mucocele, and therefore could be classified as a disorder of the salivary glands. Usually a ranula is confined to the floor of the mouth (termed a "simple ranula"). An unusual variant is the cervical ranula (also called a plunging or diving ranula), where the swelling is in the neck rather than the floor of the mouth. The term ranula is also sometimes used to refer to other similar swellings of the floor of mouth such as true salivary duct cysts, dermoid cysts and cystic hygromas. The Latin word rana means "frog" (ranula = "little frog").
Treatment
Treatment of ranulae usually involves removal of the sublingual gland. Surgery may not be required if the ranula is small and asymptomatic. Marsupialization may sometimes be used, where the intra-oral lesion is opened to the oral cavity with the aim of allowing the sublingual gland to re-establish connection with the oral cavity.
Epidemiology
The lesion is usually present in children. Ranulae are the most common pathologic lesion associated with the sublingual glands.
Other animals
References
Kahn, Michael A. Basic Oral and Maxillofacial Pathology. Volume 1. 2001.
External links
DermAtlas 259163774 |
Pai syndrome | Pai syndrome, also known as Median cleft of the upper lip-corpus callosum lipoma-midline facial cutaneous polyps syndrome, is a very rare genetic disorder which is characterized by nervous system, cutaneous, ocular, nasal and bucal anomalies with facial dysmorphisms.
Signs and symptoms
List of common symptoms:
Depressed nasal bridge
Median cleft lip
Central nervous system lipomas.
Nasal polyposis
Presence of skin tags
Subcutaneous noduleList of not-so-common symptoms:[2]
Oral frenulum abnormalities
Bifid uvula
Hypertelorism
TelecanthusList of uncommon symptoms:[2]
Missing/underdeveloped corpus callosum
Down-slanting parpebral fissures
Encephalocele
Coloboma
Nose defects
Frontal bossing
High palate
Causes
A specific, shared genetic cause hasnt been found. The closest thing to it was a case reported by Masuno et al. of a Japanese girl with symptoms of the disorder plus short stature and intellectual disabilities with a spontaneous reciprocal translocation. This translocation involved chromosome Xq28 and chromosome 16q11.2 (more specifically, 46,X,t(X;16)(q28;q11.2).
Epidemiology
According to OMIM, 18 cases have been described in medical literature, but according to ORPHAnet, 67 cases have been described.
== References == |
Acquired cystic kidney disease-associated renal cell carcinoma | Acquired cystic kidney disease-associated renal cell carcinoma is rare subtype of renal cell carcinoma. It is most commonly seen in people with end-stage kidney disease who have a much higher risk of developing acquired cystic kidney disease (ACKD). Affected individuals have small kidneys with several cysts and their risk of renal cell carcinoma is 30 times higher than people without ACKD.
Bloody urine and flank pain in a person with end-stage kidney disease raise suspicion for ACKD-associated renal cell carcinoma. Although people with ACKD have a substantially higher risk of renal cell carcinoma, routine screening is not recommended. ACKD-associated renal cell carcinoma is an uncommon cause of death for people with end-stage kidney disease.
References
== External links == |
Nevus comedonicus | Nevus comedonicus (also known as a comedo nevus) is characterized by closely arranged, grouped, often linear, slightly elevated papules that have at their center keratinous plugs resembling comedones.: 634 : 774
See also
Nevus comedonicus syndrome
Skin lesion
List of cutaneous conditions
== References == |
Cyprus facial neuromusculoskeletal syndrome | Cyprus facial neuromusculoskeletal syndrome is a rare autosomal dominant genetic disorder characterized by a "mephistophelian" appearance consisting of a ridged, thick triangular skin fold extending from the glabella up into the anterior fontanel, alongside other symptoms such as hypertelorism, widows peak, low-set ears, kyphoscoliosis congenita, congenital clubfoot, hip dislocation, and arthrogryposis. Additional findings include cataracts, decreased articular range of motion, ptosis, and ankylosis, and, less commonly, mild sensory deficits with muscle weakness and atrophy. It has been described in a large 3-generation Greek Cypriot family.
== References == |
Blighted ovum | A blighted ovum is a pregnancy in which the embryo never develops or develops and is reabsorbed. In a normal pregnancy, an embryo would be visible on an ultrasound by six weeks after the womans last menstrual period. Anembryonic gestation is one of the causes of miscarriage of a pregnancy.A blighted ovum or anembryonic gestation is characterized by a normal-appearing gestational sac, but the absence of an embryo. It likely occurs as a result of early embryonic death with continued development of the trophoblast. When small, the sac cannot be distinguished from the early normal pregnancy, as there may be a yolk sac, though a fetal pole is not seen. For diagnosis, the sac must be of sufficient size that the absence of normal embryonic elements is established. The criteria depends on the type of ultrasound exam performed. A pregnancy is anembryonic if a transvaginal ultrasound reveals a sac with a mean gestational sac diameter (MGD) greater than 25 mm and no yolk sac, or an MGD >25 mm with no embryo. Transabdominal imaging without transvaginal scanning may be sufficient for diagnosing early pregnancy failure when
an embryo whose crown–rump length is 15 mm or more has no visible cardiac activity.
See also
Ovum
Products of conception
References
External links
Blighted Ovum on WebMD
Anembryonic pregnancy on Radiopaedia.org
Johnson, MR; Riddle, AF; Sharma, V; Collins, WP; Nicolaides, KH; Grudzinskas, JG (January 1993). "Placental and ovarian hormones in anembryonic pregnancy". Human Reproduction (Oxford, England). 8 (1): 112–5. doi:10.1093/oxfordjournals.humrep.a137857. PMID 8458911. |
Hyperinsulinism | Hyperinsulinism refers to an above normal level of insulin in the blood of a person or animal. Normal insulin secretion and blood levels are closely related to the level of glucose in the blood, so that a given level of insulin can be normal for one blood glucose level but low or high for another. Hyperinsulinism can be associated with several types of medical problems, which can be roughly divided into two broad and largely non-overlapping categories: those tending toward reduced sensitivity to insulin and high blood glucose levels (hyperglycemia), and those tending toward excessive insulin secretion and low glucose levels (hypoglycemia).
Signs and symptoms
Hyperinsulinism due to reduced insulin sensitivity is usually asymptomatic. In contrast, hyperinsulinemic hypoglycemia can produce any of the entire range of hypoglycemic symptoms, from shakiness and weakness, to seizures or coma.
Diagnosis
Diminished sensitivity, associated with diabetes risk
Although many factors influence insulin secretion, the most important control is the amount of glucose moving from the blood into the beta cells of the pancreas. In healthy people, even small rises in blood glucose result in increased insulin secretion. As long as the pancreatic beta cells are able to sense the glucose level and produce insulin, the amount of insulin secreted is usually the amount required to maintain a fasting blood glucose between 70 and 100 mg/dL (3.9–5.6 mmol/L) and a non-fasting glucose level below 140 mg/dL (<7.8 mmol/L).When liver cells and other cells that remove glucose from the blood become less sensitive (more resistant) to the insulin, the pancreas increases secretion and the level of insulin in the blood rises. This increased secretion can compensate for reduced sensitivity for many years, with maintenance of normal glucose levels. However, if insulin resistance worsens or insulin secretion ability declines, the glucose levels will begin to rise. Persistent elevation of glucose levels is termed diabetes mellitus.Typical fasting insulin levels found in this type of hyperinsulinism are above 20 μU/mL. When resistance is severe, levels can exceed 100 μU/mL.In addition to being a risk factor for type 2 diabetes, hyperinsulinism due to insulin resistance may increase blood pressure and contribute to hypertension by direct action on vascular endothelial cells (the cells lining blood vessels). Hyperinsulinism has also been implicated as a contributing factor in the excessive production of androgens in polycystic ovary syndrome.The principal treatments of hyperinsulinism due to insulin resistance are measures that improve insulin sensitivity, such as weight loss, physical exercise, and drugs such as thiazolidinediones or metformin.
Inappropriate secretion, associated with hypoglycemia
Hyperinsulinism may also refer to forms of hypoglycemia caused by excessive insulin secretion. In normal children and adults, insulin secretion should be minimal when blood glucose levels fall below 70 mg/dL (3.9 mM). There are many forms of hyperinsulinemic hypoglycemia caused by various types of insulin excess. Some of those that occur in infants and young children are termed congenital hyperinsulinism. In adults, severe hyperinsulinemic hypoglycemia is often due to an insulinoma, an insulin-secreting tumor of the pancreas.Insulin levels above 3 μU/mL are inappropriate when the glucose level is below 50 mg/dL (2.8 mM), and may indicate hyperinsulinism as the cause of the hypoglycemia. The treatment of this form of hyperinsulinism depends on the cause and the severity of the hyperinsulinism, and may include surgical removal of the source of insulin, or a drug such as diazoxide or octreotide that reduces insulin secretion.That spontaneous hyperinsulinism might be a cause of symptomatic hypoglycemia was first proposed by Seale Harris, MD, 1924, in Journal of the American Medical Association.
Dr. Seale Harris first diagnosed hyperinsulinism in 1924 and also is credited with the recognition of spontaneous hypoglycemia.
Treatment
See also
Idiopathic hypoglycemia
idiopathic postprandial syndrome
References
External links
GeneReviews/NCBI/NIH/UW entry on Familial Hyperinsulinism |
Crossed renal ectopia | Crossed dystopia (syn.unilateral fusion cross fused renal ectopia) is a rare form of renal ectopia where both kidneys are on the same side of the spine. In many cases, the two kidneys are fused together, yet retain their own vessels and ureters. The ureter of the lower kidney crosses the midline to enter the bladder on the contralateral side. Both renal pelves can lie one above each other medial to the renal parenchyma (unilateral long kidney) or the pelvis of the crossed kidney faces laterally (unilateral "S" shaped kidney). Urogram is diagnostic.
The anomaly can be diagnosed through ultrasound or urography, but surgical intervention is only necessary if there are other complications, such as tumors or pyelonephritis.
== References == |
Jefferson fracture | A Jefferson fracture is a bone fracture of the anterior and posterior arches of the C1 vertebra, though it may also appear as a three- or two-part fracture. The fracture may result from an axial load on the back of the head or hyperextension of the neck (e.g. caused by diving), causing a posterior break, and may be accompanied by a break in other parts of the cervical spine.It is named after the British neurologist and neurosurgeon Sir Geoffrey Jefferson, who reported four cases of the fracture in 1920 in addition to reviewing cases that had been reported previously.
Signs and symptoms
Individuals with Jefferson fractures usually experience pain in the upper neck but no neurological signs. The fracture may also cause damage to the arteries in the neck, resulting in lateral medullary syndrome, Horners syndrome, ataxia, and the inability to sense pain or temperature.In rare cases, congenital abnormality may cause the same symptoms as a Jefferson fracture.
Cause
Jefferson fracture is often caused by an impact or load on the back of the head, and are frequently associated with diving into shallow water, impact against the roof of a vehicle and falls, and in children may occur due to falls from playground equipment. Less frequently, strong rotation of the head may also result in Jefferson fractures.Jefferson fractures are extremely rare in children, but recovery is usually complete without surgery.
Diagnosis
Treatment
The use of surgery to treat a Jefferson fracture is somewhat controversial. Non-surgical treatment varies depending on if the fracture is stable or unstable, defined by an intact or broken transverse ligament and degree of fracture of the anterior arch. An intact ligament requires the use of a soft or hard collar, while a ruptured ligament may require traction, a halo or surgery. The use of rigid halos can lead to intracranial infections and are often uncomfortable for individuals wearing them, and may be replaced with a more flexible alternative depending on the stability of the injured bones, but treatment of a stable injury with a halo collar can result in a full recovery. Surgical treatment of a Jefferson fracture involves fusion or fixation of the first three cervical vertebrae; fusion may occur immediately, or later during treatment in cases where non-surgical interventions are unsuccessful. A primary factor in deciding between surgical and non-surgical intervention is the degree of stability as well as the presence of damage to other cervical vertebrae.Though a serious injury, the long-term consequences of a Jeffersons fracture are uncertain and may not impact longevity or abilities, even if untreated. Conservative treatment with an immobilization device can produce excellent long-term recovery.
References
== External links == |
Solar purpura | Solar purpura (also known as "Actinic purpura," and "Senile purpura") is a skin condition characterized by large, sharply outlined, 1- to 5-cm, dark purplish-red ecchymoses appearing on the dorsa of the forearms and less often the hands.: 825 The condition is most common in elderly people of European descent. It is caused by sun-induced damage to the connective tissue of the skin.No treatment is necessary. The lesions typically fade over a period of up to three weeks.
See also
List of cutaneous conditions
References
== External links == |
Cortical deafness | Cortical deafness is a rare form of sensorineural hearing loss caused by damage to the primary auditory cortex. Cortical deafness is an auditory disorder where the patient is unable to hear sounds but has no apparent damage to the anatomy of the ear (see auditory system), which can be thought of as the combination of auditory verbal agnosia and auditory agnosia. Patients with cortical deafness cannot hear any sounds, that is, they are not aware of sounds including non-speech, voices, and speech sounds. Although patients appear and feel completely deaf, they can still exhibit some reflex responses such as turning their head towards a loud sound.
Cause
Cortical deafness is caused by bilateral cortical lesions in the primary auditory cortex located in the temporal lobes of the brain. The ascending auditory pathways are damaged, causing a loss of perception of sound. Inner ear functions, however, remains intact. Cortical deafness is most often caused by stroke, but can also result from brain injury or birth defects. More specifically, a common cause is bilateral embolic stroke to the area of Heschls gyri. Cortical deafness is extremely rare, with only twelve reported cases. Each case has a distinct context and different rates of recovery.
It is thought that cortical deafness could be a part of a spectrum of an overall cortical hearing disorder. In some cases, patients with cortical deafness have had recovery of some hearing function, resulting in partial auditory deficits such as auditory verbal agnosia. This syndrome might be difficult to distinguish from a bilateral temporal lesion such as described above.
Diagnosis
Since cortical deafness and auditory agnosia have many similarities, diagnosing the disorder proves to be difficult. Bilateral lesions near the primary auditory cortex in the temporal lobe are important criteria. Cortical deafness requires demonstration that brainstem auditory responses are
normal, but cortical evoked potentials are impaired. Brainstem auditory evoked potentials (BAEP), also referred to as brainstem auditory evoked responses (BAER) show the neuronal activity in the auditory nerve, cochlear nucleus, superior olive, and inferior colliculus of the brainstem. They typically have a response latency of no more than six milliseconds with an amplitude of approximately one microvolt. The latency of the responses gives critical information: if cortical deafness is applicable, LLR (long-latency responses) are completely abolished and MLR (middle latency responses) are either abolished or significantly impaired. In auditory agnosia, LLRs and MLRs are preserved.
Another important aspect of cortical deafness that is often overlooked is that patients feel deaf. They are aware of their inability to hear environmental sounds, non-speech and speech sounds. Patients with auditory agnosia can be unaware of their deficit, and insist that they are not deaf. Verbal deafness and auditory agnosia are disorders of a selective, perceptive and associative nature whereas cortical deafness relies on the anatomic and functional disconnection of the auditory cortex from acoustic impulses.
Case examples
Although cortical deafness has very specific parameters of diagnosis, its causes on the other hand can vary tremendously. The following are three case studies with different reasons for cortical deafness.
A case published in 2001 describes the patient as 20-year-old man referred for cochlear implants because of bilateral deafness following a motorcycle accident two years earlier. His CT shows hemorrhagic lesions involving both internal capsules. He was comatose for several weeks and awoke quadriparetic, cognitively impaired and completely deaf. He exhibited a response towards the occasional sudden, loud sound, however, by turning his head. Reading and writing capabilities were maintained, and he was able to communicate by lip-reading. His own speech was dysarthric, but comprehensible. Normal tympanograms and stapedial reflexes imply that the middle and inner ear remained functioning and the auditory nerve was intact. His auditory nerve was tested by evoking responses with normal auditory nerve potentials at 10 dB bilaterally. The results of the BAER waves were normal, but an abnormal complex IV-V suggested that the pathways were functioning through the brainstem, but there was a lesion present in the mid-brain. With these findings, it was determined the patient had cortical deafness due to bilateral interruption of the ascending auditory pathway associated with hemorrhagic lesions of both internal capsules. Therefore, cochlear implantation was not performed.
Published in 1994, this patient was monitored over the course of almost 20 years after exhibiting signs of hearing impairment as an infant. Audiologic and related test results in concurrence with MRI confirmed bilateral absence of considerable portions of her temporal lobes resulting in cortical deafness. Although physiologic measures demonstrate normal peripheral hearing sensitivity, this patients speech has the inflection and prosodic characteristics associated with profound peripheral hearing loss, and she is unable to understand spoken communication. Behaviorally obtained pure-tone thresholds were variable, ranging from normal to moderate hearing loss with normal middle ear muscle reflexes and normal ABRs to high- and low-intensity stimuli. Auditory middle latency and cortical evoked potentials were grossly abnormal, consistent with the central nature of cortical deafness. Because of her inability to communicate auditorily, this patient was ultimately taught American Sign Language and educated at the Louisiana School for the Deaf. At the completion of the case study, the patient was married and expecting a child.
A more recent study, published in 2013 the patient described is a 56-year-old woman a history of hypertension, hypercholesterolemia, and multiple cerebrovascular accident (CVA) who presented in March 2009 with a complaint of complete bilateral hearing loss. In March 2009, she experienced an acute right-sided insulotemporal intracerebral hemorrhage. Immediately after this event, the patient complained of hearing loss with the inability to hear all sounds except for severe bilateral tinnitus. Imaging revealed sequelae in the left cerebral cortex from her previous CVA. The new right-sided hemorrhage was centered on the posterior putamen with surrounding edema involving the posterior portion of the posterior limbs of the internal, external, and extreme capsules. Signal abnormalities extended into the right temporal lobe. The patient had no other neurologic deficits and spoke fluently, although with poor internal volume control of her voice. Otoscopic examination revealed normal-appearing external auditory canals, intact tympanic membranes bilaterally, and normal middle ear anatomy. Audiogram at that time showed bilateral profound hearing loss with no responses to pure-tone or speech testing.
Treatment
Auditory perception can improve with time. There seems to be a level of neuroplasticity that allows patients to recover the ability to perceive environmental and certain musical sounds. Patients presenting with cortical hearing loss and no other associated symptoms recover to a variable degree, depending on the size and type of the cerebral lesion. Patients whose symptoms include both motor deficits and aphasias often have larger lesions with an associated poorer prognosis in regard to functional status and recovery.Cochlear or auditory brainstem implantation could also be treatment options. Electrical stimulation of the peripheral auditory system may result in improved sound perception or cortical remapping in patients with cortical deafness. However, hearing aids are an inappropriate answer for cases like these. Any auditory signal, regardless if has been amplified to normal or high intensities, is useless to a system unable to complete its processing. Ideally, patients should be directed toward resources to aid them in lip-reading, learning American Sign Language, as well as speech and occupational therapy. Patients should follow-up regularly to evaluate for any long-term recovery.
History
Early reports, published in the late 19th century, describe patients with acute onset of deafness after experiencing symptoms described as apoplexy. The only means of definitive diagnosis in these reports were postmortem dissections. Subsequent cases throughout the 20th century reflect advancements in diagnoses of both hearing loss and stroke. With the advent of audiometric and electrophysiologic studies, investigators could diagnose cortical deafness with increasing precision. Advances in imaging techniques, such as MRI, greatly improved the diagnosis and localization of cerebral infarcts that coincide with primary or secondary auditory centers. Neurological and cognitive testing help to distinguish between total cortical deafness and auditory agnosia, resulting in the inability to perceive words, music, or specific environmental sounds.
References
Further reading
Hood L, Berlin C, Allen P (1994). "Cortical deafness: a longitudinal study". J Am Acad Audiol. 5 (5): 330–42. PMID 7987023.
== External links == |
Erythema annulare centrifugum | Erythema annulare centrifugum (EAC), is a descriptive term for a class of skin lesion presenting redness (erythema) in a ring form (anulare) that spreads from a center (centrifugum). It was first described by Darier in 1916. Many different terms have been used to classify these types of lesions and it is still controversial on what exactly defines EAC. Some of the types include annular erythema (deep and superficial), erythema perstans, erythema gyratum perstans, erythema gyratum repens, darier erythema (deep gyrate erythema) and erythema figuratum perstans.
Symptoms
Occurring at any age these lesions appear as raised pink-red ring or bulls-eye marks. They range in size from 0.5–8 cm (0.20–3.15 in). The lesions sometimes increase size and spread over time and may not be complete rings but irregular shapes. Distribution is usually on the thighs and legs but can also appear on the upper extremities, areas not exposed to sunlight, trunk or face. Currently EAC is not known to be contagious, but as many cases are incorrectly diagnosed as EAC, it is difficult to be certain.
Causes
Often no specific cause for the eruptions is found. However, it is sometimes linked to underlying diseases and conditions such as:
Food (including blue cheese or tomatoes).
Contact Dermatitis (i.e. cleaning agents, fabric softeners, etc.)
Fungal, Bacterial and Viral infections such as sinusitis, tuberculosis, candidiasis or tinea.
Drugs including finasteride, etizolam (and benzodiazepines), chloroquine, hydroxychloroquine, oestrogen, penicillin and amitriptyline.
Cancer (especially the type known as erythema gyratum perstans, in which there are concentric and whirling rings).
Primary biliary cirrhosis.
Graves disease.
Appendicitis.
Lupus
Pregnancy (EAC usually disappears/stops soon after delivery of baby).
Hormone (Contraceptive Pill, Stress, Hormone Drugs)
Lyme disease
Diagnosis
A skin biopsy can be performed to test for EAC; tests should be performed to rule out other possible diseases such as: pityriasis rosea, tinea corporis, psoriasis, nummular eczema, atopic dermatitis, drug reaction, erythema migrans and other rashes.
Differential diagnosis
Sarcoidosis
Fungal infection
Lupus erythematosus
Treatment
No treatment is usually needed as they usually go away anywhere from months to years. The lesions may last from anywhere between 4 weeks to 34 years with an average duration of 11 months. If caused by an underlying disease or malignancy, then treating and removing the disease or malignancy will stop the lesions. It usually doesnt require treatment, but topical corticosteroids may be helpful in reducing redness, swelling and itchiness.
Some supported and not supported methods of having an effect on EAC include:
Photosensitive so it can be moved/reduced with appropriate sunlight.
Vitamin D
Immune system - hence it will increase in size/number when the immune system is low or overloaded.
Hormone Drugs
Disulone
Stress reduction
Topical calcipotriol - a topical vitamin D derivative has been known to be beneficial
Epidemiology
It is very rare and estimated to affect 1 in 100,000 per year. Because of its rarity the documentation, cases and information are sparse and not a huge amount is known for certain, meaning that EAC could actually be a set of many un-classified skin lesions. It is known to occur at all ages and all genders equally. Some articles state that women are more likely to be affected than men.
See also
List of cutaneous conditions
References
== External links == |
Bilirubinuria | In medicine, bilirubinuria is an abnormality in which conjugated bilirubin is detected in the urine.The term "biliuria" is very similar, but more general. It refers to the presence of any bile pigment in the urine.
Conjugated bilirubin is detected in urine at bilirubinemia of approximately 30-34 mmol/L or 2 mg/dL. In this concentration of conjugated bilirubin in the blood appears as yellowness of the mucous membranes and sclera.
Causes
The most common cause of bilirubinuria is hepatocellular disease. More rare causes include inherited disorders, such as Dubin–Johnson syndrome and Rotor syndrome.Although Gilberts syndrome and Crigler–Najjar syndrome are characterized by increased bilirubin in the serum, the bilirubin in these inherited disorders is not conjugated and thus not excreted in the urine.
The increase of stercobilin (urobilin) in the feces and urine is caused by the enhanced intracellular hemolysis of erythrocytes. Formed an unconjugated bilirubin entering the intestine, gives a large number of stercobilinogen (urobilinogen). Last absorbed into the blood and passes into the urine.
Diagnosis
in order To properly
References
== External links == |
Crigler–Najjar syndrome | Crigler–Najjar syndrome is a rare inherited disorder affecting the metabolism of bilirubin, a chemical formed from the breakdown of the heme in red blood cells. The disorder results in a form of nonhemolytic jaundice, which results in high levels of unconjugated bilirubin and often leads to brain damage in infants. The disorder is inherited in an autosomal recessive manner. The annual incidence is estimated at 1 in 1,000,000.This syndrome is divided into types I and II, with the latter sometimes called Arias syndrome. These two types, along with Gilberts syndrome, Dubin–Johnson syndrome, and Rotor syndrome, make up the five known hereditary defects in bilirubin metabolism. Unlike Gilberts syndrome, only a few causes of Crigler–Najjar syndrome are known.
Signs and symptoms
Jaundice
Diarrhea
Vomiting
Fever
Confusion
Slurred speech
Difficulty swallowing
Change in gait, staggering frequent falling
Seizures
Cause
It is caused by abnormalities in the gene coding for uridine diphosphoglucuronate glucuronosyltransferase (UGT1A1). UGT1A1 normally catalyzes the conjugation of bilirubin and glucuronic acid within hepatocytes. Conjugated bilirubin is more water-soluble and is excreted in bile.
Diagnosis
Type I
This is a very rare disease (estimated at 0.6–1.0 per million live births), and consanguinity increases the risk of this condition (other rare diseases may be present). Inheritance is autosomal recessive.
Intense jaundice appears in the first days of life and persists thereafter. Type 1 is characterised by a serum bilirubin usually above 345 μmol/L [20 mg/dL] (range 310–755 μmol/L [18–44 mg/dL]) (whereas the reference range for total bilirubin is 2–14 μmol/L [0.1–0.8 mg/dL]).
No UDP glucuronosyltransferase 1-A1 expression can be detected in the liver tissue. Hence, there is no response to treatment with phenobarbital, which causes CYP450 enzyme induction. Most patients (type IA) have a mutation in one of the common exons (2 to 5), and have difficulties conjugating several additional substrates (several drugs and xenobiotics). A smaller percentage of patients (type IB) have mutations limited to the bilirubin-specific A1 exon; their conjugation defect is mostly restricted to bilirubin itself.
Before the availability of phototherapy, these children died of kernicterus (bilirubin encephalopathy) or survived until early adulthood with clear neurological impairment. Today, therapy includes
exchange transfusions in the immediate neonatal period
12 hours/day phototherapy
heme oxygenase inhibitors to reduce transient worsening of hyperbilirubinemia (although the effect of the drug decreases over time)
oral calcium phosphate and carbonate to form complexes with bilirubin in the gut
liver transplantation before the onset of brain damage and before phototherapy becomes ineffective at later age
Type II
The inheritance patterns of both Crigler–Najjar syndrome types I and II are autosomal recessive.However, type II differs from type I in a number of different aspects:
Bilirubin levels are generally below 345 μmol/L [20 mg/dL] (range 100–430 μmol/L [6–24 mg/dL]; thus, overlap may sometimes occur), and some cases are only detected later in life.
Because of lower serum bilirubin, kernicterus is rare in type II.
Bile is pigmented, instead of pale in type I or dark as normal, and monoconjugates constitute the largest fraction of bile conjugates.
UGT1A1 is present at reduced but detectable levels (typically <10% of normal), because of single base pair mutations.
Therefore, treatment with phenobarbital is effective, generally with a decrease of at least 25% in serum bilirubin. In fact, this can be used, along with these other factors, to differentiate type I and II.
Differential diagnosis
Neonatal jaundice may develop in the presence of sepsis, hypoxia, hypoglycemia, hypothyroidism, hypertrophic pyloric stenosis, galactosemia, fructosemia, etc.
Hyperbilirubinemia of the unconjugated type may be caused by:
increased production
hemolysis (e.g., hemolytic disease of the newborn, hereditary spherocytosis, sickle cell disease)
ineffective erythropoiesis
massive tissue necrosis or large hematomas
decreased clearance
drug-induced
physiological neonatal jaundice and prematurity
liver diseases such as advanced hepatitis or cirrhosis
breast milk jaundice and Lucey–Driscoll syndrome
Crigler–Najjar syndrome and Gilbert syndromeIn Crigler–Najjar syndrome and Gilbert syndrome, routine liver function tests are normal, and hepatic histology usually is normal, too. No evidence for hemolysis is seen. Drug-induced cases typically regress after discontinuation of the substance. Physiological neonatal jaundice may peak at 85–170 μmol/L and decline to normal adult concentrations within two weeks. Prematurity results in higher levels.
Treatment
Plasmapheresis and phototherapy are used for treatment. Liver transplant is curative.
Research
A San Francisco-based company named Audentes Therapeutics is currently investigating the treatment of Crigler–Najjar syndrome with one of their gene replacement therapy products, AT342. Preliminary success has been found in early stages of a phase 1/2 clinical trial.One 10-year-old girl with Crigler–Najjar syndrome type I was successfully treated by liver cell transplantation.The homozygous Gunn rat, which lacks the enzyme uridine diphosphate glucuronyltransferase (UDPGT), is an animal model for the study of Crigler–Najjar syndrome. Since only one enzyme is working improperly, gene therapy for Crigler-Najjar is a theoretical option which is being investigated.
Eponym
The condition is named for John Fielding Crigler (1919 – May 13, 2018), an American pediatrician and Victor Assad Najjar (1914–2002), a Lebanese-American pediatrician.
References
External links
Crigler–Najjar syndrome, type 1 at NIHs Office of Rare Diseases
Crigler–Najjar syndrome, type 2 at NIHs Office of Rare Diseases |
Mesenteric cyst | A mesenteric cyst (MeSH C04.182.473) is a cyst in the mesenterium, and is one of the rarest abdominal tumors, with approximately 822 cases reported since 1507. The incidence is between 1 per 100,000 to 1 per 250,000 hospital admissions.Tillauxs triad named after the French surgeon Paul Jules Tillaux can be seen in cases of mesenteric cyst. It consists of the following signs:
a fluctuating swelling near the umbilicus,
freely mobile in the direction perpendicular to the attachment of mesentry,
with a zone of resonance around the swelling.It is basically of two types :
1. Chylolymphatic most common type, thin wall, lined by flat endotheliun, clear chylous fluid present, separate blood vessels
2. Enterogenous-thick wall, lined by columnar, mucinous fluid present common blood supply
== References == |
Papillorenal syndrome | Papillorenal syndrome is an autosomal dominant genetic disorder marked by underdevelopment (hypoplasia) of the kidney and colobomas of the optic nerve.
Presentation
Ocular
Ocular disc dysplasia is the most notable ocular defect of the disease. An abnormal development in the optic stalk causes optic disc dysplasia, which is caused by a mutation in the Pax2 gene. The nerve head typically resembles the morning glory disc anomaly, but has also been described as a coloboma. A coloboma is the failure to close the choroid fissure, which is the opening from the ventral side of the retina in the optic stalk. Despite the similarities with coloboma and morning glory anomaly, significant differences exist such that optic disc dysplasia cannot be classified as either one entity.
Optic disc dysplasia is noted by an ill-defined inferior excavation, convoluted origin of the superior retinal vessels, excessive number of vessels, infrapapillary pigmentary disturbance, and slight band of retinal elevation adjacent to the disk. Some patients have normal or near normal vision, but others have visual impairment associated with the disease, though it is not certain if this is due only to the dysplastic optic nerves, or a possible contribution from macular and retinal malformations. The retinal vessels are abnormal or absent, in some cases having small vessels exiting the periphery of the disc. There is a great deal of clinical variability.
Kidney
The most common malformation in patients with the syndrome is kidney hypodysplasia, which are small and underdeveloped kidneys, often leading to end-stage renal disease (ESRD). Estimates show approximately 10% of children with hypoplastic kidneys are linked to the disease. Many different histological abnormalities have been noted, including:
decrease in nephron number associated with hypertrophy
focal segmental glomerulosclerosis
interstitial fibrosis and tubular atrophy
multicystic dysplastic kidneyUp to one-third of diagnosed patients develop end stage kidney disease, which may lead to complete kidney failure.
Causes
Pax2 mutations
The majority of mutations occur in exons 2,3 and 4, which encode the paired domain and frame shift mutations that lead to a null allele. The missense mutations appear to disrupt hydrogen bonds, leading to decreased transactivation of Pax2, but do not seem to effect nuclear localization, steady state mRNA levels, or the ability of Pax2 to bind to its DNA consensus sequence. Mutations related to the disease have also been noted in exons 7,8, and 9, with milder phenotypes than the other mutations.
Recent studies
Pax2 is expressed in the kidney, midbrain, hindbrain, cells in the spinal column, developing ear and developing eye. Homozygous negative Pax2 mutation is lethal, but heterozygote mutants showed many symptoms of papillorenal syndrome, including optic nerve dysplasia with abnormal vessels emerging from the periphery of the optic cup and small dysplasic kidneys. It is shown that Pax2 is under upstream control of Shh in both mice and zebrafish, which is expressed in the precordal plate.
Other genes
Approximately half of patients with papillorenal syndrome do not have defects in the Pax2. This suggests that other genes play a role in the development of the syndrome, though few downstream effectors of Pax2 have been identified.
Genetic
Papillorenal syndrome is an autosomal dominant disorder that results from a mutation of one copy of the Pax2 gene, located on chromosome 10q24.3-q25.1. The gene is important in the development of both the eye and the kidney. Autosomal dominant inheritance indicates that the gene responsible for the disorder is located on an autosome (chromosome 10 is an autosome), and only one defective copy of the gene is sufficient to cause the disorder, when inherited from a parent who has the disorder.
Diagnosis
Clinical findings in the kidney
Hypoplastic kidneys: Characterized by hypoplasia or hyperechogenicity. This typically occurs bilaterally, but there are also exceptions in which one kidney may be notably smaller while the other kidney is normal sized.
Hypodysplasia (RHD): Characterized histologically by reduced number of nephrons, smaller kidney size, or disorganized tissue.
Multicystic Dysplastic Kidney: Characterized histologically, displaying cysts or dysplasia. Shows disorganization of kidneys, and occurs in about 10% of patients with papillorenal syndrome.
Oligomeganephronia: Fewer than normal glomeruli, with a notable size increase.
Chronic kidney disease and end-stage kidney disease (ESKD)
Vesicoureteral reflux
Clinical findings in the eye
Dysplasia of the optic nerve (most common)
The severity varies, but the most severe form results in an enlarged disc where vessels exit from the periphery instead of the center. Redundant fibroglial tissue also is seen in severe cases. Milder forms of dysplasia exhibit missing portions of the optic disc located in the optic nerve pit. The least severe form of papillorenal disease shown in the eye is the exiting of blood vessels from the periphery that do not disturb the shape of the eye. Other eye malformations include scleral staphyloma, which is the bulging of the eye wall. There can also be retinal thinning and myopia. Additionally, there can be an optic nerve cyst, which is dilation of the optic nerve posterior to the globe; which most likely results from incomplete regression of the primordial optic stalk and the filling of this area with fluid. Retinal coloboma is also common, which is characterized by the absence of retinal tissue in the nasal ventral portion of the retina. However, this is an extremely rare finding.
Molecular genetic testing
Sequence analysis shows that Pax2 is the only known gene associated with the disease. Mutations in Pax2 have been identified in half of renal coloboma syndrome victims.
Treatment
Management of the disease should be focused on preventing end-stage kidney disease (ESKD) and/or vision loss. The treatment of hypertension may also preserve renal function. Renal replacement therapy is recommended, and vision experts may provide assistance to adapt to continued vision loss.
Kidney transplant is also an option. Treatment plans seem to be limited, as there is a large focus on the prevention of papillorenal syndrome and its implications. People with congenital optic nerve abnormalities should seek ophthalmologists regularly and use protective lenses. If abnormalities are present, a follow up with a nephrologist should be achieved to monitor renal function and blood pressure. Since the disease is believed to be caused by Pax2 mutations and is inherited in an autosomal dominant manner, family members may be at risk and relatives should be tested for possible features. About half of those diagnosed with the disease have an affected parent, so genetic counseling is recommended.
Prenatal testing is another possibility for prevention or awareness, and this can be done through molecular genetic testing or ultrasounds at later stages of pregnancy. Additionally, preimplantation genetic diagnosis (PGD) should be considered for families where papillorenal syndrome is known to be an issue.
References
External links
GeneReview/NCBI/NIH/UW entry on Renal Coloboma Syndrome
Papillorenal syndrome at NIHs Office of Rare Diseases
NCBI Genetic Testing Registry |
Relapsing linear acantholytic dermatosis | Relapsing linear acantholytic dermatosis is a cutaneous condition characterized by relapsing linear erosions and crusting, histologically identical to Hailey–Hailey disease.: 849 It is not to be confused with transient acantholytic dermatosis.
See also
Linear porokeratosis
List of cutaneous conditions
== References == |
Arachnoid cyst | Arachnoid cysts are cerebrospinal fluid covered by arachnoidal cells and collagen that may develop between the surface of the brain and the cranial base or on the arachnoid membrane, one of the three meningeal layers that cover the brain and the spinal cord. Primary arachnoid cysts are a congenital disorder whereas secondary arachnoid cysts are the result of head injury or trauma. Most cases of primary cysts begin during infancy; however, onset may be delayed until adolescence.
Signs and symptoms
Patients with arachnoid cysts may never show symptoms, even in some cases where the cyst is large. Therefore, while the presence of symptoms may provoke further clinical investigation, symptoms independent of further data cannot—and should not—be interpreted as evidence of a cysts existence, size, location, or potential functional impact on the patient.Symptoms vary by the size and location of the cyst(s), though small cysts usually have no symptoms and are discovered only incidentally. On the other hand, a number of symptoms may result from large cysts:
Cranial deformation or macrocephaly (enlargement of the head), particularly in children
Cysts in the suprasellar region in children have presented as bobbing and nodding of the head called bobble-head doll syndrome.
Cysts in the left middle cranial fossa have been associated with ADHD in a study on affected children.
Headaches. A patient experiencing a headache does not necessarily have an arachnoid cyst.
In a 2002 study involving 78 patients with a migraine or tension-type headache, CT scans showed abnormalities in over a third of the patients, though arachnoid cysts only accounted for 2.6% of patients in this study.
A study found 18% of patients with intracranial arachnoid cysts had non-specific headaches. The cyst was in the temporal location in 75% of these cases.
Seizures
Hydrocephalus (excessive accumulation of cerebrospinal fluid)
Increased intracranial pressure
Developmental delay
Behavioral changes
Nausea
Dysdiadokinesis
Hemiparesis (weakness or paralysis on one side of the body)
Ataxia (lack of muscle control)
Musical hallucination
Pre-senile dementia, a condition often associated with Alzheimers disease
In elderly patients (>80 years old) symptoms were similar to chronic subdural hematoma or normal pressure hydrocephalus:Dementia
Urinary incontinence
Hemiparesis
Headache
Seizures
Location-specific symptoms
A supratentorial arachnoid cyst can mimic a Ménières disease attack.
Frontal arachnoid cysts have been associated with depression.
Cysts on the left temporal lobe have been associated with psychosis. A left fronto-temporal cyst showed symptoms of alexithymia.
Cyst on the right sylvian fissure resulted in new onset of schizophrenia-like symptoms at age 61.
A patient with a cyst on the left middle cranial fossa had auditory hallucinations, migraine-like headaches, and periodic paranoia
Patients with left temporal lobe cysts had mood disturbances similar to manic depression (bipolar disorder) and were known to show outward aggression
Causes
The exact cause of arachnoid cysts is not known. Researchers believe that most cases of arachnoid cysts are developmental malformations that arise from the unexplained splitting or tearing of the arachnoid membrane.In some cases, arachnoid cysts occurring in the middle fossa are accompanied by underdevelopment (hypoplasia) or compression of the temporal lobe. The exact role that temporal lobe abnormalities play in the development of middle fossa arachnoid cysts is unknown.There are some cases where hereditary disorders have been connected with arachnoid cysts.Some complications of arachnoid cysts can occur when a cyst is damaged because of minor head trauma. Trauma can cause the fluid within a cyst to leak into other areas (e.g., subarachnoid space). Blood vessels on the surface of a cyst may tear and bleed into the cyst (intracystic hemorrhage), increasing its size. If a blood vessel bleeds on the outside of a cyst, a collection of blood (hematoma) may result. In the cases of intracystic hemorrhage and hematoma, the individual may have symptoms of increased pressure within the cranium and signs of compression of nearby nerve (neural) tissue.Some scientists debate whether arachnoid cysts are a true congenite condition or if this should be separated from secondary cysts. A recent study shows differences in communication between the arachnoid cyst and the subarachnoid space by CT cisternography. A comparison of arachnoid cyst fluid and CSF in a series of patients show differences in chemical composition.Arachnoid cysts can also occur secondary to other disorders such as Marfan syndrome, arachnoiditis, or agenesis of the corpus callosum.
Diagnosis
Diagnosis is principally by MRI. Frequently, arachnoid cysts are incidental findings on MRI scans performed for other clinical reasons. In practice, diagnosis of symptomatic arachnoid cysts requires symptoms to be present, and many with the disorder never develop symptoms.Additional clinical assessment tools that can be useful in evaluating a patient with arachnoid cysts include the mini-mental state examination (MMSE), a brief questionnaire-based test used to assess cognition.
Classification
Arachnoid cysts can be found on the brain or on the spine. Intracranial arachnoid cysts usually occur adjacent to the arachnoidal cistern. Spinal arachnoid cysts may be extradural, intradural, or perineural and tend to present with signs and symptoms indicative of a radiculopathy.Arachnoid cysts may also be classified as primary (congenital) or secondary (acquired) and have been reported in humans, cats, and dogs.Arachnoid cysts can be relatively asymptomatic or present with insidious symptoms; for this reason, diagnosis is often delayed.
Treatment
Most arachnoid cysts are asymptomatic and do not require treatment. Treatment may be necessary when symptomatic. A variety of procedures may be used to decompress (remove pressure from) the cyst.
Surgical placement of a cerebral shunt:An internal shunt drains into the subdural compartment.
A cystoperitoneal shunt drains to the peritoneal cavity.
Fenestration:
Craniotomy with excision
Various endoscopic techniques are proving effective, including laser-assisted techniques.
Drainage by needle aspiration or burr hole.
Capsular resection
Pharmacological treatments may address specific symptoms such as seizures or pain.
Prognosis
Most arachnoid cysts are asymptomatic, and do not require treatment. Where complications are present, leaving arachnoid cysts untreated may cause permanent severe neurological damage due to the progressive expansion of the cyst(s) or hemorrhage (bleeding). However, with treatment most individuals with symptomatic arachnoid cysts do well.More specific prognoses are listed below:
Patients with impaired preoperative cognition had postoperative improvement after surgical decompression of the cyst.
Surgery can resolve psychiatric manifestations in selected cases.
Epidemiology
Arachnoid cysts are seen in up to 1.1% of the population with a gender distribution of 2:1 male:female. Only 20% of these have symptoms, usually from secondary hydrocephalus.A study that looked at 2,536 healthy young males found a prevalence of 1.7% (95% CI 1.2 to 2.3%). Only a small percentage of the detected abnormalities require urgent medical attention.
See also
References
== External links == |
Somatostatinoma | Somatostatinomas are a tumor of the delta cells of the endocrine pancreas that produces somatostatin. Increased levels of somatostatin inhibit pancreatic hormones and gastrointestinal hormones. Thus, somatostatinomas are associated with mild diabetes mellitus (due to inhibition of insulin release), steatorrhoea and gallstones (due to inhibition of cholecystokinin release), and achlorhydria (due to inhibition of gastrin release). Somatostatinomas are commonly found in the head of pancreas. Only ten percent of somatostatinomas are functional tumours [9], and 60–70% of tumours are malignant. Nearly two-thirds of patients with malignant somatostatinomas will present with metastatic disease.
Pathophysiology
In a normal subject, actions of somatostatin include:
In the anterior pituitary gland, the effects of somatostatin are:Inhibit the release of growth hormone, thus opposing the effects of growth hormone-releasing hormone (GHRH)
Inhibit the release of thyroid-stimulating hormone (TSH)Somatostatin suppresses the release of gastrointestinal hormonesGastrin
Cholecystokinin (CCK)
Secretin
Motilin
Vasoactive intestinal peptide (VIP)
Gastric inhibitory polypeptide (GIP)
EnteroglucagonLowers the rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine
Suppresses the release of pancreatic hormonesInhibits the release of insulin
Inhibits the release of glucagonSuppresses the exocrine secretory action of pancreas.This explains how abnormally elevated somatostatin can cause diabetes mellitus, by inhibiting insulin secretion, steatorrhoea by inhibiting cholecystokinin and secretin, gall stones by inhibiting cholecystokinin which normally induce gallbladder myocytes to contract, and hypochlorhydria caused by inhibiting gastrin, which normally stimulate acid secretion.Somatostatinomas are associated with calcium deposits called psammoma bodies.
Diagnosis
Fasting plasma somatostatin greater than 30 pg/mL.SRS (Somatostatin Receptor Scintigraphy) – It is a radio-nucleotide scan by giving Octreotide tagged with Indium111 isotope, which shows an increase in uptake by the tumour cells.
Treatment
Treatment is by chemotherapy with streptozocin, dacarbazine, doxorubicin or by watchful waiting and surgical debulking via Whipple procedure and other resections of the gastrointestinal organs affected.
References
6. Soga J, Yakuwa Y. Somatostatinoma/inhibitory syndrome: a statistical evaluation of 173 reported cases as compared to other pancreatic endocrinomas. J Exp Clin Cancer Res, 1999; 18:13–22. [PMID: 10374671]
== External links == |
Scrofuloderma | Scrofuloderma is a skin condition caused by tuberculous involvement of the skin by direct extension, usually from underlying tuberculous lymphadenitis.: 335
See also
Scrofula
Skin lesion
List of cutaneous conditions
Tuberculosis
References
External links
Media related to Scrofuloderma at Wikimedia Commons |
Dermatopathic lymphadenopathy | In pathology, dermatopathic lymphadenopathy, is lymph node pathology due to skin disease.
Cause
Also known as lipomelanotic reticulosis or Pautrier-Woringer disease, represents a rare form of benign lymphatic hyperplasia associated with most exfoliative or eczematoid inflammatory erythrodermas, including pemphigus, psoriasis, eczema, neurodermatitis, and atrophia senilis.
Diagnosis
Dermatopathic lymphadenopathy is diagnosed by a lymph node biopsy. It has a characteristic pattern of histomorphology and immunohistochemical staining:
Paracortical histiocytosis
Melanin-laden macrophages
Eosinophils
Plasma cells (medulla of lymph node)
Differential diagnosis
Cutaneous T cell lymphoma
Hodgkins lymphoma
Melanoma
Treatment
The treatment is based on the underlying cause.
See also
Skin disease
List of cutaneous conditions
References
External links
Dermatopathic lymphadenitis - pathconsultddx.com. |
Proliferative vitreoretinopathy | Proliferative vitreoretinopathy (PVR) is a disease that develops as a complication of rhegmatogenous retinal detachment. PVR occurs in about 8–10% of patients undergoing primary retinal detachment surgery and prevents the successful surgical repair of rhegmatogenous retinal detachment. PVR can be treated with surgery to reattach the detached retina but the visual outcome of the surgery is very poor. A number of studies have explored various possible adjunctive agents for the prevention and treatment of PVR, such as methotrexate, although none have yet been licensed for clinical use.PVR was originally referred to as massive vitreous retraction and then as massive periretinal proliferation. The name Proliferative vitreo retinopathy was provided in 1989 by the Silicone Oil Study group. The name is derived from proliferation (by the retinal pigment epithelial and glial cells) and vitreo retinopathy to include the tissues which are affected, namely the vitreous humor (or simply vitreous) and the retina.
Predisposing factors
Predisposing factors for Postoperative PVR are preoperative PVR, aphakia, high levels of vitreous proteins, duration of retinal detachment before corrective surgery, the size of the retinal hole or tear, intra-ocular inflammation, vitreous hemorrhage, and trauma to the eye. An equation to calculate the patients risk for acquiring PVR is:
PVR score = 2.88 × (Grade C PVR)+ 1.85 × (Grade B PVR) + 2.92 × (aphakia) + 1.77 × (anterior uveitis) + 1.23 × (quadrants of detachment) + 0.83 × (vitreous haemorrhage) + 23 × (previous cryotherapy)1 is added if the risk factor is present and 0 if the risk factor is absent. A patient is at a high risk for developing PVR if their PVR score is >6.33.
Pathology
During rhegmatogenous retinal detachment, fluid from the vitreous humor enters a retinal hole. The mechanisms by which retinal holes or tears form are not fully understood yet. The accumulation of fluid in the subretinal space and the tractional force of the vitreous on the retina result in rhegmatogenous retinal detachment. During this process the retinal cell layers come in contact with vitreous cytokines. These cytokines trigger the ability of the retinal pigmented epithelium (RPE) to proliferate and migrate. The process involved resembles fibrotic wound healing by the RPE cells. The RPE cells undergo epithelial-mesenchymal transition (EMT) and develop the ability to migrate out into the vitreous. During this process the RPE cell layer-neural retinal adhesion and RPE-ECM (extracellular matrix) adhesions are lost. The RPE cells lay down fibrotic membranes while they migrate and these membranes contract and pull at the retina. All these finally lead to secondary retinal detachment after primary retinal detachment surgery.
A number of studies have also shown that arachidonic acid metabolic cascade (one of the major inflammatory cascades) is important in the development of PVR. COX-2 expression was found in human idiopathic epiretinal membranes. Phospholipase A2 and cyclooxygenase blocking reduced structural abnormalities of the rat retina in concanavalin model of PVR and reduced the frequency of membrane formation by 43% in the dispase model of PVR and by 31% in the concanavalin one. Lornoxicam not only normalized the expression of cyclooxygenases in both models of PVR, but also neutralized the changes of the retina and the choroid thickness caused by the injection of pro-inflammatory agents.PVR is graded as Grade A, B, or C by the Silicone Oil Study and as Grade A, B, C, or D by the Retina Society Terminology Committee.
Grade A is characterized by the appearance of vitreous haze and RPE cells in the vitreous.
Grade B is characterized by wrinkling of the edges of the retinal tear or the inner retinal surface.
Grade C is characterized by the presence of retinal membranes.
Retinal membranes
The RPE cells migrate out into the vitreous, proliferate excessively and lay down ECM on both side sides of the detached retina. The ECM laid on the vitreous side of the retina are referred to as epiretinal or preretinal membranes (ERM) and those laid down between the RPE layer and the photoreceptors are referred to as subretinal or retroretinal membranes (SRM) . The two membranes differ in composition in that the ERM is composed of RPE cells, glial cells, macrophages and fibrocytes, while the SRM is rich in RPE cells. The subretinal membranes are of two types. One forms as diffuse sheets, which are not contractile and either lack or contain very little ECM. The presence of this type of membrane does not usually affect retinal reattachment surgery. The retina can be reattached even with the membrane in place. The other type forms as very thick contractile membranes which pull at the retina. These are opaque and block the light falling on the retina so the retinal reattachment surgery needs to be performed after manually peeling the membrane off.
Cytokines involved in PVR
A number of cytokines such as tumor necrosis factor alpha (TNFα), transforming growth factor beta 2 (TGFβ2), platelet derived growth factor (PDGF) and interleukins have been shown to play a role in PVR progression.
TGFβ2 levels have been shown to be elevated up to three times normal during the progression of PVR. TGFβ2 is the most predominant isoform in the eye and is secreted as a latent inactive peptide into the vitreous by epithelial cells of the ciliary body and the lens epithelium and is also produced by the RPE cells and the Muller cells of the retina. TGFβ2 is known to induce EMT in RPE cells and fibrosis in the eye. Expression of PDGF in particular PDGF-AA is triggered during ocular injury and contributes to PVR pathology. RPE cells express the receptor for hepatocyte growth factor (HGF). HGF stimulates RPE cell migration and its presence is also strongly detected in retinal membranes. Interleukin 6 levels are elevated in the vitreous humor during PVR.
References
External links
GeneReviews/NCBI/NIH/UW entry on VCAN-Related Vitreoretinopathy |
Carotidynia | Carotidynia is a syndrome characterized by unilateral (one-sided) tenderness of the carotid artery, near the bifurcation. It was first described in 1927 by Temple Fay. The most common cause of carotidynia may be migraine, and then it is usually self-correcting. Common migraine treatments may help alleviate the carotidynia symptoms. Recent histological evidence has implicated an inflammatory component of carotidynia, but studies are limited. Carotid arteritis is a much less common cause of carotidynia, but has much more serious consequences. It is a form of giant cell arteritis, which is a condition that usually affects arteries in the head. Due to this serious condition possibly causing carotidynia, and the possibility that neck pain is related to some other non-carotidynia and serious condition, the case should be investigated by a medical doctor. Because carotidynia can be caused by numerous causes, Biousse and Bousser in 1994 recommended the term not be used in the medical literature. However, recent MRI and ultrasound studies have supported the existence of a differential diagnosis of carotidynia consistent with Fays characterization.
References
External links
Family Practice notebook.com |
Postpartum infections | Postpartum infections, also known as childbed fever and puerperal fever, are any bacterial infections of the female reproductive tract following childbirth or miscarriage. Signs and symptoms usually include a fever greater than 38.0 °C (100.4 °F), chills, lower abdominal pain, and possibly bad-smelling vaginal discharge. It usually occurs after the first 24 hours and within the first ten days following delivery.The most common infection is that of the uterus and surrounding tissues known as puerperal sepsis, postpartum metritis, or postpartum endometritis. Risk factors include Caesarean section (C-section), the presence of certain bacteria such as group B streptococcus in the vagina, premature rupture of membranes, multiple vaginal exams, manual removal of the placenta, and prolonged labour among others. Most infections involve a number of types of bacteria. Diagnosis is rarely helped by culturing of the vagina or blood. In those who do not improve, medical imaging may be required. Other causes of fever following delivery include breast engorgement, urinary tract infections, infections of an abdominal incision or an episiotomy, and atelectasis.Due to the risks following Caesarean section, it is recommended that all women receive a preventive dose of antibiotics such as ampicillin around the time of surgery. Treatment of established infections is with antibiotics, with most people improving in two to three days. In those with mild disease, oral antibiotics may be used; otherwise intravenous antibiotics are recommended. Common antibiotics include a combination of ampicillin and gentamicin following vaginal delivery or clindamycin and gentamicin in those who have had a C-section. In those who are not improving with appropriate treatment, other complications such as an abscess should be considered.In 2015, about 11.8 million maternal infections occurred. In the developed world about 1% to 2% develop uterine infections following vaginal delivery. This increases to 5% to 13% among those who have more difficult deliveries and 50% with C-sections before the use of preventive antibiotics. In 2015, these infections resulted in 17,900 deaths down from 34,000 deaths in 1990. They are the cause of about 10% of deaths around the time of pregnancy. The first known descriptions of the condition date back to at least the 5th century BCE in the writings of Hippocrates. These infections were a very common cause of death around the time of childbirth starting in at least the 18th century until the 1930s when antibiotics were introduced. In 1847, Hungarian physician Ignaz Semmelweiss decreased death from the disease in the First Obstetrical Clinic of Vienna from nearly 20% to 2% through the use of handwashing with calcium hypochlorite.
Signs and symptoms
Signs and symptoms usually include a fever greater than 38.0 °C (100.4 °F), chills, low abdominal pain, and possibly bad-smelling vaginal discharge. It usually occurs after the first 24 hours and within the first ten days following delivery.
Causes
After childbirth, a womans genital tract has a large bare surface, which is prone to infection. Infection may be limited to the cavity and wall of her uterus, or it may spread beyond to cause septicaemia (blood poisoning) or other illnesses, especially when her resistance has been lowered by long labour or severe bleeding. Puerperal infection is most common on the raw surface of the interior of the uterus after separation of the placenta (afterbirth), but pathogenic organisms may also affect lacerations of any part of the genital tract. By whatever portal, they can invade the bloodstream and lymph system to cause sepsis, cellulitis (inflammation of connective tissue), and pelvic or generalized peritonitis (inflammation of the abdominal lining). The severity of the illness depends on the virulence of the infecting organism, the resistance of the invaded tissues, and the general health of the woman. Organisms commonly producing this infection are Streptococcus pyogenes; staphylococci (inhabitants of the skin and of pimples, carbuncles, and many other pustular eruptions); the anaerobic streptococci, which flourish in devitalized tissues such as may be present after long and injurious labour and unskilled instrumental delivery; Escherichia coli and Clostridium perfringens (inhabitants of the lower bowel); and Clostridium tetani.
Risk factors
Causes (listed in order of decreasing frequency) include endometritis, urinary tract infection, pneumonia/atelectasis, wound infection, and septic pelvic thrombophlebitis. Septic risk factors for each condition are listed in order of the postpartum day (PPD) on which the condition generally occurs.
PPD 0: atelectasis risk factors include general anesthesia, cigarette smoking, and obstructive lung disease.
PPD 1–2: urinary tract infections risk factors include multiple catheterization during labor, multiple vaginal examinations during labor, and untreated bacteriuria.
PPD 2–3: endometritis ( the most common cause ) risk factors include emergency cesarean section, prolonged membrane rupture, prolonged labor, and multiple vaginal examinations during labor.
PPD 4–5: wound infection risk factors include emergency cesarean section, prolonged membrane rupture, prolonged labor, and multiple vaginal examinations during labor.
PPD 5–6: septic pelvic thrombophlebitis risk factors include emergency cesarean section, prolonged membrane rupture, prolonged labor, and diffuse difficult vaginal childbirth.
PPD 7–21: mastitis risk factors include nipple trauma from breastfeeding.
Diagnosis
Puerperal fever is diagnosed with:
A temperature rise above 38 °C (100.4 °F) maintained over 24 hours or recurring during the period from the end of the first to the end of the 10th day after childbirth or abortion. (ICD-10)
Oral temperature of 38 °C (100.4 °F) or more on any two of the first ten days postpartum. (USJCMW)Puerperal fever (from the Latin puer, male child (boy)), is no longer favored as a diagnostic category. Instead, contemporary terminology specifies:
the specific target of infection: endometritis (inflammation of the inner lining of the uterus), metrophlebitis (inflammation of the veins of the uterus), and peritonitis (inflammation of the membrane lining of the abdomen).
the severity of the infection: less serious infection (contained multiplication of microbes) or possibly life-threatening sepsis (uncontrolled and uncontained multiplication of microbes throughout the blood stream).Endometritis is a polymicrobial infection. It frequently includes organisms such as Ureaplasma, Streptococcus, Mycoplasma, and Bacteroides, and may also include organisms such as Gardnerella, Chlamydia, Lactobacillus, Escherichia, and Staphylococcus.
Differential diagnosis
A number of other conditions can cause fevers following delivery including: urinary tract infections, breast engorgement, atelectasis and surgical incisions, among others.
Management
Antibiotics have been used to prevent and treat these infections—however, the misuse of antibiotics is a serious problem for global health. It is recommended that guidelines be followed that outline when it is appropriate to give antibiotics and which antibiotics are most effective.Atelectasis: mild to moderate fever, no changes or mild rales on chest auscultation.Management: pulmonary exercises, ambulation (deep breathing and walking).
Urinary tract infection: high fever, malaise, costovertebral tenderness, positive urine culture.Management: antibiotics as per culture sensitivity (cephalosporine).
Endometritis: moderate fever, exquisite uterine tenderness, minimal abdominal findings.Management: multiple agent IV antibiotics to cover polymicrobial organisms: clindamycin, gentamicin, addition of ampicillin if no response, no cultures are necessary.
Wound infection: persistent spiking fever despite antibiotics, wound erythema or fluctuance, wound drainage.Management: antibiotics for cellulitis, open and drain wound, saline-soaked packing twice a day, secondary closure.
Septic pelvic thrombophlebitis: persistent wide fever swings despite antibiotics, usually normal abdominal or pelvic exams.Management: IV heparin for 7–10 days at rates sufficient to prolong the PTT to double the baseline values.
Mastitis: unilateral, localized erythema, edema, tenderness.Management: antibiotics for cellulitis, open and drain abscess if present.
Epidemiology
The number of cases of puerperal sepsis per year shows wide variations among published literature—this may be related to different definitions, recordings etc. Globally, bacterial infections are the cause of 10% of maternal deaths—this is more common in low income countries but is also a direct cause of maternal deaths in high-income countries.In the United States, puerperal infections are believed to occur in between 1% and 8% of all births. About three die from puerperal sepsis for every 100,000 births. The single most important risk factor is Caesarean section. The number of maternal deaths in the United States is about 13 in 100,000. They make up about 11% of pregnancy-related deaths in the United States.In the United Kingdom from 1985–2005, the number of direct deaths associated with genital tract sepsis per 100,000 pregnancies was 0.40–0.85. In 2003–2005, genital tract sepsis accounted for 14% of direct causes of maternal death.Puerperal infections in the 18th and 19th centuries affected, on average, 6 to 9 women in every 1,000 births, killing two to three of them with peritonitis or sepsis. It was the single most common cause of maternal mortality, accounting for about half of all deaths related to childbirth, and was second only to tuberculosis in killing women of childbearing age. A rough estimate is that about 250,000–500,000 died from puerperal fever in the 18th and 19th centuries in England and Wales alone.
History
Although it had been recognized from as early as the time of the Hippocratic corpus that women in childbed were prone to fevers, the distinct name, "puerperal fever" appears in historical records only from the early 18th century.The death rate for women giving birth decreased in the 20th century in developed countries. The decline may be partly attributed to improved environmental conditions, better obstetrical care, and the use of antibiotics. Another reason appears to be a lessening of the virulence or invasiveness of Streptococcus pyogenes. This organism is also the cause of scarlet fever, which over the same period had declined but has seen a rise in last decade worldwide especially in Asia with smaller outbreaks in US and Canada. UK had reported 12,906 cases between September 2015 and April 2016 which is the largest outbreak since 1969.
"The Doctors Plague"
From the 1600s through the mid-to-late 1800s, the majority of childbed fever cases were caused by the doctors themselves. With no knowledge of germs, doctors did not believe hand washing was needed.
Hospitals for childbirth became common in the 17th century in many European cities. These "lying-in" hospitals were established at a time when there was no knowledge of antisepsis or epidemiology, and women were subjected to crowding, frequent vaginal examinations, and the use of contaminated instruments, dressings, and bedding. It was common for a doctor to deliver one baby after another, without washing his hands or changing clothes between patients.
The first recorded epidemic of puerperal fever occurred at the Hôtel-Dieu de Paris in 1646. Hospitals throughout Europe and America consistently reported death rates between 20% to 25% of all women giving birth, punctuated by intermittent epidemics with up to 100% fatalities of women giving birth in childbirth wards.In the 1800s Ignaz Semmelweis noticed that women giving birth at home had a much lower incidence of childbed fever than those giving birth in the doctors maternity ward. His investigation discovered that washing hands with an antiseptic, in this case a calcium hypochlorite solution, before a delivery reduced childbed fever fatalities by 90%. Publication of his findings was not well received by the medical profession. The idea conflicted both with the existing medical concepts and with the image doctors had of themselves. The scorn and ridicule of doctors was so extreme that Semmelweis moved from Vienna and, following a breakdown, was eventually committed to a mental asylum, where he died.Semmelweis was not the only doctor ignored after sounding a warning about this issue: in Treatise on the Epidemic of Puerperal Fever (1795), ex-naval surgeon and Aberdonian obstetrician Alexander Gordon (1752–1799) warned that the disease was transmitted from one case to another by midwives and doctors. Gordon wrote, "It is a disagreeable declaration for me to mention, that I myself was the means of carrying the infection to a great number of women."Thomas Watson (1792–1882), Professor of Medicine at Kings College Hospital, London, wrote in 1842: "Wherever puerperal fever is rife, or when a practitioner has attended any one instance of it, he should use most diligent ablution." Watson recommended handwashing with chlorine solution and changes of clothing for obstetric attendants "to prevent the practitioner becoming a vehicle of contagion and death between one patient and another."
Hygienic measures
In 1843, Oliver Wendell Holmes Sr. published The Contagiousness of Puerperal Fever and controversially concluded that puerperal fever was frequently carried from patient to patient by physicians and nurses; he suggested that clean clothing and avoidance of autopsies by those aiding birth would prevent the spread of puerperal fever. Holmes quoted Dr. James Blundell as stating, "... in my own family, I had rather that those I esteemed the most should be delivered unaided, in a stable, by the mangerside, than that they should receive the best help, in the fairest apartment, but exposed to the vapors of this pitiless disease."Holmes conclusions were ridiculed by many contemporaries, including Charles Delucena Meigs, a well-known obstetrician, who stated, "Doctors are gentlemen, and gentlemens hands are clean." Richard Gordon states that Holmes exhortations "outraged obstetricians, particularly in Philadelphia". In those days, "surgeons operated in blood-stiffened frock coats—the stiffer the coat, the prouder the busy surgeon", "pus was as inseparable from surgery as blood", and "Cleanliness was next to prudishness". He quotes Sir Frederick Treves on that era: "There was no object in being clean. Indeed, cleanliness was out of place. It was considered to be finicking and affected. An executioner might as well manicure his nails before chopping off a head".In 1844, Ignaz Semmelweis was appointed assistant lecturer in the First Obstetric Division of the Vienna General Hospital (Allgemeines Krankenhaus), where medical students received their training. Working without knowledge of Holmes essay, Semmelweis noticed his wards 16% mortality rate from fever was substantially higher than the 2% mortality rate in the Second Division, where midwifery students were trained. Semmelweis also noticed that puerperal fever was rare in women who gave birth before arriving at the hospital. Semmelweis noted that doctors in First Division performed autopsies each morning on women who had died the previous day, but the midwives were not required or allowed to perform such autopsies. He made the connection between autopsies and puerperal fever after a colleague, Jakob Kolletschka, died of sepsis after accidentally cutting his hand while performing an autopsy.
Semmelweis began experimenting with various cleansing agents and, from May 1847, ordered all doctors and students working in the First Division wash their hands in chlorinated lime solution before starting ward work, and later before each vaginal examination. The mortality rate from puerperal fever in the division fell from 18% in May 1847 to less than 3% in June–November of the same year. While his results were extraordinary, he was treated with skepticism and ridicule (see Response to Semmelweis).
He did the same work in St. Rochus hospital in Pest, Hungary, and published his findings in 1860, but his discovery was again ignored.In 1935, Leonard Colebrook showed Prontosil was effective against haemolytic streptococcus and hence a cure for puerperal fever.
Notable cases
Elite status was no protection against postpartum infections, as the deaths of several English queens attest. Elizabeth of York, queen consort of Henry VII, died of puerperal fever one week after giving birth to a daughter, who also died. Her son Henry VIII had two wives who died this way, Jane Seymour and Catherine Parr.
Suzanne Barnard, mother of philosopher Jean-Jacques Rousseau, contracted childbed fever after giving birth to him and died nine days later. Her infant son was also in perilous health following the birth; the adult Rousseau later wrote that "I came into the world with so few signs of life that little hope was entertained of preserving me". He was nursed back to health by an aunt. French natural philosopher Émilie du Châtelet died in 1749. Mary Wollstonecraft, author of Vindication of the Rights of Woman, died ten days after giving birth to her second daughter, who grew up to write Frankenstein. Other notables include African-American poet Phillis Wheatley (1784), British housekeeping authority Isabella Beeton, and American author Jean Webster in 1916 died of puerperal fever.In Charles Dickens novel A Christmas Carol, it is implied that both Scrooges mother and younger sister perished from this condition, explaining the characters animosity towards his nephew Fred and also his poor relationship with his own father.
See also
Postpartum confinement, a traditional practice after childbirth
References
Further reading
Chaim W, Burstein E (August 2003). "Postpartum infection treatments: a review". Expert Opinion on Pharmacotherapy (review). 4 (8): 1297–313. doi:10.1517/14656566.4.8.1297. PMID 12877638. S2CID 26781321.
French L (August 2003). "Prevention and treatment of postpartum endometritis". Current Womens Health Reports (review). 3 (4): 274–9. PMID 12844449.
Calhoun BC, Brost B (June 1995). "Emergency management of sudden puerperal fever". Obstetrics and Gynecology Clinics of North America (review). 22 (2): 357–67. doi:10.1016/S0889-8545(21)00185-6. PMID 7651676.
== External links == |
Bifascicular block | Bifascicular block is a conduction abnormality in the heart where two of the three main fascicles of the His/Purkinje system are blocked.
Most commonly, it refers to a combination of right bundle branch block (RBBB) and either left anterior fascicular block (LAFB) or left posterior fascicular block (LPFB), with the former being more common.Some authors consider left bundle branch block (LBBB) to be a technical bifascicular block, since the block occurs above the bifurcation of the left anterior and left posterior fascicles of the left bundle branch.
Diagnosis
Diagnostic criteria:Clinically, bifascicular block presents with one of two ECG patterns:
Right bundle branch block (RBBB) with left anterior fascicular block (LAFB), manifested as left axis deviation (LAD).
RBBB and left posterior fascicular block (LPFB), manifested as right axis deviation (RAD) in the absence of other causes.
Treatment
In those with bifascicular block and no symptoms, little with respect to treatment is needed. In those with syncope, a pacemaker is recommended.
References
Olshansky B. Bradyarrhythmias – Conduction System Abnormalities. In: Arrhythmia Essentials 2e, 2017.
Vijayaraman P. Clinical Cardiac Pacing, Defibrillation and Resynchronisation Therapy 5e, 2017
Goldberger A. Ventricular Conduction Disturbances.. In: Goldberger’s Clinical Electrocardiography 9e, 2018.
== External links == |
Akinetopsia | Akinetopsia (Greek: a for "without", kine for "to move" and opsia for "seeing"), also known as cerebral akinetopsia or motion blindness, is a term introduced by Semir Zeki to describe an extremely rare neuropsychological disorder, having only been documented in a handful of medical cases, in which a patient cannot perceive motion in their visual field, despite being able to see stationary objects without issue. There are varying degrees of akinetopsia: from seeing motion as frames of a cinema reel to an inability to discriminate any motion. There is currently no effective treatment or cure for akinetopsia.
Signs and symptoms
Akinetopsia can be separated into two categories, "inconspicuous akinetopsia" or "gross akinetopsia", based on symptom severity and the amount the akinetopsia affects the patients quality of life.
Inconspicuous akinetopsia
Inconspicuous akinetopsia is often described by seeing motion as a cinema reel or a multiple exposure photograph. This is the most common kind of akinetopsia and many patients consider the stroboscopic vision as a nuisance. The akinetopsia often occurs with visual trailing (palinopsia), with afterimages being left at each frame of the motion. It is caused by prescription drugs, hallucinogen persisting perception disorder (HPPD), and persistent aura without infarction. The pathophysiology of akinetopsia palinopsia is not known, but it has been hypothesized to be due to inappropriate activation of physiological motion suppression mechanisms which are normally used to maintain visual stability during eye movements (e.g. saccadic suppression).
Gross akinetopsia
Gross akinetopsia is an extremely rare condition. Patients have profound motion blindness and struggle in performing the activities of daily living. Instead of seeing vision as a cinema reel, these patients have trouble perceiving gross motion. Most of what is known about this extremely rare condition was learned through the case study of one patient, LM. LM described pouring a cup of tea or coffee difficult "because the fluid appeared to be frozen, like a glacier". She did not know when to stop pouring, because she could not perceive the movement of the fluid rising. LM and other patients have also complained of having trouble following conversations, because lip movements and changing facial expressions were missed. LM stated she felt insecure when more than two people were walking around in a room: "people were suddenly here or there but I have not seen them moving". Movement is inferred by comparing the change in position of an object or person. LM and others have described crossing the street and driving cars to also be of great difficulty. LM started to train her hearing to estimate distance.A change in brain structure (typically lesions) disturbs the psychological process of understanding sensory information, in this case visual information. Disturbance of only visual motion is possible due to the anatomical separation of visual motion processing from other functions. Like akinetopsia, perception of color can also be selectively disturbed as in achromatopsia. There is an inability to see motion despite normal spatial acuity, flicker detection, stereo and color vision. Other intact functions include visual space perception and visual identification of shapes, objects, and faces. Besides simple perception, akinetopsia also disturbs visuomotor tasks, such as reaching for objects and catching objects. When doing tasks, feedback of ones own motion appears to be important.
Causes
Brain lesions
Akinetopsia may be an acquired deficit from lesions in the posterior side of the visual cortex. Lesions more often cause gross akinetopsia. The neurons of the middle temporal cortex respond to moving stimuli and hence the middle temporal cortex is the motion-processing area of the cerebral cortex. In the case of LM, the brain lesion was bilateral and symmetrical, and at the same time small enough not to affect other visual functions. Some unilateral lesions have been reported to impair motion perception as well. Akinetopsia through lesions is rare, because damage to the occipital lobe usually disturbs more than one visual function. Akinetopsia has also been reported as a result of traumatic brain injury.
Transcranial magnetic stimulation
Inconspicuous akinetopsia can be selectively and temporarily induced using transcranial magnetic stimulation (TMS) of area V5 of the visual cortex in healthy subjects. It is performed on a 1 cm² surface of the head, corresponding in position to area V5. With an 800-microsecond TMS pulse and a 28 ms stimulus at 11 degrees per second, V5 is incapacitated for about 20–30 ms. It is effective between −20 ms and +10 ms before and after onset of a moving visual stimulus. Inactivating V1 with TMS could induce some degree of akinetopsia 60–70 ms after the onset of the visual stimulus. TMS of V1 is not nearly as effective in inducing akinetopsia as TMS of V5.
Alzheimers disease
Besides memory problems, Alzheimers patients may have varying degrees of akinetopsia. This could contribute to their marked disorientation. While Pelak and Hoyt have recorded an Alzheimers case study, there has not been much research done on the subject yet.
Antidepressants
Inconspicuous akinetopsia can be triggered by high doses of certain antidepressants with vision returning to normal once the dosage is reduced.
Areas of visual perception
Two relevant visual areas for motion processing are V5 and V1. These areas are separated by their function in vision. A functional area is a set of neurons with common selectivity and stimulation of this area, specifically behavioral influences. There have been over 30 specialized processing areas found in the visual cortex.
V5
V5, also known as visual area MT (middle temporal), is located laterally and ventrally in the temporal lobe, near the intersection of the ascending limb of the inferior temporal sulcus and the lateral occipital sulcus. All of the neurons in V5 are motion selective, and most are directionally selective. Evidence of functional specialization of V5 was first found in primates. Patients with akinetopsia tend to have unilateral or bi-lateral damage to the V5.
V1
V1, also known as the primary visual cortex, is located in Brodmann area 17. V1 is known for its pre-processing capabilities of visual information; however, it is no longer considered the only perceptually effective gateway to the cortex. Motion information can reach V5 without passing through V1 and a return input from V5 to V1 is not required for seeing simple visual motion. Motion-related signals arrive at V1 (60–70 ms) and V5 (< 30 ms) at different times, with V5 acting independently of V1. Patients with blindsight have damage to V1, but because V5 is intact, they can still sense motion. Inactivating V1 limits motion vision, but does not stop it completely.
Ventral and dorsal streams
Another thought on visual brain organization is the theory of streams for spatial vision, the ventral stream for perception and the dorsal stream for action. Since LM has impairment in both perception and action (such as grasping and catching actions), it has been suggested that V5 provides input to both perception and action processing streams.
Case studies
Potzl and Redlichs patient
In 1911, Potzl and Redlich reported a 58-year-old female patient with bilateral damage to her posterior brain. She described motion as if the object remained stationary but appeared at different successive positions. Additionally, she also lost a significant amount of her visual field and had anomic aphasia.
Goldstein and Gelbs patient
In 1918, Goldstein and Gelb reported a 24-year-old male who suffered a gunshot wound in the posterior brain. The patient reported no impression of movement. He could state the new position of the object (left, right, up, down), but saw "nothing in between". While Goldestein and Gelb believed the patient had damaged the lateral and medial parts of the left occipital lobe, it was later indicated that both occipital lobes were probably affected, due to the bilateral, concentric loss of his visual field. He lost his visual field beyond a 30-degree eccentricity and could not identify visual objects by their proper names.
"LM"
Most of what is known about akinetopsia was learned from LM, a 43-year-old female admitted into the hospital October 1978 complaining of headache and vertigo. LM was diagnosed with thrombosis of the superior sagittal sinus which resulted in bilateral, symmetrical lesions posterior of the visual cortex. These lesions were verified by PET and MRI in 1994. LM had minimal motion perception that was preserved as perhaps a function of V1, as a function of a "higher" order visual cortical area, or some functional sparing of V5.LM found no effective treatment, so she learned to avoid conditions with multiple visual motion stimuli, i.e. by not looking at or fixating them. She developed very efficient coping strategies to do this and nevertheless lived her life. In addition, she estimated the distance of moving vehicles by means of sound detection in order to continue to cross the street.LM was tested in three areas against a 24-year-old female subject with normal vision:
Visual functions other than movement vision
LM had no evidence of a color discrimination deficit in either center or periphery of visual fields. Her recognition time for visual objects and words was slightly higher than the control, but not statistically significant. There was no restriction in her visual field and no scotoma.
Disturbance of movement vision
LMs impression of movement depended on the direction of the movement (horizontal vs vertical), the velocity, and whether she fixated in the center of the motion path or tracked the object with her eyes. Circular light targets were used as stimuli.In studies, LM reported some impression of horizontal movement at a speed of 14 degrees of her predetermined visual field per second (deg/s) while fixating in the middle of the motion path, with difficulty seeing motion both below and above this velocity. When allowed to track the moving spot, she had some horizontal movement vision up to 18 deg/s. For vertical movement, the patient could only see motion below 10 deg/s fixated or 13 deg/s when tracking the target. The patient described her perceptual experience for stimulus velocities higher than 18 and 13 deg/s, respectively as "one light spot left or right" or "one light spot up or down" and "sometimes at successive positions in between", but never as motion.
Motion in depth
To determine perception of motion in depth, studies were done in which the experimenter moved a black painted wooden cube on a tabletop either towards the patient or away in line of sight. After 20 trials at 3 or 6 deg/s, the patient had no clear impression of movement. However she knew the object had changed in position, she knew the size of the cube, and she could correctly judge the distance of the cube in relation to other nearby objects.
Inner and outer visual fields
Detection of movement in the inner and outer visual fields was tested. Within her inner visual field, LM could detect some motion, with horizontal motion more easily distinguished than vertical motion. In her peripheral visual field, the patient was never able to detect any direction of movement. LMs ability to judge velocities was also tested. LM underestimated velocities over 12 deg/s.
Motion aftereffect and Phi phenomenon
Motion aftereffect of vertical stripes moving in a horizontal direction and a rotating spiral were tested. She was able to detect motion in both patterns, but reported motion aftereffect in only 3 of the 10 trials for the stripes, and no effect for the rotating spiral. She also never reported any impression of motion in depth of the spiral. In Phi phenomenon two circular spots of light appear alternating. It appears that the spot moves from one location to the other. Under no combination of conditions did the patient report any apparent movement. She always reported two independent light spots.
Visually guided pursuit eye and finger movements
LM was to follow the path of a wire mounted onto a board with her right index finger. The test was performed under purely tactile (blindfolded), purely visual (glass over the board), or tactile-visual condition. The patient performed best in the purely tactile condition and very poorly in the visual condition. She did not benefit from the visual information in the tactile-visual condition either. The patient reported that the difficulty was between her finger and her eyes. She could not follow her finger with her eyes if she moved her finger too fast.
Additional experiments
In 1994, several other observations of LMs capabilities were made using a stimulus with a random distribution of light squares on a dark background that moved coherently. With this stimulus, LM could always determine the axis of motion (vertical, horizontal), but not always the direction. If a few static squares were added to the moving display, identification of direction fell to chance, but identification of the axis of motion was still accurate. If a few squares were moving opposite and orthogonal to the predominant direction, her performance on both direction and axis fell to chance. She was also unable to identify motion in oblique directions, such as 45, 135, 225, and 315 degrees, and always gave answers in cardinal directions, 0, 90, 180, and 270 degrees.
"TD"
In 2019, Heutink and colleagues described a 37-year old female patient (TD) with akinetopsia, who was admitted to Royal Dutch Visio, Centre of Expertise for blind and partially sighted people. TD suffered an ischaemic infarction of the occipitotemporal region in the right hemisphere and a smaller infarction in the left occipital hemisphere. MRI confirmed that the damaged brain areas contained area V5 in both hemispheres. TD experienced problems with perceiving visual motion and also reported that bright colours and sharp contrasts made her feel sick. TD also had problems perceiving objects that were more than ± 5 meters away from her. Although TD had some impairments of lower visual functions, these could not explain the problems she experienced with regard to motion perception. Neuropsychological assessment revealed no evidence of Balints Syndrome, hemispatial neglect or visual extinction, prosopagnosia or object agnosia. There was some evidence for impaired spatial processing. On several behavioural tests, TD showed a specific and selective impairment of motion perception that was comparable to LMs performance.TDs ability to determine the direction of movement was tested using a task in which small grey blocks all moved in the same direction with the same speed against a black background. The blocks could move in four directions: right to left, left to right, upward and downward. Speed of movement was varied from 2, 4.5, 9, 15 and 24 degrees per second. Speed and direction were varied randomly across trials. TD had perfect perception of motion direction at speed up to 9 degrees per second. When speed of targets was above 9 degrees per second, TDs performance dropped dramatically to 50% correct at a speed of 15 degrees per second and 0% correct at 24 degrees per second. When the blocks moved at 24 degrees per second, TD consistently reported the exact opposite direction of the actual movement.
Pelak and Hoyts Alzheimers patient
In 2000, a 70-year-old man presented with akinetopsia. He had stopped driving two years prior because he could no longer "see movement while driving". His wife noted that he could not judge the speed of another car or how far away it was. He had difficulty watching television with significant action or movement, such as sporting events or action-filled TV shows. He frequently commented to his wife that he could not "see anything going on". When objects began to move they would disappear. He could, however, watch the news, because no significant action occurred. In addition he had signs of Balints syndrome (mild simultanagnosia, optic ataxia, and optic apraxia).
Pelak and Hoyts TBI patient
In 2003, a 60-year-old man complained of the inability to perceive visual motion following a traumatic brain injury, two years prior, in which a large cedar light pole fell and struck his head. He gave examples of his difficulty as a hunter. He was unable to notice game, to track other hunters, or to see his dog coming towards him. Instead, these objects would appear in one location and then another, without any movement being seen between the two locations. He had difficulties driving and following a group conversation. He lost his place when vertically or horizontally scanning a written document and was unable to visualize three-dimensional images from two-dimensional blueprints.
== References == |
Biotin deficiency | Biotin deficiency is a nutritional disorder which can become serious, even fatal, if allowed to progress untreated. It can occur in people of any age, ancestry, or of either gender. Biotin is part of the B vitamin family. Biotin deficiency rarely occurs among healthy people because the daily requirement of biotin is low, many foods provide adequate amounts of it, intestinal bacteria synthesize small amounts of it, and the body effectively scavenges and recycles it in the kidneys during production of urine. However, deficiencies can be caused by consuming raw egg whites over a period of weeks to months. Egg whites contain high levels of avidin, a protein that binds biotin strongly. When cooked, avidin is partially denatured and binding to biotin is reduced. However one study showed that 30-40% of the avidin activity was still present in the white after frying or boiling. Genetic disorders such as biotinidase deficiency, multiple carboxylase deficiency, and holocarboxylase synthetase deficiency can also lead to inborn or late-onset forms of biotin deficiency. In all cases – dietary, genetic, or otherwise – supplementation with biotin is the primary method of treatment.
Signs and symptoms
Rashes including red, patchy ones near the mouth (erythematous periorofacial macular rash)
Fine and brittle hair
Psychological
Hallucinations
Lethargy
Mild depression, which may progress to profound fatigue and, eventually, to somnolence
Generalized muscular pains (myalgia)
Paresthesias
Causes
Total parenteral nutrition without biotin supplementation: Several cases of biotin deficiency in patients receiving prolonged total parenteral nutrition (TPN) therapy without added biotin have been reported. Therefore, all patients receiving TPN must also receive biotin at the recommended daily dose, especially if TPN therapy is expected to last more than 1 week. All hospital pharmacies currently include biotin in TPN preparations.
Protein deficiency: A shortage of proteins involved in biotin homeostasis can cause biotin deficiency. The main problems involved in biotin homeostasis are HCS, BTD (biotinidase deficiency) and SMVT
Anticonvulsant therapy: Prolonged use of certain drugs (especially highly common prescription anti-seizure medications such as phenytoin, primidone, and carbamazepine), may lead to biotin deficiency; however, valproic acid therapy is less likely to cause this condition. Some anticonvulsants (antiepileptic drugs) inhibit biotin transport across the intestinal mucosa. Evidence suggests that these anticonvulsants accelerate biotin catabolism, which means that its necessary for people to take supplemental biotin, in addition to the usual minimum daily requirements, if theyre treated with anticonvulsant medication(s) that have been linked to biotin deficiency.
Severe malnourishment
Prolonged oral antibiotic therapy: Prolonged use of oral antibiotics has been associated with biotin deficiency. Alterations in the intestinal flora caused by the prolonged administration of antibiotics are presumed to be the basis for biotin deficiency.
Genetic mutation: Mikati et al. (2006) reported a case of partial biotinidase deficiency (plasma biotinidase level of 1.3 nm/min/mL) in a 7-month-old boy. The boy presented with perinatal distress followed by developmental delay, hypotonia, seizures, and infantile spasms without alopecia or dermatitis. The childs neurologic symptoms abated following biotin supplementation and antiepileptic drug therapy. DNA mutational analysis revealed that the child was homozygous for a novel E64K mutation and that his mother and father were heterozygous for the novel E64K mutation.
Potential causes
Smoking: Recent studies suggest that smoking can lead to marginal biotin deficiency because it speeds up biotin catabolism (especially in women).
Excessive alcohol consumption
Excessive consumption of antidiuretics or inadequate levels of antidiuretic hormone
Intestinal malabsorption caused by short bowel syndrome
Biochemistry
Biotin is a coenzyme for five carboxylases in the human body (propionyl-CoA carboxylase, methylcrotonyl-CoA carboxylase, pyruvate carboxylase, and 2 forms of acetyl-CoA carboxylase.) Therefore, biotin is essential for amino acid catabolism, gluconeogenesis, and fatty acid metabolism. Biotin is also necessary for gene stability because it is covalently attached to histones. Biotinylated histones play a role in repression of transposable elements and some genes. Normally, the amount of biotin in the body is regulated by dietary intake, biotin transporters (monocarboxylate transporter 1 and sodium-dependent multivitamin transporter), peptidyl hydrolase biotinidase (BTD), and the protein ligase holocarboxylase synthetase. When any of these regulatory factors are inhibited, biotin deficiency could occur.
Diagnosis
The most reliable and commonly used methods for determining biotin status in the body are:
excretion of 3-hydroxyisovaleric acid and biotin in urine
activity of propionyl-CoA carboxylase in lymphocytes
Treatment
In the United States, biotin supplements are readily available without a prescription in amounts ranging from 300 to 10,000 micrograms (30 micrograms is identified as Adequate Intake).
Epidemiology
Since biotin is present in many foods at low concentrations, deficiency is rare except in locations where malnourishment is very common. Pregnancy, however, alters biotin catabolism and despite a regular biotin intake, half of the pregnant women in the U.S. are marginally biotin deficient.
See also
Biotinidase deficiency
Holocarboxylase synthetase deficiency
Multiple carboxylase deficiency
References
Possible references
Adhisivam B, Mahto D, Mahadevan S (March 2007). "Biotin responsive limb weakness". Indian Pediatr. 44 (3): 228–30. PMID 17413203.
Baykal T, Gokcay G, Gokdemir Y, Demir F, Seckin Y, Demirkol M, Jensen K, Wolf B (2005). "Asymptomatic adults and older siblings with biotinidase deficiency ascertained by family studies of index cases". J. Inherit. Metab. Dis. 28 (6): 903–12. doi:10.1007/s10545-005-0161-3. PMID 16435182. S2CID 22277450.
Boas MA (1927). "The Effect of Desiccation upon the Nutritive Properties of Egg-white". Biochem. J. 21 (3): 712–724.1. doi:10.1042/bj0210712. PMC 1251968. PMID 16743887.
Dobrowolski SF, Angeletti J, Banas RA, Naylor EW (February 2003). "Real time PCR assays to detect common mutations in the biotinidase gene and application of mutational analysis to newborn screening for biotinidase deficiency". Mol. Genet. Metab. 78 (2): 100–7. doi:10.1016/S1096-7192(02)00231-7. PMID 12618081.
Forbes GM, Forbes A (1997). "Micronutrient status in patients receiving home parenteral nutrition". Nutrition. 13 (11–12): 941–4. doi:10.1016/S0899-9007(97)00334-1. PMID 9433708.
Genc GA, Sivri-Kalkanoğlu HS, Dursun A, Aydin HI, Tokatli A, Sennaroglu L, Belgin E, Wolf B, Coşkun T (February 2007). "Audiologic findings in children with biotinidase deficiency in Turkey". Int. J. Pediatr. Otorhinolaryngol. 71 (2): 333–9. doi:10.1016/j.ijporl.2006.11.001. PMID 17161472.
González EC, Marrero N, Frómeta A, Herrera D, Castells E, Pérez PL (July 2006). "Qualitative colorimetric ultramicroassay for the detection of biotinidase deficiency in newborns". Clin. Chim. Acta. 369 (1): 35–9. doi:10.1016/j.cca.2006.01.009. PMID 16480705.
Hassan YI, Zempleni J (July 2006). "Epigenetic regulation of chromatin structure and gene function by biotin". J. Nutr. 136 (7): 1763–5. doi:10.1093/jn/136.7.1763. PMC 1479604. PMID 16772434.
Higuchi R, Mizukoshi M, Koyama H, Kitano N, Koike M (February 1998). "Intractable diaper dermatitis as an early sign of biotin deficiency". Acta Paediatr. 87 (2): 228–9. doi:10.1080/08035259850157732. PMID 9512215.
László A, Schuler EA, Sallay E, Endreffy E, Somogyi C, Várkonyi A, Havass Z, Jansen KP, Wolf B (2003). "Neonatal screening for biotinidase deficiency in Hungary: clinical, biochemical and molecular studies". J. Inherit. Metab. Dis. 26 (7): 693–8. doi:10.1023/B:BOLI.0000005622.89660.59. PMID 14707518. S2CID 12601233.
Mock DM (February 1999). "Biotin status: which are valid indicators and how do we know?". J. Nutr. 129 (2S Suppl): 498S–503S. doi:10.1093/jn/129.2.498S. PMID 10064317.
Mock DM (December 1991). "Skin manifestations of biotin deficiency". Semin Dermatol. 10 (4): 296–302. PMID 1764357.
Möslinger D, Mühl A, Suormala T, Baumgartner R, Stöckler-Ipsiroglu S (December 2003). "Molecular characterisation and neuropsychological outcome of 21 patients with profound biotinidase deficiency detected by newborn screening and family studies". Eur. J. Pediatr. 162 (Suppl 1): S46–9. doi:10.1007/s00431-003-1351-3. PMID 14628140. S2CID 6490712.
Neto EC, Schulte J, Rubim R, Lewis E, DeMari J, Castilhos C, Brites A, Giugliani R, Jensen KP, Wolf B (March 2004). "Newborn screening for biotinidase deficiency in Brazil: biochemical and molecular characterizations". Braz. J. Med. Biol. Res. 37 (3): 295–9. doi:10.1590/S0100-879X2004000300001. PMID 15060693.
Schulpis KH, Gavrili S, Tjamouranis J, Karikas GA, Kapiki A, Costalos C (May 2003). "The effect of neonatal jaundice on biotinidase activity". Early Hum. Dev. 72 (1): 15–24. doi:10.1016/S0378-3782(02)00097-X. PMID 12706308.
Thompson, J, Manore M, Sheeshka J (2010). "Nutrients involved in energy metabolism and blood health". In Bennett G, Swieg C, et al. (eds.). Nutrition: A functional Approach. Toronto: Pearson Canada. p. 353. ISBN 9780321740212.
Velázquez A (1997). "Biotin deficiency in protein-energy malnutrition: implications for nutritional homeostasis and individuality". Nutrition. 13 (11–12): 991–2. doi:10.1016/S0899-9007(97)00345-6. PMID 9433719.
Weber P, Scholl S, Baumgartner ER (July 2004). "Outcome in patients with profound biotinidase deficiency: relevance of newborn screening". Dev Med Child Neurol. 46 (7): 481–4. doi:10.1111/j.1469-8749.2004.tb00509.x. PMID 15230462.
Welling DB (August 2007). "Long-term follow-up of hearing loss in biotinidase deficiency". J. Child Neurol. 22 (8): 1055. doi:10.1177/0883073807305789. PMID 17761663. S2CID 39911504.
Wiznitzer M, Bangert BA (July 2003). "Biotinidase deficiency: clinical and MRI findings consistent with myelopathy". Pediatr. Neurol. 29 (1): 56–8. doi:10.1016/S0887-8994(03)00042-0. PMID 13679123.
Wolf B (2001). "Disorders of biotin metabolism". In Scriver CR, Beaudet AL, et al. (eds.). The metabolic & molecular bases of inherited disease. New York: McGraw-Hill. pp. 3935–62. ISBN 978-0-07-913035-8.
External links
GeneReviews/NCBI/NIH/UW entry on Biotinidase deficiency
OMIM entries on Biotinidasa deficiency |
Systematized epidermal nevus | Systematized epidermal nevus is a cutaneous condition, an epidermal nevus with a diffuse or extensive distribution involving a large portion of a persons body surface.: 771
See also
Linear verrucous epidermal nevus
== References == |
Pallister–Killian syndrome | The Pallister–Killian syndrome (PKS), also termed tetrasomy 12p mosaicism or the Pallister mosaic aneuploidy syndrome, is an extremely rare and severe genetic disorder. PKS is due to the presence of an extra and abnormal chromosome termed a small supernumerary marker chromosome (sSMC). sSMCs contain copies of genetic material from parts of virtually any other chromosome and, depending on the genetic material they carry, can cause various genetic disorders and neoplasms. The sSMC in PKS consists of multiple copies of the short (i.e. "p") arm of chromosome 12. Consequently, the multiple copies of the genetic material in the sSMC plus the two copies of this genetic material in the two normal chromosome 12s are overexpressed and thereby cause the syndrome. Due to a form of genetic mosaicism, however, individuals with PKS differ in the tissue distributions of their sSMC and therefore show different syndrome-related birth defects and disease severities. For example, individuals with the sSMC in their heart tissue are likely to have cardiac structural abnormalities while those without this sSMC localization have a structurally normal heart.PKS was first described by Philip Pallister in 1977 and further researched by Maria Teschler-Nicola and Wolfgang Killian in 1981.
Presentation
Individuals with PKS present prenatally or at birth with multiple birth defects. These defects include: brain atrophy, agenesis of the corpus callosum, polymicrogyria of the brain, and/or spot calcifications in the brains lateral sulcus; deafness and/or blindness; autonomic nervous system dysfunctions such as anhidrosis, hypohidrosis, and/or episodic spells of hyperventilation interspersed with breath-holding; symptoms of spinal cord malformations; profound or less commonly mild to severe intellectual disability; epileptic seizures; heart and/or anal defects; diaphragmatic hernias; marked muscle weakness; supernumerary nipples; abnormal facial features such as frontal bossing, high frontal hairline, balding around the temple and frontal areas, sparse eyebrows and lashes, hypertelorism, small and flat nose, full cheeks, long philtrum, large mouth with downturned corners, thin cupids bow-shaped upper lip, micrognathia (i.e. undersized jaw), disformed ears that are low-set, thick eyebrows, and/or prominent lips and chin; abnormal oral/dental features such as enlarged tongue, overgrowth of the alveolar ridge and/or gums, delayed teeth eruption, and/or missing or double teeth; patchy skin depigmentations; skeletal anomalies such as limb shortening, lymphedema, increased soft tissues in the extremities, short/broad palms and/or fingers, and/or clinodactyly of the fifth fingers or toes; excessive prenatal and birth weights followed by postnatal declines in growth rates; delayed closure of the anterior fontanel; and/or delayed puberty in males but not females.
Causes
PKS is caused by an sSMC that consists of two copies or, less commonly, four copies of the genetic material in the p arm of chromosome 12. Recent studies in two individuals with PKS found their sSMCs consisted specifically of genetic material located in a stretch of chromosome 12 s p arm starting at its band 11 and running to its end. This area, called the PKS critical region, contains three genes, ING4, CHD4, and MFAP5 (also termed the MAGP2 gene), which are candidates for contributing to the development of the syndrome.One suggested mechanism for the development of the sSMC in PKS involves three sequential events: 1) chromosome 12 suffers a nondisjunction, i.e. a failure of its homologous chromosomes or sister chromatids to separate properly during the second meiosis cell division that forms maternal eggs; 2) while most of the eggs with this nondisjunction die, a rare egg with the nondisjunction acquires a second structural aberration, isochromosome formation, that results in the creation of an extra chromosome consisting of copies of two or four p arms but no q arms of chromosome 12, i.e. the sSMC; and 3) the sSMC-containing egg, after being fertilized by a genetically normal sperm, develops into an offspring containing copies of this sSMC in some but not all cells, tissues, and/or organs consequently have some but not all of the defects associated with PKS. This mechanism applies only to female parents who are by far the most common originators of the sSMC in PKS. The mechanism explaining the few cases in which male parents form a sperm containing this sSMC has not yet been clearly formulated.
Diagnosis
Prenatal diagnosis
PKS is commonly diagnosed by detecting its causative sSMC as defined by identifying the overexpression of its genetic material. This method has detected the sSMC and therefore diagnosed a fetus as having PKS based on genomic analyses of fetal skin fibroblasts, placenta chorionic villi, cells isolated from the amniotic fluid, fibroblasts isolated from the fetuss umbilical cord, and cells isolated from the fetuss umbilical cord blood. PKS can also be diagnose using fetal ultasound imaging methods. Ultrasound imaging in PKS commonly find fetuses that are too large for their gestational age, contain polyhydramnios (excess amniotic fluid in their amniotic sacs), and have rhizomelic limbs (shortening of the proximal part of the limbs). Less commonly, the imaging evidences diaphragmatic hernias and/or various other major PKS structural malformations. In most cases, however, the ultrasound findings are not diagnostic of PKS. Furthermore, ultrasound diagnoses is best applied in the second or third pregnancy trimester when structural anomalies are more clearly defined and detectable.Because the prenatal diagnosis of PKS using the methods just cited is difficult, often indecisive, and/or best employed later in a womans pregnancy, prenatal cell-free DNA screening (cfDNA screening), also known as noninvasive prenatal screening, has been used to diagnose PKS. This method can diagnose PKS in 10 week and older fetuses. In cfDNA screening, DNA from a mothers blood is extracted and screened for the presence of specific chromosome abnormalities such as those associated with the Down syndrome, Patau syndrome (also termed trisomy 13), and Edwards syndrome (also termed trisomy 18). (Small amounts of a fetuss DNA escapes through the placenta to circulate in the mothers blood.) A genome-wide association study done in China used genome-wide cfDNA analyses to diagnose various chromosome-related disorders including PKS. The study scanned the DNA in the blood of 29,007 pregnant women and found three cases with abnormal amount of DNA originating from the entire p-arm of chromosome 12. All three cases were confirmed to have a fetus with PKS. Two of these cases were missed by chromosomal microarray analysis of the placenta and chorionic villi. However, the study did not define the rate of false negative cases, i.e. negative results in women actually carrying a fetus with PKS. While further studies are required, this method may turn out to be a critically useful addition for the prenatal detection of PKS, particularly during early pregnancies for the purpose of pregnancy options counseling.
Postnatal diagnosis
The postnatal diagnosis of PKS is strongly suggested or indicated in most cases based on finding the key defects of PKS in an individual on physical examination and various radiography, ultrasound, and related methods. However, some individuals with this syndrome do not have a sufficient number of these defects or have a set of defects that are also compatible with other birth defect disorders such as Fryns syndrome, trisomy 12p, and Sifrim-Hitz-Weiss syndrome (also termed CHD4 Neurodevelopmental Disorder). The diagnosis can be confirmed in these cases as well as in all cases of PKS by detecting its sSMC using special methods. This sSMC has been successfully detected (>90% of confirmed cases) in the DNA extracted by a buccal swab taken from the inside of an individuals cheek or the DNA extracted form an individuals cultured skin fibroblasts, i.e. fibroblasts from a skin biopsy grown in a laboratory for at least several days. The sSMC in these tissues or cells is identified by multiplex ligation-dependent probe amplification (i.e. MLPA) or microarray-based comparative genomic hybridization (i.e. array CGH). Because of mosaicism, testing an individuals circulating blood lymphocytes only rarely detects (i.e. gives mostly false negative results) in true PKS cases.
See also
List of cutaneous conditions
References
== External links == |
Oculodentodigital dysplasia | Oculodentodigital syndrome (ODD syndrome) is an extremely rare genetic condition that typically results in small eyes, underdeveloped teeth, and syndactyly and malformation of the fourth and fifth fingers. It is considered a kind of ectodermal dysplasia.
Signs and symptoms
People with ODD syndrome often have a characteristic appearance. Visible features of the condition include:
small teeth that are prone to dental caries because of underdeveloped tooth enamel;
a long, thin nose;
unusually small eyes; and
type III syndactyly of the fourth and fifth fingers.Iris atrophy and glaucoma are more common than average. The size of the eyes often interferes with learning to read; special eyeglasses may be required. Hair may be fine, thin, dry, or fragile; in some families, it is curly.Neurologic abnormalities may be seen in adults. The neurologic changes may appear earlier in each subsequent generation and can include abnormal white matter, conductive deafness, and various kinds of paresis, including ataxia, spastic paraplegia, difficulty controlling the eyes, and bladder and bowel disturbances.
Genetics
ODD is typically an autosomal dominant condition, but can be inherited as a recessive trait. It is generally believed to be caused by a mutation in the gene GJA1, which codes for the gap junction protein connexin 43. Slightly different mutations in this gene may explain the different way the condition manifests in different families. Most people inherit this condition from one of their parents, but new cases do arise through novel mutations. The mutation has high penetrance and variable expression, which means that nearly all people with the gene show signs of the condition, but these signs can range from very mild to very obvious.
Diagnosis
Epidemiology
The actual incidence of this disease is not known, but only 243 cases have been reported in the scientific literature, suggesting an incidence of on the order of one affected person in ten million people.
References
== External links == |
Trench fever | Trench fever (also known as "five-day fever", "quintan fever" (Latin: febris quintana), and "urban trench fever") is a moderately serious disease transmitted by body lice. It infected armies in Flanders, France, Poland, Galicia, Italy, Salonika, Macedonia, Mesopotamia, Russia and Egypt in World War I. Three noted cases during WWI were the authors J. R. R. Tolkien, A. A. Milne, and C. S. Lewis. From 1915 to 1918 between one-fifth and one-third of all British troops reported ill had trench fever while about one-fifth of ill German and Austrian troops had the disease. The disease persists among the homeless. Outbreaks have been documented, for example, in Seattle and Baltimore in the United States among injection drug users and in Marseille, France, and Burundi.Trench fever is also called Wolhynia fever, shin bone fever, Meuse fever, His disease and His–Werner disease or Werner-His disease (after Wilhelm His Jr. and Heinrich Werner).
The disease is caused by the bacterium Bartonella quintana (older names: Rochalimea quintana, Rickettsia quintana), found in the stomach walls of the body louse. Bartonella quintana is closely related to Bartonella henselae, the agent of cat scratch fever and bacillary angiomatosis.
Signs and symptoms
The disease is classically a five-day fever of the relapsing type, rarely exhibiting a continuous course. The incubation period is relatively long, at about two weeks. The onset of symptoms is usually sudden, with high fever, severe headache, pain on moving the eyeballs, soreness of the muscles of the legs and back, and frequently hyperaesthesia of the shins. The initial fever is usually followed in a few days by a single, short rise but there may be many relapses between periods without fever. The most constant symptom is pain in the legs. Recovery takes a month or more. Lethal cases are rare, but in a few cases "the persistent fever might lead to heart failure". Aftereffects may include neurasthenia, cardiac disturbances and myalgia.
Pathophysiology
Bartonella quintana is transmitted by contamination of a skin abrasion or louse-bite wound with the faeces of an infected body louse (Pediculus humanus corporis). There have also been reports of an infected louse bite passing on the infection.
Diagnosis
Serological testing is typically used to obtain a definitive diagnosis. Most serological tests would succeed only after a certain period of time past the symptom onset (usually a week). The differential diagnosis list includes typhus, ehrlichiosis, leptospirosis, Lyme disease, and virus-caused exanthema (measles or rubella).
Treatment
The treatment of trench fever can vary from case to case, as the human body has the ability to rid itself of the disease without medical intervention. Some patients will require treatment, and others will not. For those who do require treatment, the best treatment comes by way of doxycycline in combination with gentamicin. Chloramphenicol is an alternative medication recommended under circumstances that render use of tetracycline derivates undesirable, such as severe liver disease, kidney dysfunction, in children under nine years and in pregnant women. The medication is administered for seven to ten days.
Epidemiology
Trench fever is a vector borne disease in which humans are primarily the main hosts. The vector through which the disease is typically transmitted is referred to as the human body louse "Pediculus humanus humanus", which is better known as lice. The British Expeditionary Force Pyrexia of Unknown Origin Enquiry Sub-Committee concluded that the specific means by which the vector infected the host was louse waste entering the body through abraded skin. Although the disease is typically found in humans, the gram negative bacterium which induce the disease have been seen in mammals such as dogs, cats, and macaques in small numbers.Being that the vector of the disease is human body louse, it can be determined that the main risk factors for infection are mostly in relation to contracting body louse. Specifically, some risk factors include: body louse infestation, overcrowded and unhygienic conditions, body hygiene, war, famine, malnutrition, alcoholism, homelessness, and intravenous drug abuse.The identified risk factors directly correlate with the subpopulations of identified infected persons throughout the duration of the known disease. Historically, trench fever was found in young male soldiers of World War I, whereas in the 21st century the disease mostly has a prevalence in middle aged homeless men. This can be seen when looking at a 21st-century outbreak of the disease in Denver, Colorado, where researcher David McCormick and his colleagues came across the gram negative bacterium in 15% of the 241 homeless persons who were tested. Another study done in Marseille, France found the bacterium in 5.4% of the 930 homeless individuals they tested.
History
Trench fever was first described and reported by British major John Graham in June 1915. He reported symptoms such as dizziness, headaches, and pain in the shins and back. The disease was most common in the military and consequently took much longer to identify than usual. These cases were originally confused for dengue, sandfly, or paratyphoid fever. Because insects were the suspected vector of transmission, Alexander Peacock published a study of the body louse in 1916. Due in part to his findings, the louse was determined to be the primary cause of transmission by many, but this was still contested by multiple voices in the field such as John Muir who believed the disease was of the viral nature. In 1917, the Trench Fever Investigation Commission (TFIC) had its first meeting. The TFIC performed experiments with infected blood and louse, and learned much about the disease and louse behavior. Also in 1917 the American Red Cross started the Medical Research Committee (MRC). The MRC performed human experiments on trench fever, and their research was published in March 1918. The MRC and TFIC findings were very similar essentially confirming the louse as the vector of transmission. It was not until the 1920s that the bacteria B Quintana was identified as the cause of trench fever.
References
== External links == |
Pachygyria | Pachygyria (from the Greek "pachy" meaning "thick" or "fat" gyri) is a congenital malformation of the cerebral hemisphere. It results in unusually thick convolutions of the cerebral cortex. Typically, children have developmental delay and seizures, the onset and severity depending on the severity of the cortical malformation. Infantile spasms are common in affected children, as is intractable epilepsy.
Presentation
The term pachygyria does not directly relate to a specific malformation but rather is used to generally describe physical characteristics of the brain in association with several neuronal migration disorders; most commonly disorders relating to varied degrees of lissencephaly. Lissencephaly is present in 1 of 85,470 births and the life span of those affected is short as only a few survive past the age of 20.
Pachygyria is a condition identified by a type of cortical genetic malformation. Clinicians will subjectively determine the malformation based on the degree of malposition and the extent of thickened abnormal grey differentiation present.
Connections to epilepsy, lissencephaly, and subcortical band heterotopia
Various degrees of intensity and locations of epilepsy are associated with malformations of cortical development. Researchers suggest that approximately 40% of children diagnosed with drug-resistant epilepsy have some degree of cortical malformation.Lissencephaly (to which pachygyria is most closely linked) is associated with severe mental retardation, epilepsy, and motor disability. Two characteristics of lissencephaly include its absence of convolutions (agyria) and decreased presence of convolutions (pachygyria). The types of seizures associated with lissencephaly include:
persisting spasms
focal seizures
tonic seizures
atypical seizures
atonic seizures Other possible symptoms of lissencephaly include telecanthus, estropia, hypertelorism, varying levels of mental retardation, cerebellar hypoplasia, corpus callosum aplasia, and decreased muscle tone and tendon reflexes. Over 90% of children affected with lissencephaly have seizures.Patients with subcortical band heterotopia (another disorder associated with pachygyria) typically have milder symptoms and their cognitive function is closely linked to the thickness of the subcortical band and the degree of pachygyria present.
Causes
Pachygyria is caused by a breakdown in the fetal neuronal migration process due to genetic or possibly environmental influences. The affected cerebral cortex will typically have only four developed layers instead of the normal six.
One of the best known and most common types of neuronal migration disorders is lissencephaly, a diffuse cortical malformation relating directly to agyria and pachygyria. Incomplete neuronal migration during the early fetal brain development is the precursor to lissencephaly.
Should neurons follow an abnormal migration during development possible cortical malformations include classical lissencephaly (as stated above) and subcortical band heterotopia with an agyria-pachygyria band spectrum.
Normal neuronal migration
Normal neuronal migration involves the development of six cortical layers, each one performing distinct functions.Normal cerebral development occurs in three dynamic and overlapping stages:
first stage: stem cells proliferate and differentiate into neurons or glial cells within the forebrain and the ventricular and subventricular zones lining the cerebral cavity;
in humans this stage lasts from gestational weeks 5-6 to 16-20;
second stage: migration away from the origin in a radial fashion along the glial fibers from the periventricular region of the ganglionic eminences towards the pial surface;
the generations settle into a pattern within the cortical plate during this stage;
in humans this stage lasts from gestational weeks 6-7 to 20-24;
third stage: apoptosis and synaptogenesis within the six cortical layers to develop correct cortical organization;
in humans this stage lasts from gestational week 16 until long after birth.Most types of incomplete neuronal migration to the cortex occur during the third and fourth gestational months. The abnormal migration of the neurons causes them to not reach their proper final destinations, which results in failure of the sulci and gyri to form.The stage of cortical development at which migration is arrested is directly related to the level of structural malposition.One of the most critical stages in brain development is when the post-mitotic neurons migrate from the ventricular zone to form the cortical plate. Migration arrested toward the latter part of development usually restricts the abnormal cell position to the cortex level.
Neuronal migration disorder caused by genetic mutations
Several genetic mutations have been isolated and linked to specific malformations of the cerebral cortex. Genes shown to cause lissencephaly include both autosomal and X-linked genes. Below, the mutations of LIS1 or DCX genes are discussed as they are most commonly linked to neuronal migration disorders including lissencephaly-pachygyria and subcortical band heterotopia.
LIS1
LIS1 is responsible for the autosomal form of lissencephaly. Mutations of the LIS1 gene are associated with about 80% of those affected with lissencephaly.
LIS1 was the first human neuronal migration gene to be cloned. It is responsible for encoding the alpha subunit of the intracellular Ib isoform of platelet-activating factor acetylhydrolase. It is located on chromosome 17p13.3 and has 11 exons with a coding region of 1233bp. LIS1 protein appears to interact with tubulin to suppress microtubule dynamics. The protein is highly conserved and studies have shown that it participates in cytoplasmic dynein-mediated nucleokinesis, somal translocation, cell motility, mitosis, and chromosome segregation. LIS1 encodes for a 45kDa protein called PAFAH1B1 that contains seven WD40 repeats required for proper neuronal migration. The LIS1 gene encodes for a protein similar to the β subunit of G proteins responsible for degrading bioactive lipid platelet-activating factor (PAF). This leads to theories that LIS1 might exert its effect on migration through microtubules. Specific concentrations of PAF may be necessary for optimal neuronal migration by influencing cell morphology adhesion properties. Studies have shown that addition of PAF or inhibition of platelet-activating factor acetylhydrolase (PAF-AH) decreases cerebellar granule cell migration in vitro. Addition of PAF to hippocampal cells have shown growth cone collapse and neurite retraction. LIS1 knockout homozygous null mice die during embryogenesis and heterozygous mice survive with delayed neuronal migration confirmed by in vitro and in vivo cell migration assays.
Most lissencephaly cases are associated with deletions of mutations of the LIS1 gene and the results are usually more severe in the posterior brain regions.One study showed that of an isolated group of patients with lissencephaly, 40% resulted from an LIS1 deletion and another 25% resulted from an intragenic mutation of the gene. Patients with missense mutations tend to have less severe symptoms, pachygyria, and rare cases of subcortical band heterotopia. Truncated (shortened) mutations of LIS1 tend to cause severe lissencephaly.
Doublecortin
Doublecortin (DCX or XLIS) mutations are responsible for X-linked disorders. While LIS1 mutations tend to cause severe malformations in the posterior brain, DCX mutations focus much of their destruction on anterior malformations and are linked to lissencephaly in males and subcortical band heterotopias in females. Women with DCX mutations tend to have an anteriorly-predominant subcortical band heterotopia and pachygyria. DCX was the first known gene causing X-linked lissencephaly and subcortical band heterotopia. It is found on chromosome Xq22.3-q23 and has nine exons that code for 360 proteins. DCX is expressed exclusively in the fetal brain.Spastic cerebral palsy is by far the most common type, occurring in 70% to 80% of all cases. Moreover, spastic CP accompanies one of the other types in 30% of all cases. People with this type are hypertonic and have a neuromuscular condition stemming from damage to the corticospinal tract or the motor cortex that affects the nervous systems ability to receive gamma amino butyric acid in the area(s) affected by the disability.Spastic CP is further classified by topography dependent on the region of the body affected; these include:
Spastic hemiplegia (one side being affected). Generally, injury to muscle-nerves controlled by the brains left side will cause a right body deficit, and vice versa. Typically, people that have spastic hemiplegia are the most ambulatory, although they generally have dynamic equinus on the affected side and are primarily prescribed ankle-foot orthoses to prevent said equinus.[11]
Spastic diplegia (the lower extremities are affected with little to no upper-body spasticity). The most common form of the spastic forms. Most people with spastic diplegia are fully ambulatory and have a scissors gait. Flexed knees and hips to varying degrees are common. Hip problems, dislocations, and in three-quarters of spastic diplegics, also strabismus (crossed eyes), can be present as well. In addition, these individuals are often nearsighted. The intelligence of a person with spastic diplegia is unaffected by the condition.
Spastic tetraplegia (all four limbs affected equally). People with spastic quadriplegia are the least likely to be able to walk, or if they can, to want to walk, because their muscles are too tight and it is too much effort to do so. Some children with quadriplegia also have hemiparetic tremors, an uncontrollable shaking that affects the limbs on one side of the body and impairs normal movement.
Occasionally, terms such as monoplegia, paraplegia, triplegia, and pentaplegia may also be used to refer to specific manifestations of the spasticity.
Pathogenesis
Pachygyria, lissencephaly (smooth brain), and polymicrogyria (multiple small gyri) are all the results of abnormal cell migration. The abnormal migration is typically associated with a disorganized cellular architecture, failure to form six layers of cortical neurons (a four-layer cortex is common), and functional problems. The abnormal formation of the brain may be associated with seizures, developmental delay, and mental dysfunctions.Normally, the brain cells begin to develop in the periventricular region (germinal matrix) and then migrate from medial to lateral, to form the cerebral cortex.
Diagnosis
Different imaging modalities are commonly used for diagnosis. While computed tomography (CT) provides higher spatial resolution imaging of the brain, cerebral cortex malformations are more easily visualized in vivo and classified using magnetic resonance imaging (MRI) which provides higher contrast imaging and better delineation of white and gray matter.Diffuse pachygyria (a mild form of lissencephaly) can be seen on an MRI as thickened cerebral cortices with few and large gyri and incomplete development of the Sylvian fissures.
severe epilepsy
reduced longevity
varying degrees of mental retardation
intractable epilepsy
spasticityCognitive ability correlates with the thickness of any subcortical band present and the degree of pachygyria.
Classifications
The degree of cerebral cortex malformation caused by genetic mutations is classified by the degree of malposition and the extent of faulty grey matter differentiation.Neuronal migration disorders are generally classified into three groups:
lissencephaly/subcortical band heterotopia
cobblestone
‘other’ heterotopias The ‘other’ types are associated with corpus callosum agenesis or cerebellar hypoplasia while the cobblestone lissencephalies are associated with eye and muscle disorders.Classical lissencephaly, also known as type I or generalized agyria-pachygyria, is a severe brain malformation of a smooth cerebral surface, abnormally thick (10-20mm) cortex with four layers, widespread neuronal heterotopia, enlarged ventricles, and agenesis or malformation of the corpus callosum. Classical lissencephaly can range from agyria to regional pachygyria and is usually present along with subcortical band heterotopia (known as ‘double cortex’ to describe the circumferential bands of heterotopic neurons located beneath the cortex). Subcortical band heterotopia is a malformation slightly different from lissencephaly that is now classified under the agyria-pachygyria-band spectrum because it consists of a gyral pattern consistent with broad convolutions and an increased cortical thickness.
The established classification scheme for lissencephaly is based on the severity (grades 1-6) and the gradient.
Grade 1: generalized agyria
Grade 2: variable degree of agyria
Grade 3: variable degree of pachygyria
Grade 4: generalized pachygyria
Grade 5: mixed pachygyria and subcortical band heterotopia
Grade 6: subcortical band heterotopia alone
Gradient ‘a’: from posterior to anterior gradient
Gradient ‘b’: from anterior to posterior gradient Grade 1 and Grade 4 are very rare. Grade 2 is observed in children with Miller–Dieker syndrome (a combination of lissencephaly with dysmorphic facial features, visceral abnormalities, and polydactyly). The most common lissencephaly observed, consisting of frontotemporal pachygyria and posterior agyria, is Grade 3.
Another malformation worth mentioning because of its connections to pachygyria is polymicrogyria. Polymicrogyria is characterized by many small gyri separated by shallow sulci, slightly thin cortex, neuronal heterotopia and enlarged ventricle and is often superimposed on pachygyria.
Treatment
Because pachygyria is a structural defect no treatments are currently available other than symptomatic treatments, especially for associated seizures. Another common treatment is a gastrostomy (insertion of a feeding tube) to reduce possible poor nutrition and repeated aspiration pneumonia.
Microcephalic osteodysplastic primordial dwarfism
Microcephalic osteodysplastic primordial dwarfism (MOPD) type II is an autosomal multisystem disorder including severe pre- and post-natal growth retardation, microcephaly with Seckel syndrome-like facial appearance, and distinctive skeletal alterations. Usually those affected have mild to moderate mental retardation.
See also
Lissencephaly
Polymicrogyria
References
Phadke SR, Girisha KM, Phadke RV (2007). "A new autosomal recessive disorder of bilateral frontotemporal pachygyria without microcephaly: report of a case and review of literature". Neurol India. 55 (1): 57–60. doi:10.4103/0028-3886.30429. PMID 17272902.
External links
Online Mendelian Inheritance in Man (OMIM): 600176 |
Ileus | Ileus is a disruption of the normal propulsive ability of the intestine. It can be caused by lack of peristalsis or by mechanical obstruction.
The word ileus is from Ancient Greek eileós (εἰλεός, "intestinal obstruction"). The term subileus refers to a partial obstruction.
Signs and symptoms
Symptoms of ileus include, but are not limited to:
moderate to severe, diffuse abdominal pain
constipation
abdominal distension
nausea/vomiting, especially after meals
vomiting of bilious fluid
lack of bowel movement and/or flatulence
excessive belching
Cause
Decreased propulsive ability may be broadly classified as caused either by bowel obstruction or intestinal atony or paralysis. However, instances with symptoms and signs of a bowel obstruction occur, but with the absence of a mechanical obstruction, mainly in acute colonic pseudo-obstruction, Ogilvies syndrome.
Bowel obstruction
A bowel obstruction is generally a mechanical obstruction of the gastrointestinal tract.
Intestinal paralysis
Paralysis of the intestine is often termed paralytic ileus, in which the intestinal paralysis need not be complete, but it must be sufficient to prohibit the passage of food through the intestine and lead to intestinal blockage. Paralytic ileus is a common side effect of some types of surgery, commonly called postsurgical ileus. It can also result from certain drugs and from various injuries and illnesses, such as acute pancreatitis. Paralytic ileus causes constipation and bloating. On listening to the abdomen with a stethoscope, no bowel sounds are heard because the bowel is inactive.A temporary paralysis of a portion of the intestines occurs typically after abdominal surgery. Since the intestinal content of this portion is unable to move forward, food or drink should be avoided until peristaltic sound is heard, by auscultation (use of a stethoscope) of the area where this portion lies. Intestinal atony or paralysis may be caused by inhibitory neural reflexes, inflammation or other implication of neurohumoral peptides.
Risk factors
gastrointestinal surgery or other GI procedures
electrolyte imbalance (Namely hypokalemia and hypercalcemia)
diabetic ketoacidosis (DKA), and other causes of metabolic acidosis
hypothyroidism
diabetes
medications (e.g. opioids or antimuscarinics)
severe illness (Inflammation with peritonitis)
spinal cord injury, those with injury above thoracic vertebrae 5 (T5) will have hypomotility problems within the bowel
acute intermittent porphyria
Treatment
Traditionally, nothing by mouth was considered to be mandatory in all cases, but gentle feeding by enteral feeding tube may help to restore motility by triggering the guts normal feedback signals, so this is the recommended management initially. When the patient has severe, persistent signs that motility is completely disrupted, nasogastric suction and parenteral nutrition may be required until passage is restored. In such cases, continuing aggressive enteral feeding causes a risk of perforating the gut.
Several options are available in the case of paralytic ileus. Most treatment is supportive. If caused by medication, the offending agent is discontinued or reduced. Bowel movements may be stimulated by prescribing lactulose, erythromycin or, in severe cases that are thought to have a neurological component (such as Ogilvies syndrome), neostigmine. There is also evidence from a systematic review of randomized controlled trials that chewing gum, as a form of sham feeding, may stimulate gastrointestinal motility in the post-operative period and reduce the duration of postoperative ileus.If possible the underlying cause is corrected (e.g. replace electrolytes).
Other animals
Ileus is a cause of colic in horses due to functional obstruction of the intestines. It is most commonly seen in horses postoperatively, especially following colic surgery. Horses experiencing ileus are at risk for gastric rupture due to rapid reflux build-up, and require intense medical management with frequent nasogastric intubation. Ileus may increase adhesion formation, because intestinal segments have more prolonged contact and intestinal distention causes serosal injury and ischemia. It is usually treated with aggressive fluid support, prokinetics, and anti-inflammatories.
Terminology
ICD-10 coding reflects both impaired-peristalsis senses and mechanical-obstruction senses of the term as modified by various adjectives. Some authors have argued for trying to reserve the term for the impaired-peristalsis senses, under which prescription certain older terms such as "gallstone ileus" and "meconium ileus", although now technically misnomers, are still accepted as correct owing to their long-established usage.
References
External links
MedlinePlus Encyclopedia: Intestinal Obstruction
Patient UK: Intestinal Obstruction and Ileus
PubMed Health: Intestinal obstruction
Ileus at eMedicine
Merck Manual Professional: Ileus |
Endometrial cancer | Endometrial cancer is a cancer that arises from the endometrium (the lining of the uterus or womb). It is the result of the abnormal growth of cells that have the ability to invade or spread to other parts of the body. The first sign is most often vaginal bleeding not associated with a menstrual period. Other symptoms include pain with urination, pain during sexual intercourse, or pelvic pain. Endometrial cancer occurs most commonly after menopause.Approximately 40% of cases are related to obesity. Endometrial cancer is also associated with excessive estrogen exposure, high blood pressure and diabetes. Whereas taking estrogen alone increases the risk of endometrial cancer, taking both estrogen and a progestogen in combination, as in most birth control pills, decreases the risk. Between two and five percent of cases are related to genes inherited from the parents. Endometrial cancer is sometimes loosely referred to as "uterine cancer", although it is distinct from other forms of uterine cancer such as cervical cancer, uterine sarcoma, and trophoblastic disease. The most frequent type of endometrial cancer is endometrioid carcinoma, which accounts for more than 80% of cases. Endometrial cancer is commonly diagnosed by endometrial biopsy or by taking samples during a procedure known as dilation and curettage. A pap smear is not typically sufficient to show endometrial cancer. Regular screening in those at normal risk is not called for.The leading treatment option for endometrial cancer is abdominal hysterectomy (the total removal by surgery of the uterus), together with removal of the Fallopian tubes and ovaries on both sides, called a bilateral salpingo-oophorectomy. In more advanced cases, radiation therapy, chemotherapy or hormone therapy may also be recommended. If the disease is diagnosed at an early stage, the outcome is favorable, and the overall five-year survival rate in the United States is greater than 80%.In 2012, endometrial cancers newly occurred in 320,000 women and caused 76,000 deaths. This makes it the third most common cause of death in cancers which only affect women, behind ovarian and cervical cancer. It is more common in the developed world and is the most common cancer of the female reproductive tract in developed countries. Rates of endometrial cancer have risen in a number of countries between the 1980s and 2010. This is believed to be due to the increasing number of elderly people and increasing rates of obesity.
Signs and symptoms
Vaginal bleeding or spotting in women after menopause occurs in 90% of endometrial cancer. Bleeding is especially common with adenocarcinoma, occurring in two-thirds of all cases. Abnormal menstrual cycles or extremely long, heavy, or frequent episodes of bleeding in women before menopause may also be a sign of endometrial cancer.Symptoms other than bleeding are not common. Other symptoms include thin white or clear vaginal discharge in postmenopausal women. More advanced disease shows more obvious symptoms or signs that can be detected on a physical examination. The uterus may become enlarged or the cancer may spread, causing lower abdominal pain or pelvic cramping. Painful sexual intercourse or painful or difficult urination are less common signs of endometrial cancer. The uterus may also fill with pus (pyometrea). Of women with these less common symptoms (vaginal discharge, pelvic pain, and pus), 10–15% have cancer.
Risk factors
Risk factors for endometrial cancer include obesity, insulin resistance and diabetes mellitus, breast cancer, use of tamoxifen, never having had a child, late menopause, high levels of estrogen, and increasing age. Immigration studies (migration studies), which examine the change in cancer risk in populations moving between countries with different rates of cancer, show that there is some environmental component to endometrial cancer. These environmental risk factors are not well characterized.
Hormones
Most of the risk factors for endometrial cancer involve high levels of estrogens. An estimated 40% of cases are thought to be related to obesity. In obesity, the excess of adipose tissue increases conversion of androstenedione into estrone, an estrogen. Higher levels of estrone in the blood causes less or no ovulation, and exposes the endometrium continuously to high levels of estrogens. Obesity also causes less estrogen to be removed from the blood. Polycystic ovary syndrome (PCOS), which also causes irregular or no ovulation, is associated with higher rates of endometrial cancer for the same reasons as obesity. Specifically, obesity, type II diabetes, and insulin resistance are risk factors for Type I endometrial cancer. Obesity increases the risk for endometrial cancer by 300–400%.Estrogen replacement therapy during menopause when not balanced (or "opposed") with progestin is another risk factor. Higher doses or longer periods of estrogen therapy have higher risks of endometrial cancer. Women of lower weight are at greater risk from unopposed estrogen. A longer period of fertility—either from an early first menstrual period or late menopause—is also a risk factor. Unopposed estrogen raises an individuals risk of endometrial cancer by 2–10 fold, depending on weight and length of therapy. In trans men who take testosterone and have not had a hysterectomy, the conversion of testosterone into estrogen via androstenedione may lead to a higher risk of endometrial cancer.
Genetics
Genetic disorders can also cause endometrial cancer. Overall, hereditary causes contribute to 2–10% of endometrial cancer cases. Lynch syndrome, an autosomal dominant genetic disorder that mainly causes colorectal cancer, also causes endometrial cancer, especially before menopause. Women with Lynch syndrome have a 40–60% risk of developing endometrial cancer, higher than their risk of developing colorectal (bowel) or ovarian cancer. Ovarian and endometrial cancer develop simultaneously in 20% of people. Endometrial cancer nearly always develops before colon cancer, on average, 11 years before. Carcinogenesis in Lynch syndrome comes from a mutation in MLH1 or MLH2: genes that participate in the process of mismatch repair, which allows a cell to correct mistakes in the DNA. Other genes mutated in Lynch syndrome include MSH2, MSH6, and PMS2, which are also mismatch repair genes. Women with Lynch syndrome represent 2–3% of endometrial cancer cases; some sources place this as high as 5%. Depending on the gene mutation, women with Lynch syndrome have different risks of endometrial cancer. With MLH1 mutations, the risk is 54%; with MSH2, 21%; and with MSH6, 16%.Women with a family history of endometrial cancer are at higher risk. Two genes most commonly associated with some other womens cancers, BRCA1 and BRCA2, do not cause endometrial cancer. There is an apparent link with these genes but it is attributable to the use of tamoxifen, a drug that itself can cause endometrial cancer, in breast and ovarian cancers. The inherited genetic condition Cowden syndrome can also cause endometrial cancer. Women with this disorder have a 5–10% lifetime risk of developing endometrial cancer, compared to the 2–3% risk for unaffected women.Common genetic variation has also been found to affect endometrial cancer risk in large-scale genome-wide association studies. Sixteen genomic regions have been associated with endometrial cancer and the common variants explain up to 7% of the familial relative risk.
Other health problems
Some therapies for other forms of cancer increase the lifetime risk of endometrial cancer, which is a baseline 2–3%. Tamoxifen, a drug used to treat estrogen-positive breast cancers, has been associated with endometrial cancer in approximately 0.1% of users, particularly older women, but the benefits for survival from tamoxifen generally outweigh the risk of endometrial cancer. A one to two-year course of tamoxifen approximately doubles the risk of endometrial cancer, and a five-year course of therapy quadruples that risk. Raloxifene, a similar drug, did not raise the risk of endometrial cancer. Previously having ovarian cancer is a risk factor for endometrial cancer, as is having had previous radiotherapy to the pelvis. Specifically, ovarian granulosa cell tumors and thecomas are tumors associated with endometrial cancer.
Low immune function has also been implicated in endometrial cancer. High blood pressure is also a risk factor, but this may be because of its association with obesity. Sitting regularly for prolonged periods is associated with higher mortality from endometrial cancer. The risk is not negated by regular exercise, though it is lowered.
Protective factors
Smoking and the use of progestin are both protective against endometrial cancer. Smoking provides protection by altering the metabolism of estrogen and promoting weight loss and early menopause. This protective effect lasts long after smoking is stopped. Progestin is present in the combined oral contraceptive pill and the hormonal intrauterine device (IUD). Combined oral contraceptives reduce risk more the longer they are taken: by 56% after four years, 67% after eight years, and 72% after twelve years. This risk reduction continues for at least fifteen years after contraceptive use has been stopped. Obese women may need higher doses of progestin to be protected. Having had more than five infants (grand multiparity) is also a protective factor, and having at least one child reduces the risk by 35%. Breastfeeding for more than 18 months reduces risk by 23%. Increased physical activity reduces an individuals risk by 38–46%. There is preliminary evidence that consumption of soy is protective.
Pathophysiology
Endometrial cancer forms when there are errors in normal endometrial cell growth. Usually, when cells grow old or get damaged, they die, and new cells take their place. Cancer starts when new cells form unneeded, and old or damaged cells do not die as they should. The buildup of extra cells often forms a mass of tissue called a growth or tumor. These abnormal cancer cells have many genetic abnormalities that cause them to grow excessively.In 10–20% of endometrial cancers, mostly Grade 3 (the highest histologic grade), mutations are found in a tumor suppressor gene, commonly p53 or PTEN. In 20% of endometrial hyperplasias and 50% of endometrioid cancers, PTEN has a loss-of-function mutation or a null mutation, making it less effective or completely ineffective. Loss of PTEN function leads to up-regulation of the PI3k/Akt/mTOR pathway, which causes cell growth. The p53 pathway can either be suppressed or highly activated in endometrial cancer. When a mutant version of p53 is overexpressed, the cancer tends to be particularly aggressive. P53 mutations and chromosome instability are associated with serous carcinomas, which tend to resemble ovarian and Fallopian carcinomas. Serous carcinomas are thought to develop from endometrial intraepithelial carcinoma.
PTEN and p27 loss of function mutations are associated with a good prognosis, particularly in obese women. The Her2/neu oncogene, which indicates a poor prognosis, is expressed in 20% of endometrioid and serous carcinomas. CTNNB1 (beta-catenin; a transcription gene) mutations are found in 14–44% of endometrial cancers and may indicate a good prognosis, but the data is unclear. Beta-catenin mutations are commonly found in endometrial cancers with squamous cells. FGFR2 mutations are found in approximately 10% of endometrial cancers, and their prognostic significance is unclear. SPOP is another tumor suppressor gene found to be mutated in some cases of endometrial cancer: 9% of clear cell endometrial carcinomas and 8% of serous endometrial carcinomas have mutations in this gene.Type I and Type II cancers (explained below) tend to have different mutations involved. ARID1A, which often carries a point mutation in Type I endometrial cancer, is also mutated in 26% of clear cell carcinomas of the endometrium, and 18% of serous carcinomas. Epigenetic silencing and point mutations of several genes are commonly found in Type I endometrial cancer. Mutations in tumor suppressor genes are common in Type II endometrial cancer. PIK3CA is commonly mutated in both Type I and Type II cancers. In women with Lynch syndrome-associated endometrial cancer, microsatellite instability is common.Development of an endometrial hyperplasia (overgrowth of endometrial cells) is a significant risk factor because hyperplasias can and often do develop into adenocarcinoma, though cancer can develop without the presence of a hyperplasia. Within ten years, 8–30% of atypical endometrial hyperplasias develop into cancer, whereas 1–3% of non-atypical hyperplasias do so. An atypical hyperplasia is one with visible abnormalities in the nuclei. Pre-cancerous endometrial hyperplasias are also referred to as endometrial intraepithelial neoplasia. Mutations in the KRAS gene can cause endometrial hyperplasia and therefore Type I endometrial cancer. Endometrial hyperplasia typically occurs after the age of 40. Endometrial glandular dysplasia occurs with an overexpression of p53, and develops into a serous carcinoma.
Diagnosis
Diagnosis of endometrial cancer is made first by a physical examination, endometrial biopsy, or dilation and curettage (removal of endometrial tissue; D&C). This tissue is then examined histologically for characteristics of cancer. If cancer is found, medical imaging may be done to see whether the cancer has spread or invaded tissue.
Examination
Routine screening of asymptomatic people is not indicated since the disease is highly curable in its early, symptomatic stages. Instead, women, particularly menopausal women, should be aware of the symptoms and risk factors of endometrial cancer. A cervical screening test, such as a Pap smear, is not a useful diagnostic tool for endometrial cancer because the smear will be normal 50% of the time. A Pap smear can detect disease that has spread to the cervix. Results from a pelvic examination are frequently normal, especially in the early stages of disease. Changes in the size, shape or consistency of the uterus or its surrounding, supporting structures may exist when the disease is more advanced. Cervical stenosis, the narrowing of the cervical opening, is a sign of endometrial cancer when pus or blood is found collected in the uterus (pyometra or hematometra).Women with Lynch syndrome should begin to have annual biopsy screening at the age of 35. Some women with Lynch syndrome elect to have a prophylactic hysterectomy and salpingo-oophorectomy to greatly reduce the risk of endometrial and ovarian cancer.Transvaginal ultrasound to examine the endometrial thickness in women with postmenopausal bleeding is increasingly being used to aid in the diagnosis of endometrial cancer in the United States. In the United Kingdom, both an endometrial biopsy and a transvaginal ultrasound used in conjunction are the standard of care for diagnosing endometrial cancer. The homogeneity of the tissue visible on transvaginal ultrasound can help to indicate whether the thickness is cancerous. Ultrasound findings alone are not conclusive in cases of endometrial cancer, so another screening method (for example endometrial biopsy) must be used in conjunction. Other imaging studies are of limited use. CT scans are used for preoperative imaging of tumors that appear advanced on physical exam or have a high-risk subtype (at high risk of metastasis). They can also be used to investigate extrapelvic disease. An MRI can be of some use in determining if the cancer has spread to the cervix or if it is an endocervical adenocarcinoma. MRI is also useful for examining the nearby lymph nodes.Dilation and curettage or an endometrial biopsy are used to obtain a tissue sample for histological examination. Endometrial biopsy is the less invasive option, but it may not give conclusive results every time. Hysteroscopy only shows the gross anatomy of the endometrium, which is often not indicative of cancer, and is therefore not used, unless in conjunction with a biopsy. Hysteroscopy can be used to confirm a diagnosis of cancer. New evidence shows that D&C has a higher false negative rate than endometrial biopsy.Before treatment is begun, several other investigations are recommended. These include a chest x-ray, liver function tests, kidney function tests, and a test for levels of CA-125, a tumor marker that can be elevated in endometrial cancer.
Classification
Endometrial cancers may be tumors derived from epithelial cells (carcinomas), mixed epithelial and mesenchymal tumors (carcinosarcomas), or mesenchymal tumors.
Traditional classification of endometrial carcinomas is based either on clinical and endocrine features (Type I and Type II), or histopathological characteristics (endometrioid, serous, and clear-cell). Some tumors are difficult to classify and have features overlapping more than one category. High grade endometrioid tumors, in particular, tend to have both type I and type II features.
Carcinoma
The vast majority of endometrial cancers are carcinomas (usually adenocarcinomas), meaning that they originate from the single layer of epithelial cells that line the endometrium and form the endometrial glands. There are many microscopic subtypes of endometrial carcinoma, but they are broadly organized into two categories, Type I and Type II, based on clinical features and pathogenesis. The two subtypes are genetically distinct.Type I endometrial carcinomas occur most commonly before and around the time of menopause. In the United States, they are more common in white women, particularly those with a history of endometrial hyperplasia. Type I endometrial cancers are often low-grade, minimally invasive into the underlying uterine wall (myometrium), estrogen-dependent, and have a good outcome with treatment. Type I carcinomas represent 75–90% of endometrial cancer.Type II endometrial carcinomas usually occur in older, post-menopausal people, in the United States are more common in black women, and are not associated with increased exposure to estrogen or a history of endometrial hyperplasia. Type II endometrial cancers are often high-grade, with deep invasion into the underlying uterine wall (myometrium), are of the serous or clear cell type, and carry a poorer prognosis. They can appear to be epithelial ovarian cancer on evaluation of symptoms. They tend to present later than Type I tumors and are more aggressive, with a greater risk of relapse and/or metastasis.
Endometrioid adenocarcinoma
In endometrioid adenocarcinoma, the cancer cells grow in patterns reminiscent of normal endometrium, with many new glands formed from columnar epithelium with some abnormal nuclei. Low-grade endometrioid adenocarcinomas have well differentiated cells, have not invaded the myometrium, and are seen alongside endometrial hyperplasia. The tumors glands form very close together, without the stromal tissue that normally separates them. Higher-grade endometrioid adenocarcinomas have less well-differentiated cells, have more solid sheets of tumor cells no longer organized into glands, and are associated with an atrophied endometrium. There are several subtypes of endometrioid adenocarcinoma with similar prognoses, including villoglandular, secretory, and ciliated cell variants. There is also a subtype characterized by squamous differentiation. Some endometrioid adenocarcinomas have foci of mucinous carcinoma.The genetic mutations most commonly associated with endometrioid adenocarcinoma are in the genes PTEN, a tumor suppressor; PIK3CA, a kinase; KRAS, a GTPase that functions in signal transduction; and CTNNB1, involved in adhesion and cell signaling. The CTNNB1 (beta-catenin) gene is most commonly mutated in the squamous subtype of endometrioid adenocarcinoma.
Serous carcinoma
Serous carcinoma is a Type II endometrial tumor that makes up 5–10% of diagnosed endometrial cancer and is common in postmenopausal women with atrophied endometrium and black women. Serous endometrial carcinoma is aggressive and often invades the myometrium and metastasizes within the peritoneum (seen as omental caking) or the lymphatic system. Histologically, it appears with many atypical nuclei, papillary structures, and, in contrast to endometrioid adenocarcinomas, rounded cells instead of columnar cells. Roughly 30% of endometrial serous carcinomas also have psammoma bodies. Serous carcinomas spread differently than most other endometrial cancers; they can spread outside the uterus without invading the myometrium.The genetic mutations seen in serous carcinoma are chromosomal instability and mutations in TP53, an important tumor suppressor gene.
Clear cell carcinoma
Clear cell carcinoma is a Type II endometrial tumor that makes up less than 5% of diagnosed endometrial cancer. Like serous cell carcinoma, it is usually aggressive and carries a poor prognosis. Histologically, it is characterized by the features common to all clear cells: the eponymous clear cytoplasm when H&E stained and visible, distinct cell membranes. The p53 cell signaling system is not active in endometrial clear cell carcinoma. This form of endometrial cancer is more common in postmenopausal women.
Mucinous carcinoma
Mucinous carcinomas are a rare form of endometrial cancer, making up less than 1–2% of all diagnosed endometrial cancer. Mucinous endometrial carcinomas are most often stage I and grade I, giving them a good prognosis. They typically have well-differentiated columnar cells organized into glands with the characteristic mucin in the cytoplasm. Mucinous carcinomas must be differentiated from cervical adenocarcinoma.
Mixed or undifferentiated carcinoma
Mixed carcinomas are those that have both Type I and Type II cells, with one making up at least 10% of the tumor. These include the malignant mixed Müllerian tumor, which derives from endometrial epithelium and has a poor prognosis.Undifferentiated endometrial carcinomas make up less than 1–2% of diagnosed endometrial cancers. They have a worse prognosis than grade III tumors. Histologically, these tumors show sheets of identical epithelial cells with no identifiable pattern.
Other carcinomas
Non-metastatic squamous cell carcinoma and transitional cell carcinoma are very rare in the endometrium. Squamous cell carcinoma of the endometrium has a poor prognosis. It has been reported fewer than 100 times in the medical literature since its characterization in 1892. For primary squamous cell carcinoma of the endometrium (PSCCE) to be diagnosed, there must be no other primary cancer in the endometrium or cervix and it must not be connected to the cervical epithelium. Because of the rarity of this cancer, there are no guidelines for how it should be treated, nor any typical treatment. The common genetic causes remain uncharacterized. Primary transitional cell carcinomas of the endometrium are even more rare; 16 cases had been reported as of 2008. Its pathophysiology and treatments have not been characterized. Histologically, TCCE resembles endometrioid carcinoma and is distinct from other transitional cell carcinomas.
Sarcoma
In contrast to endometrial carcinomas, the uncommon endometrial stromal sarcomas are cancers that originate in the non-glandular connective tissue of the endometrium. They are generally non-aggressive and, if they recur, can take decades. Metastases to the lungs and pelvic or peritoneal cavities are the most frequent. They typically have estrogen and/or progesterone receptors. The prognosis for low-grade endometrial stromal sarcoma is good, with 60–90% five-year survival. High-grade undifferentiated endometrial sarcoma (HGUS) has a worse prognosis, with high rates of recurrence and 25% five-year survival. HGUS prognosis is dictated by whether or not the cancer has invaded the arteries and veins. Without vascular invasion, the five-year survival is 83%; it drops to 17% when vascular invasion is observed. Stage I ESS has the best prognosis, with five-year survival of 98% and ten-year survival of 89%. ESS makes up 0.2% of uterine cancers.
Metastasis
Endometrial cancer frequently metastasizes to the ovaries and Fallopian tubes when the cancer is located in the upper part of the uterus, and the cervix when the cancer is in the lower part of the uterus. The cancer usually first spreads into the myometrium and the serosa, then into other reproductive and pelvic structures. When the lymphatic system is involved, the pelvic and para-aortic nodes are usually first to become involved, but in no specific pattern, unlike cervical cancer. More distant metastases are spread by the blood and often occur in the lungs, as well as the liver, brain, and bone. Endometrial cancer metastasizes to the lungs 20–25% of the time, more than any other gynecologic cancer.
Histopathology
There is a three-tiered system for histologically classifying endometrial cancers, ranging from cancers with well-differentiated cells (grade I), to very poorly-differentiated cells (grade III). Grade I cancers are the least aggressive and have the best prognosis, while grade III tumors are the most aggressive and likely to recur. Grade II cancers are intermediate between grades I and III in terms of cell differentiation and aggressiveness of disease.The histopathology of endometrial cancers is highly diverse. The most common finding is a well-differentiated endometrioid adenocarcinoma, which is composed of numerous, small, crowded glands with varying degrees of nuclear atypia, mitotic activity, and stratification. This often appears on a background of endometrial hyperplasia. Frank adenocarcinoma may be distinguished from atypical hyperplasia by the finding of clear stromal invasion, or "back-to-back" glands which represent nondestructive replacement of the endometrial stroma by the cancer. With progression of the disease, the myometrium is infiltrated.
Staging
Endometrial carcinoma is surgically staged using the FIGO cancer staging system. The 2009 FIGO staging system is as follows:
Myometrial invasion and involvement of the pelvic and para-aortic lymph nodes are the most commonly seen patterns of spread. A Stage 0 is sometimes included, in this case it is referred to as "carcinoma in situ". In 26% of presumably early-stage cancers, intraoperative staging revealed pelvic and distant metastases, making comprehensive surgical staging necessary.
Management
Surgery
The initial treatment for endometrial cancer is surgery; 90% of women with endometrial cancer are treated with some form of surgery. Surgical treatment typically consists of hysterectomy including a bilateral salpingo-oophorectomy, which is the removal of the uterus, and both ovaries and Fallopian tubes. Lymphadenectomy, or removal of pelvic and para-aortic lymph nodes, is performed for tumors of histologic grade II or above. Lymphadenectomy is routinely performed for all stages of endometrial cancer in the United States, but in the United Kingdom, the lymph nodes are typically only removed with disease of stage II or greater. The topic of lymphadenectomy and what survival benefit it offers in stage I disease is still being debated. In women with presumed stage I disease, a 2017 systematic review found no evidence that lymphadenectomy reduces the risk of death or relapse of cancer when compared with no lymphadenectomy. Women who undergo lymphadenectomy are more likely to experience systemic morbidity related to surgery or lymphoedema/lymphocyst formation. In stage III and IV cancers, cytoreductive surgery is the norm, and a biopsy of the omentum may also be included. In stage IV disease, where there are distant metastases, surgery can be used as part |
Endometrial cancer | of palliative therapy. Laparotomy, an open-abdomen procedure, is the traditional surgical procedure; however, in those with presumed early stage primary endometrial cancer, laparoscopy (keyhole surgery) is associated with reduced operative morbidity and similar overall and disease free survival. Removal of the uterus via the abdomen is recommended over removal of the uterus via the vagina because it gives the opportunity to examine and obtain washings of the abdominal cavity to detect any further evidence of cancer. Staging of the cancer is done during the surgery.The few contraindications to surgery include inoperable tumor, massive obesity, a particularly high-risk operation, or a desire to preserve fertility. These contraindications happen in about 5–10% of cases. Women who wish to preserve their fertility and have low-grade stage I cancer can be treated with progestins, with or without concurrent tamoxifen therapy. This therapy can be continued until the cancer does not respond to treatment or until childbearing is done. Uterine perforation may occur during a D&C or an endometrial biopsy. Side effects of surgery to remove endometrial cancer can specifically include sexual dysfunction, temporary incontinence, and lymphedema, along with more common side effects of any surgery, including constipation.
Add-on therapy
There are a number of possible additional therapies. Surgery can be followed by radiation therapy and/or chemotherapy in cases of high-risk or high-grade cancers. This is called adjuvant therapy.
Chemotherapy
Adjuvant chemotherapy is a recent innovation, consisting of some combination of paclitaxel (or other taxanes like docetaxel), doxorubicin (and other anthracyclines), and platins (particularly cisplatin and carboplatin). Adjuvant chemotherapy has been found to increase survival in stage III and IV cancer more than added radiotherapy. Mutations in mismatch repair genes, like those found in Lynch syndrome, can lead to resistance against platins, meaning that chemotherapy with platins is ineffective in people with these mutations. Side effects of chemotherapy are common. These include hair loss, low neutrophil levels in the blood, and gastrointestinal problems.In cases where surgery is not indicated, palliative chemotherapy is an option; higher-dose chemotherapy is associated with longer survival. Palliative chemotherapy, particularly using capecitabine and gemcitabine, is also often used to treat recurrent endometrial cancer.Low certainty evidence suggests that in women with recurrent endometrial cancer who have had chemotherapy, receiving drugs that inhibit the mTOR pathway may reduce the risk of disease worsening compared to having more chemotherapy or hormonal therapy. Though, mTOR inhibitors may increase the chance of experiencing digestive tract ulcers.
Radiotherapy
Adjuvant radiotherapy is commonly used in early-stage (stage I or II) endometrial cancer. It can be delivered through vaginal brachytherapy (VBT), which is becoming the preferred route due to its reduced toxicity, or external beam radiotherapy (EBRT). Brachytherapy involves placing a radiation source in the organ affected; in the case of endometrial cancer a radiation source is placed directly in the vagina. External beam radiotherapy involves a beam of radiation aimed at the affected area from outside the body. VBT is used to treat any remaining cancer solely in the vagina, whereas EBRT can be used to treat remaining cancer elsewhere in the pelvis following surgery. However, the benefits of adjuvant radiotherapy are controversial. Though EBRT significantly reduces the rate of relapse in the pelvis, overall survival and metastasis rates are not improved. VBT provides a better quality of life than EBRT.Radiotherapy can also be used before surgery in certain cases. When pre-operative imaging or clinical evaluation shows tumor invading the cervix, radiation can be given before a total hysterectomy is performed. Brachytherapy and EBRT can also be used, singly or in combination, when there is a contraindication for hysterectomy. Both delivery methods of radiotherapy are associated with side effects, particularly in the gastrointestinal tract.
Hormonal therapy
Hormonal therapy is only beneficial in certain types of endometrial cancer. It was once thought to be beneficial in most cases. If a tumor is well-differentiated and known to have progesterone and estrogen receptors, progestins may be used in treatment. There is no evidence to support the use of progestagen in addition to surgery for newly diagnosed endometrial cancer. About 25% of metastatic endometrioid cancers show a response to progestins. Also, endometrial stromal sarcomas can be treated with hormonal agents, including tamoxifen, hydroxyprogesterone caproate, letrozole, megestrol acetate, and medroxyprogesterone. This treatment is effective in endometrial stromal sarcomas because they typically have estrogen and/or progestin receptors. Progestin receptors function as tumor suppressors in endometrial cancer cells. Preliminary research and clinical trials have shown these treatments to have a high rate of response even in metastatic disease.In 2010 hormonal therapy is of unclear effect in those with advanced or recurrent endometrial cancer. There is insufficient evidence to inform women considering hormone replacement therapy after treatment for endometrial cancer.
Targeted therapy
Dostarlimab has been approved by the FDA for therapy of endometrial cancer with specific biomarker
Monitoring
The tumor marker CA-125 is frequently elevated in endometrial cancer and can be used to monitor response to treatment, particularly in serous cell cancer or advanced disease. Periodic MRIs or CT scans may be recommended in advanced disease and women with a history of endometrial cancer should receive more frequent pelvic examinations for the five years following treatment. Examinations conducted every three to four months are recommended for the first two years following treatment, and every six months for the next three years.Women with endometrial cancer should not have routine surveillance imaging to monitor the cancer unless new symptoms appear or tumor markers begin rising. Imaging without these indications is discouraged because it is unlikely to detect a recurrence or improve survival, and because it has its own costs and side effects. If a recurrence is suspected, PET/CT scanning is recommended.
Prognosis
Survival rates
The five-year survival rate for endometrial adenocarcinoma following appropriate treatment is 80%. Most women, over 70%, have FIGO stage I cancer, which has the best prognosis. Stage III and especially Stage IV cancers has a worse prognosis, but these are relatively rare, occurring in only 13% of cases. The median survival time for stage III–IV endometrial cancer is nine to ten months. Older age indicates a worse prognosis. In the United States, white women have a higher survival rate than black women, who tend to develop more aggressive forms of the disease by the time of their diagnosis. Tumors with high progesterone receptor expression have a good prognosis compared to tumors with low progesterone receptor expression; 93% of women with high progesterone receptor disease survived to three years, compared with 36% of women with low progesterone receptor disease. Heart disease is the most common cause of death among those who survive endometrial cancer, with other obesity-related health problems also being common. Following diagnosis, quality of life is also positively associated with a healthy lifestyle (no obesity, high-quality diet, physical activity).
Recurrence rates
Recurrence of early stage endometrial cancer ranges from 3 to 17%, depending on primary and adjuvant treatment. Most recurrences (75–80%) occur outside of the pelvis, and most occur within two to three years of treatment—64% within two years and 87% within three years.Higher-staged cancers are more likely to recur, as are those that have invaded the myometrium or cervix, or that have metastasized into the lymphatic system. Papillary serous carcinoma, clear cell carcinoma, and endometrioid carcinoma are the subtypes at the highest risk of recurrence. High-grade histological subtypes are also at elevated risk for recurrence.The most common site of recurrence is in the vagina; vaginal relapses of endometrial cancer have the best prognosis. If relapse occurs from a cancer that has not been treated with radiation, EBRT is the first-line treatment and is often successful. If a cancer treated with radiation recurs, pelvic exenteration is the only option for curative treatment. Palliative chemotherapy, cytoreductive surgery, and radiation are also performed. Radiation therapy (VBT and EBRT) for a local vaginal recurrence has a 50% five-year survival rate. Pelvic recurrences are treated with surgery and radiation, and abdominal recurrences are treated with radiation and, if possible, chemotherapy. Other common recurrence sites are the pelvic lymph nodes, para-aortic lymph nodes, peritoneum (28% of recurrences), and lungs, though recurrences can also occur in the brain (<1%), liver (7%), adrenal glands (1%), bones (4–7%; typically the axial skeleton), lymph nodes outside the abdomen (0.4–1%), spleen, and muscle/soft tissue (2–6%).
Epidemiology
As of 2014, approximately 320,000 women are diagnosed with endometrial cancer worldwide each year and 76,000 die, making it the sixth most common cancer in women. It is more common in developed countries, where the lifetime risk of endometrial cancer in women is 1.6%, compared to 0.6% in developing countries. It occurs in 12.9 out of 100,000 women annually in developed countries.In the United States, endometrial cancer is the most frequently diagnosed gynecologic cancer and, in women, the fourth most common cancer overall, representing 6% of all cancer cases in women. In that country, as of 2014 it was estimated that 52,630 women were diagnosed yearly and 8,590 would die from the disease. Northern Europe, Eastern Europe, and North America have the highest rates of endometrial cancer, whereas Africa and West Asia have the lowest rates. Asia saw 41% of the worlds endometrial cancer diagnoses in 2012, whereas Northern Europe, Eastern Europe, and North America together comprised 48% of diagnoses. Unlike most cancers, the number of new cases has risen in recent years, including an increase of over 40% in the United Kingdom between 1993 and 2013. Some of this rise may be due to the increase in obesity rates in developed countries, increasing life expectancies, and lower birth rates. The average lifetime risk for endometrial cancer is approximately 2–3% in people with uteruses. In the UK, approximately 7,400 cases are diagnosed annually, and in the EU, approximately 88,000.Endometrial cancer appears most frequently during perimenopause (the period just before, just after, and during menopause), between the ages of 50 and 65; overall, 75% of endometrial cancer occurs after menopause. Women younger than 40 make up 5% of endometrial cancer cases and 10–15% of cases occur in women under 50 years of age. This age group is at risk for developing ovarian cancer at the same time. The worldwide median age of diagnosis is 63 years of age; in the United States, the average age of diagnosis is 60 years of age. White American women are at higher risk for endometrial cancer than black American women, with a 2.88% and 1.69% lifetime risk respectively. Japanese-American women and American Latina women have a lower rates and Native Hawaiian women have higher rates.
Research
There are several experimental therapies for endometrial cancer under research, including immunologic, hormonal, and chemotherapeutic treatments. Trastuzumab (Herceptin), an antibody against the Her2 protein, has been used in cancers known to be positive for the Her2/neu oncogene, but research is still underway. Immunologic therapies are also under investigation, particularly in uterine papillary serous carcinoma.Cancers can be analyzed using genetic techniques (including DNA sequencing and immunohistochemistry) to determine if certain therapies specific to mutated genes can be used to treat it. PARP inhibitors are used to treat endometrial cancer with PTEN mutations, specifically, mutations that lower the expression of PTEN. The PARP inhibitor shown to be active against endometrial cancer is olaparib. Research is ongoing in this area as of the 2010s.Research is ongoing on the use of metformin, a diabetes medication, in obese women with endometrial cancer before surgery. Early research has shown it to be effective in slowing the rate of cancer cell proliferation. Preliminary research has shown that preoperative metformin administration can reduce expression of tumor markers. Long-term use of metformin has not been shown to have a preventative effect against developing cancer, but may improve overall survival.Temsirolimus, an mTOR inhibitor, is under investigation as a potential treatment. Research shows that mTOR inhibitors may be particularly effective for cancers with mutations in PTEN. Ridaforolimus (deforolimus) is also being researched as a treatment for people who have previously had chemotherapy. Preliminary research has been promising, and a stage II trial for ridaforolimus was completed by 2013. There has also been research on combined ridaforolimus/progestin treatments for recurrent endometrial cancer. Bevacizumab and tyrosine kinase inhibitors, which inhibit angiogenesis, are being researched as potential treatments for endometrial cancers with high levels of vascular endothelial growth factor. Ixabepilone is being researched as a possible chemotherapy for advanced or recurrent endometrial cancer. Treatments for rare high-grade undifferentiated endometrial sarcoma are being researched, as there is no established standard of care yet for this disease. Chemotherapies being researched include doxorubicin and ifosfamide.There is also research in progress on more genes and biomarkers that may be linked to endometrial cancer. The protective effect of combined oral contraceptives and the IUD is being investigated. Preliminary research has shown that the levonorgestrel IUD placed for a year, combined with six monthly injections of gonadotropin-releasing hormone, can stop or reverse the progress of endometrial cancer in young women; specifically complex atypical hyperplasia however the results have been inconclusive. An experimental drug that combines a hormone with doxorubicin is also under investigation for greater efficacy in cancers with hormone receptors. Hormone therapy that is effective in treating breast cancer, including use of aromatase inhibitors, is also being investigated for use in endometrial cancer. One such drug is anastrozole, which is currently being researched in hormone-positive recurrences after chemotherapy. Research into hormonal treatments for endometrial stromal sarcomas is ongoing as well. It includes trials of drugs like mifepristone, a progestin antagonist, and aminoglutethimide and letrozole, two aromatase inhibitors.Research continues into the best imaging method for detecting and staging endometrial cancer. As current diagnostic methods are invasive and inaccurate, researchers are looking into new ways to catch endometrial cancer, especially in its early stages. A study found that using a technique involving infrared light on simple blood test samples detected uterine cancer with high accuracy (87%), and could detect precancerous growths in all cases. In surgery, research has shown that complete pelvic lymphadenectomy along with hysterectomy in stage 1 endometrial cancer does not improve survival and increases the risk of negative side effects, including lymphedema. Other research is exploring the potential of identifying the sentinel lymph nodes for biopsy by injecting the tumor with dye that shines under infrared light. Intensity modulated radiation therapy is currently under investigation, and already used in some centers, for application in endometrial cancer, to reduce side effects from traditional radiotherapy. Its risk of recurrence has not yet been quantified. Research on hyperbaric oxygen therapy to reduce side effects is also ongoing. The results of the PORTEC 3 trial assessing combining adjuvant radiotherapy with chemotherapy were awaited in late 2014.There is not enough evidence to determine if people with endometrial cancer benefit from additional behavioural and life style interventions that are aimed at losing excess weight.
History and culture
Endometrial cancer is not widely known by the general populace, despite its frequency. There is low awareness of the symptoms, which can lead to later diagnosis and worse survival.
References
External links
American Cancer Societys Detailed Guide: Endometrial Cancer
U.S. National Cancer Institute: Uterine cancer
Anatomical pathology images |
Neu–Laxova syndrome | Neu–Laxova syndrome (also known as Neu syndrome or Neu-Povysilová syndrome, abbreviated as NLS) is a rare autosomal recessive disorder characterized by severe intrauterine growth restriction and multiple congenital malformations. Neu–Laxova syndrome is a very severe disorder, leading to stillbirth or death shortly after birth. It was first described by Dr. Richard Neu in 1971 and Dr. Renata Laxova in 1972 as a lethal disorder in siblings with multiple malformations. Neu–Laxova syndrome is an extremely rare disorder with less than 100 cases reported in medical literature.
Signs and symptoms
Neu-Laxova syndrome presents with severe malformations leading to prenatal or neonatal death. Typically, NLS involves characteristic facial features, decreased fetal movements and skin abnormalities.
Fetuses or newborns with Neu–Laxova syndrome have typical facial characteristics which include proptosis (bulging eyes) with eyelid malformations, nose malformations, round and gaping mouth, micrognathia (small jaw) and low set or malformed ears. Additional facial malformations may be present, such as cleft lip or cleft palate. Limb malformations are common and involve the fingers (syndactyly), hands or feet. Additionally, edema and flexion deformities are often present. Other features of NLS are severe intrauterine growth restriction, skin abnormalities (ichthyosis and hyperkeratosis) and decreased movement.
Malformations in the central nervous system are frequent and may include microcephaly, lissencephaly or microgyria, hypoplasia of the cerebellum and agenesis of the corpus callosum. Other malformations may also be present, such as neural tube defects.
Genetics
Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by homozygous or compound heterozygous mutations in one of three genes: PHGDH, PSAT1 and PSPH These genes are involved in the serine biosynthesis pathway and are essential for cell proliferation.
Mutations in all three genes had been previously identified as the cause of serine-deficiency syndromes. Although there is some clinical overlap between NLS and these neurometabolic disorders, the phenotype in other serine-deficiency disorders is milder.
Diagnosis
The diagnosis is usually based on clinical features present at birth.
Ultrasound in the second trimester may show abnormalities associates with NLS, including polyhydramnios, intrauterine growth restriction, microcephaly, proptosis and decreased fetal motility.
Treatment
Serine and glycine supplementation has shown tentative benefits in those with related serine biosynthesis defects and milder forms of NLS.
Prognosis
The prognosis is poor; affected individuals are either stillborn or die shortly after birth. The longest survival reported in literature is of 134 days.
This syndrome is transmitted as an autosomal recessive disorder and there is a risk for recurrence of 25% in future pregnancies.
References
== External links == |
Haber syndrome | Haber syndrome is a cutaneous disorder of hyperpigmentation characterized by reticulated pigmentation of the persons skin. A rare genodermatosis, its key features include "rosacea-like facial eruption[,] reticulated hyperpigmentation of major flexures, comedones on the back and neck, and pitted facial scars."
See also
List of cutaneous conditions
References
== External links == |
Pressure urticaria | Pressure urticaria is a physical urticaria caused by pressure applied to the skin, and is characterized by the development of swelling and pain that usually occurs 3 to 12 hours after local pressure has been applied.: 155
See also
Urticaria
Skin lesion
List of cutaneous conditions
References
== External links == |
Leigh syndrome | Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who first described the condition in 1951. Normal levels of thiamine, thiamine monophosphate, and thiamine diphosphate are commonly found but there is a reduced or absent level of thiamine triphosphate. This is thought to be caused by a blockage in the enzyme thiamine-diphosphate kinase, and therefore treatment in some patients would be to take thiamine triphosphate daily.
Signs and symptoms
The symptoms of Leigh syndrome are classically described as beginning in infancy and leading to death within a span of several years; however, as more cases are recognized, it is apparent that symptoms can emerge at any age—including adolescence or adulthood—and patients can survive for many years following diagnosis. Symptoms are often first seen after a triggering event that taxes the bodys energy production, such as an infection or surgery. The general course of Leigh syndrome is one of episodic developmental regression during times of metabolic stress. Some patients have long periods without disease progression while others develop progressive decline.Infants with the syndrome have symptoms that include diarrhea, vomiting, and dysphagia (trouble swallowing or sucking), leading to a failure to thrive. Children with early Leigh disease also may appear irritable and cry much more than healthy babies. Seizures are often seen. Excess lactate may be seen in the urine, cerebrospinal fluid, and blood of a person with Leigh syndrome.As the disease progresses, the muscular system is debilitated throughout the body, as the brain cannot control the contraction of muscles. Hypotonia (low muscle tone and strength), dystonia (involuntary, sustained muscle contraction), and ataxia (lack of control over movement) are often seen in people with Leigh disease. The eyes are particularly affected; the muscles that control the eyes become weak, paralyzed, or uncontrollable in conditions called ophthalmoparesis (weakness or paralysis) and nystagmus (involuntary eye movements). Slow saccades are also sometimes seen. The heart and lungs can also fail as a result of Leigh disease. Hypertrophic cardiomyopathy (thickening of part of the heart muscle) is also sometimes found and can cause death; asymmetric septal hypertrophy has also been associated with Leigh syndrome. In children with Leigh-syndrome associated ventricular septal defects, caused by pyruvate dehydrogenase deficiency, high forehead and large ears are seen; facial abnormalities are not typical of Leigh syndrome.However, respiratory failure is the most common cause of death in people with Leigh syndrome. Other neurological symptoms include peripheral neuropathy, loss of sensation in extremities caused by damage to the peripheral nervous system.Hypertrichosis is seen in Leigh syndrome caused by mutations in the nuclear gene SURF1.
Genomics
Mutations in mitochondrial DNA (mtDNA) and over 30 genes in nuclear DNA (gene SURF1 and some COX assembly factors) have been implicated in Leigh disease.Disorders of oxidative phosphorylation, the process by which cells produce their main energy source of adenosine triphosphate (ATP), may be caused by mutations in either mtDNA or in nuclear encoded genes. The latter account for the majority of Leigh disease, although it is not always possible to identify the specific mutation responsible for the condition in a particular individual. Four out of the five protein complexes involved in oxidative phosphorylation are most commonly disrupted in Leigh syndrome, either because of malformed protein or because of an error in the assembly of these complexes. Regardless of the genetic basis, it results in an inability of the complexes affected by the mutation to perform their role in oxidative phosphorylation. In the case of Leigh disease, crucial cells in the brain stem and basal ganglia are affected. This causes a chronic lack of energy in the cells, which leads to cell death and in turn, affects the central nervous system and inhibits motor functions. The heart and other muscles also require a lot of energy and are affected by cell death caused by chronic energy deficiencies in Leigh syndrome.
Mitochondrial DNA mutations
Mitochondria are essential organelles in eukaryotic cells. Their function is to convert the potential energy of glucose, amino acids, and fatty acids into adenosine triphosphate (ATP) in a process called oxidative phosphorylation. Mitochondria carry their own DNA, called mitochondrial DNA (mtDNA). The information stored in the mtDNA is used to produce several of the enzymes essential to the production of ATP.Between 20 and 25 percent of Leigh syndrome cases are caused by mutations in mitochondrial DNA. The most common of these mutations is found in 10 to 20 percent of Leigh syndrome and occurs in MT-ATP6, a gene that codes for a protein in the last complex of the oxidative phosphorylation chain, ATP synthase, an enzyme that directly generates ATP. Without ATP synthase, the electron transport chain will not produce any ATP. The most common MT-ATP6 mutation found with Leigh syndrome is a point mutation at nucleotide 8993 that changes a thymine to a guanine. This and other point mutations associated with Leigh syndrome destabilize or malform the protein complex and keep energy production down in affected cells. Several mitochondrial genes involved in creating the first complex of the oxidative phosphorylation chain can be implicated in a case of Leigh syndrome, including genes MT-ND2, MT-ND3, MT-ND5, MT-ND6 and MT-CO1.Mitochondrial DNA is passed down matrilineally in a pattern called maternal inheritance — a mother can transmit the genes for Leigh syndrome to both male and female children, but fathers cannot pass down mitochondrial genes.
Nuclear DNA mutations
Nuclear DNA comprises most of the genome of an organism and in sexually reproducing organisms is inherited from both parents, in contrast to mitochondrial DNAs maternal pattern of inheritance. Leigh syndrome caused by nuclear DNA mutations is inherited in an autosomal recessive pattern. This means that two copies of the mutated gene are required to cause the disease, so two unaffected parents, each of whom carries one mutant allele, can have an affected child if that child inherits the mutant allele from both parents.75 to 80 percent of Leigh syndrome is caused by mutations in nuclear DNA; mutations affecting the function or assembly of the fourth complex involved in oxidative phosphorylation, cytochrome c oxidase (COX), cause most cases of Leigh disease. Mutations in a gene called SURF1 (surfeit1) are the most common cause of this subtype of Leigh syndrome. The protein that SURF1 codes for is terminated early and therefore cannot perform its function, shepherding the subunits of COX together into a functional protein complex. This results in a deficit of COX protein, reducing the amount of energy produced by mitochondria. SURF1 is located on the long arm of chromosome 9. Another nuclear DNA mutation that causes Leigh syndrome affects another protein complex in the mitochondria, pyruvate dehydrogenase, which is an enzyme in the Link reaction pathway. Some types of SURF1 mutations cause a subtype of Leigh syndrome that has a particularly late onset but similarly variable clinical course.Other nuclear genes associated with Leigh syndrome are located on chromosome 2 (BCS1L and NDUFA10); chromosome 5 (SDHA, NDUFS4, NDUFAF2, and NDUFA2); chromosome 8 (NDUFAF6), chromosome 10 (COX15); chromosome 11 (NDUFS3, NDUFS8, and FOXRED1); chromosome 12 (NDUFA9 and NDUFA12); and chromosome 19 (NDUFS7). Many of these genes affect the first oxidative phosphorylation complex.
X-linked Leigh syndrome
Leigh syndrome can also be caused by deficiency of the pyruvate dehydrogenase complex (PDHC), most commonly involving a PDHC subunit which is encoded by an X-linked gene (OMIM 308930). The neurological features of Leigh syndrome caused by PDHC deficiency are indistinguishable from other forms. However, non-neurological features (other than lactic acidosis) are not seen in PDHC deficiency.X-linked recessive Leigh syndrome affects male children far more often than female children because they only have one copy of the X chromosome. Female children would need two copies of the faulty gene to be affected by X-linked Leigh syndrome.
French Canadian Leigh syndrome
The type of Leigh syndrome found at a much higher rate in the Saguenay-Lac-Saint-Jean region of Quebec is caused by a mutation in the LRPPRC gene, located on the small (p) arm of chromosome 2. Both compound heterozygosity and homozygous mutations have been observed in French Canadian Leigh syndrome. This subtype of the disease was first described in 1993 in 34 children from the region, all of whom had a severe deficiency in cytochrome c oxidase (COX), the fourth complex in the mitochondrial electron transport chain. Though the subunits of the protein found in affected cells were functional, they were not properly assembled. The deficiency was found to be almost complete in brain and liver tissues and substantial (approximately 50% of normal enzyme activity) in fibroblasts (connective tissue cells) and skeletal muscle. Kidney and heart tissues were found to not have a COX deficiency.French Canadian Leigh syndrome has similar symptoms to other types of Leigh syndrome. The age of onset is, on average, 5 months and the median age of death is 1 year and 7 months. Children with the disease are developmentally delayed, have mildly dysmorphic facial features, including hypoplasia of the midface and wide nasal bridge, chronic metabolic acidosis, and hypotonia (decreased muscular strength). Other symptoms include tachypnea (unusually quick breathing rate), poor sucking ability, hypoglycemia (low blood sugar), and tremors. Severe, sudden metabolic acidosis is a common cause of mortality.Estimates of the rate of genetic carriers in the Saguenay-Lac-Saint-Jean region range from 1 in 23 to 1 in 28; the number of children born with the disease has been estimated at 1 in 2063 to 1 in 2473 live births. Genealogic studies suggest that the responsible mutation was introduced to the region by early European settlers.
Pathophysiology
The characteristic symptoms of Leigh syndrome are at least partially caused by bilateral, focal lesions in the brainstem, basal ganglia, cerebellum, and other regions of the brain. The lesions take on different forms, including areas of demyelination, spongiosis, gliosis, necrosis, and capillary proliferation. Demyelination is the loss of the myelin sheath around the axons of neurons, inhibiting their ability to communicate with other neurons. The brain stem is involved in maintaining basic life functions such as breathing, swallowing, and circulation; the basal ganglia and cerebellum control movement and balance. Damage to these areas therefore results in the major symptoms of Leigh syndrome—loss of control over functions controlled by these areas.The lactic acidosis sometimes associated with Leigh syndrome is caused by the buildup of pyruvate, which is unable to be processed in individuals with certain types of oxidative phosphorylation deficiencies. The pyruvate is either converted into alanine via alanine aminotransferase or converted into lactic acid by lactate dehydrogenase; both of these substances can then build up in the body.
Diagnosis
Leigh syndrome is suggested by clinical findings and confirmed with laboratory and genetic testing.
Clinical findings
Dystonia, nystagmus, and problems with the autonomic nervous system suggest damage to the basal ganglia and brain stem potentially caused by Leigh syndrome. Other symptoms are also indicative of brain damage, such as hypertrichosis and neurologically caused deafness. Laboratory findings of lactic acidosis or acidemia and hyperalaninemia (elevated levels of alanine in the blood) can also suggest Leigh syndrome. Assessing the level of organic acids in urine can also indicate a dysfunction in the metabolic pathway.
Differential diagnosis
Other diseases can have a similar clinical presentation to Leigh syndrome; excluding other causes of similar clinical symptoms is often a first step to diagnosing Leigh syndrome. Conditions that can appear similar to Leigh disease include perinatal asphyxia, kernicterus, carbon monoxide poisoning, methanol toxicity, thiamine deficiency, Wilsons disease, biotin-responsive basal ganglia disease, and some forms of encephalitis. Perinatal asphyxia can cause bilateral ganglial lesions and damage to the thalamus, which are similar to the signs seen with Leigh syndrome. When hyperbilirubinemia is not treated with phototherapy, the bilirubin can accumulate in the basal ganglia and cause lesions similar to those seen in Leigh syndrome. This is not common since the advent of phototherapy.
Treatment
Succinic acid has been studied, and shown effective for both Leigh syndrome, and MELAS syndrome. A high-fat, low-carbohydrate diet may be followed if a gene on the X chromosome is implicated in an individuals Leigh syndrome. Thiamine (vitamin B1) may be given if pyruvate dehydrogenase deficiency is known or suspected. The symptoms of lactic acidosis are treated by supplementing the diet with sodium bicarbonate (baking soda) or sodium citrate, but these substances do not treat the cause of Leigh syndrome. Dichloroacetate may also be effective in treating Leigh syndrome-associated lactic acidosis; research is ongoing on this substance. Coenzyme Q10 supplements have been seen to improve symptoms in some cases.Clinical trials of the drug EPI-743 for Leigh syndrome are ongoing.In 2016, John Zhang and his team at New Hope Fertility Center in New York, USA, performed a spindle transfer mitochondrial donation technique on a mother in Mexico who was at risk of producing a baby with Leigh disease. A healthy boy was born on 6 April 2016. However, it is not yet certain if the technique is completely reliable and safe.
Prognosis
Different genetic causes and types of Leigh syndrome have different prognoses, though all are poor. The most severe forms of the disease, caused by a full deficiency in one of the affected proteins, cause death at a few years of age. If the deficiency is not complete, the prognosis is somewhat better and an affected child is expected to survive 6–7 years, and in rare cases, to their teenage years.
Epidemiology
Leigh syndrome occurs in at least 1 of 40,000 live births, though certain populations have much higher rates. In the Saguenay-Lac-Saint-Jean region of central Quebec, Leigh syndrome occurs at a rate of 1 in 2000 newborns.
History
Leigh syndrome was first described by Denis Leigh in 1951 and distinguished from similar Wernickes encephalopathy in 1954. In 1968, the diseases link with mitochondrial activity was first ascertained, though the mutations in cytochrome c oxidase and other electron transport chain proteins were not discovered until 1977.
See also
Joseph Maraachli case
Neuropathy, ataxia, and retinitis pigmentosa
References
Further reading
GeneReviews/NCBI/NIH/UW entry on Mitochondrial DNA-Associated Leigh Syndrome and NARP
OMIM entries on Mitochondrial DNA-Associated Leigh Syndrome and NARP
Leigh syndrome; Subacute necrotizing encephalopathy; Leighs disease at NIHs Office of Rare Diseases
leighsdisease at NINDS
Maternally Inherited Leigh Syndrome at NIHs Office of Rare Diseases
== External links == |
Fourth nerve palsy | Fourth cranial nerve palsy or trochlear nerve palsy, is a condition affecting cranial nerve 4 (IV), the trochlear nerve, which is one of the cranial nerves. It causes weakness or paralysis of the superior oblique muscle that it innervates. This condition often causes vertical or near vertical double vision as the weakened muscle prevents the eyes from moving in the same direction together.
Because the trochlear nerve is the thinnest and has the longest intracranial course of the cranial nerves, it is particularly vulnerable to traumatic injury.
To compensate for the double-vision resulting from the weakness of the superior oblique, patients characteristically tilt their head down and to the side opposite the affected muscle.
When present at birth, it is known as congenital fourth nerve palsy.
See also
Harada–Ito procedure
References
== External links == |
Cotard delusion | Cotards delusion, also known as walking corpse syndrome or Cotards syndrome, is a rare mental disorder in which the affected person holds the delusional belief that they are dead, do not exist, are putrefying, or have lost their blood or internal organs. Statistical analysis of a hundred-patient cohort indicated that denial of self-existence is present in 45% of the cases of Cotards syndrome; the other 55% of the patients presented with delusions of immortality.In 1880, the neurologist Jules Cotard described the condition as le délire des négations ("the delirium of negation"), a psychiatric syndrome of varied severity. A mild case is characterized by despair and self-loathing, while a severe case is characterized by intense delusions of negation, and chronic psychiatric depression.The case of "Mademoiselle X" describes a woman who denied the existence of parts of her body (somatoparaphrenia) and of her need to eat. She claimed that she was condemned to eternal damnation, and therefore could not die a natural death. In the course of experiencing "the delirium of negation", Mademoiselle X died of starvation.Cotards delusion is not mentioned in either the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the 10th edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) of the World Health Organization.
Signs and symptoms
Delusions of negation are the central symptom in Cotards syndrome. The patient usually denies their own existence, the existence of a certain body part, or the existence of a portion of their body. Cotards syndrome exists in three stages:
Germination stage: symptoms of psychotic depression and of hypochondria appear;
Blooming stage: full development of the syndrome and delusions of negation; and;
Chronic stage: continued severe delusions along with chronic psychiatric depression.Cotards syndrome withdraws the person with the condition from other people due to neglect of their personal hygiene and physical health. Delusions of negation of self prevent the patient from making sense of external reality, which then produces a distorted view of the external world. Such delusions of negation are usually found in schizophrenia. Although a diagnosis of Cotards syndrome does not require the patient to have had hallucinations, the strong delusions of negation are comparable to those found in schizophrenic patients.
Distorted reality
The article Betwixt Life and Death: Case Studies of the Cotard Delusion (1996) describes a contemporary case of Cotards delusion which occurred in a Scotsman whose brain was damaged in a motorcycle accident:
[The patients] symptoms occurred in the context of more general feelings of unreality and [of] being dead. In January 1990, after his discharge from hospital in Edinburgh, his mother took him to South Africa. He was convinced that he had been taken to Hell (which was confirmed by the heat) and that he had died of sepsis (which had been a risk early in his recovery), or perhaps from AIDS (he had read a story in The Scotsman about someone with AIDS who died from sepsis), or from an overdose of a yellow fever injection. He thought he had "borrowed [his] mothers spirit to show [him] around Hell" and that she was asleep in Scotland.
The article Recurrent Postictal Depression with Cotard Delusion (2005) describes the case of a 14-year-old epileptic boy who experienced Cotards syndrome after seizures. His mental health history showed themes of death, chronic sadness, decreased physical activity in leisure time, social withdrawal, and disturbed biological functions.
About twice a year, the boy had episodes that lasted between three weeks and three months. In the course of each episode, he said that everyone and everything was dead (including trees), described himself as a dead body, and warned that the world would be destroyed within hours. Throughout the episode, the boy showed no response to pleasurable stimuli, and had no interest in social activities.
Pathophysiology
The underlying neurophysiology and psychopathology of Cotards syndrome might be related to problems of delusional misidentification. Neurologically, Cotards delusion (negation of the self) is thought to be related to Capgras delusion (people replaced by impostors); each type of delusion is thought to result from neural misfiring in the fusiform face area of the brain, which recognizes faces, and in the amygdalae, which associate emotions to a recognized face.The neural disconnection creates in the patient a sense that the face they are observing is not the face of the person to whom it belongs; therefore, that face lacks the familiarity (recognition) normally associated with it. This results in derealization or a disconnection from the environment. If the observed face is that of a person known to the patient, they experience that face as the face of an impostor (Capgras delusion). If the patient sees their own face, they might perceive no association between the face and their own sense of self—which results in the patient believing that they do not exist (Cotards syndrome).
Cotards syndrome is usually encountered in people with psychosis, as in schizophrenia. It is also found in clinical depression, derealization, brain tumor, and migraine headaches. The medical literature indicate that the occurrence of Cotards delusion is associated with lesions in the parietal lobe. As such, the Cotards delusion patient presents a greater incidence of brain atrophy—especially of the median frontal lobe—than do people in control groups.Cotards delusion also has resulted from a patients adverse physiological response to a drug (e.g., acyclovir) and to its prodrug precursor (e.g., valaciclovir). The occurrence of Cotards delusion symptoms was associated with a high serum-concentration of 9-carboxymethoxymethylguanine (CMMG), the principal metabolite of acyclovir.As such, the patient with weak kidneys (impaired renal function) continued risking the occurrence of delusional symptoms despite the reduction of the dose of acyclovir. Hemodialysis resolved the patients delusions (of negating the self) within hours of treatment, which suggests that the occurrence of Cotards delusion symptoms might not always be cause for psychiatric hospitalization of the patient.
Treatment
Pharmacological treatments, both mono-therapeutic and multi-therapeutic, using antidepressants, antipsychotics, and mood stabilizers have been successful. Likewise, with the depressed patient, electroconvulsive therapy (ECT) is more effective than pharmacotherapy.Cotards syndrome resulting from an adverse drug reaction to valacyclovir is attributed to elevated serum concentration of one of valacyclovirs metabolites, 9-carboxymethoxymethylguanine (CMMG). Successful treatment warrants cessation of valacyclovir. Hemodialysis was associated with timely clearance of CMMG and resolution of symptoms.
Case studies
Society and culture
The protagonist of Charlie Kaufmans 2008 movie Synecdoche, New York, is named Caden Cotard. Throughout the film Cotard thinks he is dying, and we see other examples of Cotard delusion with scenes such as when his daughter, Olive, begins to scream about having blood in her body and, as the film goes on, Cotard disappears from the play he is writing about his own life and is portrayed by other actors as he takes the role of a cleaning lady.It is speculated that Per "Dead" Ohlin, lead vocalist for the black metal bands Mayhem and Morbid, had Cotard delusion as a result of a bullying incident in his youth that left him clinically dead for a short time. He developed an obsession with death shortly after (hence his stage name and use of corpse paint), often self-harmed onstage and among friends, and became increasingly depressed and introverted eventually resulting in his suicide in 1991. His suicide note contained the lines "I belong in the woods and have always done so. No one will understand the reason for this anyway. To give some semblance of an explanation Im not a human, this is just a dream and soon I will wake."
See also
Depersonalization disorder
Mortality salience
Prosopagnosia
Solipsism
Mirrored-self misidentification
Capgras delusion
Fregoli delusion
Dead (musician)
References
Young, A., Robertson, I., Hellawell, D., De Pauw, K., & Pentland, B. (1992). Cotard delusion after brain injury. Psychological Medicine, 22(3), 799–804. doi:10.1017/S003329170003823X
== External links == |
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency | 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is an uncommon inherited disorder in which the body cannot properly process the amino acid leucine. Additionally, the disorder prevents the body from making ketones, which are used for energy during fasting.
Presentation
This disorder usually appears within the first year of life. The signs and symptoms of HMG-CoA lyase deficiency include vomiting, dehydration, lethargy, convulsions, and coma. When episodes occur in an infant or child, blood sugar becomes extremely low (hypoglycemia), and harmful compounds can build up and cause the blood to become too acidic (metabolic acidosis). These episodes are often triggered by an infection, fasting, strenuous exercise, or sometimes other types of stress.
Cause
Mutations in the HMGCL gene cause 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. The enzyme made by the HMGCL gene plays an essential role in breaking down dietary proteins and fats for energy. Specifically, the enzyme is responsible for processing leucine, an amino acid that is part of many proteins. This enzyme also produces ketones during the breakdown of fats. If a mutation in the HMGCL gene reduces or eliminates the activity of this enzyme, the body is unable to process leucine or make ketones properly. A lack of ketones leads to hypoglycemia, and compounds called organic acids (which are formed as products of amino acid and fat breakdown) can cause the blood to become too acidic. Metabolic acidosis and hypoglycemia impair tissue function, especially in the central nervous system.
Diagnosis
Differential diagnosis
This condition is sometimes mistaken for Reye syndrome, a severe disorder that develops in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.
Epidemiology
Less than 20 patients with MGA type I have been reported in the literature (Mol Genet Metab. 2011 Nov;104(3):410-3. Epub 2011 Jul 26.)
See also
3-hydroxy-3-methylglutaryl-CoA lyase
References
This article incorporates public domain text from The U.S. National Library of Medicine
== External links == |
Intravenous leiomyomatosis | Intravenous leiomyomatosis is a rare condition seen exclusively in women in which leiomyomata, benign smooth muscle tumors, are found in veins. The masses are benign-appearing but can spread throughout the venous system leaving the uterus and even cause death when growing into the heart from the IVC. While the possibility that these arose de novo from the smooth muscle in the blood vessel wall was considered, chromosomal analysis suggests a uterine origin. Intravenous leiomyomata are usually but not always associated with uterine fibroids, and tend to recur.
This condition is related to benign metastasizing leiomyoma, in which the masses appear in more distant locations such as the lung and lymph nodes.
See also
Uterine fibroids
References
External links
IV Leiomyomas Video |
Gangliosidosis | Gangliosidosis contains different types of lipid storage disorders caused by the accumulation of lipids known as gangliosides. There are two distinct genetic causes of the disease. Both are autosomal recessive and affect males and females equally.
Types
GM1 gangliosidoses - GM1
GM2 gangliosidoses - GM2
See also
Sphingolipidoses#Overview
References
== External links == |
Uveitis–glaucoma–hyphema syndrome | Uveitis–glaucoma–hyphaema (UGH) syndrome, also known as Ellingson syndrome, is a complication of cataract surgery, caused by intraocular lens subluxation or dislocation. The chafing of mispositioned intraocular lens over iris, ciliary body or iridocorneal angle cause elevated intraocular pressure (IOP) anterior uveitis and hyphema. It is most commonly caused by anterior chamber IOLs and sulcus IOLs but, the condition can be seen with any type of IOL, including posterior chamber lenses and cosmetic iris implants.
Pathophysiology
The mechanical irritation of mispositioned intraocular lens over iris, ciliary body or iridocorneal angle cause spectrum of iris transillumination defects including anterior uveitis, hyphema and elevated intraocular pressure (IOP). Uveitis results from mechanical breakdown of the blood–aqueous barrier and resultant intraocular inflammation. A hyphema results from damage to vascular tissue of the iris, ciliary body, or angle by mispositioned IOL. Elevated intraocular pressure can be caused by pigment dispersion, uveitis, hyphema or direct blocking of aqueous humor drainage system.UGH syndrome is most commonly caused by anterior chamber IOLs and sulcus IOLs, but it can be seen with any type of IOL, including posterior chamber lenses and cosmetic iris implants. The condition has significantly reduced due to increased use of posterior chamber IOLs, advancements in lens design, IOL material and surgical techniques etc. Currently, majority of IOLs are implanted in the capsular bag, minimizing the chance of IOL contacting uveal structures.
Signs and symptoms
Uvietis, Glaucoma, and Hyphema are the classic sins of UGH syndrome, but the term is often used when one, two, or all three signs are present in the presence of any IOL causing mechanical irritation of the iris or angle structures. Blurred vision, transient vision loss, eye pain, photophobia, erythropsia (objects appear red) are the main symptoms.
Diagnosis
The diagnosis of UGH Syndrome is mainly based on patient history and eye examination. Patient will have history of cataract surgery with intraocular lens implantation. Slit-lamp examination may reveal hyphaema, aqueous cells and flare, iris neovascularization, mispositioned IOL, iris-lens contact, iris transillumination defects etc.
Variations
UGH Plus and IPUGH (Incomplete Posterior UGH) are the variations of UGH syndrome. IPUGH is defined as bleeding into the posterior chamber with/ without glaucoma and no uveitis. UGH Plus is defined as a UGH syndrome plus a vitreous hemorrhage and occurs more frequently with anterior chamber IOLs but can occur with any IOLs.
Treatment
Initially, topical and systemic medication to control inflammation and raised IOP is appropriate, but the definitive treatment is an IOL reposition or exchange. Topical corticosteroids may be used to control anterior inflammation. Raised IOP can be lowered using topical and systemic anti-glaucoma medications such as prostaglandin analogs, beta-adrenergic antagonists, alpha-adrenergic agonists, and carbonic anhydrase inhibitors etc.
History
The UGH Syndrome was originally described by Ellingson in 1978 and classically included uveitis, glaucoma, and hyphaema in the setting of an anterior chamber IOL.
== References == |
Ventricular escape beat | In cardiology, a ventricular escape beat is a self-generated electrical discharge initiated by, and causing contraction of the ventricles of the heart; normally the heart rhythm is begun in the atria of the heart and is subsequently transmitted to the ventricles. The ventricular escape beat follows a long pause in ventricular rhythm and acts to prevent cardiac arrest. It indicates a failure of the electrical conduction system of the heart to stimulate the ventricles (which would lead to the absence of heartbeats, unless ventricular escape beats occur).
Causes
Ventricular escape beats occur when the rate of electrical discharge reaching the ventricles (normally initiated by the hearts sinoatrial node (SA node), transmitted to the atrioventricular node (AV node), and then further transmitted to the ventricles) falls below the base rate determined by the rate of Phase 4 spontaneous depolarisation of ventricular pacemaker cells.
An escape beat usually occurs 2–3 seconds after an electrical impulse has failed to reach the ventricles.This phenomenon can be caused by the sinoatrial node (SA node) failing to initiate a beat, by a failure of the conductivity from the SA node to the atrioventricular node (AV node), or by atrioventricular block (especially third degree AV block). Normally, the pacemaker cells of the sinoatrial node discharge at the highest frequency and are thus dominant over other cells with pacemaker activity. The AV node normally has the second fastest discharge rate. When the sinus rate falls below the discharge rate of the AV node, this becomes the dominant pacemaker, and the result is called a junctional escape beat. If the rate from both the SA and AV node fall below the discharge rate of ventricular pacemaker cells, a ventricular escape beat ensues.An escape beat is a form of cardiac arrhythmia, in this case known as an ectopic beat. It can be considered a form of ectopic pacemaker activity that is unveiled by lack of other pacemakers to stimulate the ventricles. Ventricular pacemaker cells discharge at a slower rate than the SA or AV node. While the SA node typically initiates a rate of 70 beats per minute (BPM), the atrioventricular node (AV node) is usually only capable of generating a rhythm at 40-60 BPM or less. Ventricular contraction rate is thus reduced by 15-40 beats per minute.If there are only one or two ectopic beats, they are considered escape beats. If this causes a semi-normal rhythm to arise it is considered an idioventricular rhythm.The escape arrhythmia is a compensatory mechanism that indicates a serious underlying problem with the SA node or conduction system (commonly due to heart attack or medication side effect), and because of its low rate, it can cause a drop in blood pressure and syncope.
Diagnosis
An electrocardiogram can be used to identify a ventricular escape beat. The QRS portion of the electrocardiogram represents the ventricular depolarisation; in normal circumstances the QRS complex forms a sharp sudden peak. For a patient with a ventricular escape beat, the shape of the QRS complex is broader as the impulse can not travel quickly via the normal electrical conduction system.
Ventricular escape beats differ from ventricular extrasystoles (or premature ventricular contractions), which are spontaneous electrical discharges of the ventricles. These are not preceded by a pause; on the contrary they are often followed by a compensatory pause.
Management
Cilostazol
Third degree AV block can be treated with Cilostazol which acts to increase Ventricular escape rate
Ouabain
Ouabain infusion decreases ventricular escape time and increases ventricular escape rhythm. However, a high dose of ouabain can lead to ventricular tachycardia.
== References == |
Dopamine transporter deficiency syndrome | Dopamine transporter deficiency syndrome (DTDS), also known as infantile parkinsonism-dystonia, is a rare movement disorder that causes progressively worsening dystonia and parkinsonism. It is the first known inherited dopamine transportophathy.
DTDS is an extremely rare disease; only about 20 affected individuals have been described in the medical literature. Researchers believe this condition is likely underdiagnosed because its signs and symptoms overlap with other movement disorders, including cerebral palsy.The onset of DTDS is a continuum that ranges from early-onset DTDS (in the first 6 months) to atypical later-onset DTDS (in childhood, adolescence, or adulthood).
Signs and symptoms
The main symptom of DTDS, presenting in 80-99% of DTDS patients, is Parkinsonism. This is a neurological anomaly resulting from degeneration of dopamine-generating cells in the substantia nigra, and is characterized by shaking and tremors, rigidity, slowness of movement, and difficulty with walking and gait.Various other symptoms present less commonly (30-79%), including bradykinesia (slowness of movement), acid reflux, muscular hypertonia, and chorea.
Causes
DTDS is caused by mutations in the SLC6A3 gene, which codes for the dopamine transporter protein DAT. In contrast to various mutations that up-regulate DAT activity, which is implicated in clinical depression, this mutation results in DAT down-regulation and, consequently, DTDS. Known DTDS-related SLC6A3 mutations include:
R85L
A314V
G386R
R445C
Y470SIn vitro replication of SLC6A3 mutations like those present in DTDS demonstrate multifaceted loss of dopamine transporter functions. Dopamine intake is universally impaired. These mutants also demonstrated diminished dopamine binding affinity, reduced cell surface transporter, loss of post-translational dopamine transporter glycosylation, and failure of amphetamine-mediated dopamine efflux.The age at which signs and symptoms appear seems to be related to the severity of DAT dysfunction. Early-onset DTDS movement problems in infancy most often have transporter activity that is less than 5 percent of normal. Those whose movement problems appear in childhood or later tend to have somewhat higher levels of transporter activity, although they are still lower than normal. Researchers speculate that higher levels of transporter activity may delay the onset of the disease in these individuals.
DTDS is inherited in an autosomal recessive pattern, which means, for affected individuals, both copies of the gene in each cell have SLC6A3 mutations. As such, each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and 25% chance of being unaffected and not a carrier. Once a SLC6A3 pathogenic variant is identified within an affected family member, carrier testing for at-risk relatives and prenatal testing or preimplantation genetic diagnosis for pregnancies can be options considered for genetic counseling.
Diagnosis
Diagnosis of SLC6A3-negative DTDS is established in a proband via molecular genetic testing, looking for biallelic (i.e. homozygous or compound heterozygous) pathogenic SLC6A3 variants. DTDS-positive patients are further identified by matching their genetic testing results with known characteristic clinical, laboratory, and imaging findings.To date, another potential diagnostic tool is neurotransmitter analysis of patient cerebrospinal fluid. All individuals tested with classical early-onset, SLC6A3-related DTDS display raised homovanillic acid (HVA) levels with normal 5-hydroxyindoleacetic acid (5-HIAA, a serotonin metabolite) levels. DTDS patients demonstrate a HVA:5-HIAA ratio of 5.0-13.0, above the normal range of 1.0-4.0. In addition, the patients have normal pterin profiles.Mutant constructs of human dopamine transporter can be used for in vitro functional analysis of any particular mutants dopamine uptake and cocaine-analogue binding.
Treatment
A multidisciplinary approach to long-term management of this progressive disorder is optimal. Treatment can be split into three categories: treatment of DTDS manifestations, prevention of secondary complications, and monitoring of overall disease progression.
Manifestations
Treatment to control the chorea and dyskinesia in the early stages of DTDS is done with tetrabenazine and benzodiazepines. The dystonia is more difficult to control and the first-line agents include pramipexole and ropinirole; adjuncts include trihexyphenidyl, baclofen, gabapentin, and clonidine for severe dystonia, and chloral hydrate and benzodiazepines for exacerbations of dystonia or status dystonicus.
Prevention of secondary complications
Regular physiotherapy is recommended to reduce the risk of contractures, shortening and hardening of the muscles. Feeding may become difficult and alternative feeding strategies including nasogastric tubes or percutaneous endoscopic gastrostomies may become necessary due to progressive bulbar dysfunction. The influenza vaccine is used in combination with prophylactic antibiotics to prevent chest infections.
Monitoring
Patients are evaluated every six to 12 months for early evidence of hip dislocation and spinal deformities. Risk of pulmonary aspiration is evaluated with regular swallowing assessments. Nutritional assessments are performed regularly to ensure adequate caloric intake.
Treatment
Preliminary experiments have examined the potential of drugs to act as pharmacological chaperones of DAT to rescue DTDS mutations. Bupropion and ibogaine appear to promote DAT maturation and functional activity by acting as pharmacological chaperones in the endoplasmic reticulum. These two drugs rescue DAT maturation and functional activity of two DTDS-associated mutations (A314V and R445C). Preclinical experiments in mice have demonstrated efficacy and safety of a potential treatment using stereotactic injection of AAV vector to deliver working copies of the DAT gene.
Support organizations
A variety of support and advocacy groups exist to connect with other patients and families or provide valuable services.
International Parkinson and Movement Disorder Society
Parkinson & Movement Disorder Alliance
Parkinsons Foundation
Pediatric Neurotransmitter Disease Association
== References == |
Branchial cleft cyst | A branchial cleft cyst is a cyst as a swelling in the upper part of neck anterior to sternocleidomastoid. It can, but does not necessarily, have an opening to the skin surface, called a fistula. The cause is usually a developmental abnormality arising in the early prenatal period, typically failure of obliteration of the second, third, and fourth branchial cleft, i.e. failure of fusion of the second branchial arches and epicardial ridge in lower part of the neck. Branchial cleft cysts account for almost 20% of neck masses in children. Less commonly, the cysts can develop from the first, third, or fourth clefts, and their location and the location of associated fistulas differs accordingly.
Symptoms and signs
Most branchial cleft cysts present in late childhood or early adulthood as a solitary, painless mass, which went previously unnoticed, that has now become infected (typically after an upper respiratory tract infection). Fistulas, if present, are asymptomatic until infection arises.
Pathophysiology
Branchial cleft cysts are remnants of embryonic development and result from a failure of obliteration of one of the branchial clefts, which are homologous to the structures in fish that develop into gills.
Pathology
The cyst wall is composed of squamous epithelium (90%), columnar cells with or without cilia, or a mixture of both, with lymphoid infiltrate, often with prominent germinal centers and few subcapsular lymph sinuses. The cyst is typically surrounded by lymphoid tissue that has attenuated or absent overlying epithelium due to inflammatory changes. The cyst may or may not contain granular and keratinaceous cellular debris. Cholesterol crystals may be found in the fluid extracted from a branchial cyst.
Diagnosis
The diagnosis of branchial cleft cysts is typically done clinically due to their relatively consistent location in the neck, typically anterior to the sternocleidomastoid muscle. For masses presenting in adulthood, the presumption should be a malignancy until proven otherwise, since carcinomas of the tonsil, tongue base and thyroid may all present as cystic masses of the neck. Unlike a thyroglossal duct cyst, when swallowing, the mass should not move up or down.
Types
Four branchial clefts (also called "grooves") form during the development of a human embryo. The first cleft normally develops into the external auditory canal, but the remaining three arches are obliterated and have no persistent structures in normal development. Persistence or abnormal formation of these four clefts can all result in branchial cleft cysts which may or may not drain via sinus tracts.
First branchial cleft cysts account for 8% of the sinuses and cysts of the neck. The cysts are usually located in the front or behind the ears, lateral to the facial nerve, parallel to the external auditory canal.
Second branchial cleft cysts account for 90 to 95% of the neck cysts. It is located medial to the facial nerve, at the anterior neck, anterior to the sternocleidomastoid muscle, above the hyoid bone. Skin pit can be found in this location. However, if skin pits are found on both sides of the neck, then, branchio-oto-renal syndrome should be ruled out. Infection of the cysts in this region can compress trachea, causing respiratory problems, or it can compress the oesophagus, causing dysphagia, and irritating the sternocleidomastoid muscle, causing torticollis.
Third and fourth branchial cleft cysts are rare, usually consisting of 2% of all branchial arch abnormalities, located below the second branchial arch. They usually have sinus tracts that start from the anterior neck at the thyroid gland until pyriform sinus posteriorly. If infected, it can cause acute infectious thyroiditis in children and if enlarge rapidly, can cause tracheal compression in children.
Treatment
Conservative (i.e. no treatment), or surgical excision. With surgical excision, recurrence is common, usually due to incomplete excision. Often, the tracts of the cyst will pass near important structures, such as the internal jugular vein, carotid artery, or facial nerve, making complete excision impractical due to the high risk of complications.
See also
Cutaneous columnar cyst
Cystic hygroma
Gingival cyst
Mucocele
Ranula
Thyroglossal duct cyst
References
External links
Pictures and Imaging of Branchial Cleft Cysts |
Chemical burn | A chemical burn occurs when living tissue is exposed to a corrosive substance (such as a strong acid, base or oxidizer) or a cytotoxic agent (such as mustard gas, lewisite or arsine). Chemical burns follow standard burn classification and may cause extensive tissue damage. The main types of irritant and/or corrosive products are: acids, bases, oxidizers / reducing agents, solvents, and alkylants. Additionally, chemical burns can be caused by some types of cytotoxic chemical weapons, e.g., vesicants such as mustard gas and Lewisite, or urticants such as phosgene oxime.
Chemical burns may:
need no source of heat
occur immediately on contact
not be immediately evident or noticeable
be extremely painful
diffuse into tissue and damage cellular structures under skin without immediately apparent damage to skin surface
Presentation
The exact symptoms of a chemical burn depend on the chemical involved. Symptoms include itching, bleaching or darkening of skin, burning sensations, trouble breathing, coughing blood and/or tissue necrosis. Common sources of chemical burns include sulfuric acid (H2SO4), hydrochloric acid (HCl), sodium hydroxide (NaOH), lime (CaO), silver nitrate (AgNO3), and hydrogen peroxide (H2O2). Effects depend on the substance; hydrogen peroxide removes a bleached layer of skin, while nitric acid causes a characteristic color change to yellow in the skin, and silver nitrate produces noticeable black stains. Chemical burns may occur through direct contact on body surfaces, including skin and eyes, via inhalation, and/or by ingestion. Lipophilic substances that diffuse efficiently in human tissue, e.g., hydrofluoric acid, sulfur mustard, and dimethyl sulfate, may not react immediately, but instead produce the burns and inflammation hours after the contact. Chemical fabrication, mining, medicine, and related professional fields are examples of occupations where chemical burns may occur. Hydrofluoric acid leaches into the bloodstream, reacts with calcium and magnesium, and the resulting salts can cause cardiac arrest after eating through skin.
Prevention
In Belgium, the Conseil Supérieur de la Santé gives a scientific advisory report on public health policy. The Superior Health Council of Belgium provides an overview of products that are authorized in Belgium for consumer use and that contain caustic substances, as well as of the risks linked to exposure to these products. This report aims at suggesting protection measures for the consumers, and formulates recommendations that apply to the different stages of the chain, which begins with the formulation of the product, followed by its regulation, marketing, application, post-application and ends with its monitoring.
Gallery
See also
Acid throwing
References
== External links == |
Immunoproliferative disorder | Immunoproliferative disorders are disorders of the immune system that are characterized by the abnormal proliferation of the primary cells of the immune system, which includes B cells, T cells and natural killer (NK) cells, or by the excessive production of immunoglobulins (also known as antibodies).
Classes
These disorders are subdivided into three main classes, which are lymphoproliferative disorders, hypergammaglobulinemia, and paraproteinemia. The first is cellular, and the other two are humoral (however, humoral excess can be secondary to cellular excess.)
Lymphoproliferative disorders (LPDs) refer to several conditions in which lymphocytes are produced in excessive quantities. They typically occur in patients who have compromised immune systems. This subset is sometimes incorrectly equated with "immunoproliferative disorders".
Humoral
Hypergammaglobulinemia is characterized by increased levels of immunoglobulins in the blood serum. Five different hypergammaglobulinemias are caused by an excess of immunoglobulin M (IgM), and some types are caused by a deficiency in the other major types of immunoglobulins.
Paraproteinemia or monoclonal gammopathy is the presence of excessive amounts of a single monoclonal gammaglobulin (called a paraprotein) in the blood.
See also
Myeloproliferative disease
References
== External links == |
Spider angioma | A spider angioma or spider naevus (plural: spider naevi), also nevus araneus, is a type of telangiectasis (swollen, spider-like blood vessels on the skin) found slightly beneath the skins surface, often containing a central red spot and deep reddish extensions (see Blood color) which radiate outwards like a spiders web or a spiders legs. They are common and often benign, presenting in around 10–15% of healthy adults and young children. However, having more than three spider angiomas is likely to be abnormal and may be a sign of liver disease and/or hepatitis C (HCV virus); it also suggests the probability of esophageal varices.
Signs and symptoms
Spider angiomas are found only in the distribution of the superior vena cava, and are thus commonly found on the face, neck, upper part of the torso, and arms.
Cause
Spider angiomas form due to failure of the sphincteric muscle surrounding a cutaneous arteriole. The central red dot is the dilated arteriole and the red "spider legs" are small capillaries carrying away the freely flowing blood. If momentary pressure is applied, it is possible to see the emptied capillaries refilling from the center. No other angiomas show this phenomenon.The dilation, in turn, is caused by increased estrogen levels in the blood. Many pregnant women and women using hormonal contraception have spider angiomas, which is due to high estrogen levels in their blood. Individuals with significant liver disease also show many spider angiomas, as their liver cannot metabolize circulating estrogens, specifically estrone, which derives from the androgen androstenedione. About 33% of patients with cirrhosis have spider angiomas.Hepatitis C is an infection that can lead to irreversible liver damage. The hepatitis C virus (HCV) spreads through contaminated blood, and people are often infected by sharing drug paraphernalia or unsanitized tattoo guns and needles, piercing equipment, or manicure tools. To make matters worse, symptoms of the HCV virus can take years to appear, and this is likely why most of those infected with hepatitis C do not even realize that they are infected, and can continue to spread the virus unknowingly.Unfortunately, many symptoms do not start to appear until some damage to the liver has been done. Unlike in the past when hepatitis C was not curable and continued to worsen as years passed, today most positive hepatitis C (HCV virus) cases (95-98%) are now curable by taking a fairly newer treatment in the form of a prescribed daily oral medication for the full duration of 12 weeks. This treatment is usually well tolerated, with little to no side effects whatsoever.
Spider angiomas (spider-like blood vessels on the skin) are one of the main symptoms caused by a hepatitis C (HCV virus) infection. Discovering an infected patient with hepatitis C early on in the infection phase increases the chances of the virus being successfully treated and cured by oral medication. Some patients can be infected with hepatitis C for decades without knowing, and without experiencing any signs or symptoms of the virus. Unfortunately, while hepatitis A and B have a protective vaccine available, there are no vaccines available to protect against the HCV virus (hepatitis C), Once contracted, if left untreated, hepatitis C can cause the liver to swell or become inflamed, making it difficult to function adequately in order to properly filter out chemicals and toxins. When the hepatits C (HCV) infection turns chronic, it can cause full-blown cirrhosis of the liver (scarring of the liver), making it difficult for the liver to filter out waste and to store nutrients. This can also lead to liver cancer and eventually will lead to liver failure.
Diagnosis
Diagnosis is by clinical examination. Spider naevi are most commonly seen by general practitioners, or dermatologists. Whilst a lesion can be identified as a spider naevus, this is not a diagnosis in itself. The clinical picture should be indicative of whether there is underlying disease that should be investigated.
Treatment
Spider angiomas are asymptomatic and usually resolve spontaneously. This is common in the case of children, although they may take several years to disappear. If the spider angiomas are associated with pregnancy, they may resolve after childbirth. In women taking oral contraceptives, they may resolve after stopping these contraceptives.For spider angiomas on the face, techniques such as electrodesiccation and laser treatment can be used to remove the lesion. There is a small risk of a scar, however it usually leaves nothing.
See also
List of cutaneous conditions
References
== External links == |
Farber disease | Farber disease (also known as Farbers lipogranulomatosis, acid ceramidase deficiency, "Lipogranulomatosis", and ASAH1-related disorders) is an extremely rare, progressive, autosomal recessive lysosomal storage disease caused by a deficiency of the acid ceramidase enzyme. Acid ceramidase is responsible for breaking down ceramide into sphingosine and fatty acid. When the enzyme is deficient, this leads to an accumulation of fatty material (called ceramide) in the lysosomes of the cells, leading to the signs and symptoms of this disorder.
Signs and Symptoms
The symptoms of Farber disease develop over time. The onset of symptoms and how quickly they progress vary from person to person.The most common symptoms include:
Bumps under the skin located at pressure points and joints, also called subcutaneous nodules, lipogranulomas, or granulomas
Swollen, painful joints with progressive limitation of range of motion resulting in contracture
Hoarse voice/cryOther symptoms observed in some individuals with Farber disease include:
Respiratory disease, e.g. lung infections, labored breathing, respiratory distress
Central nervous system disease, e.g. developmental delay, muscle weakness, seizures
Systemic inflammation
Failure to thrive
Bone disease, e.g. erosion of bone near joints, osteoporosis, peripheral osteolysis
Enlarged liver (hepatomegaly)
Eye disease, e.g. cherry-red spot, corneal opacities
Genetics
Farber disease is caused by variants in the ASAH1 gene. This gene codes for the acid ceramidase enzyme. Individuals with Farber disease have two copies of this gene that are not functioning properly leading to the enzyme deficiency. Over 73 different gene variants have been reported to cause Farber disease. No definitive genotype-phenotype correlations are known.Farber disease is inherited in an autosomal recessive manner. Affected individuals inherit one copy of the gene that is not functioning properly from each parent. Each parent is a called a carrier and has one copy of the gene that is functioning properly and one that is not. Siblings of individuals with Farber disease have a 25% chance to also have Farber disease, a 50% chance to be a carrier like the parents, and a 25% chance of being unaffected and not a carrier.The ASAH1 gene is also known to cause a condition called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Farber disease and SMA-PME have been classified as separate disorders, however more recent case reports have identified some individuals with overlapping symptoms of both disorders. Some individuals with SMA symptoms without seizures have also been described.
Diagnosis
Disease onset is typically in early infancy but may occur later in life. Children who have the classic form of Farber disease develop symptoms within the first few weeks to months of life. Individuals with moderate or attenuated forms may develop symptoms at any time in childhood. Sometimes it is difficult to diagnose Farber disease because the symptoms can be misdiagnosed as Juvenile Idiopathic Arthritis (JIA). Diagnosis is confirmed by molecular genetic testing of the ASAH1 gene or by measuring acid ceramidase enzyme activity.
Treatment
There is no disease specific treatment for Farber disease. Anti-inflammatory medications, specifically tocilizumab (an interleukin-6 receptor inhibitor), has been shown to improve inflammation and pain in some patients. Bone marrow transplant may improve granulomas (small masses of inflamed tissue) and inflammation in patients with little or no lung or nervous system complications. Supportive therapies such as physical therapy, respiratory support, and mobility aids may be required.
Studies in cells and mice have shown proof-of-concept for enzyme replacement therapy for Farber disease. Aceragen, a biopharmaceutical company, is currently developing an investigational enzyme replacement therapy with a clinical study planned for late 2022.
Prognosis
Children with the most severe forms of Farber disease generally die by age 2-3 years. The life expectancy of individuals with moderate or attenuated forms is unknown. The oldest reported individuals living with Farber disease were in their 50s and 60s.
Prevalence
To date, there have been approximately 200 reported cases of Farber disease and SMA-PME in the literature. The disorders are ultra-rare and estimated to occur in fewer than one per million.
Eponym
It is named for Sidney Farber.
References
External links
National Organization for Rare Disorders (NORD): ASAH1-Related Disorders
GeneReviews: ASAH1-Related Disorders
Aceragen Pipeline with Farber
Free Genetic Testing for ASAH1 |
MOMO syndrome | MOMO syndrome is an extremely rare genetic disorder which belongs to the overgrowth syndromes and has been diagnosed in only seven cases around the world, and occurs in 1 in 100 million births. The name is an acronym of the four primary aspects of the disorder: Macrosomia (excessive birth weight), Obesity, Macrocephaly (excessive head size) and Ocular abnormalities. It is unknown if it is a life-limiting condition. MOMO syndrome was first diagnosed in 1993 by Professor Danilo Moretti-Ferreira, a Brazilian researcher in the Genetic and Clinical Studies of neurodevelopmental disorders.
This syndromes acronym is an intended pun. It refers to the traditionally tall and obese king of Carnivals, Momus—Rei Momo in Portuguese.
Signs and symptoms
Along with the four aspects of the disorder that give it its name, there are also other common symptoms:
A downward slant of the forehead
Delayed bone maturation
Mental retardationThe ocular abnormalities are generally retinal coloboma and nystagmus.
Pathophysiology
Because MOMO is such a rare disorder, very few studies have been conducted into its causes. Current research suggests that it is linked to a de novo (new) autosomal dominant mutation.
Diagnosis
History
Archie Thompson was born in 2002 in Icklesham, England and weighed 8 lb 4 oz (3740 g). By 15 months his weight had increased to 4 stone (56 lb; 25 kg) and by 24 months it was up to 6 stone (84 pounds; 38 kg). The condition placed a large strain on his heart and lungs. The Thompson family were featured in a documentary for Five first shown on 3 October 2004. It has since aired on Discovery Fit & Health in the United States.Danielle Falan, from São Paulo, Brazil, is one of the oldest surviving people with MOMO syndrome. At age 17 she was featured in the Archie Thompson documentary as her mother traveled to visit her in Brazil. Falan attended school as normal, and hopes to attend college.Six other cases have been diagnosed, in Italy, in Brazil [1], two in Germany,, in Cuba, 2018 Diorkeblin Hernández Durruthy [2] [3], and in Poland. An additional case was reported in 2010.
References
== External links == |
Accessory spleen | An accessory spleen is a small nodule of splenic tissue found apart from the main body of the spleen. Accessory spleens are found in approximately 10 percent of the population and are typically around 1 centimetre in diameter. They may resemble a lymph node or a small spleen. They form either by the result of developmental anomalies or trauma. They are medically significant in that they may result in interpretation errors in diagnostic imaging or continued symptoms after therapeutic splenectomy. Polysplenia is the presence of multiple accessory spleens rather than one normal spleen.
Causes and locations
Accessory spleens may be formed during embryonic development when some of the cells from the developing spleen are deposited along the path from the midline, where the spleen forms, over to its final location on the left side of the abdomen by the 9th–11th ribs. The most common locations for accessory spleens are the hilum of the spleen and adjacent to the tail of the pancreas. They may be found anywhere along the splenic vessels, in the gastrosplenic ligament, the splenorenal ligament, the walls of the stomach or intestines, the pancreatic tail, the greater omentum, the mesentery, the renal fossa, or the gonads and their path of descent. The typical size is approximately 1 centimeter, but sizes ranging from a few millimeters up to 2–3 centimeters are not uncommon.Splenogonadal fusion can result in one or more accessory spleens along a path from the abdomen into the pelvis or scrotum. The developing spleen forms near the urogenital ridge from which the gonads develop. The gonads may pick up some tissue from the spleen, and as they descend through the abdomen during development, they can produce either a continuous or a broken line of deposited splenic tissue.Splenosis is a condition where foci of splenic tissue undergo autotransplantation, most often following physical trauma or splenectomy. Displaced tissue fragments can implant on well vascularized surfaces in the abdominal cavity, or, if the diaphragmatic barrier is broken, the thorax.
Significance
If splenectomy is performed for conditions in which blood cells are sequestered in the spleen, failure to remove accessory spleens may result in the failure of the condition to resolve. During medical imaging, accessory spleens may be confused for enlarged lymph nodes or neoplastic growth in the tail of the pancreas, gastrointestinal tract, adrenal glands or gonads.
References
External links
eMedicine Search: Accessory spleen
Image at brown.edu |
Crutch paralysis | Crutch paralysis is a form of paralysis which can occur when either the radial nerve or part of the brachial plexus, containing various nerves that innervate sense and motor function to the arm and hand, is under constant pressure, such as by the use of a crutch. This can lead to paralysis of the muscles innervated by the compressed nerve. Generally, crutches that are not adjusted to the correct height can cause the radial nerve to be constantly pushed against the humerus. This can cause any muscle that is innervated by the radial nerve to become partially or fully paralyzed. An example of this is wrist drop, in which the fingers, hand, or wrist is chronically in a flexed position because the radial nerve cannot innervate the extensor muscles due to paralysis. This condition, like other injuries from compressed nerves, normally improves quickly through therapy.
See also
Brachial plexus injury
References
External links
"Crutch paralysis - definition of crutch paralysis in the Medical dictionary - by the Free Online Medical Dictionary, Thesaurus and Encyclopedia". Medical-dictionary.thefreedictionary.com. Retrieved 2011-12-04. |
Craniopagus parasiticus | Craniopagus parasiticus is an extremely rare type of parasitic twinning occurring in about 2 to 3 of 5,000,000 births. In craniopagus parasiticus, a parasitic twin head with an undeveloped body is attached to the head of a developed twin. Fewer than a dozen cases of this type of conjoined twin have been documented in literature.
Development
The exact development of craniopagus parasiticus is not well known. However, it is known that the underdeveloped twin is a parasitic twin. Parasitic twins are known to occur in utero when monozygotic twins start to develop as an embryo, but the embryo fails to completely split. When this happens, one embryo will dominate development, while the others development is severely altered. The key difference between a parasitic twin and conjoined twins is that in parasitic twins, one twin, the parasite, stops development during gestation, whereas the other twin, the autosite, develops completely.In normal monozygotic twin development, one egg is fertilized by a single sperm. The egg will then completely split into two, normally at the two-cell stage. If the egg splits in the early blastocyst stage, two inner cell masses will be present, eventually leading to the twins sharing the same chorion and placenta, but with separate amnions. However, the egg can split into two, but still have one blastocyst. This will lead to one inner cell mass and one blastocyst. Then, as the twins develop, they will share the same placenta, chorion, and amnion. This is thought to be the most likely reason why conjoined twins occur, and could possibly play a role in the development of craniopagus parasiticus.One hypothesis is that craniopagus parasiticus starts with the development of two fetuses from a single zygote that fail to separate at the head region around the second week of gestation. Some believe, however, that it occurs later in development, around the fourth week of gestation, at which time the two embryos fuse together near the anterior open neuropore.Another hypothesis is that there is joining of the somatic and placental vascular system of the twins, as well as a degeneration of the umbilical cord of the parasitic twin. This suggests that craniopagus parasiticus develops due to the lack of blood supply to one of the twins.
Diagnosis
Related conditions
In addition to craniopagus parasiticus, a few other conditions involve a childs, or animals, birth with two heads or faces.
Dicephalic parapagus
Dicephalic parapagus is a condition where two heads are side by side on a single torso, with varying degrees of twinning of organs and structures within the torso.
Diprosopus
Diprosopus occurs when a single body and neck are present, but there is a duplication of the structures of the face. This is different from craniopagus parasiticus in that there is only one head, although there is a duplication of the craniofacial features. Diprosopus can range from having two fully formed faces to just a duplication of the nose or eyes. Cats with the condition are referred to as Janus cats. A cat named Frankenlouie was a famous example noted by the Guinness Book of World Records in 2012 for being the longest surviving Janus cat.
Treatment
Few individuals survive until birth. For those who do, the only treatment available is to surgically remove the parasitic twin. Of the two documented attempts, however, one child died within hours and neither reached their second birthday. The problem with surgical intervention is that the arterial supplies of the head are so intertwined that it is very hard to control the bleeding, but it has been suggested that cutting off the parasitic twins arterial supply might improve the odds of the developed twins survival.
Prevalence
Only ten cases of craniopagus parasiticus have been documented, out of a total of at least eighty known cases of craniopagus in general.Only four cases have been documented by modern medicine to have survived birth:
An earlier case was the so-called "Two-Headed Boy of Bengal", who was born in 1783 and died of a cobra bite in 1787. His skull remains in the collection of the Hunterian Museum of the Royal College of Surgeons of London.
On December 10, 2003, Rebeca Martínez was born in the Dominican Republic with this rare condition. She was the first baby born with the condition to undergo an operation to remove the second head. She died on February 7, 2004, after an 11-hour operation.
On March 30, 2004, Manar Maged was born with the rare condition. On February 19, 2005, 10-month-old Manar underwent a successful 13-hour surgery in Egypt. The underdeveloped conjoined twin, Islaam, was attached to Manars head and was facing upward. Islaam could blink and even smile, but doctors determined she had to be removed, and that she could not survive on her own. Manar was featured on an episode of The Oprah Winfrey Show and in the British documentary series Body Shock. Manar died on March 26, 2006, fourteen months after the surgery, just days before her second birthday, due to a severe infection in her brain.
On January 20, 2021, a baby was born with two heads, at the Elias Hospital in Bucharest, Romania, but died some hours after being born.
History
Only ten cases of craniopagus parasiticus have been reported in the medical research literature. Of those cases, only four have survived birth. The first case on record is that of Everard Homes Two-Headed Boy of Bengal, whose skull is preserved at the Hunterian Museum at the Royal Society of Surgeons.
Terminology
In the past, the use of terminology when describing parasitic twins has been somewhat inconsistent. By definition, a parasitic twin is joined to another twin in a certain anatomical location or position on the developed twins body. The underdeveloped twin is termed the parasite, and the developed twin is termed the autosite. The autosite can have some abnormalities, as well. For the most part, however, it has developed enough that it can live on its own.
See also
Pasqual Piñón, a sideshow performer billed as the Two-headed Mexican
Janus, ancient Roman god depicted with two faces
Edward Mordrake, an urban legend with a similar trait
Futakuchi-onna, Japanese yōkai with a similar trait
Tomie Kawakami, a titular character of Tomie whom possess with the two-headed appearance
References
Bibliography
External links
Image File of craniopagus parasiticus |
Chronic atrophic rhinitis | Chronic atrophic rhinitis, or simply atrophic rhinitis, is a chronic inflammation of the nose characterised by atrophy of nasal mucosa, including the glands, turbinate bones and the nerve elements supplying the nose. Chronic atrophic rhinitis may be primary and secondary. Special forms of chronic atrophic rhinitis are rhinitis sicca anterior and ozaena. It can also be described as the empty nose syndrome.
Signs and symptoms
It is most commonly seen in females.
It is reported among patients from lower socioeconomic groups.
The nasal cavities become roomy and are filled with foul smelling crusts which are black or dark green and dry, making expiration painful and difficult.
Microorganisms are known to multiply and produce a foul smell from the nose, though the patients may not be aware of this, because the nerve endings (responsible for the perception of smell) have become atrophied. This is called merciful anosmia.
Patients usually complain of nasal obstruction despite the roomy nasal cavity, which can be caused either by the obstruction produced by the discharge in the nose, or as a result of sensory loss due to atrophy of nerves in the nose, so the patient is unaware of the air flow. In the case of the second cause, the sensation of obstruction is subjective.
Bleeding from the nose, also called epistaxis, may occur when the dried discharge (crusts) are removed.
Septal perforation and dermatitis of nasal vestibule can occur. The nose may show a saddle-nose deformity.
Atrophic rhinitis is also associated with similar atrophic changes in the pharynx or larynx, producing symptoms pertaining to these structures. Hearing impairment can occur due to Eustachian tube blockage causing middle ear effusion.
Etiology
Causes can be remembered by the mnemonic HERNIA:
Hereditary factors: the disease runs in families
Endocrine imbalance: the disease tends to start at puberty and mostly involves females
Racial factors: white people are more susceptible than natives of equatorial Africa
Nutritional deficiency: vitamins A or D, or iron
Infection: Klebsiella ozaenae, diphtheroids, Proteus vulgaris, E. coli, etc.
Autoimmune factors: viral infection or some other unidentified insult may trigger antigenicity of the nasal mucosa.
Secondary atrophic rhinitis
Specific infections, such as syphilis, leprosy and rhinoscleroma, may cause destruction of the nasal structures leading to atrophic changes. Atrophic rhinitis can also result from long-standing purulent sinusitis or radiotherapy of the nose, or as a complication of surgery of the turbinates. The United Kingdom National Health Service has stated that "Most cases of atrophic rhinitis in the UK occur when the turbinates are damaged or removed during surgery". Some authors refer to as Atrophic rhinitis secondary to sinus surgery as the empty nose syndrome.
Unilateral atrophic rhinitis
Extreme deviation of nasal septum may be accompanied by atrophic rhinitis on the wider side.
Pathology
The ciliated columnar epithelium of the nasal mucosa is replaced by stratified squamous epithelium.
Atrophy of mucosa, turbinal bones and seromucinous glands tends to occur, due to obliterative endarteritis and periarteritis causing decreased blood supply, hence the supplying area atrophies.
Arrested development of paranasal sinuses.
Diagnosis
Diagnosis is based on clinical history and examination. Examination is clinical, via anterior rhinoscopy and fibreoptic, using nasendoscopy. A CT scan can be used to confirm the diagnosis and review disease extent.
Treatment
Treatment of atrophic rhinitis can be either medical or surgical.
Medical measures include:
Nasal irrigation using normal saline
Nasal irrigation and removal of crusts using alkaline nasal solutions.
25% glucose in glycerine can be applied to the nasal mucosa to inhibit the growth of proteolytic organisms which produce foul smell.
Local antibiotics, such as chloromycetine.
Vitamin D2 .
Estradiol spray for regeneration of seromucinous glands and vascularization of mucosa.
Systemic streptomycin (1g/day) against Klebsiella organisms.
Oral potassium iodide for liquefaction of secretion.
Placental extract injected in the submucosa.
Rifampicin 600 mg once daily for 12 weeks.Surgical interventions include:
Youngs operation.
Modified Youngs operation.
Narrowing of nasal cavities, submucosal injection of Teflon paste (Williams operation), section and medial displacement of the lateral wall of the nose.
Transposition of parotid duct to maxillary sinus or nasal mucosa (Wittmacks operation)
Complete inversion of mucoperiosteum of maxillary antrum to create a neoturbinate (Raghav Sharans operation)
Repeated Stellate ganglion block (Sardanas operation)
Vestibuloplasty
History
This disorder was known since the time of ancient Egypt, almost 4,000 years ago, and descriptions of it are found in the historical medical papyri. In the Edwin Smith Papyrus (1700 BC) it was prescribed a treatment based on wine and breast milk to cure this disease. The ancient Greek and Indian civilizations were aware of atrophic rhinitis.
See also
Empty nose syndrome
References
== External links == |
Motor neuron disease | Motor neuron diseases or motor neurone diseases (MNDs) are a group of rare neurodegenerative disorders that selectively affect motor neurons, the cells which control voluntary muscles of the body. They include amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP), pseudobulbar palsy, progressive muscular atrophy (PMA), primary lateral sclerosis (PLS), spinal muscular atrophy (SMA) and monomelic amyotrophy (MMA), as well as some rarer variants resembling ALS.
Motor neuron diseases affect both children and adults. While each motor neuron disease affects patients differently, they all cause movement-related symptoms, mainly muscle weakness. Most of these diseases seem to occur randomly without known causes, but some forms are inherited. Studies into these inherited forms have led to discoveries of various genes (e.g. SOD1) that are thought to be important in understanding how the disease occurs.Symptoms of motor neuron diseases can be first seen at birth or can come on slowly later in life. Most of these diseases worsen over time; while some, such as ALS, shorten ones life expectancy, others do not. Currently, there are no approved treatments for the majority of motor neuron disorders, and care is mostly symptomatic.
Signs and symptoms
Signs and symptoms depend on the specific disease, but motor neuron diseases typically manifest as a group of movement-related symptoms. They come on slowly, and worsen over the course of more than three months. Various patterns of muscle weakness are seen, and muscle cramps and spasms may occur. One can have difficulty breathing with climbing stairs (exertion), difficulty breathing when lying down (orthopnea), or even respiratory failure if breathing muscles become involved. Bulbar symptoms, including difficulty speaking (dysarthria), difficulty swallowing (dysphagia), and excessive saliva production (sialorrhea), can also occur. Sensation, or the ability to feel, is typically not affected. Emotional disturbance (e.g. pseudobulbar affect) and cognitive and behavioural changes (e.g. problems in word fluency, decision-making, and memory) are also seen. There can be lower motor neuron findings (e.g. muscle wasting, muscle twitching), upper motor neuron findings (e.g. brisk reflexes, Babinski reflex, Hoffmans reflex, increased muscle tone), or both.Motor neuron diseases are seen both in children and adults. Those that affect children tend to be inherited or familial, and their symptoms are either present at birth or appear before learning to walk. Those that affect adults tend to appear after age 40. The clinical course depends on the specific disease, but most progress or worsen over the course of months. Some are fatal (e.g. ALS), while others are not (e.g. PLS).
Patterns of weakness
Various patterns of muscle weakness occur in different motor neuron diseases. Weakness can be symmetric or asymmetric, and it can occur in body parts that are distal, proximal, or both. According to Statland et al., there are three main weakness patterns that are seen in motor neuron diseases, which are:
Asymmetric distal weakness without sensory loss (e.g. ALS, PLS, PMA, MMA)
Symmetric weakness without sensory loss (e.g. PMA, PLS)
Symmetric focal midline proximal weakness (neck, trunk, bulbar involvement; e.g. ALS, PBP, PLS)
Lower and upper motor neuron findings
Motor neuron diseases are on a spectrum in terms of upper and lower motor neuron involvement. Some have just lower or upper motor neuron findings, while others have a mix of both. Lower motor neuron (LMN) findings include muscle atrophy and fasciculations, and upper motor neuron (UMN) findings include hyperreflexia, spasticity, muscle spasm, and abnormal reflexes.Pure upper motor neuron diseases, or those with just UMN findings, include PLS.Pure lower motor neuron diseases, or those with just LMN findings, include PMA.Motor neuron diseases with both UMN and LMN findings include both familial and sporadic ALS.
Causes
Most cases are sporadic and their causes are usually not known. It is thought that environmental, toxic, viral, or genetic factors may be involved.
DNA damage
TARDBP (TAR DNA-binding protein 43), also referred to as TDP-43, is a critical component of the non-homologous end joining (NHEJ) enzymatic pathway that repairs DNA double-strand breaks in pluripotent stem cell-derived motor neurons. TDP-43 is rapidly recruited to double-strand breaks where it acts as a scaffold for the recruitment of the XRCC4-DNA ligase protein complex that then acts to repair double-strand breaks. About 95% of ALS patients have abnormalities in the nucleus-cytoplasmic localization in spinal motor neurons of TDP43. In TDP-43 depleted human neural stem cell-derived motor neurons, as well as in sporadic ALS patients’ spinal cord specimens there is significant double-strand break accumulation and reduced levels of NHEJ.
Associated risk factors
In adults, men are more commonly affected than women.
Diagnosis
Differential diagnosis can be challenging due to the number of overlapping symptoms, shared between several motor neuron diseases. Frequently, the diagnosis is based on clinical findings (i.e. LMN vs. UMN signs and symptoms, patterns of weakness), family history of MND, and a variation of tests, many of which are used to rule out disease mimics, which can manifest with identical symptoms.
Classification
Motor neuron disease describes a collection of clinical disorders, characterized by progressive muscle weakness and the degeneration of the motor neuron on electrophysiological testing. The term "motor neuron disease" has varying meanings in different countries. Similarly, the literature inconsistently classifies which degenerative motor neuron disorders can be included under the umbrella term "motor neuron disease". The four main types of MND are marked (*) in the table below.All types of MND can be differentiated by two defining characteristics:
Is the disease sporadic or inherited?
Is there involvement of the upper motor neurons (UMN), the lower motor neurons (LMN), or both?Sporadic or acquired MNDs occur in patients with no family history of degenerative motor neuron disease. Inherited or genetic MNDs adhere to one of the following inheritance patterns: autosomal dominant, autosomal recessive, or X-linked. Some disorders, like ALS, can occur sporadically (85%) or can have a genetic cause (15%) with the same clinical symptoms and progression of disease.UMNs are motor neurons that project from the cortex down to the brainstem or spinal cord. LMNs originate in the anterior horns of the spinal cord and synapse on peripheral muscles. Both motor neurons are necessary for the strong contraction of a muscle, but damage to an UMN can be distinguished from damage to a LMN by physical exam.
Tests
Cerebrospinal fluid (CSF) tests: Analysis of the fluid from around the brain and spinal cord could reveal signs of an infection or inflammation.
Magnetic resonance imaging (MRI): An MRI of the brain and spinal cord is recommended in patients with UMN signs and symptoms to explore other causes, such as a tumor, inflammation, or lack of blood supply (stroke).
Electromyogram (EMG) & nerve conduction study (NCS): The EMG, which evaluates muscle function, and NCS, which evaluates nerve function, are performed together in patients with LMN signs.
For patients with MND affecting the LMNs, the EMG will show evidence of: (1) acute denervation, which is ongoing as motor neurons degenerate, and (2) chronic denervation and reinnervation of the muscle, as the remaining motor neurons attempt to fill in for lost motor neurons.
By contrast, the NCS in these patients is usually normal. It can show a low compound muscle action potential (CMAP), which results from the loss of motor neurons, but the sensory neurons should remain unaffected.
Tissue biopsy: Taking a small sample of a muscle or nerve may be necessary if the EMG/NCS is not specific enough to rule out other causes of progressive muscle weakness, but it is rarely used.
Treatment
There are no known curative treatments for the majority of motor neuron disorders. Please refer to the articles on individual disorders for more details.
Prognosis
The table below lists life expectancy for patients who are diagnosed with MND.
Terminology
In the United States and Canada, the term motor neuron disease usually refers to the group of disorders while amyotrophic lateral sclerosis is frequently called Lou Gehrigs disease. In the United Kingdom and Australia, the term motor neuron(e) disease is used for amyotrophic lateral sclerosis, although is not uncommon to refer to the entire group.While MND refers to a specific subset of similar diseases, there are numerous other diseases of motor neurons that are referred to collectively as "motor neuron disorders", for instance the diseases belonging to the spinal muscular atrophies group. However, they are not classified as "motor neuron diseases" by the 11th edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-11), which is the definition followed in this article.
See also
Spinal muscular atrophies
Hereditary motor and sensory neuropathies
References
External links
Media related to Motor neuron diseases at Wikimedia Commons
Motor neuron diseases at NINDS |
Psorosperm | Psorosperm (from the Greek ψωρα itch and σπερμα seed) is a former name of a number of parasitic protozoa that produce cystlike or sporelike structures in the tissue of hosts. The term is now essentially obsolete.
Some that affect vertebrate hosts are now called coccidia.
Others, such as the cause of pébrine in silkworms, are now recognized as microsporidians, and some are myxosporidians.
The genus Psorospermium (which includes the species Psorospermium haeckeli) itself is a parasite of crayfishes, and belongs to an enigmatic group of unicellular organisms that some biologists think may be related to the common ancestors of animals and fungi.J. Müller introduced the term in German (as Psorospermien) in 1841.Psorosperm was at one point believed to be the cause of Dariers disease."Psorospermiasis" is classified under 136.4 in ICD-9.
== References == |
Tennis elbow | Tennis elbow, also known as lateral epicondylitis or enthesopathy of the extensor carpi radialis origin, is a condition in which the outer part of the elbow becomes painful and tender. The pain may also extend into the back of the forearm. Onset of symptoms is generally gradual although they can seem sudden and be misinterpreted as an injury. Golfers elbow is a similar condition that affects the inside of the elbow.Enthesopathies are idiopathic, meaning science has not yet determined the cause. Enthesopathies are most common in middle age (ages 35 to 60).It is often stated that the condition is caused by excessive use of the muscles of the back of the forearm, but this is not supported by experimental evidence and is a common misinterpretation or unhelpful thought about symptoms. It may be associated with work or sports, classically racquet sports, but most people with the condition are not exposed to these activities. The diagnosis is based on the symptoms and examination. Medical imaging is not particularly useful. Signs consistent with the diagnosis include pain when a subject tries to bend back the wrist when the wrist is against resistance.Treatment involves decreasing activities that bring on the symptoms together with physical therapy or other treatment gradually increasing loads. Pain medications such as NSAIDS or acetaminophen (paracetamol) may be used. A brace over the upper forearm may also be helpful. The role of corticosteroid injections is debated.
Signs and symptoms
Pain on the outer part of the elbow (lateral epicondyle)
Point tenderness over the lateral epicondyle—a prominent part of the bone on the outside of the elbow
Pain with resisted wrist extension or passive wrist flexionSymptoms associated with tennis elbow include, but are not limited to, pain from the outside of the elbow to the forearm and wrist and pain during extension of wrist.
Terminology
The term "tennis elbow" is widely used (although informal), but the condition should be understood as not limited to tennis players. Historically, the medical term "lateral epicondylitis" was most commonly used for the condition, but "itis" implies inflammation and the condition is not inflammatory.Since histological findings reveal noninflammatory tissue, the terms “lateral elbow tendinopathy" and "tendinosis” are suggested. In 2019, a group of international experts suggested that "lateral elbow tendinopathy" was the most appropriate terminology. But a disease of an attachment point (or enthesia) is most accurately referred to as an "enthesopathy."
Causes
Enthesopathy of the extensor carpi radialis brevis origin is idiopathic, meaning that it has no known cause.Tennis players generally believe tennis elbow is caused by the repetitive nature of hitting thousands of tennis balls, which leads to tiny tears in the forearm tendon attachment at the elbow. Traditionally, people have speculated that tennis elbow is a type of repetitive strain injury resulting from tendon overuse and failed healing of the tendon, but there is no evidence of injury or repair on histopathology, and misinterpretation of painful activities as a source of damage is common.
Early experiments suggested that tennis elbow was primarily caused by overexertion. However, studies show that trauma such as direct blows to the epicondyle, a sudden forceful pull, or forceful extension cause more than half of these injuries. Repeatedly mis-hitting a tennis ball in the early stages of learning the sport causes shock to the elbow joint and may contribute to contracting the condition.
Pathophysiology
Histological findings include granulation tissue, micro-rupture, degenerative changes, and there is no traditional inflammation. Therefore, the disorder is more appropriately referred to as tendinosis or tendinopathy—more accurately an enthesopathy—rather than tendinitis. There is no evidence of inflammation or repair.The extensor digiti minimi also has a small origin site medial to the elbow that this condition can affect. The muscle involves the extension of the little finger and some extension of the wrist allowing for adaption to "snap" or flick the wrist—usually associated with a racquet swing. Most often, the extensor muscles become painful due to tendon breakdown from over-extension. Improper form or movement allows for power in a swing to rotate through and around the wrist—creating a moment on that joint instead of the elbow joint or rotator cuff. This moment causes pressure to build impact forces to act on the tendon causing irritation and inflammation.Other speculative risk factors for lateral epicondylitis include taking up tennis later in life, unaccustomed strenuous activity, decreased mental chronometry and speed and repetitive eccentric contraction of muscle (controlled lengthening of a muscle group).
Diagnosis
Physical examination
Diagnosis is based on symptoms and clinical signs that are discrete and characteristic. For example, extension of the elbow and flexion of the wrist cause outer elbow pain. There is point tenderness at the origin of the extensor carpi radialis brevis muscle from the lateral epicondyle (extensor carpi radialis brevis origin), 1 cm distal and slightly anterior to the lateral epicondyle. There is also pain with resisted wrist extension (Cozens test).
Medical imaging
Medical imaging is not necessary or helpful.X-rays can confirm and distinguish possibilities of existing causes of pain that are unrelated to tennis elbow, such as fracture or arthritis. Rarely, calcification can be found where the extensor muscles attach to the lateral epicondyle. Medical ultrasonography and magnetic resonance imaging (MRI) are other valuable tools for diagnosis but are frequently avoided due to the high cost.Longitudinal sonogram of the lateral elbow displays thickening and heterogeneity of the common extensor tendon that is consistent with tendinosis, as the ultrasound reveals calcifications, intrasubstance tears, and marked irregularity of the lateral epicondyle. Although the term “epicondylitis” is frequently used to describe this disorder, most histopathologic findings of studies have displayed no evidence of an acute, or a chronic inflammatory process. Histologic studies have demonstrated that this condition is the result of tendon degeneration, which replaces normal tissue with a disorganized arrangement of collagen.
Treatment
In some cases, severity of tennis elbow symptoms mend without any treatment, within six to 24 months. Tennis elbow left untreated can lead to chronic pain that degrades quality of daily living.
Physical therapy
There are several recommendations regarding prevention, treatment, and avoidance of recurrence that are largely speculative including stretches and progressive strengthening exercises to prevent re-irritation of the tendon and other exercise measures.One way to help treat minor cases of tennis elbow is simply to relax the affected arm. The rest lets stress and tightness within the forearm slowly relax and eventually have the arm in working condition—in a day or two, depending on the case.Other approaches that are not experimentally tested include eccentric exercise using a rubber bar. The exercise involves grasping a rubber bar, twisting it, then slowly untwisting it. Although it can be considered an evidence-based practice, long-term results have not yet been determined.There are differences in opinions on whether it is okay if pain occurs during these exercises. Some suggest pain of less than 5/10 is okay.Moderate evidence exists demonstrating that joint manipulation directed at the elbow and wrist and spinal manipulation directed at the cervical and thoracic spinal regions results in clinical changes to pain and function. There is also moderate evidence for short-term and mid-term effectiveness of cervical and thoracic spine manipulation as an add-on therapy to concentric and eccentric stretching plus mobilisation of wrist and forearm. Although not yet conclusive, the short-term analgesic effect of manipulation techniques may allow more vigorous stretching and strengthening exercises, resulting in a better and faster recovery process of the affected tendon in lateral epicondylitis.Low level laser therapy, administered at specific doses and wavelengths directly to the lateral elbow tendon insertions, may result in short-term pain relief and less disability.Extracorporeal shockwave therapy, while safe, is of unclear benefit.
Orthotic devices
Orthosis is a device externally used on the limb to improve the function or reduce the pain. Orthotics may be useful in tennis elbow, however long-term effects are unknown. There are two main types of orthoses prescribed for this problem: counterforce elbow orthoses and wrist extension orthoses. Counterforce orthosis has a circumferential structure surrounding the arm. This orthosis usually has a strap which applies a binding force over the origin of the wrist extensors. The applied force by orthosis reduces the elongation within the musculotendinous fibers. Wrist extensor orthosis maintains the wrist in the slight extension. This position reduces the overloading strain at the lesion area.
Medication
Although anti-inflammatories are a commonly prescribed treatment for tennis elbow, the evidence for their effect is usually anecdotal with only limited studies showing a benefit. A systematic review found that topical non-steroidal anti-inflammatory drugs (NSAIDs) may improve pain in the short term (up to 4 weeks) but was unable to draw firm conclusions due to methodological issues. Evidence for oral NSAIDs is mixed.Evidence is poor for long term improvement from injections of any type, whether corticosteroids, botulinum toxin, prolotherapy or other substances. Corticosteroid injection may be effective in the short term however are of little benefit after a year, compared to a wait-and-see approach. A randomized control trial comparing the effect of corticosteroid injection, physiotherapy, or a combination of corticosteroid injection and physiotherapy found that patients treated with corticosteroid injection versus placebo had lower complete recovery or improvement at 1 year (Relative risk 0.86). Patients that received corticosteroid injection also had a higher recurrence rate at 1 year versus placebo (54% versus 12%, relative risk 0.23).
Complications from repeated steroid injections include skin problems such as hypopigmentation and fat atrophy leading to indentation of the skin around the injection site. Steroid injections against appear to be more effective than shock wave therapy. Botulinum toxin type A to paralyze the forearm extensor muscles in those with chronic tennis elbow that has not improved with conservative measures may be viable.
Surgery
Surgery is an option. Surgical methods include:
Lengthening, release, debridement, or repair of the origin of the extrinsic extensor muscles of the hand at the lateral epicondyleSurgical techniques for lateral epicondylitis can be done by open surgery, percutaneous surgery or arthroscopic surgery, with no high-quality evidence that any particular type is better or worse than another. Side effects include infection, damage to nerves and inability to straighten the arm. A review of the evidence related to surgery found that published studies were of low quality and did not show that surgery was any more effective than other treatments. A subsequent research trial showed that surgery was no more effective than sham surgery, where patients only received a skin incision, although the trial was limited by a small number of patients.
Prognosis
Response to initial therapy is common, but so is relapse (25% to 50%) and/or prolonged, moderate discomfort (40%).Depending upon severity and quantity of multiple tendon injuries that have built up, the extensor carpi radialis brevis may not be fully healed by conservative treatment. Nirschl defines four stages of lateral epicondylitis, showing the introduction of permanent damage beginning at Stage 2.
Inflammatory changes that are reversible
Nonreversible pathologic changes to origin of the extensor carpi radialis brevis muscle
Rupture of ECRB muscle origin
Secondary changes such as fibrosis or calcification.
Epidemiology
In tennis players, about 39.7% have reported current or previous problems with their elbow. Less than one quarter (24%) of these athletes under the age of 50 reported that the tennis elbow symptoms were "severe" and "disabling," while 42% over the age of 50 did. More women (36%) than men (24%) considered their symptoms severe and disabling. Tennis elbow is more prevalent in individuals over 40, where there is about a four-fold increase among men and two-fold increase among women. Tennis elbow equally affects both sexes and, although men have a marginally higher overall prevalence rate as compared to women, this is not consistent within each age group, nor is it a statistically significant difference.Playing time is a significant factor in tennis elbow occurrence, with increased incidence with increased playing time being greater for respondents under 40. Individuals over 40 who played over two hours doubled their chance of injury. Those under 40 increased it 3.5 fold compared to those who played less than two hours per day.
History
German physician F. Runge is usually credited for the first description of the condition, calling it "writers cramp" (Schreibekrampf) in 1873. Later, it was called "washer womens elbow". British surgeon Henry Morris published an article in The Lancet describing "lawn tennis arm" in 1883. The popular term "tennis elbow" first appeared the same year in a paper by H. P. Major, described as "lawn-tennis elbow".
See also
Olecranon bursitis
Radial tunnel syndrome
Repetitive strain injury
References
External links
Wilson JJ, Best TM (September 2005). "Common overuse tendon problems: A review and recommendations for treatment". American Family Physician. 72 (5): 811–818. PMID 16156339. Archived from the original on 2007-09-29. Retrieved 2006-03-11. |
Sleep-related hypermotor epilepsy | Sleep-related hypermotor epilepsy (SHE), previously known as nocturnal frontal lobe epilepsy, is a form of focal epilepsy characterized by seizures which arise during sleep. The seizures are most typically characterized by complex motor behaviors. It is a relatively uncommon form of epilepsy that constitutes approximately 9-13% of cases. This disorder is associated with cognitive impairment in at least half of patients as well as excessive daytime sleepiness due to poor sleep quality. This disorder is sometimes misdiagnosed as a non-epileptic sleep disorder. There are many potential causes of SHE including genetic, acquired injuries and structural abnormalities.
History
In 1981, Lugaresi and Cirignotta described a group of 5 patients with paroxysmal attacks of violent movements of the extremities and dystonic-tonic posturing. It was initially uncertain whether these events constituted seizures or something else. However, the patients had a good clinical response to the anti-seizure medication carbamazepine. Ultimately, the epileptic nature of this condition was confirmed with EEG and suggested that they were coming from the frontal lobe. The term “nocturnal frontal lobe epilepsy” was suggested as a name for this condition. Later in 2014, a consensus conference recommended that the name be changed to sleep-related hypermotor epilepsy. There were three main justifications for this change: (1) not all seizures arise from the frontal lobe; (2) seizures do not necessarily occur during the night but rather from sleep; (3) hypermotor describes the most common visible clinical manifestation of the seizures.
Symptoms
Seizures in SHE are brief and usually have an abrupt onset and offset. The observable clinical manifestations may consist of rapid, hyperkinetic movements as well as tonic/dystonic posturing of the limbs. Other potential manifestations include brief arousals from sleep or wandering ambulatory behavior. Non-motor manifestations (such as sensory or emotional phenomenon) are common and retained awareness during seizures may occur. Seizures usually occur during non-REM sleep. The frequency of seizures can be very high and as many as dozens may occur every night which results in poor sleep quality. In addition, many patients with SHE suffer from cognitive impairment and have behavioral/psychological problems. There are many risks associated with nocturnal seizures including concussion, suffocation and sudden unexpected death (SUDEP).
Cause
Approximately 86% of SHE cases are sporadic, 14% of patients have a family history of epilepsy and 5% are inherited in an autosomal dominant manner (i.e. autosomal dominant sleep-related hypermotor epilepsy). Both genetic, structural and multifactorial etiologies can occur. In structural cases, the most common pathology is focal cortical dysplasia.The first described mutation in SHE was found in genes coding for the neuronal nicotinic acetylcholine receptor. Since then multiple other genes have been identified including KCNT1, DEPDC5, NPRL2, NPRL3, PRIMA1, CABP4, CRH and others. In some cases, structural and genetic etiologies can coexist such as with mutations in DEPDC5.
Diagnosis
The condition may be difficult to diagnose and misdiagnosis is common. The subject may be unaware they have a seizure disorder. To others, the involuntary movements made during sleep may appear no different from those typical of normal sleep. People who have nocturnal seizures may notice unusual conditions upon awakening in the morning, such as a headache, having wet the bed, having bitten the tongue, a bone or joint injury, muscle strains or weakness, fatigue, or lightheadedness. Others may notice unusual mental behaviors consistent with the aftermath of a seizure. Objects near the bed may have been knocked to the floor, or the subject may be surprised to find themselves on the floor.
Diagnosis is based on clinical history but often EEG and/or polysomnography is required. In many patients the EEG can also be unhelpful as seizures may originate from deep in the brain. Polysomnography can be helpful distinguishing SHE from parasomnias as they often arise from different stages of sleep.
Treatment
Like other forms of epilepsy, SHE can be treated with anti-seizure medications. Adequate control of seizures occur in approximately two-thirds of patients with anti-seizure medications while approximately one-third of patients do not appropriately respond. The relative efficacy of different medications has not been systematically investigated. Historically, low-dose carbamazepine has been the preferred medication for SHE and is often considered to be first-line. Other anti-seizure medications which have been studied for the treatment of SHE and found to have efficacy include: oxcarbazepine, topiramate, lacosamide and perampanel. Epilepsy surgery can be efficacious in refractory patients. In addition, there have been reports of successfully treating SHE due to mutations in CHRNA4 with nicotine patches.
References
Sources
Manford, Mark (2003), Practical Guide to Epilepsy, Butterworth-Heinemann, ISBN 978-0-7506-4621-5 |
Factitious dermatitis | Factitious dermatitis, also known as dermatitis artefacta, is a form of factitious disorder in which patients will intentionally feign symptoms and produce signs of disease in an attempt to assume the patient role. It is also self-inflicted skin damage, most commonly from prolonged deliberate scratching, but sometimes by means of sharp instruments or another agency.: 391 : 61
See also
List of cutaneous conditions
References
== External links == |
Favus | Favus (Latin for "honeycomb") or tinea favosa is the severe form of tinea capitis, a skin infectious disease caused by the dermatophyte fungus Trichophyton schoenleinii. Typically the species affects the scalp, but occasionally occurs as onychomycosis, tinea barbae, or tinea corporis.
The word favid is more used than French word favus, which is close to the Latin etymology.
Presentation
The uncomplicated appearance is that of a number of yellowish, circular, cup-shaped crusts (scutulum or shield) grouped in patches like a honeycomb, each crust about the size of a split pea, with a bundle of hair projecting in the center. These increase in size and become crusted over, so that the characteristic lesion can only be seen round the edge of the scab. A mousy odour is often present. Growth continues to take place for several months, when scab and scutulum go away, leaving a shining bare patch destitute of hair. The disease is essentially chronic, lasting from ten to twenty years. It is caused by the growth of a fungus, and pathologically is the reaction of the tissues to the growth.The fungus was named after a microscopic structure termed "achorion" (a term not used in modern science), seen in scrapings of infected skin, which consists of slender, mycelial threads matted together, bearing oval, nucleated fungal substrate-arthroconidia either free or jointed. This structure is currently called "scutula." The fungus itself is now called Trichophyton schoenleinii.
During initial infection, the fungal spores would appear to enter through the unbroken cutaneous surface, and to germinate mostly in and around the hair follicle and sometimes in the shaft of the hair.
Species
Favus is the first human fungal disease in which a fungus was definitely identified by J. L. Schönlein in 1839. The discovery was published in a brief note of twenty lines in Müllers Archiv for that year (p. 82). In 1841, the Hungary-born French physician David Gruby independently described the fungus associated favus. The fungus was subsequently named by Robert Remak as Achorion schoenleinii in honor of its discoverer.
In 1892, two additional "species" of the fungus were described by Paul Gerson Unna, the Favus griseus, giving rise to greyish-yellow scutula, and the Favus sulphureus celerior, causing sulfur-yellow scutula of a rapid growth. This was in the days before scientists learned to rigorously distinguish microorganism identities from disease identities, and these antique, ambiguous disease-based names no longer have status either in mycology or in dermatology today.
Similar looking infections, sometimes diagnosed as favid but more often as atypical inflammatory tinea, may be caused by more common dermatophyte infections, in particular Microsporum gypseum, the most common soil-borne dermatophyte, and Trichophyton quinckeanum. The latter was previously called Trichophyton mentagrophytes var. quinckeanum, the agent of mouse favus infection.
Treatment
Up until the advent of modern therapies, favus was widespread worldwide; prior to Schönleins recognition of it as a fungal disease, it was frequently confused with Hansens disease, better known as leprosy, and affected Europeans were sometimes committed to leprosaria. Today, due to this species high susceptibility to the antifungal drug griseofulvin, it has been eliminated from most parts of the world except rural central Asia and scattered rural areas of Africa. It is mainly a disease connected to demographic poverty and isolation, but is so readily treatable that it is among the diseases most likely to be eliminated by modern medicine.
References
This article incorporates text from a publication now in the public domain: Chisholm, Hugh, ed. (1911). "Favus". Encyclopædia Britannica. Vol. 10 (11th ed.). Cambridge University Press. p. 215.
Kane, J., R.C. Summerbell, L. Sigler, S. Krajden, G. Land. 1997. Laboratory Handbook of Dermatophytes: A clinical guide and laboratory manual of dermatophytes and other filamentous fungi from skin, hair and nails. Star Publishers, Belmont, CA.
Gräser Y, Kuijpers AF, Presber W, De Hoog GS (October 1999). "Molecular taxonomy of Trichophyton mentagrophytes and T. tonsurans". Med. Mycol. 37 (5 Cpages=315–30): 315–30. doi:10.1046/j.1365-280x.1999.00234.x. PMID 10520156.
== External links == |
Multiple carboxylase deficiency | Multiple carboxylase deficiency is a form of metabolic disorder involving failures of carboxylation enzymes.
The deficiency can be in biotinidase or holocarboxylase synthetase.These conditions respond to biotin.Forms include:
Holocarboxylase synthetase deficiency - neonatal;
Biotinidase deficiency - late onset;If left untreated, the symptoms can include feeding problems, decreased body tone, generalized red rash with skin exfoliation and baldness, failure to thrive, seizure, coma, developmental delay, foul smelling urine, lactic acidosis, and high levels of ketones and ammonia in the blood.
References
External links
http://www.pmh.health.wa.gov.au/services/newborn/health_professionals/disorders/mcd_prof.htm |
Macular corneal dystrophy | Macular corneal dystrophy, also known as Fehr corneal dystrophy named for German ophthalmologist Oskar Fehr (1871-1959), is a rare pathological condition affecting the stroma of cornea. The first signs are usually noticed in the first decade of life, and progress afterwards, with opacities developing in the cornea and attacks of pain. The condition was first described by Arthur Groenouw in 1890.
Signs and symptoms
Onset occurs in the first decade, usually between ages 5 and 9. The disorder is progressive, vision changes with ageing from 2nd decade to 3rd visual impairment may seen in 4th and 5th decade severe visual impairment can be seen Minute, gray, punctate opacities develop. Corneal sensitivity is usually reduced. Painful attacks with photophobia, foreign body sensations, and recurrent erosions occur in most patients. Macular corneal dystrophy is very common in Iceland and accounts for almost one-third of all corneal grafts performed there.
Genetics
Macular corneal dystrophy is inherited in autosomal recessive fashion and is thought to be caused by the lack or abnormal configuration of keratan sulfate. Most cases of MCD are caused by mutations in CHST6 gene.The gene CHST6 is a carbohydrate sulfotransferase encoding an enzyme designated corneal N-acetylglucosamine-6-sulfotransferase. In MCD type I, various mutations lead to inactivation of the enzyme, in MCD type II, inactivation is caused by large deletions and/or replacements in the gene.
Diagnosis
Treatment
Corneal transplantation is often required.
See also
Corneal dystrophy
References
== External links == |
Septal panniculitis | Septal panniculitis is a condition of the subcutaneous fat affecting the layer of adipose tissue that lies between the dermis and underlying fascia, of which there are two forms: acute erythema nodosum and chronic erythema nodosum.: 487–9
See also
Erythema nodosum
List of cutaneous conditions
Panniculitis
Skin lesion
== References == |
Gauchers disease | Gauchers disease or Gaucher disease () (GD) is a genetic disorder in which glucocerebroside (a sphingolipid, also known as glucosylceramide) accumulates in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low blood platelet count and enlargement of the liver and spleen, and is caused by a hereditary deficiency of the enzyme glucocerebrosidase (also known as glucosylceramidase), which acts on glucocerebroside. When the enzyme is defective, glucocerebroside accumulates, particularly in white blood cells and especially in macrophages (mononuclear leukocytes). Glucocerebroside can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow.
Manifestations may include enlarged spleen and liver, liver malfunction, skeletal disorders or bone lesions that may be painful, severe neurological complications, swelling of lymph nodes and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood platelet count, and yellow fatty deposits on the white of the eye (sclera). Persons seriously affected may also be more susceptible to infection. Some forms of Gauchers disease may be treated with enzyme replacement therapy.
The disease is caused by a recessive mutation in the GBA gene located on chromosome 1 and affects both males and females. About one in 100 people in the United States are carriers of the most common type of Gaucher disease. The carrier rate among Ashkenazi Jews is 8.9% while the birth incidence is one in 450.Gauchers disease is the most common of the lysosomal storage diseases. It is a form of sphingolipidosis (a subgroup of lysosomal storage diseases), as it involves dysfunctional metabolism of sphingolipids.The disease is named after the French physician Philippe Gaucher, who originally described it in 1882.
Signs and symptoms
Painless hepatomegaly and splenomegaly: the size of the spleen can be 1500–3000 g, as opposed to the normal size of 50–200 g. Splenomegaly may decrease the affected individuals capacity for eating by exerting pressure on the stomach. While painless, enlargement of spleen increases the risk of splenic rupture.
Hypersplenism and pancytopenia, the rapid and premature destruction of blood cells, leads to anemia, neutropenia, leukopenia, and thrombocytopenia (with an increased risk of infection and bleeding).
Cirrhosis of the liver is rare.
Severe pain associated with joints and bones occurs, frequently presenting in hips and knees.
Neurological symptoms occur only in some types of Gauchers (see below):
Type I: impaired olfaction and cognition
Type II: serious convulsions, hypertonia, intellectual disability, and apnea
Type III: muscle twitches known as myoclonus, convulsions, dementia, and ocular muscle apraxia
Parkinsons disease is recognized as being more common in Gauchers disease patients and their heterozygous carrier relatives.
Osteoporosis: 75% of patients develop visible bony abnormalities due to the accumulated glucosylceramide. A deformity of the distal femur in the shape of an Erlenmeyer flask is commonly described.
Yellowish-brown skin pigmentation
Genetics
The three types of Gauchers disease are autosomal recessive. Both parents must be carriers for a child to be affected. If both parents are carriers, the chance of the disease is one in four, or 25%, with each pregnancy for an affected child. Genetic counseling and genetic testing are recommended for families who may be carriers of mutations.Each type has been linked to particular mutations. In all, about 80 known GBA gene mutations are grouped into three main types:
Type I (N370S homozygote), the most common, also called the "non-neuropathic" type occurs mainly in Ashkenazi Jews, at 100 times the occurrence in the general populace. The median age at diagnosis is 28 years of age, and life expectancy is mildly decreased.
Type II (one or two alleles L444P) is characterized by neurological problems in small children. The enzyme is hardly released into the lysosomes. Prognosis is poor: most die before the age of three.
Type III (also one or two copies of L444P, possibly delayed by protective polymorphisms) occurs in Swedish patients from the Norrbotten region. This group develops the disease somewhat later, but most die before their 30th birthday.The Gaucher-causing mutations may have entered the Ashkenazi Jewish gene pool in the early Middle Ages (48–55 generations ago).
Pathophysiology
The disease is caused by a defect in the housekeeping gene for lysosomal glucocerebrosidase (also known as beta-glucosidase, EC 3.2.1.45, PDB: 1OGS) on the first chromosome (1q22). The enzyme is a 55.6-kilodalton, 497-amino acid-long protein that catalyses the breakdown of glucocerebroside, a cell membrane constituent of red and white blood cells. In Gaucher disease, the enzyme is unable to function correctly and glucocerebroside accumulates. The macrophages that clear these cells are unable to eliminate the waste product, which accumulates in fibrils, and turn into Gaucher cells, which appear on light microscopy to resemble crumpled-up paper.The exact mechanism of neurotoxicity is not understood, but it is thought to involve a reaction to glucosylsphingosine.Different mutations in the GBA (beta-glucosidase) gene determine the remaining activity of the enzyme. In type I, there is some residual activity of the enzyme, accounting for the lack of neuropathology in this type. Although there is some correlation between genotype and phenotype, neither the amount of stored lipids, nor the residual enzyme activity correlates well with disease symptoms. This circumstance has called for alternative explanations accounting for disease symptoms including
jamming of the endo/lysosomal system
ER stress
altered lipid composition of membranes throughout the cell, including the plasma membrane, and consequent changes in the dynamic and signaling properties of the cell membrane
inflammation caused by cytokine secretion as a result of sphingolipid accumulation, and neurodegeneration caused by the accumulation of glucosylsphingosine, a neurotoxinHeterozygotes for particular acid beta-glucosidase mutations carry about a five-fold risk of developing Parkinsons disease, making this the most common known genetic risk factor for Parkinsons.Cancer risk may be increased, particularly myeloma. This is thought to be due to accumulation of glucosylceramide and complex glycosphingolipids.The role of inflammatory processes in Gaucher disease is poorly elucidated. However, sphingolipids are known to participate in inflammation and apoptosis, and markers of macrophage activation are elevated in people with Gaucher disease. These markers include angiotensin-converting enzyme, cathepsin S, chitotriosidase, and CCL18 in the blood plasma; and tumor necrosis factor alpha in splenic Gaucher cells (engorged macrophages).
Diagnosis
Gaucher disease is suggested based on the overall clinical picture. Initial laboratory testing may include enzyme testing. As a result, lower than 15% of mean normal activity is considered to be diagnostic. Decreased enzyme levels will often be confirmed by genetic testing. Numerous different mutations occur; sequencing of the beta-glucosidase gene is sometimes necessary to confirm the diagnosis. Prenatal diagnosis is available and is useful when a known genetic risk factor is present.A diagnosis can also be implied by biochemical abnormalities such as high alkaline phosphatase, angiotensin-converting enzyme, and immunoglobulin levels, or by cell analysis showing "crinkled paper" cytoplasm and glycolipid-laden macrophages.Some lysosomal enzymes are elevated, including tartrate-resistant acid phosphatase, hexosaminidase, and a human chitinase, chitotriosidase. This latter enzyme has proved to be very useful for monitoring Gauchers disease activity in response to treatment, and may reflect the severity of the disease
Classification
Gauchers disease (GD) has three common clinical subtypes. These subtypes have come under some criticism for not taking account of the full spectrum of observable symptoms (the phenotypes). Also, compound heterozygous variations occur which considerably increase the complexity of predicting disease course.
GD type I (non-neuropathic) is the most common and least severe form of the disease. Symptoms may begin early in life or in adulthood and mainly affect the liver, spleen, and bone. Enlarged liver and grossly enlarged spleen (together hepatosplenomegaly) are common; the spleen can rupture and cause additional complications. Skeletal weakness and bone disease may be extensive. Spleen enlargement and bone marrow replacement cause anemia, thrombocytopenia, and leukopenia. The brain and nervous system are not affected pathologically, but lung and, rarely, kidney impairment may occur. Patients in this group usually bruise easily (due to low levels of platelets) and experience fatigue due to low numbers of red blood cells. Depending on disease onset and severity, type I patients may live well into adulthood. The range and severity of symptoms can vary dramatically between patients.GD type II (acute infantile neuropathic) typically begins within 6 months of birth and has an incidence rate around one 1 in 100,000 live births. Symptoms include an enlarged liver and spleen, extensive and progressive brain damage, eye movement disorders, spasticity, seizures, limb rigidity, and a poor ability to suck and swallow. Affected children usually die by age two.
GD type III (chronic neuropathic) can begin at any time in childhood or even in adulthood, and occurs in about one in 100,000 live births. It is characterized by slowly progressive, but milder neurologic symptoms compared to the acute or type II version. Major symptoms include an enlarged spleen and/or liver, seizures, poor coordination, skeletal irregularities, eye movement disorders, blood disorders including anemia, and respiratory problems. Patients often live into their early teen years and adulthood.
Treatment
For those with type-I and most type-III, enzyme replacement treatment with intravenous recombinant glucocerebrosidase can decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations. This treatment costs about US$200,000 annually for a single person and should be continued for life. The rarity of the disease means dose-finding studies have been difficult to conduct, so controversy remains over the optimal dose and dosing frequency. Due to the low incidence, this has become an orphan drug in many countries, meaning a government recognizes and accommodates the financial constraints that limit research into drugs that address a small population.The first drug for Gauchers was alglucerase (Ceredase), which was a version of glucocerebrosidase that was harvested from human placental tissue and then modified with enzymes. It was approved by the FDA in 1991 and has been withdrawn from the market due to the approval of similar drugs made with recombinant DNA technology instead of being harvested from tissue; drugs made recombinantly are preferable, since there is no concern about diseases being transmitted from the tissue used in harvesting, there are fewer risks of variations in enzyme structure from batch to batch, and they are less expensive to manufacture.Available recombinant glucocerebrosidases are:
Imiglucerase (approved in 1995)
Velaglucerase (approved in 2010)
Taliglucerase alfa (Elelyso) (approved in 2012)Miglustat is a small molecule, orally available drug that was first approved for Gauchers Disease in Europe in 2002. It works by preventing the formation of glucocerebroside, the substance that builds up and causes harm in Gauchers. This approach is called substrate reduction therapy.Eliglustat (Cerdelga) (approved in 2014) is also a small molecule. The compound is believed to work by inhibition of glucosylceramide synthase.
Epidemiology
The National Gaucher Foundation (United States) states the incidence of Gauchers disease is about one in 20,000 live births. Around one in 100 people in the general US population is a carrier for type I Gauchers disease, giving a prevalence of one in 40,000. Among Ashkenazi Jews, the rate of carriers is considerably higher, at roughly one in 15.Type II Gauchers disease shows no particular preference for any ethnic group.Type III Gauchers disease is especially common in the population of the northern Swedish region of Norrbotten, where the incidence of the disease is one in 50,000.
History
The disease was first recognized by the French doctor Philippe Gaucher, who originally described it in 1882 and lent his name to the condition. In 1902, its mode of inheritance was discovered by Nathan Brill. The neuronal damage associated with the disease was discovered in the 1920s, and the biochemical basis for the disease was elucidated in the 1960s by Roscoe Brady. The first effective treatment for the disease, the drug alglucerase (Ceredase), was approved by the FDA in April 1991. An improved drug, imiglucerase (Cerezyme), was approved by the FDA in May 1994 and has replaced the use of Ceredase.
October is National Gauchers Disease Awareness Month in the United States.
Prominent people with disease
Wallace Chapman; New Zealand radio and television personality
Anne Begg; Scottish politician
Adam Rose; American Actor
Gallery
See also
References
External links
Gaucher Disease at NINDS |
Chorioangioma | Chorioangioma, or chorangioma, is a benign tumor of placenta. It is a hamartoma-like growth in the placenta consisting of blood vessels, and is seen in approximately 0.5 to 1% pregnancies. It is mostly diagnosed ultrasonically in the second trimester of pregnancy. Large chorioangiomas are known to cause complications in pregnancy, while the smaller ones are asymptomatic.
Presentation
Most chorangiomas are not clinically significant, i.e. they do not have an adverse effect on placental function.
Complications
Large (greater than 4 or 5 cm.) or multiple chorioangiomas may lead to complication. The complications are polyhydramnios, preterm labour, hemolytic anemia, fetal cardiomegaly, fetal thrombocytopenia, intrauterine growth retardation, preeclampsia, abruption of placenta and congenital anomalies.
Pathogenesis
The origin of chorioangioma is from primitive chorionic mesenchyme. It develops when the blood vessels and stroma undergo rapid proliferation independent of the surrounding tissue. Based on histological features, chorioangioma is classified by Marchetti into three types:
Cellular type : This type is immature and contains mostly cellular elements packed compactly.
Angiomatous (vascular) type : This is the most common type of choriocarcinoma. It is distinguished by the presence of numerous small blood vessels.
Degenerative type : This is the mature type with degenerative changes.Each type is believed to represent a phase of tumor development. Chorioangioma has no malignant potential.
Diagnosis
Most chorioangiomas are asymptomatic. They are generally picked up in second trimester scan. Chorioangioma is seen as a hypo- or hyperechoic circumscribed mass that is distinct from the placenta at gray-scale US examination. Large lesions may contain fibrous septa. It is seen protruding into the amniotic cavity near the insertion of the cord. Doppler examination shows anechoic cystic areas, with pulsatile flow in spectral analysis. Some chorioangiomas may be solid masses, and may not be identifiable in gray-scale imaging. Therefore, the investigation of choice is Colour Doppler, which also distinguishes it from placental hematoma.They can also be detected with MRI.Histologically, chorioangiomas consist of abundant vascular channels and may be cellular.
Management
Expectant management is recommended for chorioangioma as majority of them are asymptomatic. Large tumors are monitored with ultrasonogram every 1–2 weeks. In case of maternal or foetal complications, possible interventions are serial foetal transfusions, fetoscopic laser coagulation of vessels supplying the tumor, endoscopic surgical devascularization and chemosclerosis using absolute alcohol.
Prognosis
Large chorioangiomas with decreased echogenicity, decreased tumor volume and decreased blood flow in colour doppler images are may undergo spontaneous infarction. When chorioangiomas have deceased blood flow, fetal hemodynamics and clinical outcome are found to be improved.
Epidemiology
It is the most common tumor of the placenta. Chorioangiomas over the size of 5 cm in diameter are rare, and occur at a rate of 1:3500 to 1:16,000 births. Smaller chorioangiomas are more frequent, with an incidence of 14‑139:10,000 births. However, many small chorioangiomas may not be sonologically visible and hence go unreported. In a clinical study, more than half of all tumors were discovered only by histological techniques.
History
Chorioangioma was first described by Clarke in 1798.
See also
Hemangioma
Chorangiosis
References
External links
Chorangioma (pathweb.uchc.edu)
Chorangioma (humpath.com) |
Factor I deficiency | Factor I deficiency, also known as fibrinogen deficiency, is a rare inherited bleeding disorder related to fibrinogen function in the blood coagulation cascade. It is typically subclassified into four distinct fibrinogen disorders: afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia.
Afibrinogenemia is defined as a lack of fibrinogen in the blood, clinically <20 mg/deciliter of plasma. The frequency of this disorder is estimated at between 0.5 and 2 per million. Within the United States, afibrinogenemia accounts for 24% of all inherited abnormalities of fibrinogen, while hypofibrinogenemia and dysfibrinogenemia account for 38% each.
Congenital hypofibrinogenemia is defined as a partial deficiency of fibrinogen, clinically 20–80/deciliter of plasma. Estimated frequency varies from <0.5 to 3 per million.
Dysfibrinogenemia is defined as malfunctioning or non-functioning fibrinogen in the blood, albeit at normal concentrations: 200–400 mg/deciliter of plasma. Dysfibrinogenemia may be an inherited disease and therefore termed congenital dysfibrinogenemia or secondary to another disease and therefore termed acquired dysfibrinogenemia. The congenital disorder is estimated to a frequency varying between 1 and 3 per million.
Hypodysfibrinogenemia is a partial deficiency of fibrinogen that is also malfunctioning. Hypodysfibrinogenemia is an extremely rare inherited disease.Clinically, these disorders are generally associated with an increased diathesis, i.e. propensity, to develop spontaneous bleeding episodes and excessive bleeding after even minor tissue injuries and surgeries; however, individuals with any of these disorders may also exhibit a propensity to pathological thrombosis episodes.Treatment of these disorders generally involves specialized centers and the establishment of preventive measures designed based on each individuals personal and family histories of the frequency and severity of previous bleeding and thrombosis episodes, and, in a select few cases, the predicted propensity of the genetic mutations which underlie their disorders to cause bleeding and thrombosis.
Signs and symptoms
Afibrinogenemia is typically the most severe of the three disorders. Common symptoms include bleeding of the umbilical cord at birth, traumatic and surgical bleeding, GI tract, oral and mucosal bleeding, spontaneous splenic rupture, and rarely intracranial hemorrhage and articular bleeding.
Symptoms of hypofibrinogenemia varies from mild to severe, but can include bleeding of the GI tract, oral and mucosal bleeding, and very rarely intracranial bleeding. More commonly it presents during traumatic bleeding or surgical procedures. Most cases (60%) of dysfibrinogenemia are asymptomatic, but 28% exhibit hemorrhaging similar to that described above while 20% exhibit thrombosis (i.e. excessive clotting).
Causes
The disorders associated with Factor I deficiency are generally inherited, although certain liver diseases can also affect fibrinogen levels and function (e.g. cirrhosis). Afibrinogenemia is a recessive inherited disorder, where both parents must be carriers. Hypofibrinogenemia and dysfibrinogenemia can be dominant (i.e. only one parent needs to be a carrier) or recessive. The origin of the disorders is traced back to three possible genes: FGA, FGB, or FGG. Because all three are involved in forming the hexameric glycoprotein fibrinogen, mutations in any one of the three genes can cause the deficiency.
Diagnosis
Treatment
The most common type of treatment is cryoprecipitate or fibrinogen concentrate drip to increase fibrinogen levels to normal during surgical procedures or after trauma. RiaSTAP, a factor I concentrate, was approved by the U.S. FDA in 2009 for use when the fibrinogen level was below 50 mg/deciliter of plasma. Recently, antifibrinolytics have also been used to inhibit fibrinolysis (breaking down of the fibrin clot). In the case of dysfibrinogenemia that manifests by thrombosis, anticoagulants can be used. Due to the inhibited clotting ability associated with a- and hypofibrinogenemia, physicians advise against the use of Aspirin as it inhibits platelet function.
See also
Congenital afibrinogenemia
Hypodysfibrinogenemia
References
== External links == |
Uterine inversion | Uterine inversion is when the uterus turns inside out, usually following childbirth. Symptoms include postpartum bleeding, abdominal pain, a mass in the vagina, and low blood pressure. Rarely inversion may occur not in association with pregnancy.Risk factors include pulling on the umbilical cord or pushing on the top of the uterus before the placenta has detached. Other risk factors include uterine atony, placenta previa, and connective tissue disorders. Diagnosis is by seeing the inside of the uterus either in or coming out of the vagina.Treatment involves standard resuscitation together with replacing the uterus as rapidly as possible. If efforts at manual replacement are not successful surgery is required. After the uterus is replaced oxytocin and antibiotics are typically recommended. The placenta can then be removed if it is still attached.Uterine inversion occurs in about 1 in 2,000 to 1 in 10,000 deliveries. Rates are higher in the developing world. The risk of death of the mother is about 15% while historically it has been as high as 80%. The condition has been described since at least 300 BC by Hippocrates.
Signs and symptoms
Uterine inversion is often associated with significant postpartum bleeding. Traditionally it was thought that it presented with haemodynamic shock "out of proportion" with blood loss, however blood loss has often been underestimated. The parasympathetic effect of traction on the uterine ligaments may cause bradycardia.
Causes
The most common cause is the mismanagement of 3rd stage of labor, such as:
Fundal pressure
Excess cord traction during the 3rd stage of laborOther natural causes can be:
Uterine weakness, congenital or not
Precipitate delivery
Short umbilical cordIt is more common in multiple gestation than in singleton pregnancies.
Associations
Placenta praevia
Fundal Placental Implantation
Use of Magnesium Sulfate
Vigorous fundal pressure
Repeated cord traction
short umbilical cord
Types
One: Complete. Visible outside the cervix.
Two: Incomplete. Visible only at the cervix.
Treatment
Treatment involves standard resuscitation together with replacing the uterus as rapidly as possible. If efforts at manual replacement are not successful surgery is required. After the uterus is replaced oxytocin and antibiotics are typically recommended. The placenta can then be removed if it is still attached.
Epidemiology
Uterine inversion occurs in about 1 in 2,000 to 1 in 10,000 deliveries. Rates are higher in the developing world.
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Subsets and Splits