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Juvenile myelomonocytic leukemia | Juvenile myelomonocytic leukemia (JMML) is a serious chronic leukemia (cancer of the blood) that affects children mostly aged 4 and younger. The name JMML now encompasses all diagnoses formerly referred to as juvenile chronic myeloid leukemia (JCML), chronic myelomonocytic leukemia of infancy, and infantile monosomy 7 syndrome. The average age of patients at diagnosis is 2 years old. The World Health Organization has included JMML in the category of myelodysplastic and myeloproliferative disorders.
Signs and symptoms
The following symptoms are typical ones which lead to testing for JMML, though children with JMML may exhibit any combination of them: pallor, fever, infection, bleeding, cough, poor weight gain, a maculopapular rash (discolored but not raised, or small and raised but not containing pus), lymphadenopathy (enlarged lymph nodes), moderate hepatomegaly (enlarged liver), marked splenomegaly (enlarged spleen), leukocytosis (high white blood cell count in blood), absolute monocytosis (high monocyte count in blood), anemia (low red blood cell count in blood), and thrombocytopenia (low platelet count in blood). Most of these conditions are common, nonspecific signs and symptoms.
Children with JMML and neurofibromatosis 1 (NF1) (about 14% of children with JMML are also clinically diagnosed with NF1, though up to 30% carry the NF1 gene mutation) may also exhibit any of the following symptoms associated with NF1 (in general, only young children with NF1 are at an increased risk of developing JMML):
6 or more café-au-lait (flat, coffee-colored) spots on the skin
2 or more neurofibromas (pea-size bumps that are noncancerous tumors) on or under the skin
Plexiform neurofibromas (larger areas on skin that appear swollen)
Optic glioma (a tumor on the optic nerve that affects vision)
Freckles under the arms or in the groin
2 or more Lisch nodules (tiny tan or brown-colored spots on the iris of the eye)
Various bone deformations including bowing of the legs below the knee, scoliosis, or thinning of the shin boneNoonan syndrome (NS) may predispose to the development of JMML or a myeloproliferative disorder (MPD) associated with NS (MPD/NS) which resembles JMML in the first weeks of life. However, MPD/NS may resolve without treatment. Children with JMML and Noonans syndrome may also exhibit any of the following most-common symptoms associated with Noonans syndrome:
Congenital heart defects, in particular, pulmonic stenosis (a narrowing of the valve from the heart to the lungs)
Undescended testicles in males
Excess skin and low hair line on back of neck
Widely set eyes
Diamond-shaped eyebrows
Ears that are low-set, backward-rotated, thick outer rim
Deeply grooved philtrum (upper lip line)
Learning delays
Genetics
About 90% of JMML patients have some sort of genetic abnormality in their leukemia cells that can be identified with laboratory testing. This includes:
15-20% of patients with neurofibromatosis 1 (NF1)
25% of patients with mutations in one of the RAS family of oncogenes (only in their leukemia cells)
Another 35% of patients with a mutation in a gene called PTPN11 (again, only in their leukemia cells).
Diagnosis
The following criteria are required in order to diagnose JMML:All 4 of the following:
No Philadelphia chromosome or BCR/ABL fusion gene.
Peripheral blood monocytosis >1 x 109/L.
Less than 20% blasts (including promonocytes) in the blood and bone marrow (blast count is less than 2% on average)
SplenomegalyAt least one of:
Mutation in RAS or PTPN11
Diagnosis of neurofibromatosis 1
Chromosome 7 monosomyOr two or more of the following criteria:
Hemoglobin F increased for age.
Immature granulocytes and nucleated red cells in the peripheral blood.
White blood cell count >10 x 109/L.
Clonal chromosomal abnormality (e.g., monosomy 7).
Granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity of myeloid progenitors in vitro.These criteria are identified through blood tests and bone marrow tests.
The differential diagnosis list includes infectious diseases like Epstein–Barr virus, cytomegalovirus, human herpesvirus 6, histoplasma, mycobacteria, and toxoplasma, which can produce similar symptoms.
Treatment
There are two internationally accepted treatment protocols, which are geographically based:
North America: the Childrens Oncology Group (COG) JMML study
Europe: the European Working Group for Myelodysplastic Syndromes (EWOG-MDS) JMML studyThe following procedures are used in one or both of the current clinical approaches listed above:
Splenectomy
The theory behind splenectomy in JMML is that the spleen may trap leukemic cells, leading to the spleens enlargement, by harboring dormant JMML cells that are not eradicated by radiation therapy or chemotherapy for the active leukemia cells, thus leading to later relapse if the spleen is not removed. However, the impact of splenectomy on post-transplant relapse, though, is unknown. The COG JMML study includes splenectomy as a standard component of treatment for all clinically stable patients. The EWOG-MDS JMML study allows each childs physician to determine whether or not a splenectomy should be done, and large spleens are commonly removed prior to bone marrow transplant. When a splenectomy is scheduled, JMML patients are advised to receive vaccines against Streptococcus pneumoniae and Haemophilus influenza at least 2 weeks prior to the procedure. Following splenectomy, penicillin may be administered daily in order to protect the patient against bacterial infections that the spleen would otherwise have protected against; this daily preventative regimen will often continue indefinitely.
Chemotherapy
The role of chemotherapy or other pharmacologic treatments against JMML before bone marrow transplant has not been studied completely and its importance is still unknown. Chemotherapy by itself has proven unable to bring about long-term survival in JMML.
Low-dose conventional chemotherapy: Studies have shown no influence from low-dose conventional chemotherapy on JMML patients’ length of survival. Some combinations of 6-mercaptopurine with other chemotherapy drugs have produced results such as decrease in organ size and increase or normalization of platelet and leukocyte count.
Intensive chemotherapy: Complete remission with ongoing durability from JMML has not been possible through use of intensive chemotherapy, but it is still used at times because it has improved the condition of a small but significant number of JMML patients who do not display an aggressive disease. The COG JMML study administers 2 cycles of fludarabine and cytarabine for 5 consecutive days along with 13-cis retinoic acid during and afterwards. The EWOG-MDS JMML study, however, does not recommend intensive chemotherapy before bone marrow transplant.
13-cis retinoic acid (Isotretinoin): In the lab, 13-cis-retinoic acid has inhibited the growth of JMML cells. The COG JMML study therefore includes 13-cis-retinoic acid in its treatment protocol, though its therapeutic value for JMML remains controversial.
Radiation
Radiation to the spleen does not generally result in a decrease in spleen size or reduction of platelet transfusion requirement.
Stem cell transplantation
The only treatment that has resulted in cures for JMML is stem cell transplantation, also known as a bone marrow transplant, with about a 50% survival rate. The risk of relapsing after transplant is high, and has been recorded as high as 50%. Generally, JMML clinical researchers recommend that a patient have a bone marrow transplant scheduled as soon as possible after diagnosis. A younger age at bone marrow transplant appears to predict a better outcome.
Donor: Transplants from a matched family donor (MFD), matched unrelated donor (MUD), and matched unrelated umbilical cord blood donors have all shown similar relapse rates, though transplant-related deaths are higher with MUDs and mostly due to infectious causes. Extra medicinal protection, therefore, is usually given to recipients of MUD transplants to protect the child from Graft Versus Host Disease (GVHD). JMML patients are justified for MUD transplants if no MFD is available due to the low rate of survival without a bone marrow transplant.
Conditioning regimen: The COG JMML study involves 8 rounds of total-body irradiation (TBI) and doses of cyclophosphamide to prepare the JMML childs body for bone marrow transplant. Use of TBI is controversial, though, because of the possibility of late side-effects such as slower growth, sterility, learning disabilities, and secondary cancers, and the fact that radiation can have devastating effects on very young children. It is used in this study, however, due to the concern that chemotherapy alone might not be enough to kill dormant JMML cells. The EWOG-MDS JMML Study includes busulfan in place of TBI due to its own research findings that appeared to show that busulfan was more effective against leukemia in JMML than TBI. The EWOG-MDS study also involves cyclophosphamide and melphalan in its conditioning regimen.
Post transplant management: patients can experience relapse, causing treatment failure. It can be prevented by starting the patient with withdrawal of immunosuppressants and/or begin donor lymphocyte infusion.
Graft versus leukemia: Graft versus leukemia has been shown many times to play an important role in curing JMML, and it is usually evidenced in a child after bone marrow transplant through some amount of acute or chronic Graft Versus Host Disease (GVHD). Evidence of either acute or chronic GVHD is linked to a lower relapse rate in JMML. Careful management of immunosuppressant drugs for control of GVHD is essential in JMML; importantly, children who receive less of this prophylaxis have a lower relapse rate. After bone marrow transplant, reducing ongoing immunosuppressive therapy has worked successfully to reverse the course of a bone marrow with a dropping donor percentage and to prevent a relapse. Donor lymphocyte infusion (DLI), on the other hand, does not frequently work to bring children with JMML back into remission.
Prognosis
Prognosis refers to how well a patient is expected to respond to treatment based on their individual characteristics at time of diagnosis. In JMML, three characteristic areas have been identified as significant in the prognosis of patients:
Without treatment, the survival [5 years?] of children with JMML is approximately 5%. Only Hematopoietic Stem Cell Transplantation (HSCT), commonly referred to as a bone marrow or (umbilical) cord blood transplant, has been shown to be successful in curing a child of JMML. With HSCT, recent research studies have found the survival rate to be approximately 50%. Relapse is a significant risk after HSCT for children with JMML. It is the greatest cause of death in JMML children who have had stem cell transplants. Relapse rate has been recorded as high as 50%. Many children have been brought into remission after a second stem cell transplant.After bone marrow transplant, the relapse rate for children with JMML may be as high as 50%. Relapse often occurs within a few months after transplant and the risk of relapse drops considerably at the one-year point after transplant. A significant number of JMML patients do achieve complete remission and long-term cure after a second bone marrow transplant, so this additional therapy should always be considered for children who relapse.
Frequency
JMML accounts for 1–2% of childhood leukemias each year; in the United States, an estimated 25-50 new cases are diagnosed each year, which also equates to about 3 cases per million children. There is no known environmental cause for JMML. Since about 10% of patients are diagnosed before 3 months of age, it is thought that JMML is a congenital condition in these infants
History
Juvenile myelomonocytic leukemia (JMML) is a myelodysplastic and myeloproliferative disorder. The diagnostic criteria were originally laid down by Neimeyer et al. in 1997 and 1998 and were incorporated in the WHO classification in 2008.
See also
List of cutaneous conditions
Hematologic disease
List of cancer types
References
== External links == |
Slipped capital femoral epiphysis | Slipped capital femoral epiphysis (SCFE or skiffy, slipped upper femoral epiphysis, SUFE or souffy, coxa vara adolescentium) is a medical term referring to a fracture through the growth plate (physis), which results in slippage of the overlying end of the femur (metaphysis).
Normally, the head of the femur, called the capital, should sit squarely on the femoral neck. Abnormal movement along the growth plate results in the slip. The term slipped capital femoral epiphysis is actually a misnomer, because the epiphysis (end part of a bone) remains in its normal anatomical position in the acetabulum (hip socket) due to the ligamentum teres femoris. It is actually the metaphysis (neck part of a bone) which slips in an anterior direction with external rotation.
SCFE is the most common hip disorder in adolescence. SCFEs usually cause groin pain on the affected side, but sometimes cause knee or thigh pain. One in five cases involves both hips, resulting in pain on both sides of the body. SCFEs occurs slightly more commonly in adolescent males, especially young black males, although it also affects females. Whilst it can occur in any child, the major risk factor is childhood obesity. Symptoms include the gradual, progressive onset of thigh or knee pain with a painful limp. Hip motion will be limited, particularly internal rotation. Running, and other strenuous activity on legs, will also cause the hips to abnormally move due to the condition and can potentially worsen the pain. Stretching is very limited.
Signs and symptoms
Usually, a SCFE causes groin pain, but it may cause pain in only the thigh or knee, because the pain may be referred along the distribution of the obturator nerve. The pain may occur on both sides of the body (bilaterally), as up to 40 percent of cases involve slippage on both sides. In cases of bilateral SCFEs, they typically occur within one year of each other. About 20 percent of all cases include a SCFE on both sides at the time of presentation.Signs of a SCFE include a waddling gait, decreased range of motion. Often the range of motion in the hip is restricted in internal rotation, abduction, and flexion. A person with a SCFE may prefer to hold their hip in flexion and external rotation.
Complications
Failure to treat a SCFE may lead to: death of bone tissue in the femoral head (avascular necrosis), degenerative hip disease (hip osteoarthritis), gait abnormalities and chronic pain. SCFE is associated with a greater risk of arthritis of the hip joint later in life. 17–47 percent of acute cases of SCFE lead to the death of bone tissue (osteonecrosis) effects.
Cause
In general, SCFE is caused by increased force applied across the epiphysis, or a decrease in the resistance within the physis to shearing. Obesity is the by far the most significant risk factor. A study in Scotland looked at the weight of 600,000 infants, and followed them up to see who got SCFE. This study identified that obese children had an almost twenty times greater risk than thin children, with a dose-response- so the greater the weight of the child, the greater the risk of SCFE. In 65 percent of cases of SCFE, the person is over the 95th percentile for weight. Endocrine diseases may also contribute (though are far less of a risk than obesity), such as hypothyroidism, hypopituitarism, and renal osteodystrophy.Sometimes no single cause accounts for SCFE, and several factors play a role in the development of a SCFE i.e. both mechanical and endocrine (hormone-related) factors. Skeletal changes may also make someone at risk of SCFE, including femoral or acetabular retroversion, those these may simply be chronic skeletal manifestations of childhood obesity.
Pathophysiology
SCFE is a Salter-Harris type 1 fracture through the proximal femoral physis. Stress around the hip causes a shear force to be applied at the growth plate. While trauma has a role in the manifestation of the fracture, an intrinsic weakness in the physeal cartilage also is present. The almost exclusive incidence of SCFE during the adolescent growth spurt indicates a hormonal role. Obesity is another key predisposing factor in the development of SCFE.The fracture occurs at the hypertrophic zone of the physeal cartilage. Stress on the hip causes the epiphysis to move posteriorly and medially. By convention, position and alignment in SCFE is described by referring to the relationship of the proximal fragment (capital femoral epiphysis) to the normal distal fragment (femoral neck). Because the physis has yet to close, the blood supply to the epiphysis still should be derived from the femoral neck; however, this late in childhood, the supply is tenuous and frequently lost after the fracture occurs. Manipulation of the fracture frequently results in osteonecrosis and the acute loss of articular cartilage (chondrolysis) because of the tenuous nature of the blood supply.
Diagnosis
The diagnosis is a combination of clinical suspicion plus radiological investigation. Children with a SCFE experience a decrease in their range of motion, and are often unable to complete hip flexion or fully rotate the hip inward. 20–50% of SCFE are missed or misdiagnosed on their first presentation to a medical facility. SCFEs may be initially overlooked, because the first symptom is knee pain, referred from the hip. The knee is investigated and found to be normal.
The diagnosis requires x-rays of the pelvis, with anteriorposterior (AP) and frog-leg lateral views. The appearance of the head of the femur in relation to the shaft likens that of a "melting ice cream cone", visible with Kleins line. The severity of the disease can be measured using the Southwick angle.
Classification
Atypical/Typical
Loder classification
Stable
Unstable, practically defined as when the patient is unable to ambulate even with crutches
Temporal
Acute
Chronic
Acute-on-chronic
Radiological
Grade I = 0–33% slippage
Grade II = 34–50% slippage
Grade III = >50% slippage
Treatment
The disease can be treated with external in-situ pinning or open reduction and pinning. Consultation with an orthopaedic surgeon is necessary to repair this problem. Pinning the unaffected side prophylactically is not recommended for most patients, but may be appropriate if a second SCFE is very likely.Once SCFE is suspected, the patient should be non-weight bearing and remain on strict bed rest. In severe cases, after enough rest the patient may require physical therapy to regain strength and movement back to the leg. A SCFE is an orthopaedic emergency, as further slippage may result in occlusion of the blood supply and avascular necrosis (risk of 25 percent). Almost all cases require surgery, which usually involves the placement of one or two pins into the femoral head to prevent further slippage. The recommended screw placement is in the center of the epiphysis and perpendicular to the physis. Chances of a slippage occurring in the other hip are 20 percent within 18 months of diagnosis of the first slippage and consequently the opposite unaffected femur may also require pinning.The risk of reducing this fracture includes the disruption of the blood supply to the bone. It has been shown in the past that attempts to correct the slippage by moving the head back into its correct position can cause the bone to die. Therefore the head of the femur is usually pinned as is. A small incision is made in the outer side of the upper thigh and metal pins are placed through the femoral neck and into the head of the femur. A dressing covers the wound.
Epidemiology
SCFE affects approximately 1–10 per 100,000 children. The incidence varies by geographic location, season of the year, and ethnicity. In eastern Japan, the incidence is 0.2 per 100,000 and in the northeastern U.S. it is about 10 per 100,000. Africans and Polynesians have higher rates of SCFE.SCFEs are most common in adolescents 11–15 years of age, and affects boys more frequently than girls (male 2:1 female). It is strongly linked to obesity, and weight loss may decrease the risk. Other risk factors include: family history, endocrine disorders, radiation / chemotherapy, and mild trauma.
The left hip is more often affected than the right. Over half of cases may have involvement on both sides (bilateral).
See also
Legg–Calvé–Perthes syndrome – another cause of avascular necrosis of the femoral head, seen in younger children than SCFE
Hip dysplasia
Drehmann sign – Clinical test examining for SCFE
References
== External links == |
Blastomycosis | Blastomycosis or blasto is a fungal infection caused by inhaling spores of a Blastomyces fungus. Only about half of people with the disease have symptoms, which can include fever, cough, night sweats, muscle pains, weight loss, chest pain, and feeling tired. Symptoms usually develop between three weeks and three months after breathing in the spores. Most blastomycosis infections affect the lungs. In 25 to 40% of cases, the infection also spreads to other parts of the body, such as the skin, bones or central nervous system. Although blastomycosis is especially dangerous for those with weak immune systems, most people diagnosed with blastomycosis have healthy immune systems.Blastomyces dermatitidis is found in the soil and decaying organic matter like wood or leaves. Outdoor activities like hunting or camping in wooded areas increase the risk of developing blastomycosis. There is no vaccine, but the risk of the disease can be reduced by not disturbing the soil. Treatment is typically with an azole drug such as itraconazole for mild or moderate disease. In severe cases, patients are treated with amphotericin B before azole treatment. In either event, the azole treatment lasts for 6–12 months. Overall, 4-6% of people who develop blastomycosis die; however, if the central nervous system is involved, this rises to 18%. People with AIDS or on medications that suppress the immune system have the highest risk of death at 25-40%.Blastomycosis is endemic to the eastern United States and Canada, especially the Ohio and Mississippi River valleys, the Great Lakes, and the St. Lawrence River valley. In these areas, there are about 1 to 2 cases per 100,000 per year. Less frequently, blastomycosis also occurs in Africa, the Middle East, India, and western North America. Blastomycosis also affects a broad range of non-human mammals, and dogs in particular are an order of magnitude more likely to contract the disease than humans. The ecological niche of Blastomyces in the wild is poorly understood, and it is unknown if there are any significant host animals.Blastomycosis has existed for millions of years but was first described by Thomas Caspar Gilchrist in 1894. Because of this, it is sometimes called "Gilchrists disease".
Signs and symptoms
The symptoms of blastomycosis cover a wide range, overlapping with more common conditions; for this reason, blastomycosis has often been called "the great pretender". Many cases are asymptomatic or subclinical. Lung symptoms are common, because the lungs are infected in 79% of blastomycosis cases. However, in 25-40% of cases the disease also disseminates to other organs, including the skin.The extent and severity of symptoms depends in part on a persons immune status; less than 50% of healthy people with blastomycosis have symptoms, while immunocompromised patients are especially likely to have the disease spread beyond the lungs to other organs like the skin and bones.Blastomycosis manifests as a primary lung infection in about 79% of cases. The onset is relatively slow and symptoms are suggestive of bacterial pneumonia, often leading to initial treatment with antibacterials. Because the symptoms are variable and nonspecific, blastomycosis is often not even considered in differential diagnosis until antibacterial treatment has failed, unless there are known risk factors or skin lesions. The disease may be misdiagnosed as a carcinoma, leading in some cases to surgical removal of the affected tissue. Upper lung lobes are involved somewhat more frequently than lower lobes. If untreated, many cases progress over a period of months to years to become disseminated blastomycosis.
Blastomycosis in the lungs may present a variety of symptoms, or no symptoms at all. If symptoms are present they may range from mild pneumonia resembling a pneumococcal infection to acute respiratory distress syndrome (ARDS). Common symptoms include fever, chills, headache, coughing, difficulty breathing, chest pain, and malaise. Without treatment, cases may progress to chronic pneumonia or ARDS.ARDS is an uncommon but dangerous manifestation of blastomycosis. It was seen in 9 of 72 blastomycosis cases studied in northeast Tennessee. Such cases may follow massive exposure, such during brush clearing operations. In the Tennessee study, the fatality rate was 89% in the ARDS cases, but only 10% in the non-ARDS cases.In disseminated blastomycosis, the large Blastomyces yeast cells translocate from the lungs and are trapped in capillary beds elsewhere in the body, where they cause lesions. The skin is the most common organ affected, being the site of lesions in approximately 60% of cases. The signature image of blastomycosis in textbooks is the indolent, verrucous or ulcerated dermal lesion seen in disseminated disease. Osteomyelitis is also common (12–60% of cases). Other recurring sites of dissemination are the genitourinary tract (kidney, prostate, epididymis; collectively ca. 25% of cases) and the brain (3–10% of cases). 40% of immunocompromised individuals have CNS involvement and present as brain abscess, epidural abscess or meningitis.
Blastomycosis in non-lung organs such as the skin may present a very wide range of symptoms, including the following:
skin lesions, which may be verrucous (wart-like) or ulcerated with small pustules at the margins.
bone or joint pain due to bone lytic lesions.
pain when urinating due to prostatitis.
hoarseness due to laryngeal involvement.
headache, confusion or other neurological symptoms caused by central nervous system involvement.
Cause
Blastomycosis is caused by dimorphic fungi in the genus Blastomyces, in the phylum Ascomycota and family Ajellomycetaceae. In eastern North America, the most common cause of blastomycosis is Blastomyces dermatitidis, but Blastomyces gilchristii has been associated with some outbreaks. In western North America, many cases of blastomycosis are caused by Blastomyces helicus, which most commonly attacks immunodeficient people and domestic animals. The species Blastomyces percursus causes many cases of blastomycosis in Africa and the Middle East. In Africa, blastomycosis may also be caused by Blastomyces emzantsi, which is often associated with infections outside the lungs.In endemic areas, Blastomyces dermatitidis lives in soil and rotten wood near lakes and rivers. Although it has never been directly observed growing in nature, it is thought to grow there as a cottony white mold, similar to the growth seen in artificial culture at 25 °C. The moist, acidic soil in the surrounding woodland harbors the fungus.
Pathogenesis
Inhaled conidia of Blastomyces are phagocytosed by neutrophils and macrophages in alveoli. Some of these escape phagocytosis and transform into yeast phase rapidly. Having thick walls, these are resistant to phagocytosis. Once they have transitioned to the yeast phase, the Blastomyces cells express the protein BAD-1, which helps the yeast cells attach to host cells, and also impairs activation of immune cells while inhibiting release of tumor necrosis factor.
In lung tissue, the cells multiply and may also disseminate through blood and lymphatics to other organs, including the skin, bone, genitourinary tract, and brain. The incubation period for pulmonary blastomycosis is 3 to 15 weeks, although 30–50% of infections are asymptomatic.
Diagnosis
Because the symptoms of blastomycosis resemble those of many other conditions, including tuberculosis and lung cancer, diagnosis is often delayed. In 40% of cases, the diagnosis takes more than a month. A rapid diagnosis can however be made based on microscopic examination of sputum samples or samples obtained from a tissue biopsy or bronchoalveolar lavage.Once suspected, the diagnosis of blastomycosis can usually be confirmed by demonstration of the characteristic broad based budding organisms in sputum or tissues by KOH prep, cytology, or histology. Tissue biopsy of skin or other organs may be required in order to diagnose extra-pulmonary disease. Blastomycosis is histologically associated with granulomatous nodules.
Commercially available urine antigen testing appears to be quite sensitive in suggesting the diagnosis in cases where the organism is not readily detected. However, commercial antigen tests have a high degree of cross-reactivity with other endemic fungal conditions such as histoplasmosis, and thus cannot distinguish blastomycosis from other similar conditions. This cross-reactivity is caused by these related fungal organisms using similar galactomannans in the cell wall.While culture of the Blastomyces organism remains the definitive diagnostic standard, its slow growing nature can lead to a delay of up to four weeks. In addition, sometimes blood and sputum cultures may not detect blastomycosis. Cultures of the cerebrospinal fluid also have poor sensitivity compared to histopathological examination of the affected tissue.
Treatment
Under Infectious Disease Society of America guidelines, severe cases of blastomycosis and cases with central nervous system (CNS) involvement are treated initially with amphotericin B, followed by a lengthy course of an azole drug such as itraconazole. In most cases the amphotericin treatment lasts for 1–2 weeks, but in cases of CNS involvement it may last for up to 6 weeks. Cases that do not require amphotericin B treatment are treated with a lengthy course of an azole drug.Among azole drugs, itraconazole is generally the treatment of choice. Voriconazole is often recommended for CNS blastomycosis cases due to its ability to pass the blood-brain barrier. Other azole drugs that may be used include fluconazole. Ketoconazole was the azole drug first used for blastomycosis treatment, but has been largely replaced by itraconazole because ketoconazole is less effective and less tolerated by patients. The azole treatment generally lasts for a minimum of six months. Cure rates from itraconazole treatment are nearly 95%. Relapse is rare but does occur even after a full course of treatment.
Prognosis
Published estimates of the case fatality rate for blastomycosis have varied from 4% to 78%. A 2020 meta-analysis of published studies found an overall mortality rate of 6.6%. This rose to 37% for immunocompromised patients and 75% for patients with ARDS. A 2021 analysis of 20 years of disease surveillance data from the five US states where blastomycosis is reportable found an overall mortality rate of 8% and a hospitalization rate of 57%. These numbers may be affected by the under-reporting of mild cases.
Epidemiology
Incidence in most endemic areas is about 0.5 per 100,000 population, with occasional local areas attaining as high as 12 per 100,000. Most Canadian data fit this picture. In Ontario, Canada, considering both endemic and non-endemic areas, the overall incidence is around 0.3 cases per 100,000; northern Ontario, mostly endemic, has 2.44 per 100,000. Manitoba is calculated at 0.62 cases per 100,000. Remarkably higher incidence was shown for the Kenora, Ontario region: 117 per 100,000 overall, with aboriginal reserve communities experiencing 404.9 per 100,000. In the United States, the incidence of blastomycosis is similarly high in hyperendemic areas. For example, the city of Eagle River, Vilas County, Wisconsin, which has an incidence rate of 101.3 per 100,000; the county as a whole has been shown in two successive studies to have an incidence of about 40 cases per 100,000. An incidence of 277 per 100,000 was roughly calculated based on 9 cases seen in a Wisconsin aboriginal reservation during a time in which extensive excavation was done for new housing construction. The new case rates are greater in northern states such as Wisconsin, where from 1986 to 1995 there were 1.4 cases per 100,000 people.The study of outbreaks as well as trends in individual cases of blastomycosis has clarified a number of important matters. Some of these relate to the ongoing effort to understand the source of infectious inoculum of this species, while others relate to which groups of people are especially likely to become infected. Human blastomycosis is primarily associated with forested areas and open watersheds; It primarily affects otherwise healthy, vigorous people, mostly middle-aged, who acquire the disease while working or undertaking recreational activities in sites conventionally considered clean, healthy and in many cases beautiful. Repeatedly associated activities include hunting, especially raccoon hunting, where accompanying dogs also tend to be affected, as well as working with wood or plant material in forested or riparian areas, involvement in forestry in highly endemic areas, excavation, fishing and possibly gardening and trapping.
Urban infections
There is also a developing profile of urban and other domestic blastomycosis cases, beginning with an outbreak tentatively attributed to construction dust in Westmont, Illinois. The city of Rockford, Illinois, was also documented as a hyperendemic area based on incidence rates as high as 6.67 per 100,000 population for some areas of the city. Though proximity to open watersheds was linked to incidence in some areas, suggesting that outdoor activity within the city may be connected to many cases, there is also an increasing body of evidence that even the interiors of buildings may be risk areas. An early case concerned a prisoner who was confined to prison during the whole of his likely blastomycotic incubation period. An epidemiological survey found that although many patients who contracted blastomycosis had engaged in fishing, hunting, gardening, outdoor work and excavation, the most strongly linked association in patients was living or visiting near waterways. Based on a similar finding in a Louisiana study, it has been suggested that place of residence might be the most important single factor in blastomycosis epidemiology in north central Wisconsin. Follow-up epidemiological and case studies indicated that clusters of cases were often associated with particular domiciles, often spread out over a period of years, and that there were uncommon but regularly occurring cases in which pets kept mostly or entirely indoors, in particular cats, contracted blastomycosis. The occurrence of blastomycosis, then, is an issue strongly linked to housing and domestic circumstances.
Seasonal trends
Seasonality and weather also appear to be linked to contraction of blastomycosis. Many studies have suggested an association between blastomycosis contraction and cool to moderately warm, moist periods of the spring and autumn or, in relatively warm winter areas. However, the entire summer or a known summer exposure date is included in the association in some studies. Occasional studies fail to detect a seasonal link. In terms of weather, both unusually dry weather and unusually moist weather have been cited. The seemingly contradictory data can most likely be reconciled by proposing that B. dermatitidis prospers in its natural habitats in times of moisture and moderate warmth, but that inoculum formed during these periods remains alive for some time and can be released into the air by subsequent dust formation under dry conditions. Indeed, dust per se or construction potentially linked to dust has been associated with several outbreaks The data, then, tend to link blastomycosis to all weather, climate and atmospheric conditions except freezing weather, periods of snow cover, and extended periods of hot, dry summer weather in which soil is not agitated.
Gender bias
Sex is another factor inconstantly linked to contraction of blastomycosis: though many studies show more men than women affected, some show no sex-related bias. As mentioned above, most cases are in middle aged adults, but all age groups are affected, and cases in children are not uncommon.
Ethnic populations
Ethnic group or race is frequently investigated in epidemiological studies of blastomycosis, but is potentially confounded by differences in residence and in quality and accessibility of medical care, factors that have not been stringently controlled for to date. In the United States, some studies show a disproportionately high incidence and/or mortality rate for blastomycosis among Black people.In Canada, some studies, but not others, indicate that First Nations people have a disproportionately high incidence of blastomycosis. Incidence in First Nations children may be unusually high. The Canadian data in some areas may be confounded or explained by the tendency to establish indigenous communities in wooded, riparian, northern areas corresponding to the core habitat of B. dermatitidis, often with known B. dermatitidis habitats such as woodpiles and beaver constructions in the near vicinity.
Communicability
Blastomycosis is not considered contagious, either among humans or between animals and humans. However, there are a very small number of cases of human-to-human transmission of B. dermatitidis related to dermal contact or sexual transmission of disseminated blastomycosis of the genital tract among spouses.
History
The organisms causing blastomycosis have existed for millions of years. The pathogenic group of onygenalean fungi that give rise to conditions including blastomycosis and histoplasmosis emerged approximately 150 million years ago. The most closely related blastomycosis-causing fungi, Blastomyces dermatitidis and Blastomyces gilchristii, diverged during the Pleistocene, approximately 1.9 million years ago.At the Koster Site in Illinois, evidence pointing to possible blastomycosis infections among Late Woodland Native Americans has been identified. At that site, Dr. Jane Buikstra found evidence for what may have been an epidemic of a serious spinal disease in adolescents and young adults. Several of the skeletons showed lesions in the spinal vertebrae in the lower back. There are two modern diseases that produce lesions in the bone similar to the ones Dr. Buikstra found in these prehistoric specimens: spinal TB and blastomycosis. The bony lesions in these two diseases are practically identical. Blastomycosis seems more probable as these young people in Late Woodland and Mississippian times may have been affected because they were spending more time cultivating plants than their Middle Woodland predecessors had done. If true, it would be another severe penalty Late Woodland people had to pay as they shifted to agriculture as a way of life, and it would be a contributing factor to shortening their lifespans compared to those of the Middle Woodland people.Blastomycosis was first described by Thomas Caspar Gilchrist in 1894, as a skin disease. Because of this, blastomycosis is sometimes called "Gilchrists disease". Gilchrist initially identified the cause of the disease as a protozoan, but later correctly identified it as a fungus. In 1898 he and William Royal Stokes published the first description of Blastomyces dermatitidis. Gilchrist referred to the disease as "blastomycetic dermatitis".
The systemic spread of blastomycosis was first described in 1902, in a case that had been misdiagnosed as a combination of tuberculosis and a blastomycosis skin infection. In 1907, the dimorphic nature of the Blastomyces fungus was first identified. In 1912, the first case of canine blastomycosis was reported.Prior to the 1930s, blastomycosis was not clearly distinguished from similar fungal conditions. A paper by Rhoda Williams Benham in 1934 distinguished the causative agent of blastomycosis from cryptococcosis and coccidioidomycosis.In the early 1950s, blastomycosis was first determined to be a primarily respiratory disease, with most skin lesions caused by systemic spread from an initial lung infection. In 1952, the first documented case outside North or Central America, in Tunisia, was reported. The 1950s also saw the first introduction of antifungal drugs including amphotericin B. Before 1950, the fatality rate for disseminated blastomycosis was 92%, and treatment options were limited to iodide compounds, radiation therapy, and surgery. The first azole antifungal drug, ketoconazole, was developed in the 1970s and approved in the United States in 1981.Prior to 2013, the only species known to cause blastomycosis was B. dermatitidis. Since that time, genomic analysis has identified multiple other Blastomyces species causing blastomycosis, including B. gilchristii (2013), B. helicus (reassigned from the genus Emmonsia in 2017), B. percursus (2017), and B. emzantsi (2020).
Other animals
Blastomycosis affects a broad range of mammals. As with humans, most animals that become infected were formerly healthy and immunocompetent. Dogs are frequently affected; blastomycosis is eight to ten times more common in dogs than in humans. Sporting and hound breeds are at the greatest risk. Cats and horses can also be infected. Cats with feline immunodeficiency virus are particularly at risk. However, the overall risk of blastomycosis in cats is 28 to 100 times lower than in dogs. Cases of blastomycosis have also been reported in captive lions and tigers, in a wild North American black bear, and in marine mammals such as the Atlantic bottlenose dolphin.The nonspecific symptoms that make blastomycosis difficult to diagnose in humans also complicate veterinary diagnosis. Cats in particular are often only diagnosed after death.Dogs and humans frequently acquire blastomycosis from the same exposure event. In most such cases, the infection in the dog becomes apparent before the human infection. This may be due to a shortened incubation period, caused by the dog inhaling larger quantities of Blastomyces spores than the human.In veterinary care, blastomycosis is typically treated with itraconazole. 70% of treated dogs respond to medication and recover. In dogs as in humans, the prognosis for blastomycosis depends on the severity of the symptoms.
Additional images
See also
Histoplasmosis
Paracoccidioidomycosis
References
Further reading
Castillo CG, Kauffman CA, Miceli MH (2016). "Blastomycosis". Infectious Disease Clinics of North America. 30 (1): 247–264. doi:10.1016/j.idc.2015.10.002. PMID 26739607. (Review).
McBride JA, Gauthier GM, Klein BS (2017). "Clinical Manifestations and Treatment of Blastomycosis". Clinics in Chest Medicine. 38 (3): 435–449. doi:10.1016/j.ccm.2017.04.006. PMC 5657236. PMID 28797487. PMC 5657236 (Review)
External links
Media related to Blastomycosis at Wikimedia Commons
Blastomyces at the US National Library of Medicine Medical Subject Headings (MeSH)
NIH Encyclopedia Blastomycosis |
Erythrokeratodermia variabilis | Erythrokeratodermia variabilis (also known as "erythrokeratodermia figurata variabilis", "keratosis extremitatum progrediens", "keratosis palmoplantaris transgrediens et progrediens",: 509 "Mendes da Costa syndrome", "Mendes da Costa type erythrokeratodermia", and "progressive symmetric erythrokeratoderma") is a rare autosomal dominant disorder that usually presents at birth or during the first year of life. To date, it is thought to be caused by mutations in genes encoding for connexin channels proteins in the epidermis, leading to the misregulation of homeostasis in keratinocytes.One type is characterized by generalized, persistent, brown hyperkeratosis with accentuated skin markings, while a second type is localized, with involvement that is limited in extent and characterized by sharply demarcated, hyperkeratotic plaques.: 565 It can be associated with GJB3 and GJB4. It was characterized in 1925.
See also
List of cutaneous conditions
== References == |
Indiana vesiculovirus | Indiana vesiculovirus, formerly Vesicular stomatitis Indiana virus (VSIV or VSV) is a virus in the family Rhabdoviridae; the well-known Rabies lyssavirus belongs to the same family. VSIV can infect insects, cattle, horses and pigs. It has particular importance to farmers in certain regions of the world where it infects cattle. This is because its clinical presentation is identical to the very important foot and mouth disease virus.The virus is zoonotic and leads to a flu-like illness in infected humans.
It is also a common laboratory virus used to study the properties of viruses in the family Rhabdoviridae, as well as to study viral evolution.
Properties
Indiana vesiculovirus is the prototypic member of the genus Vesiculovirus of the family Rhabdoviridae. VSIV is an arbovirus, and its replication occurs in the cytoplasm. Natural VSIV infections encompass two steps, cytolytic infections of mammalian hosts and transmission by insects. In insects, infections are noncytolytic persistent. One confirmed vector of the virus is the phlebotomine sand fly Lutzomyia shannoni. The genome of VSIV is on a single molecule of negative-sense RNA that has 11,161 nucleotides in length, that encodes five major proteins: G protein (G), large protein (L), phosphoprotein (P), matrix protein (M) and nucleoprotein (N):
The VSIV G protein, aka VSVG, enables viral entry. It mediates viral attachment to an LDL receptor (LDLR) or an LDLR family member present on the host cell. Following binding, the VSIV-LDLR complex is rapidly endocytosed. It then mediates fusion of the viral envelope with the endosomal membrane. VSIV enters the cell through partially clathrin-coated vesicles; virus-containing vesicles contain more clathrin and clathrin adaptor than conventional vesicles. Virus-containing vesicles recruit components of the actin machinery for their interaction, thus inducing its own uptake. VSIV G does not follow the same path as most vesicles because transport of the G protein from the ER to the plasma membrane is interrupted by incubation at 15 °C. Under this condition, the molecules accumulate in both the ER and a subcellular vesicle fraction of low density called the lipid-rich vesicle fraction. The material in the lipid-rich vesicle fraction appears to be a post-ER intermediate in the transport process to the plasma membrane (PM). After infection, the VSIV G gene is expressed and is commonly studied as a model for N-linked glycosylation in the endoplasmic reticulum (ER). It is translated into the rough ER where the Glc3-Man9-GlcNac2 oligosaccharide is added by a dolichol-containing protein, to an NXS motif on VSIV G. Sugars are removed gradually as the protein travels to the Golgi apparatus, and it becomes resistant to endoglycosidase H. When synthesized in polarized epithelial cells, the envelope glycoprotein VSV G is targeted to the basolateral PM. VSVG is also a common coat protein for lentiviral vector expression systems used to introduce genetic material into in vitro systems or animal models, mainly because of its extremely broad tropism.
The VSIV L protein is encoded by half the genome, and combines with the phosphoprotein to catalyze replication of the mRNA.
The VSIV M protein is encoded by an mRNA that is 831 nucleotides long and translates to a 229 amino acid-protein. The predicted M protein sequence does not contain any long hydrophobic or nonpolar domains that might promote membrane association. The protein is rich in basic amino acids and contains a highly basic amino terminal domain.
The VSV N protein is required to initiate genome synthesis.
Vesicular stomatitis
Clinical signs and diagnosis
The main sign in animals is oral disease appearing as mucosal vesicles and ulcers in the mouth, but also on the udder and around the coronary band. Animals may show systemic signs such as anorexia, lethargy and pyrexia (fever). Disease usually resolves within two weeks, and animals usually recover completely.Cases of human infection with vesicular stomatitis virus have been described. Most of these cases have been among laboratory workers, veterinarians, and livestock handlers. In most cases, VSV infection has resulted in a short 3 to 5 day illness characterized by fever, headache, myalgia, weakness and occasionally vesicular lesions of the mouth. Serological testing is most commonly performed with an ELISA or complement fixation, and viral isolation can also be attempted.
Treatment and control
No specific treatment is available, but some animals may require supportive fluids or antibiotics for secondary infections.Control relies on biosecurity protocols, quarantine, isolation and disinfection to ensure the viral disease does not enter a country or herd.
Medical applications
Oncolytic therapy
In healthy human cells the virus cannot reproduce, likely because of the interferon response, which allows the cells to adequately respond to viral infection. The same cannot be said of interferon non-responsive cancer cells, a quality which allows VSIV to grow and lyse oncogenic cells preferentially.Recently, attenuated VSIV with a mutation in its M protein has been found to have oncolytic properties. Research is ongoing, and has shown VSIV to reduce tumor size and spread in melanoma, lung cancer, colon cancer and certain brain tumors in laboratory models of cancer.
Anti-HIV therapy
VSIV was modified to attack HIV-infected T-cells. The modified virus was called a "trojan horse" virus [1]
Ebola vaccine
Recombinant VSIV has undergone phase 1 trials as a vaccine for Ebola virus.Recombinant VSIV expressing the Ebola virus glycoprotein has undergone phase III trials in Africa as a vaccine for Ebola virus disease. The vaccine was shown to be 76-100% effective in preventing Ebola virus disease. (see also rVSV-ZEBOV vaccine) In December 2019, Merck & Co.s rVSV-ZEBOV vaccine Ervebo was approved by the Food and Drug Administration to treat individuals 18 and older.
Other Uses
Replication competent rVSV has also been created expressing proteins of Lassa fever and Marburg virus.
Other applications
The VSIV G protein is routinely used in biomedical research to pseudotype retroviral and lentiviral vectors, conferring the ability to transduce a broad range of mammalian cell types with genes of interest.The VSIV G protein has also been used in cytological studies of trafficking in the endomembrane system. Immunoelectron microscopy suggests that VSIV G protein moves from cis to trans Golgi bodies without being transported between them in vesicles, supporting the cisternal maturation model of Golgi trafficking.VSV is often used to perform quantitative and computational studies on viral genome replication and transcription. Such studies help build a better understanding of viral behavior in the presence and absence of innate immune response.
In 2020, a possible vaccine against COVID-19, the disease caused by SARS-CoV-2, was developed based on modified VSV. The modification involved replacing the VSVs surface protein genes with those for SARS-CoV-2s spike proteins.
See also
Vesiculovirus matrix proteins
Viral neuronal tracing
rVSV-ZEBOV vaccine
References
External links
ViralZone: Vesiculovirus
Vesicular Stomatitis Virus from The Lab-On-Site Project.
Disease card on World Organisation for Animal Health |
Microphthalmia | Microphthalmia (Greek: μικρός, mikros, small, ὀφθαλμός, ophthalmos, eye, also referred as microphthalmos, is a developmental disorder of the eye in which one (unilateral microphthalmia) or both (bilateral microphthalmia) eyes are abnormally small and have anatomic malformations. Microphthalmia is a distinct condition from anophthalmia and nanophthalmia. Although sometimes referred to as simple microphthalmia, nanophthalmia is a condition in which the size of the eye is small but no anatomical alterations are present.
Presentation
Microphthalmia is a congenital disorder in which the globe of the eye is as unusually small and structurally disorganized. While the axis of an adult human eye has an average length of about 23.8 mm (0.94 in), a diagnosis of microphthalmia generally corresponds to an axial length below 21 mm (0.83 in) in adults. Additionally, the diameter of the cornea is about 9–10.5 mm (0.35–0.41 in) in affected newborns and 10.5–12 mm (0.41–0.47 in) in adults with the condition. The presence of a small eye within the orbit can be a normal incidental finding but in many cases it is atypical and results in visual impairment. The prevalence of this condition is around 1 in 10,000 births, and it affects roughly 3–11% of blind children.
Causes
It has been postulated that microphthalmia arises as a result of interference with postnatal eye growth, in contrast to anophthalmia which originates much earlier during fetal development.
Genetic causes of microphthalmia include chromosomal abnormalities (e.g. Patau syndrome, mosaic trisomy 9, 13q deletion syndrome, Wolf–Hirschhorn syndrome) or monogenetic Mendelian disorders (e.g. CHARGE syndrome, Fraser syndrome, oculofaciocardiodental syndrome, Lenz microphthalmia syndrome).
Microphthalmia in newborns is sometimes associated with fetal alcohol spectrum disorder or infections during pregnancy, particularly herpes simplex virus, rubella and cytomegalovirus (CMV), but the evidence is inconclusive.The following genes, many of which are transcription and regulatory factors, have been implicated in microphthalmia, anophthalmia, and coloboma:
SOX2 has been implicated in a substantial number (10–15%) of cases and in many other cases failure to develop the ocular lens often results in microphthalmia.Microphthalmia-associated transcription factor (MITF), located on chromosome 14q32, is associated with one form of isolated microphthalmia (MCOP1). In mammals, the failure of expression of MITF in the retinal pigment epithelium prevents this structure from fully differentiating, causing a malformation of the choroid fissure of the eye and drainage of vitreous body fluid. Without this fluid, the eye fails to enlarge, resulting in microphthalmia. Waardenburg syndrome type 2 in humans may also be caused by mutations in MITF The human MITF gene is homologous to the mouse microphthalmia gene (gene symbol mi); mouse with mutations in this gene are hypopigmented in their fur. The identification of the genetics of WS type 2 owes a lot to observations of phenotypes of MITF-mutant mice.
Diagnosis
Microphthalmia is often diagnosed soon after birth. An initial diagnosis usually occurs after the eyes are inspected through the lids. In addition to visual examinations, measurements of the cornea are used in the diagnosis of this condition. An ultrasound may also be conducted to confirm whether the axial length of the eye is clinically below average (i.e. at least 2 standard deviations below the age-adjusted mean).When a case of microphthalmia is detected, the patient should visit an eye specialist as soon as possible. It is important for an ophthalmologist to conduct a thorough examination within 2 weeks after birth. The ophthalmologist will confirm the preliminary diagnosis and look for signs of other anomalies in both eyes. These abnormalities may include coloboma, optic nerve hypoplasia, retinal dystrophy, and cataract. Ultrasound may also be used to determine the presence of any internal eye issues, which may not otherwise be visible. It is possible for individuals with microphthalmia to have some vision in the affected eye(s). For this reason, the vision of infants with microphthalmia should be evaluated early on, even in severe cases. Pediatric vision tests along with electrodiagnostics are typically used to assess visual acuity.If no related symptoms are present, microphthalmia is defined as non-syndromic or isolated microphthalmia (MCOP). When occurring in conjunction with other developmental defects, it may be diagnosed as syndromic microphthalmia (MCOPS). Approximately 60 to 80% of microphthalmia cases are syndromic. Several types of MCOPS have been recognized based on their genetic causes:
Treatment
Microphthalmia cannot be cured. However, there are treatments options to manage the condition and its associated symptoms. When the affected eye(s) display some visual function, a patients eyesight can be improved (sometimes up to good state) by plus lenses, as a small eye is usually far-sighted. When one of the eyes is unaffected, caution should be taken to guard this good eye and preserve its vision. In these unilateral cases, eye glasses may be worn to offer a measure of physical protection.A key aspect of managing this condition is accounting for the small volume of the eye. The small orbit size characteristic of microphthalmia can impact the growth and structural development of the face after birth. As a result, microphthalmia can cause hemifacial asymmetry. This possibility is a particular concern for individuals with unilateral cases of microphthalmia. With one eye of average size, the asymmetry often becomes much more severe as the child ages. An axial length of less than 16 mm (0.63 in) indicates that a microphthalmic eyes growth will not be sufficient, and intervention will be necessary to reduce the degree of facial asymmetry.Minimizing facial asymmetry is important for cosmetic and structural reasons. In order to address the size discrepancy of the affected eye(s), it is important to begin eye socket expansion early in life. The face reaches 70% of its adult size by roughly 2 years of age, and 90% of its adult size by about 5.5 years of age. Additionally, the symmetry fostered by early socket expansion allows for a better prosthetic fit later in life. Typically, an infant begins wearing a conformer, or an unpainted ocular prosthesis, in the first weeks of life. The conformer is repeatedly replaced with a prothesis of a slightly larger size. This process, which takes place during the first 5 years of life, gradually enlarges the eye socket. Socket expansion through the use of implants of increasing size is another effective strategy.After socket expansion is complete, a painted prosthetic eye can be worn for cosmetic reasons. If the microphthalmic eye has functional vision, an affected individual may opt against wearing a painted prothesis. Lenses are also sometimes used for cosmetic purposes, such as a plus lens to enlarge the microphthalmic eye.
Epidemiology
Microphthalmia and anophthalmia combined are estimated to occur in about 1 in 10,000 births, though estimates have varied from 2 and 23 in 100,000 births. Approximately 3–11% of all blind children born globally have microphthalmia.
See also
References
Further reading
GeneReviews/NCBI/NIH/UW entry on Anophthalmia / Microphthalmia Overview
GeneReviews/NCBI/NIH/UW entry on Microphthalmia with Linear Skin Defects Syndrome
OMIM-Online Mendelian Inheritance in Man
== External links == |
Fragile X syndrome | Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features may include a long and narrow face, large ears, flexible fingers, and large testicles. About a third of those affected have features of autism such as problems with social interactions and delayed speech. Hyperactivity is common, and seizures occur in about 10%. Males are usually more affected than females.This disorder and finding of Fragile X syndrome has an X-linked dominant inheritance. It is typically caused by an expansion of the CGG triplet repeat within the FMR1 (fragile X messenger ribonucleoprotein 1) gene on the X chromosome. This results in silencing (methylation) of this part of the gene and a deficiency of the resultant protein (FMRP), which is required for the normal development of connections between neurons. Diagnosis requires genetic testing to determine the number of CGG repeats in the FMR1 gene. Normally, there are between 5 and 40 repeats; fragile X syndrome occurs with more than 200. A premutation is said to be present when the gene has between 55 and 200 repeats; women with a premutation have an increased risk of having an affected child. Testing for premutation carriers may allow for genetic counseling.There is no cure. Early intervention is recommended, as it provides the most opportunity for developing a full range of skills. These interventions may include special education, speech therapy, physical therapy, or behavioral therapy. Medications may be used to treat associated seizures, mood problems, aggressive behavior, or ADHD. Fragile X syndrome is estimated to occur in 1.4 per 10,000 males and 0.9 per 10,000 females.
Signs and symptoms
Most young children do not show any physical signs of FXS. It is not until puberty that physical features of FXS begin to develop. Aside from intellectual disability, prominent characteristics of the syndrome may include an elongated face, large or protruding ears, flat feet, larger testes (macroorchidism), and low muscle tone. Recurrent otitis media (middle ear infection) and sinusitis is common during early childhood. Speech may be cluttered or nervous. Behavioral characteristics may include stereotypic movements (e.g., hand-flapping) and atypical social development, particularly shyness, limited eye contact, memory problems, and difficulty with face encoding. Some individuals with fragile X syndrome also meet the diagnostic criteria for autism.Males with a full mutation display virtually complete penetrance and will therefore almost always display symptoms of FXS, while females with a full mutation generally display a penetrance of about 50% as a result of having a second, normal X chromosome. Females with FXS may have symptoms ranging from mild to severe, although they are generally less affected than males.
Physical phenotype
Large, protruding ears (both)
Long face (vertical maxillary excess)
High-arched palate (related to the above)
Hyperextensible finger joints
Hyperextensible thumbs (double-jointed)
Flat feet
Soft skin
Postpubescent macroorchidism (large testicles in men after puberty)
Hypotonia (low muscle tone)
Intellectual development
Individuals with FXS may present anywhere on a continuum from learning disabilities in the context of a normal intelligence quotient (IQ) to severe intellectual disability, with an average IQ of 40 in males who have complete silencing of the FMR1 gene. Females, who tend to be less affected, generally have an IQ which is normal or borderline with learning difficulties. The main difficulties in individuals with FXS are with working and short-term memory, executive function, visual memory, visual-spatial relationships, and mathematics, with verbal abilities being relatively unaffected.Data on intellectual development in FXS are limited. However, there is some evidence that standardized IQ decreases over time in the majority of cases, apparently as a result of slowed intellectual development. A longitudinal study looking at pairs of siblings where one child was affected and the other was not found that affected children had an intellectual learning rate which was 55% slower than unaffected children.Individuals with FXS often demonstrated language and communicative problems. This may be related to muscle function of the mouth and frontal-lobe deficits.
Autism
Fragile X syndrome co-occurs with autism in many cases and is a suspected genetic cause of the autism in these cases. This finding has resulted in screening for FMR1 mutation to be considered mandatory in children diagnosed with autism. Of those with fragile X syndrome, prevalence of concurrent autism spectrum disorder (ASD) has been estimated to be between 15 and 60%, with the variation due to differences in diagnostic methods and the high frequency of autistic features in individuals with fragile X syndrome not meeting the DSM criteria for an ASD.Although individuals with FXS have difficulties in forming friendships, those with FXS and ASD characteristically also have difficulties with reciprocal conversation with their peers. Social withdrawal behaviors, including avoidance and indifference, appear to be the best predictors of ASD in FXS, with avoidance appearing to be correlated more with social anxiety while indifference was more strongly correlated to ASD. When both autism and FXS are present, a greater language deficit and lower IQ is observed as compared to children with only FXS.Genetic mouse models of FXS have also been shown to have autistic-like behaviors.
Social interaction
FXS is characterized by social anxiety, including poor eye contact, gaze aversion, prolonged time to commence social interaction, and challenges forming peer relationships. Social anxiety is one of the most common features associated with FXS, with up to 75% of males in one series characterized as having excessive shyness and 50% having panic attacks. Social anxiety in individuals with FXS is related to challenges with face encoding, the ability to recognize a face that one has seen before.It appears that individuals with FXS are interested in social interaction and display greater empathy than groups with other causes of intellectual disability, but display anxiety and withdrawal when placed in unfamiliar situations with unfamiliar people. This may range from mild social withdrawal, which is predominantly associated with shyness, to severe social withdrawal, which may be associated with co-existing autism spectrum disorder.Females with FXS frequently display shyness, social anxiety and social avoidance or withdrawal. In addition, premutation in females has been found to be associated with social anxiety.
Female individuals with FXS show decreased activation in the prefrontal regions of the brain.
Mental health
Attention deficit hyperactivity disorder (ADHD) is found in the majority of males with FXS and 30% of females, making it the most common psychiatric diagnosis in those with FXS. Children with fragile X have very short attention spans, are hyperactive, and show hypersensitivity to visual, auditory, tactile, and olfactory stimuli. These children have difficulty in large crowds due to the loud noises and this can lead to tantrums due to hyperarousal. Hyperactivity and disruptive behavior peak in the preschool years and then gradually decline with age, although inattentive symptoms are generally lifelong.Aside from the characteristic social phobia features, a range of other anxiety symptoms are very commonly associated with FXS, with symptoms typically spanning a number of psychiatric diagnoses but not fulfilling any of the criteria in full. Children with FXS pull away from light touch and can find textures of materials to be irritating. Transitions from one location to another can be difficult for children with FXS. Behavioral therapy can be used to decrease the childs sensitivity in some cases. Behaviors such as hand flapping and biting, as well as aggression, can be an expression of anxiety.Perseveration is a common communicative and behavioral characteristic in FXS. Children with FXS may repeat a certain ordinary activity over and over. In speech, the trend is not only in repeating the same phrase but also talking about the same subject continually. Cluttered speech and self-talk are commonly seen. Self-talk includes talking with oneself using different tones and pitches. Although only a minority of FXS cases will meet the criteria for obsessive–compulsive disorder (OCD), a significant majority will have symptoms of obsession. However, as individuals with FXS generally find these behaviors pleasurable, unlike individuals with OCD, they are more frequently referred to as stereotypic behaviors.Mood symptoms in individuals with FXS rarely meet diagnostic criteria for a major mood disorder as they are typically not of sustained duration. Instead, these are usually transient and related to stressors, and may involve labile (fluctuating) mood, irritability, self-injury and aggression.Individuals with fragile X-associated tremor/ataxia syndrome (FXTAS) are likely to experience combinations of dementia, mood, and anxiety disorders. Males with the FMR1 premutation and clinical evidence of FXTAS were found to have increased occurrence of somatization, obsessive–compulsive disorder, interpersonal sensitivity, depression, phobic anxiety, and psychoticism.
Vision
Ophthalmologic problems include strabismus. This requires early identification to avoid amblyopia. Surgery or patching are usually necessary to treat strabismus if diagnosed early. Refractive errors in patients with FXS are also common.
Neurology
Individuals with FXS are at a higher risk of developing seizures, with rates between 10% and 40% reported in the literature. In larger study populations the frequency varies between 13% and 18%, consistent with a recent survey of caregivers which found that 14% of males and 6% of females experienced seizures. The seizures tend to be partial, are generally not frequent, and are amenable to treatment with medication.Individuals who are carriers of premutation alleles are at risk for developing fragile X-associated tremor/ataxia syndrome (FXTAS), a progressive neurodegenerative disease. It is seen in approximately half of male carriers over the age of 70, while penetrance in females is lower. Typically, onset of tremor occurs in the sixth decade of life, with subsequent progression to ataxia (loss of coordination) and gradual cognitive decline.
Working memory
From their 40s onward, males with FXS begin developing progressively more severe problems in performing tasks that require the central executive of working memory. Working memory involves the temporary storage of information in mind, while processing the same or other information. Phonological memory (or verbal working memory) deteriorates with age in males, while visual-spatial memory is not found to be directly related to age. Males often experience an impairment in the functioning of the phonological loop. The CGG length is significantly correlated with central executive and the visual–spatial memory. However, in a premutation individual, CGG length is only significantly correlated with the central executive, not with either phonological memory or visual–spatial memory.
Fertility
About 20% of women who are carriers for the fragile X premutation are affected by fragile X-related primary ovarian insufficiency (FXPOI), which is defined as early menopause, which is menopause occurring before 40 ayears of age (average age at menopause is 51 years old in the US). The number of CGG repeats correlates with penetrance and age of onset, but it is not a linear relationship. However premature menopause is more common in premutation carriers than in women with the full mutation, and the highest risk for FXPOI is observed in women with between 70-100 repeats the risk of FXPOI. Fragile X-associated primary ovarian insufficiency (FXPOI) is one of three Fragile X-associated Disorders (FXD) caused by changes in the FMR1 gene. FXPOI affects female premutation carriers of which is caused by the FMR1 gene, when their ovaries are not functioning properly. Women with FXPOI may exhibit changes in menstrual cycles and have changes in hormone leves but not bec considered menopausal. Women with FXPOI still have the change get pregnant in some cases, about 10%, because their ovaries occasionally release viable eggs through "escape" ovulation.FMRP is a chromatin-binding protein that functions in the DNA damage response. FMRP also occupies sites on meiotic chromosomes and regulates the dynamics of the DNA damage response machinery during spermatogenesis.
Causes
Fragile X syndrome is a genetic disorder which occurs as a result of a mutation of the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene on the X chromosome, most commonly an increase in the number of CGG trinucleotide repeats in the 5 untranslated region of FMR1. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 259 females. Incidence of the disorder itself is about 1 in every 3600 males and 1 in 4000–6000 females. Although this accounts for over 98% of cases, FXS can also occur as a result of point mutations affecting FMR1.In unaffected individuals, the FMR1 gene contains 5–44 repeats of the sequence CGG, most commonly 29 or 30 repeats. Between 45 and 54 repeats is considered a "grey zone", with a premutation allele generally considered to be between 55 and 200 repeats in length. Individuals with fragile X syndrome have a full mutation of the FMR1 allele, with over 200 CGG repeats. In these individuals with a repeat expansion greater than 200, there is methylation of the CGG repeat expansion and FMR1 promoter, leading to the silencing of the FMR1 gene and a lack of its product.
This methylation of FMR1 in chromosome band Xq27.3 is believed to result in constriction of the X chromosome which appears fragile under the microscope at that point, a phenomenon that gave the syndrome its name. One study found that FMR1 silencing is mediated by the FMR1 mRNA. The FMR1 mRNA contains the transcribed CGG-repeat tract as part of the 5 untranslated region, which hybridizes to the complementary CGG-repeat portion of the FMR1 gene to form an RNA·DNA duplex.A subset of people with intellectual disability and symptoms resembling fragile X syndrome are found to have point mutations in FMR1. This subset lacked the CGG repeat expansion in FMR1 traditionally associated with fragile x syndrome.
Inheritance
Fragile X syndrome has traditionally been considered an X-linked dominant condition with variable expressivity and possibly reduced penetrance. However, due to genetic anticipation and X-inactivation in females, the inheritance of Fragile X syndrome does not follow the usual pattern of X-linked dominant inheritance, and some scholars have suggested discontinuing labeling X-linked disorders as dominant or recessive. Females with full FMR1 mutations may have a milder phenotype than males due to variability in X-inactivation.Before the FMR1 gene was discovered, analysis of pedigrees showed the presence of male carriers who were asymptomatic, with their grandchildren affected by the condition at a higher rate than their siblings suggesting that genetic anticipation was occurring. This tendency for future generations to be affected at a higher frequency became known as the Sherman paradox after its description in 1985. Due to this, male children often have a greater degree of symptoms than their mothers.The explanation for this phenomenon is that male carriers pass on their premutation to all of their daughters, with the length of the FMR1 CGG repeat typically not increasing during meiosis, the cell division that is required to produce sperm. Incidentally, males with a full mutation only pass on premutations to their daughters. However, females with a full mutation are able to pass this full mutation on, so theoretically there is a 50% chance that a child will be affected. In addition, the length of the CGG repeat frequently does increase during meiosis in female premutation carriers due to instability and so, depending on the length of their premutation, they may pass on a full mutation to their children who will then be affected. Repeat expansion is considered to be a consequence of strand slippage either during DNA replication or DNA repair synthesis.
Pathophysiology
FMRP is found throughout the body, but in highest concentrations within the brain and testes. It appears to be primarily responsible for selectively binding to around 4% of mRNA in mammalian brains and transporting it out of the cell nucleus and to the synapses of neurons. Most of these mRNA targets have been found to be located in the dendrites of neurons, and brain tissue from humans with FXS and mouse models shows abnormal dendritic spines, which are required to increase contact with other neurons. The subsequent abnormalities in the formation and function of synapses and development of neural circuits result in impaired neuroplasticity, an integral part of memory and learning. Connectome changes have long been suspected to be involved in the sensory pathophysiology and most recently a range of circuit alterations have been shown, involving structurally increased local connectivity and functionally decreased long-range connectivity.In addition, FMRP has been implicated in several signalling pathways that are being targeted by a number of drugs undergoing clinical trials. The group 1 metabotropic glutamate receptor (mGluR) pathway, which includes mGluR1 and mGluR5, is involved in mGluR-dependent long term depression (LTD) and long term potentiation (LTP), both of which are important mechanisms in learning. The lack of FMRP, which represses mRNA production and thereby protein synthesis, leads to exaggerated LTD. FMRP also appears to affect dopamine pathways in the prefrontal cortex which is believed to result in the attention deficit, hyperactivity and impulse control problems associated with FXS. The downregulation of GABA pathways, which serve an inhibitory function and are involved in learning and memory, may be a factor in the anxiety symptoms which are commonly seen in FXS.
Diagnosis
Cytogenetic analysis for fragile X syndrome was first available in the late 1970s when diagnosis of the syndrome and carrier status could be determined by culturing cells in a folate deficient medium and then assessing for "fragile sites" (discontinuity of staining in the region of the trinucleotide repeat) on the long arm of the X chromosome. This technique proved unreliable, however, as the fragile site was often seen in less than 40% of an individuals cells. This was not as much of a problem in males, but in female carriers, where the fragile site could generally only be seen in 10% of cells, the mutation often could not be visualised.Since the 1990s, more sensitive molecular techniques have been used to determine carrier status. The fragile X abnormality is now directly determined by analysis of the number of CGG repeats using polymerase chain reaction (PCR) and methylation status using Southern blot analysis. By determining the number of CGG repeats on the X chromosome, this method allows for more accurate assessment of risk for premutation carriers in terms of their own risk of fragile X associated syndromes, as well as their risk of having affected children. Because this method only tests for expansion of the CGG repeat, individuals with FXS due to missense mutations or deletions involving FMR1 will not be diagnosed using this test and should therefore undergo sequencing of the FMR1 gene if there is clinical suspicion of FXS.Prenatal testing with chorionic villus sampling or amniocentesis allows diagnosis of FMR1 mutation while the fetus is in utero and appears to be reliable.Early diagnosis of fragile X syndrome or carrier status is important for providing early intervention in children or fetuses with the syndrome, and allowing genetic counselling with regards to the potential for a couples future children to be affected. Most parents notice delays in speech and language skills, difficulties in social and emotional domains as well as sensitivity levels in certain situations with their children.
Management
There is no cure for the underlying defects of FXS. Management of FXS may include speech therapy, behavioral therapy, occupational therapy, special education, or individualised educational plans, and, when necessary, treatment of physical abnormalities. Persons with fragile X syndrome in their family histories are advised to seek genetic counseling to assess the likelihood of having children who are affected, and how severe any impairments may be in affected descendants.
Medication
Current trends in treating the disorder include medications for symptom-based treatments that aim to minimize the secondary characteristics associated with the disorder. If an individual is diagnosed with FXS, genetic counseling for testing family members at risk for carrying the full mutation or premutation is a critical first-step. Due to a higher prevalence of FXS in boys, the most commonly used medications are stimulants that target hyperactivity, impulsivity, and attentional problems. For co-morbid disorders with FXS, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are utilized to treat the underlying anxiety, obsessive-compulsive behaviors, and mood disorders. Following antidepressants, antipsychotics such as risperidone and quetiapine are used to treat high rates of self-injurious, aggressive and aberrant behaviors in this population (Bailey Jr et al., 2012). Anticonvulsants are another set of pharmacological treatments used to control seizures as well as mood swings in 13%–18% of individuals with FXS. Drugs targeting the mGluR5 (metabotropic glutamate receptors) that are linked with synaptic plasticity are especially beneficial for targeted symptoms of FXS. Lithium is also currently being used in clinical trials with humans, showing significant improvements in behavioral functioning, adaptive behavior, and verbal memory. Few studies suggested using folic acid, but more researches are needed due to the low quality of that evidence. Alongside pharmacological treatments, environmental influences such as home environment and parental abilities as well as behavioral interventions such as speech therapy, sensory integration, etc. all factor in together to promote adaptive functioning for individuals with FXS. While metformin may reduce body weight in persons with fragile X syndrome, it is uncertain whether it improves neurological or psychiatric symptoms.Current pharmacological treatment centers on managing problem behaviors and psychiatric symptoms associated with FXS. However, as there has been very little research done in this specific population, the evidence to support the use of these medications in individuals with FXS is poor.ADHD, which affects the majority of boys and 30% of girls with FXS, is frequently treated using stimulants. However, the use of stimulants in the fragile X population is associated with a greater frequency of adverse events including increased anxiety, irritability and mood lability. Anxiety, as well as mood and obsessive-compulsive symptoms, may be treated using SSRIs, although these can also aggravate hyperactivity and cause disinhibited behavior. Atypical antipsychotics can be used to stabilise mood and control aggression, especially in those with comorbid ASD. However, monitoring is required for metabolic side effects including weight gain and diabetes, as well as movement disorders related to extrapyramidal side effects such as tardive dyskinesia. Individuals with coexisting seizure disorder may require treatment with anticonvulsants.
Prognosis
A 2013 review stated that life expectancy for FXS was 12 years lower than the general population and that the causes of death were similar to those found for the general population.
Research
Fragile X syndrome is the most "translated" human neurodevelopmental disorder under study. Hence, research into the etiology of FXS has given rise to many attempts at drug discovery. The increased understanding of the molecular mechanisms of disease in FXS has led to the development of therapies targeting the affected pathways. Evidence from mouse models shows that mGluR5 antagonists (blockers) can rescue dendritic spine abnormalities and seizures, as well as cognitive and behavioral problems, and may show promise in the treatment of FXS. Two new drugs, AFQ-056 (mavoglurant) and dipraglurant, as well as the repurposed drug fenobam are currently undergoing human trials for the treatment of FXS. There is also early evidence for the efficacy of arbaclofen, a GABAB agonist, in improving social withdrawal in individuals with FXS and ASD. In addition, there is evidence from mouse models that minocycline, an antibiotic used for the treatment of acne, rescues abnormalities of the dendrites. An open trial in humans has shown promising results, although there is currently no evidence from controlled trials to support its use.The first complete DNA sequence of the repeat expansion in someone with the full mutation was generated by scientists in 2012 using SMRT sequencing.
History
In 1943, British neurologist James Purdon Martin and British geneticist Julia Bell described a pedigree of X-linked intellectual disability, without considering the macroorchidism (larger testicles). In 1969, Herbert Lubs first sighted an unusual "marker X chromosome" in association with intellectual disability. In 1970, Frederick Hecht coined the term "fragile site". And, in 1985, Felix F. de la Cruz outlined extensively the physical, psychological, and cytogenetic characteristics of those with the condition in addition to prospects for therapy. Continued advocacy later won him an honour through the FRAXA Research Foundation in December 1998.
References
External links
CDC’s National Center on Birth Defects and Developmental Disabilities
Gene Reviews |
Distal spinal muscular atrophy type 1 | Distal spinal muscular atrophy type 1 (DSMA1), also known as spinal muscular atrophy with respiratory distress type 1 (SMARD1), is a rare neuromuscular disorder involving death of motor neurons in the spinal cord which leads to a generalised progressive atrophy of body muscles.
The condition is caused by a genetic mutation in the IGHMBP2 gene and is inherited in an autosomal recessive manner. There is no known cure to DSMA1, and research of the disorder is still in early stages due to low incidence and high mortality rates.
Signs and symptoms
Usually, the first respiratory symptoms are shortness of breath (dyspnea) and paradoxical respirations which then escalate within the first few months of life to diaphragmatic paralysis. The symptoms of diaphragmatic paralysis come on very rapidly and without warning, and the patient is often rushed to a hospital where they are placed on a ventilator for respiratory support. Due to the severe nature of diaphragmatic paralysis, the patient eventually needs continuous ventilation support to survive. Continuous ventilation, however, may in itself cause damage to the anatomy of the lungs.In addition to diaphragmatic paralysis, other issues may arise: as the name suggests, the distal limbs are most affected with symptoms of weakness, restricting mobility due to (near-)paralysis of the distal limbs as well as the head and neck. Also, dysfunction of the peripheral nerves and the autonomic nervous system may occur. Due to these dysfunctions, the patients have been shown to suffer from excessive sweating and irregular heartbeat. The deep tendon reflex is also lost in patients with DSMA1.Uterine growth retardation and poor foetal movement have been observed in severe DSMA1 cases.
Causes
DSMA1 is caused by a genetic mutation in the IGHMBP2 gene (located on chromosome 11, locus 11q13.3), which codes the immunoglobulin helicase μ-binding protein 2. The role of the IGHMBP2 protein is not fully understood, but it is known to affect mRNA processing. The cellular mechanisms of the mutation, as well as the protein mechanisms disrupted by the mutation, are unknown. IGHMBP2 mutations are usually random mutations which are normally not passed down through generations.
Pathophysiology
The pathology underlying the observable characteristics of DSMA1 is cell body degeneration of motor nerves. Specifically, the anterior horn α-motorneurons degenerate within the first six months of life leading to a variety of symptoms. Muscle deterioration increases at around 1–2 years of age, resulting in reduced motor function. The most severely affected muscles include facial muscles and the tongue (which may develop a twitch due to hypoglossal nerve paralysis). Reduced pain sensation and excessive sweating are sometimes observed. Non-ambulant patients may develop pressure ulcers, severe constipation, urinary incontinence, and (rarely) reflux nephropathy in the advanced stages of the disease.
Diagnosis
The diagnosis for DMSA1 is usually masked by a diagnosis for a respiratory disorder. In infants, DMSAI is usually the cause of acute respiratory insufficiency in the first 6 months of life. The respiratory distress should be confirmed as diaphragmatic palsy by fluoroscopy or by electromyography. Although the patient may have a variety of other symptoms the diaphragmatic palsy confirmed by fluoroscopy or other means is the main criteria for diagnosis. This is usually confirmed with genetic testing looking for mutations in the IGHMBP2 gene. The patient can be misdiagnosed if the respiratory distress is mistaken for a severe respiratory infection or DMSA1 can be mistaken for SMA1 because their symptoms are so similar but the genes which are affected are different. This is why genetic testing is necessary to confirm the diagnosis of DMSA.
Classification
DSMA1 was identified and classified as a sub-group of spinal muscular atrophies (SMA) in 1974. Currently, various classifications include DSMA1 among general spinal muscular atrophies or distal hereditary motor neuropathies, though the latter has been argued to be more correct.
Treatment
There is no known cure to DSMA1, and care is primarily supportive. Patients require respiratory support which may include non-invasive ventilation or tracheal intubation. The child may also undergo additional immunisations and offered antibiotics to prevent respiratory infections. Maintaining a healthy weight is also important. Patients are at risk of undernutrition and weight loss because of the increased energy spent for breathing. Physical and occupational therapy for the child can be very effective in maintaining muscle strength.There is no published practice standard for the care in DSMA1, even though the Spinal Muscular Atrophy Standard of Care Committee has been trying to come to a consensus on the care standards for DSMA1 patients. The discrepancies in the practitioners’ knowledge, family resources, and differences in patients culture and/or residency have played a part in the outcome of the patient.
Prognosis
DSMA1 is usually fatal in early childhood. The patient, normally a child, suffers a progressive degradation of the respiratory system until respiratory failure. There is no consensus on the life expectancy in DSMA1 despite a number of studies being conducted. A small number of patients survive past two years of age but they lack signs of diaphragmatic paralysis or their breathing is dependent on a ventilation system.
Research directions
The disease has only been identified as distinct from SMA recently, so research is still experimental, taking place mostly in animal models. Several therapy pathways have been devised which include gene therapy, whereby an IGHMBP2 transgene is delivered to the cell using a viral vector, and small-molecule drugs like growth factors (e.g., IGF-1 and VEGF) or olesoxime. Studies in amyotrophic lateral sclerosis are also considered helpful because the condition is relatively similar to DSMA1.
See also
Distal hereditary motor neuropathies
Spinal muscular atrophies
Spinal muscular atrophy
References
Further reading
== External links == |
Elephantiasis | Elephantiasis is the enlargement and hardening of limbs or body parts due to tissue swelling. It is characterised by edema, hypertrophy, and fibrosis of skin and subcutaneous tissues, due to obstruction of lymphatic vessels. It may affect the genitalia. The term elephantiasis is often used in reference to (symptoms caused by) parasitic worm infections, but may refer to a variety of diseases where parts of a persons body swell to massive proportions.
Cause
Some conditions that present with elephantiasis include:
Elephantiasis nostras, due to longstanding chronic lymphangitis
Elephantiasis tropica (known as lymphatic filariasis), caused by a number of parasitic worms, particularly Wuchereria bancrofti. More than 120 million people, mostly in Africa and Southeast Asia, are affected.
Nonfilarial elephantiasis (or podoconiosis), an immune disease affecting the lymph vessels
Leishmaniasis
Elephantiasis, Grade 3 lymphedema which may occur in people with breast cancer
Genital elephantiasis, result of lymphogranuloma venereum
Proteus syndrome, a genetic disorder best known as the condition possibly experienced by Joseph Merrick, the so-called "Elephant Man."Other causes may include:
Repeated streptococcal infection
Lymphadenectomy
Hereditary birth defects
Pretibial myxedema
References
External links
"Lymphatic filariasis". World Health Organization. Retrieved 1 June 2018. |
Anencephaly | Anencephaly is the absence of a major portion of the brain, skull, and scalp that occurs during embryonic development. It is a cephalic disorder that results from a neural tube defect that occurs when the rostral (head) end of the neural tube fails to close, usually between the 23rd and 26th day following conception. Strictly speaking, the Greek term translates as "without a brain" (or totally lacking the inside part of the head), but it is accepted that children born with this disorder usually only lack a telencephalon, the largest part of the brain consisting mainly of the cerebral hemispheres, including the neocortex, which is responsible for cognition. The remaining structure is usually covered only by a thin layer of membrane—skin, bone, meninges, etc., are all lacking. With very few exceptions, infants with this disorder do not survive longer than a few hours or days after birth.
Signs and symptoms
The National Institute of Neurological Disorders and Stroke (NINDS) describes the presentation of this condition as follows: "A baby born with anencephaly is usually blind, deaf, unaware of its surroundings and unable to feel pain. Although some individuals with anencephaly may be born with a main brain stem, the lack of a functioning cerebrum permanently rules out the possibility of ever gaining awareness of their surroundings. Reflex actions such as breathing and responses to sound or touch may occur."Due to the presence of the brainstem, children with anencephaly have almost all the primitive reflexes of a newborn, responding to auditory, vestibular and painful stimuli. This means that the child can move, smile, suckle and breathe without the aid of devices.
Causes
Folic acid has been shown to be important in neural tube formation since at least 1991, and as a subtype of neural tube defect, folic acid may play a role in anencephaly. Studies have shown that the addition of folic acid to the diet of women of child-bearing age may significantly reduce, although not eliminate, the incidence of neural tube defects. Therefore, it is recommended that all women of child-bearing age consume 0.4 mg of folic acid daily, especially those attempting to conceive or who may possibly conceive, as this can reduce the risk to 0.03%. It is not advisable to wait until pregnancy has begun, since, by the time a woman knows she is pregnant, the critical time for the formation of a neural tube defect has usually already passed. A physician may prescribe even higher dosages of folic acid (5 mg/day) for women having had a previous pregnancy with a neural tube defect.Neural tube defects can follow patterns of heredity, with direct evidence of autosomal recessive inheritance. As reported by Bruno Reversade and colleagues, the homozygous inactivation of the NUAK2 kinase leads to anencephaly in humans. Animal models indicate a possible association with deficiencies of the transcription factor TEAD2. Studies show that a woman who has had one child with a neural tube defect such as anencephaly has about a 3% risk of having another child with a neural tube defect, as opposed to the background rate of 0.1% occurrence in the population at large. Genetic counseling is usually offered to women at a higher risk of having a child with a neural tube defect to discuss available testing.
It is known that people taking certain anticonvulsants and people with insulin-dependent diabetes have a higher risk of having a child with a neural tube defect.
Relation to genetic ciliopathy
Until recently, medical literature did not indicate a connection among many genetic disorders, both genetic syndromes and genetic diseases, that are now being found to be related. As a result of new genetic research, some of these are, in fact, highly related in their root cause despite the widely varying set of medical symptoms that are clinically visible in the disorders. Anencephaly is one such disease, part of an emerging class of diseases called ciliopathies. The underlying cause may be a dysfunctional molecular mechanism in the primary cilia structures of the cell, organelles present in many cellular types throughout the human body. The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development and, thus, offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases. Known ciliopathies include primary ciliary dyskinesia, Bardet–Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Alström syndrome, Meckel–Gruber syndrome, and some forms of retinal degeneration.
Diagnosis
Anencephaly can often be diagnosed before birth through an ultrasound examination. The maternal serum alpha-fetoprotein (AFP screening) and detailed fetal ultrasound can be useful for screening for neural tube defects such as spina bifida or anencephaly.
Meroanencephaly
Meroanencephaly is a rare form of anencephaly characterized by malformed cranial bones, a median cranial defect, and a cranial protrusion called area cerebrovasculosa. Area cerebrovasculosa is a section of abnormal, spongy, vascular tissue admixed with glial tissue ranging from simply a membrane to a large mass of connective tissue, hemorrhagic vascular channels, glial nodules, and disorganized choroid plexuses.
Holoanencephaly
The most common type of anencephaly, where the brain has entirely failed to form, except for the brain stem. Infants rarely survive more than one day after birth with holoanencephaly.
Craniorachischisis
The most severe type of anencephaly where area cerebrovasculosa and area medullovasculosa fill both cranial defects and the spinal column. Craniorachischisis is characterized by anencephaly accompanied by bony defects in the spine and the exposure of neural tissue as the vault of the skull fails to form. Craniorachischisis occurs in about 1 of every 1000 live births, but various physical and chemical tests can detect neural tube closure during early pregnancy.
Prognosis
There is no cure or standard treatment for anencephaly. Prognosis is extremely poor, as many anencephalic fetuses do not survive birth and infants that are not stillborn will usually die within a few hours or days after birth from cardiorespiratory arrest.
Epidemiology
In the United States, anencephaly occurs in about 1 out of every 10,000 births. Rates may be higher among Africans with rates in Nigeria estimated at 3 per 10,000 in 1990 while rates in Ghana estimated at 8 per 10,000 in 1992. Rates in China are estimated at 5 per 10,000.Research has suggested that, overall, female babies are more likely to be affected by the disorder.
Ethical issues
Organ donation
One issue concerning anencephalic newborns is organ donation. Initial legal guidance came from the case of Baby Theresa in 1992, in which the boundaries of organ donation were tested for the first time. Infant organs are scarce, and the high demand for pediatric organ transplants poses a major public health issue. In 1999, it was found that for American children under the age of two who are waiting for a transplant, 30–50% die before an organ becomes available.Within the medical community, the main ethical issues with organ donation are a misdiagnosis of anencephaly, the slippery slope argument, that anencephalic neonates would rarely be a source of organs, and that it would undermine confidence in organ transplantation. Slippery slope concerns are a major issue in personhood debates, across the board. In regards to anencephaly, those who oppose organ donation argue that it could open the door for involuntary organ donors such as an elderly person with severe dementia. Another point of contention is the number of children who would actually benefit. There are discrepancies in statistics; however, it is known that most anencephalic children are stillborn.Proposals have been made to bypass the legal and ethical issues surrounding organ donation. These include waiting for death to occur before procuring organs, expanding the definition of death, creating a special legal category for anencephalic infants, and defining them as non-persons.In the United Kingdom, a child born with anencephaly was reported as the countrys youngest organ donor. Teddy Houlston was diagnosed as anencephalic at 12 weeks of gestation. His parents, Jess Evans and Mike Houlston, decided against abortion and instead proposed organ donation. Teddy was born on 22 April 2014, in Cardiff, Wales, and lived for 100 minutes, after which his heart and kidneys were removed. His kidneys were later transplanted into an adult in Leeds. Teddys twin, Noah, was born healthy.
Brain death
There are four different concepts used to determine brain death: failure of heart, failure of lungs, whole brain death, and neocortical death.Neocortical death, similar to a persistent vegetative state (PVS), involves loss of cognitive functioning of the brain. A proposal by law professor David Randolph Smith, in an attempt to prove that neocortical death should legally be treated the same as brain death, involved PET scans to determine the similarities. However, this proposal has been criticized on the basis that confirming neocortical death by PET scan may risk indeterminacy.
Pregnancy termination
Anencephaly can be diagnosed before delivery with a high degree of accuracy. Although anencephaly is a fatal condition, the option of abortion is dependent on the abortion laws in the state. According to a 2013 report, 26% of the worlds population reside in a country where abortion is generally prohibited. In 2012, Brazil extended the right of abortion to mothers with anencephalic fetuses. This decision is, however, receiving much disapproval by several religious groups.
Legal proceedings
The case of baby Theresa was the beginning of the ethical debate over anencephalic infant organ donation. The story of baby Theresa remains a focus of basic moral philosophy. Baby Theresa was born with anencephaly in 1992. Her parents, knowing that their child was going to die, requested that her organs be given for transplantation. Although her physicians agreed, Florida law prohibited the infants organs from being removed while she was still alive. By the time she died nine days after birth, her organs had deteriorated past the point of being viable.
United States uniform acts
The Uniform Determination of Death Act (UDDA) is a model bill, adopted by many US states, stating that an individual who has sustained either 1) irreversible cessation of circulatory and respiratory functions or 2) irreversible cessation of all functions of the entire brain, including the brain stem, is dead. This bill was a result of much debate over the definition of death and is applicable to the debate over anencephaly. A related bill, the Uniform Anatomical Gift Act (UAGA), grants individuals and, after death, their family members the right to decide whether or not to donate organs. Because it is against the law for any person to pay money for an organ, the person in need of an organ transplant must rely on a volunteer.There have been two state bills that proposed to change current laws regarding death and organ donation. California Senate Bill 2018 proposed to amend the UDDA to define anencephalic infants as already dead, while New Jersey Assembly Bill 3367 proposed to allow anencephalic infants to be organ sources even if they are not dead.
Research
Some genetic research has been conducted to determine the causes of anencephaly. It has been found that cartilage homeoprotein (CART1) is selectively expressed in chondrocytes (cartilage cells). The CART1 gene to chromosome 12q21.3–q22 has been mapped. Also, it has been found that mice homozygous for deficiency in the Cart1 gene manifested acrania and meroanencephaly, and prenatal treatment with folic acid will suppress acrania and meroanencephaly in the Cart1-deficient mutants.
See also
Acalvaria
Microcephaly
References
== External links == |
Autosomal recessive bestrophinopathy | Autosomal recessive bestrophinopathy is a rare genetic disorder characterized by central vision loss, retinopathy, absence of an electrooculogram light rise, and decreased electroretinogram. Other findings include dispersed punctate flecks, macular neurosensory retina fluid build-up, hyperopia, macular thinning, and (less commonly) angle-closure glaucoma.It is caused by hereditary autosomal recessive mutations in the BEST1 gene, located in chromosome 11, and it has been described in less than 20 individuals from 10 families worldwide.
== References == |
Hypovolemic shock | Hypovolemic shock is a form of shock caused by severe hypovolemia (insufficient blood volume or extracellular fluid in the body). It could be the result of severe dehydration through a variety of mechanisms or blood loss. Hypovolemic shock is a medical emergency; if left untreated, the insufficient blood flow can cause damage to organs, leading to multiple organ failure.In treating hypovolemic shock, it is important to determine the cause of the underlying hypovolemia, which may be the result of bleeding or other fluid losses. To minimize ischemic damage to tissues, treatment involves quickly replacing lost blood or fluids, with consideration of both rate and the type of fluids used.Tachycardia, a fast heart rate, is typically the first abnormal vital sign. When resulting from blood loss, trauma is the most common root cause, but severe blood loss can also happen in various body systems without clear traumatic injury. The body in hypovolemic shock prioritizes getting oxygen to the brain and heart, which reduces blood flow to nonvital organs and extremities, causing them to grow cold, look mottled, and exhibit delayed capillary refill. The lack of adequate oxygen delivery ultimately leads to a worsening increase in the acidity of the blood (acidosis). The "lethal triad" of ways trauma can lead to death is acidosis, hypothermia, and coagulopathy. It is possible for trauma to cause clotting problems even without resuscitation efforts.Damage control resuscitation is based on three principles:
permissive hypotension: tries to balance temporary suboptimal perfusion to organs with conditions for halting blood loss by setting a goal of 90 mmHg systolic blood pressure
hemostatic resuscitation: restoring blood volume in ways (with whole blood or equivalent) that interfere minimally with the natural process of stopping bleeding.
damage control surgery.
Signs and symptoms
Symptoms of hypovolemic shock can be related to volume depletion, electrolyte imbalances, or acid–base disorders that accompany hypovolemic shock.Patients with volume depletion may complain of thirst, muscle cramps, and/or orthostatic hypotension. Severe hypovolemic shock can result in mesenteric and coronary ischemia that can cause abdominal or chest pain. Agitation, lethargy, or confusion may characterize brain mal-perfusion.Dry mucous membranes, decreased skin turgor, low jugular venous distention, tachycardia, and hypotension can be seen along with decreased urinary output. Patients in shock can appear cold, clammy, and cyanotic.Early signs and symptoms include tachycardia given rise to by catecholamine release; skin pallor due to vasoconstriction triggered by catecholamine release; hypotension followed by hypovolaemia and perhaps arising after myocardial insufficiency; and confusion, aggression, drowsiness and coma caused by cerebral hypoxia or acidosis. Tachypnoea owing to hypoxia and acidosis, general weakness caused by hypoxia and acidosis, thirst induced by hypovolaemia, and oliguria caused by reduced perfusion may also arise.Abnormal growing central venous pressure indicates either hypotension or hypovolemia. Tachycardia accompanied by declined urine outflow implies either tension pneumothorax, cardiac tamponade or cardiac failure which is thought secondary to cardiac contusion or ischaemic heart disease. Echocardiography in such case may be helpful to distinguish cardiac failure from other diseases. Cardiac failure manifests a weak contractibility myocardium; treatment with an inotropic drug such as dobutamine may be appropriate.
Cause
The annual incidence of shock of any etiology is 0.3 to 0.7 per 1000, with hemorrhagic shock being most common in the intensive care unit. Hypovolemic shock is the most common type of shock in children, most commonly due to diarrheal illness in the developing world.Hypovolemic shock occurs as a result of either blood loss or extracellular fluid loss.
Blood loss
Hemorrhagic shock is hypovolemic shock from blood loss. Traumatic injury is by far the most common cause of hemorrhagic shock, particularly blunt and penetrating trauma, followed by upper and lower gastrointestinal sources, such as gastrointestinal (GI) bleed. Other causes of hemorrhagic shock include bleed from an ectopic pregnancy, bleeding from surgical intervention, vaginal bleeding, and splenic rupture.Obstetrical, vascular, iatrogenic, and even urological sources have all been described. Bleeding may be either external or internal. A substantial amount of blood loss to the point of hemodynamic compromise may occur in the chest, abdomen, or the retroperitoneum. The thigh itself can hold up to 1 L to 2 L of blood.Localizing and controlling the source of bleeding is of utmost importance to the treatment of hemorrhagic shock.The sequence of the most-commonly-seen causes that lead to hemorrhagic type of hypovolemic shock is given in order of frequencies: blunt or penetrating trauma including multiple fractures absent from vessel impairment, upper gastrointestinal bleeding e.g., variceal hemorrhage, peptic ulcer., or lower GI bleeding e.g., diverticular, and arteriovenous malformation.Except for the two most common causes, the less common causes are intra-operative and post-operative bleeding, abdominal aortic rupture or left ventricle aneurysm rupture, aortic–enteric fistula, hemorrhagic pancreatitis, iatrogenic e.g., inadvertent biopsy of arteriovenous malformation, severed artery., tumors or abscess erosion into major vessels, post-partum hemorrhage, uterine or vaginal hemorrhage owing to infection, tumors, lacerations, spontaneous peritoneal hemorrhage caused by bleeding diathesis, and ruptured hematoma.
Fluid loss
In spite of hemorrhage, the amount of circulating blood in the body may drop as well when one loses excessive body fluid owing to non-hemorrhagic reasons.
Hypovolemic shock as a result of extracellular fluid loss can be of the 4 etiologies.
Gastrointestinal
Gastrointestinal (GI) losses can occur via many different etiologies. The gastrointestinal tract usually secretes between 3 and 6 liters of fluid per day. However, most of this fluid is reabsorbed as only 100 to 200 mL are lost in the stool. Volume depletion occurs when the fluid ordinarily secreted by the GI tract cannot be reabsorbed. This occurs when there is retractable vomiting, diarrhea, or external drainage via stoma or fistulas.
Kidneys
Renal losses of salt and fluid can lead to hypovolemic shock. The kidneys usually excrete sodium and water in a manner that matches sodium intake and water intake.Diuretic therapy and osmotic diuresis from hyperglycemia can lead to excessive renal sodium and volume loss. In addition, there are several tubular and interstitial diseases beyond the scope of this article that cause severe salt-wasting nephropathy.
Skin
Fluid loss also can occur from the skin. In a hot and dry climate, skin fluid losses can be as high as 1 to 2 liters/hour. Patients with a skin barrier interrupted by burns or other skin lesions also can experience large fluid losses that lead to hypovolemic shock.
Third-spacing
Sequestration of fluid into a third space also can lead to volume loss and hypovolemic shock. Third-spacing of fluid can occur in intestinal obstruction, pancreatitis, obstruction of a major venous system, vascular endothelium or any other pathological condition that results in a massive inflammatory response.
Pathophysiology
Blood loss
Hemorrhagic shock is due to the depletion of intravascular volume through blood loss to the point of being unable to match the tissues demand for oxygen. As a result, mitochondria are no longer able to sustain aerobic metabolism for the production of oxygen and switch to the less efficient anaerobic metabolism to meet the cellular demand for adenosine triphosphate. In the latter process, pyruvate is produced and converted to lactic acid to regenerate nicotinamide adenine dinucleotide (NAD+) to maintain some degree of cellular respiration in the absence of oxygen.The body compensates for volume loss by increasing heart rate and contractility, followed by baroreceptor activation resulting in sympathetic nervous system activation and peripheral vasoconstriction. Typically, there is a slight increase in the diastolic blood pressure with narrowing of the pulse pressure. As diastolic ventricular filling continues to decline and cardiac output decreases, systolic blood pressure drops.Due to sympathetic nervous system activation, blood is diverted away from noncritical organs and tissues to preserve blood supply to vital organs such as the heart and brain. While prolonging heart and brain function, this also leads to other tissues being further deprived of oxygen causing more lactic acid production and worsening acidosis. This worsening acidosis along with hypoxemia, if left uncorrected, eventually causes the loss of peripheral vasoconstriction, worsening hemodynamic compromise, and death.The bodys compensation varies by cardiopulmonary comorbidities, age, and vasoactive medications. Due to these factors, heart rate and blood pressure responses are extremely variable and, therefore, cannot be relied upon as the sole means of diagnosis.A key factor in the pathophysiology of hemorrhagic shock is the development of trauma-induced coagulopathy. Coagulopathy develops as a combination of several processes. The simultaneous loss of coagulation factors via hemorrhage, hemodilution with resuscitation fluids, and coagulation cascade dysfunction secondary to acidosis and hypothermia have been traditionally thought to be the cause of coagulopathy in trauma. However, this traditional model of trauma-induced coagulopathy may be too limited. Further studies have shown that a degree of coagulopathy begins in 25% to 56% of patients before initiation of the resuscitation. This has led to the recognition of trauma-induced coagulopathy as the sum of two distinct processes: acute coagulopathy of trauma and resuscitation-induced coagulopathy.Trauma-induced coagulopathy is acutely worsened by the presence of acidosis and hypothermia. The activity of coagulation factors, fibrinogen depletion, and platelet quantity are all adversely affected by acidosis. Hypothermia (less than 34 C) compounds coagulopathy by impairing coagulation and is an independent risk factor for death in hemorrhagic shock.
Fluid loss
Hypovolemic shock results from depletion of intravascular volume, whether by extracellular fluid loss or blood loss. The body compensates with increased sympathetic tone resulting in increased heart rate, increased cardiac contractility, and peripheral vasoconstriction. The first changes in vital signs seen in hypovolemic shock include an increase in diastolic blood pressure with narrowed pulse pressure.As volume status continues to decrease, systolic blood pressure drops. As a result, oxygen delivery to vital organs is unable to meet the oxygen needs of the cells. Cells switch from aerobic metabolism to anaerobic metabolism, resulting in lactic acidosis. As sympathetic drive increases, blood flow is diverted from other organs to preserve blood flow to the heart and brain. This propagates tissue ischemia and worsens lactic acidosis. If not corrected, there will be worsening hemodynamic compromise and, eventually, death.
Diagnosis
Shock index (SI) has been defined as heart rate/systolic blood pressure ; SI≥0.6 is a clinical shock.
Such ratio value is clinically employed to determine the scope or emergence of shock. The SI correlates with the extent of hypovolemia and thus may facilitate the early identification of severely injured patients threatened by complications due to blood loss and therefore need urgent treatment, i.e. blood transfusion.
Data presented as n (%), mean ± standard deviation or median (interquartile range (IQR)). n = 21,853; P <0.001 for all parameters. ED Emergency department, GCS Glasgow coma scale, HR Heart rate, SBP Systolic blood pressure, SI = Shock index.
Bleeding
Recognizing the degree of blood loss via vital sign and mental status abnormalities is important. The American College of Surgeons Advanced Trauma Life Support (ATLS) hemorrhagic shock classification links the amount of blood loss to expected physiologic responses in a healthy 70 kg patient. As total circulating blood volume accounts for approximately 7% of total body weight, this equals approximately five liters in the average 70 kg male patient.
Class 1: Volume loss up to 15% of total blood volume, approximately 750 mL. Heart rate is minimally elevated or normal. Typically, there is no change in blood pressure, pulse pressure, or respiratory rate.
Class 2: Volume loss from 15% to 30% of total blood volume, from 750 mL to 1500 mL. Heart rate and respiratory rate become elevated (100 BPM to 120 BPM, 20 RR to 24 RR). Pulse pressure begins to narrow, but systolic blood pressure may be unchanged to slightly decreased.
Class 3: Volume loss from 30% to 40% of total blood volume, from 1500 mL to 2000 mL. A significant drop in blood pressure and changes in mental status occur. Heart rate and respiratory rate are significantly elevated (more than 120 BPM). Urine output declines. Capillary refill is delayed.
Class 4: Volume loss over 40% of total blood volume. Hypotension with narrow pulse pressure (less than 25 mmHg). Tachycardia becomes more pronounced (more than 120 BPM), and mental status becomes increasingly altered. Urine output is minimal or absent. Capillary refill is delayed.Again, the above is outlined for a healthy 70 kg individual. Clinical factors must be taken into account when assessing patients. For example, elderly patients taking beta blockers can alter the patients physiologic response to decreased blood volume by inhibiting mechanism to increase heart rate. As another, patients with baseline hypertension may be functionally hypotensive with a systolic blood pressure of 110 mmHg.
Non-bleeding
Various laboratory values can be abnormal in hypovolemic shock. Patients can have increased BUN and serum creatinine as a result of pre-renal kidney failure. Hypernatremia or hyponatremia can result, as can hyperkalemia or hypokalemia.Lactic acidosis can result from increased anaerobic metabolism. However, the effect of acid–base balance can be variable as patients with large GI losses can become alkalotic.
In cases of hemorrhagic shock, hematocrit and hemoglobin can be severely decreased. However, with a reduction in plasma volume, hematocrit and hemoglobin can be increased due to hemoconcentration.Low urinary sodium is commonly found in hypovolemic patients as the kidneys attempt to conserve sodium and water to expand the extracellular volume. However, sodium urine can be low in a euvolemic patient with heart failure, cirrhosis, or nephrotic syndrome. Fractional excretion of sodium under 1% is also suggestive of volume depletion. Elevated urine osmolality can also suggest hypovolemia. However, this number also can be elevated in the setting of impaired concentrating ability by the kidneys.Central venous pressure (CVP) is often used to assess volume status. However, its usefulness in determining volume responsiveness has recently come into question. Ventilator settings, chest wall compliance, and right-sided heart failure can compromise CVPs accuracy as a measure of volume status. Measurements of pulse pressure variation via various commercial devices has also been postulated as a measure of volume responsiveness. However, pulse pressure variation as a measure of fluid responsiveness is only valid in patients without spontaneous breaths or arrhythmias. The accuracy of pulse pressure variation also can be compromised in right heart failure, decreased lung or chest wall compliance, and high respiratory rates.Similar to examining pulse pressure variation, measuring respiratory variation in inferior vena cava diameter as a measure of volume responsiveness has only been validated in patients without spontaneous breaths or arrhythmias.Measuring the effect of passive leg raises on cardiac contractility by echo appears to be the most accurate measurement of volume responsiveness, although it is also subject to limitations.History and physical can often make the diagnosis of hypovolemic shock. For patients with hemorrhagic shock, a history of trauma or recent surgery is present. For hypovolemic shock due to fluid losses, history and physical should attempt to identify possible GI, renal, skin, or third-spacing as a cause of extracellular fluid loss.Although relatively nonsensitive and nonspecific, physical exam can be helpful in determining the presence of hypovolemic shock. Physical findings suggestive of volume depletion include dry mucous membranes, decreased skin turgor, and low jugular venous distention. Tachycardia and hypotension can be seen along with decreased urinary output.
Differential diagnosis
While hemorrhage is the most common cause of shock in the trauma patient, other causes of shock are to remain on the differential. Obstructive shock can occur in the setting of tension pneumothorax and cardiac tamponade. These etiologies should be uncovered in the primary survey. In the setting of head or neck trauma, an inadequate sympathetic response, or neurogenic shock, is a type of distributive shock that is caused by a decrease in peripheral vascular resistance. This is suggested by an inappropriately low heart rate in the setting of hypotension. Cardiac contusion and infarctions can result in cardiogenic shock. Finally, other causes should be considered that are not related to trauma or blood loss. In the undifferentiated patient with shock, septic shock and toxic causes are also on the differential.
Management
The first step in managing hemorrhagic shock is recognition. Ideally, This should occur before the development of hypotension. Close attention should be paid to physiological responses to low-blood volume. Tachycardia, tachypnea, and narrowing pulse pressure may be the initial signs. Cool extremities and delayed capillary refill are signs of peripheral vasoconstriction.
Bleeding
In the setting of trauma, an algorithmic approach via the primary and secondary surveys is suggested by ATLS. Physical exam and radiological evaluations can help localize sources of bleeding. A trauma ultrasound, or Focused Assessment with Sonography for Trauma (FAST), has been incorporated in many circumstances into the initial surveys. The specificity of a FAST scan has been reported above 99%, but a negative ultrasound does not rule out intra-abdominal pathology.With a broader understanding of the pathophysiology of hemorrhagic shock, treatment in trauma has expanded from a simple massive transfusion method to a more comprehensive management strategy of "damage control resuscitation". The concept of damage control resuscitation focuses on permissive hypotension, hemostatic resuscitation, and hemorrhage control to adequately treat the "lethal triad" of coagulopathy, acidosis, and hypothermia that occurs in trauma.Hypotensive resuscitation has been suggested for the hemorrhagic shock patient without head trauma. The aim is to achieve a systolic blood pressure of 90 mmHg in order to maintain tissue perfusion without inducing re-bleeding from recently clotted vessels. Permissive hypotension is a means of restricting fluid administration until hemorrhage is controlled while accepting a short period of suboptimal end-organ perfusion. Studies regarding permissive hypotension have yielded conflicting results and must take into account type of injury (penetrating versus blunt), the likelihood of intracranial injury, the severity of the injury, as well as proximity to a trauma center and definitive hemorrhage control.The quantity, type of fluids to be used, and endpoints of resuscitation remain topics of much study and debate. For crystalloid resuscitation, normal saline and lactated ringers are the most commonly used fluids. Normal saline has the drawback of causing a non-anion gap hyperchloremic metabolic acidosis due to the high chloride content, while lactated ringers can cause a metabolic alkalosis as lactate metabolism regenerates into bicarbonate.Recent trends in damage control resuscitation focus on "hemostatic resuscitation" which pushes for early use of blood products rather than an abundance of crystalloids in order to minimize the metabolic derangement, resuscitation-induced coagulopathy, and the hemodilution that occurs with crystalloid resuscitation. The end goal of resuscitation and the ratios of blood products remain at the center of much study and debate. A recent study has shown no significant difference in mortality at 24 hours or 30 days between ratios of 1:1:1 and 1:1:2 of plasma to platelets to packed RBCs. However, patients that received the more balanced ratio of 1:1:1 were less likely to die as a result of exsanguination in 24 hours and were more likely to achieve hemostasis. Additionally, reduction in time to first plasma transfusion has shown a significant reduction in mortality in damage control resuscitation.In addition to blood products, products that prevent the breakdown of fibrin in clots, or antifibrinolytics, have been studied for their utility in the treatment of hemorrhagic shock in the trauma patient. Several antifibrinolytics have been shown to be safe and effective in elective surgery. The CRASH-2 study was a randomized control trial of tranexamic acid versus placebo in trauma has been shown to decrease overall mortality when given in the first three hours of injury. Follow-up analysis shows additional benefit to tranexamic acid when given in the first three hours after surgery.Damage control resuscitation is to occur in conjunction with prompt intervention to control the source of bleeding. Strategies may differ depending on proximity to definitive treatment.For patients in hemorrhagic shock, early use of blood products over crystalloid resuscitation results in better outcomes. Balanced transfusion using 1:1:1 or 1:1:2 of plasma to platelets to packed red blood cells results in better hemostasis. Anti-fibrinolytic administration to patients with severe bleed within 3 hours of traumatic injury appears to decrease death from major bleed as shown in the CRASH-2 trial. Research on oxygen-carrying substitutes as an alternative to packed red blood cells is ongoing, although no blood substitutes have been approved for use in the United States.
Fluid loss
For patients in hypovolemic shock due to fluid losses, the exact fluid deficit cannot be determined. Therefore, it is prudent to start with 2 liters of isotonic crystalloid solution infused rapidly as an attempt to quickly restore tissue perfusion. Fluid repletion can be monitored by measuring blood pressure, urine output, mental status, and peripheral edema. Multiple modalities exist for measuring fluid responsiveness such as ultrasound, central venous pressure monitoring, and pulse pressure fluctuation as described above. Vasopressors may be used if blood pressure does not improve with fluids.
Crystalloid fluid resuscitation is preferred over colloid solutions for severe volume depletion not due to bleeding. The type of crystalloid used to resuscitate the patient can be individualized based on the patients chemistries, estimated volume of resuscitation, acid/base status, and physician or institutional preferences.Isotonic saline is hyperchloremic relative to blood plasma, and resuscitation with large amounts can lead to hyperchloremic metabolic acidosis. Several other isotonic fluids with lower chloride concentrations exist, such as lactated Ringers solution or PlasmaLyte. These solutions are often referred to as buffered or balanced crystalloids. Some evidence suggests that patients who need large volume resuscitation may have a less renal injury with restrictive chloride strategies and use of balanced crystalloids. Crystalloid solutions are equally as effective and much less expensive than colloid. Commonly used colloid solutions include those containing albumin or hyperoncotic starch. Studies examining albumin solutions for resuscitation have not shown improved outcomes, while other studies have shown resuscitation with hyper-oncotic starch leads to increased mortality rate and renal failure. Patients in shock can appear cold, clammy, and cyanotic.Hypothermia increases the mortality rate of patients with hypovolemic shock. It is advised to keep the patient warm for the sake of maintaining the temperatures of all kinds of fluids inside the patient.
Monitoring parameters
Oxygen saturation by pulse oximetry (SpO2).
Respiratory rate.
Pulse rate.
Arterial blood pressure.
Pulse pressure.
Central venous pressure.
Urine output.
Base deficit and/or lactic acid.
Temperature.
Mental state.
Changes in the electrocardiogram.
Prognosis
If the vital organs are deprived of perfusion for more than just a short time, the prognosis is generally not good. Shock is still a medical emergency characterized by a high mortality rate. Early identification of patients who are likely to succumb to their illness is of utmost importance.
Epidemiology
Blood loss
Trauma remains a leading cause of death worldwide with approximately half of these attributed to hemorrhage. In the United States in 2001, trauma was the third leading cause of death overall, and the leading cause of death in those aged 1 to 44 years. While trauma spans all demographics, it disproportionately affects the young with 40% of injuries occurring in ages 20 to 39 years by one countrys account. Of this 40%, the greatest incidence was in the 20 to 24-year-old range.The preponderance of hemorrhagic shock cases resulting from trauma is high. During one year, one trauma center reported 62.2% of massive transfusions occur in the setting of trauma. The remaining cases are divided among cardiovascular surgery, critical care, cardiology, obstetrics, and general surgery, with trauma utilizing over 75% of the blood products.As patients age, physiological reserves decrease the likelihood of anticoagulant use increases and the number of comorbidities increases. Due to this, elderly patients are less likely to handle the physiological stresses of hemorrhagic shock and may decompensate more quickly.
Fluid loss
While the incidence of hypovolemic shock from extracellular fluid loss is difficult to quantify, it is known that hemorrhagic shock is most commonly due to trauma. In one study, 62.2% of massive transfusions at a level 1 trauma center were due to traumatic injury. In this study, 75% of the blood products used were related to traumatic injury. Elderly patients are more likely to experience hypovolemic shock due to fluid losses as they have a less physiologic reserve.Hypovolemia secondary to diarrhea and/or dehydration is thought to be predominant in low-income countries.
See also
Adipsia
Anemia
Cardiac index
Heart murmur
== References == |
Pallister–Hall syndrome | Pallister–Hall syndrome (abbreviated PHS) is a disorder that affects the development of many parts of the body.
It is named for Judith Hall and Philip Pallister.
Presentation
Most people with this condition have extra fingers and/or toes (polydactyly), and the skin between some fingers or toes may be fused (cutaneous syndactyly). An abnormal growth in the brain called a hypothalamic hamartoma is characteristic of this disorder. In many cases, these growths do not cause any medical problems; however, some hypothalamic hamartomas lead to seizures or hormone abnormalities that can be life-threatening in infancy. Other features of Pallister–Hall syndrome include a malformation of the airway called a bifid epiglottis, laryngeal cleft, an obstruction of the anal opening (imperforate anus), and kidney abnormalities. Although the signs and symptoms of this disorder vary from mild to severe, only a small percentage of affected people have serious complications.
Seizures
As noted above, the hypothalamic hamartoma can cause seizures.
The most common types of seizures that occur are known as gelastic epilepsy.
The term gelastic originates from the Greek word "gelos which means "laughter". Seizures may begin at any age but usually before three or four years of age. The seizures usually start with laughter and the laughter is often described as being "hollow" or "empty" and not very pleasant. The laughter occurs suddenly, comes on for no obvious reason and is usually completely out of place. The most common areas of the brain which give rise to gelastic seizures are the hypothalamus (a small but extremely important structure deep in the centre of the brain), the temporal lobes and the frontal lobes. If the child has gelastic seizures and precocious puberty, then it is likely that the child will be found to have a hypothalamic hamartoma (a hamartoma in the hypothalamus part of the brain).
Genetics
This condition is very rare; its prevalence is unknown. Mutations in the GLI3 gene cause Pallister–Hall syndrome. The GLI3 gene provides instructions for making a protein that controls gene expression, which is a process that regulates whether genes are turned on or off in particular cells. By interacting with certain genes at specific times during development, the GLI3 protein plays a role in the normal shaping (patterning) of many organs and tissues before birth. Defects in the same gene also cause Greig cephalopolysyndactyly syndrome.
Mutations that cause Pallister–Hall syndrome typically lead to the production of an abnormally short version of the GLI3 protein. Unlike the normal GLI3 protein, which can turn target genes on or off, the short protein can only turn off (repress) target genes. Researchers are working to determine how this change in the proteins function affects early development. It remains uncertain how GLI3 mutations can cause polydactyly, hypothalamic hamartoma, and the other features of Pallister–Hall syndrome.
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits a mutation in the GLI3 gene from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.
Diagnosis
Treatment
Notable Cases
George William Helon (Australian author and businessman) is a Pallister-Hall Syndrome (PHS) patient, mentor, counsellor and advocate.
References
Pallister–Hall syndrome at NLM Genetics Home Reference
External links
GeneReviews/NCBI/NIH/UW entry on Pallister–Hall Syndrome
Genetics Home Reference |
Pyaemia | Pyaemia (or pyemia) is a type of sepsis that leads to widespread abscesses of a metastatic nature. It is usually caused by the staphylococcus bacteria by pus-forming organisms in the blood. Apart from the distinctive abscesses, pyaemia exhibits the same symptoms as other forms of septicaemia. It was almost universally fatal before the introduction of antibiotics.
Sir William Osler included a three-page discussion of pyaemia in his textbook The Principles and Practice of Medicine, published in 1892. He defined pyaemia as follows:
A general disease, characterized by recurring chills and intermittent fever and the formation of abscesses in various parts, all of which result from the contamination of the blood by products arising from a focus contaminated by the bacteria of suppuration.
Earlier still, Ignaz Semmelweis – who later died of the disease – included a section titled "Childbed fever is a variety of pyaemia" in his treatise, The Etiology of Childbed Fever (1861). Jane Grey Swisshelm, in her autobiography titled Half a Century, describes the treatment of pyaemia in 1862 during the American Civil War.
Types
arterial p. Pyaemia resulting from dissemination of emboli from a thrombus in cardiac vessels.
cryptogenic p. Pyaemia of an origin that is hidden in the deeper tissues.
metastatic p. Multiple abscesses resulting from infected pyaemic thrombi.
portal p. Suppurative inflammation of the portal vein.
Symptoms
The disease is characterized by intermittent high temperature with recurrent chills; metastatic processes in various parts of the body, especially in the lungs; septic pneumonia; empyema. It may be fatal.
Clinical sign and symptoms can be differ according to system it involves.
Diagnosis
features of systemic inflammatory response syndrome tachycardia >90beats/min
tachypnea >24/min
temperature >38 or <36
Treatment
Antibiotics are effective. Prophylactic treatment consists in prevention of suppuration.
Cultural references
Ignaz Semmelweis, the original proponent of hand-washing in the practice of medicine, was widely scorned for his belief and was committed to an insane asylum where he died at age 47 of pyaemia, after being beaten by the guards, only 14 days after he was committed.
The nihilistic character Bazarov in Ivan Turgenevs Fathers and Sons dies of pyaemia.
Miller Huggins, manager of the New York Yankees, died of pyaemia while managing the team during the 1929 season.
Blind Boy Fuller died at his home in Durham, North Carolina on February 13, 1941, at 5 p.m. of pyemia due to an infected bladder, gastrointestinal tract and perineum, plus kidney failure.
Casper, a wounded soldier in "Nostalgia," by Dennis McFarland, is dying of pyemia after his lower arm is amputated.
References
== External links == |
Accessory bone | An accessory bone or supernumerary bone is a bone that is not normally present in the body, but can be found as a variant in a significant number of people. It poses a risk of being misdiagnosed as bone fractures on radiography.
Wrist and hand
Os ulnostyloideum
The os ulnostyloideum is an ulnar styloid process that is not fused to the rest of the ulna bone. On X-rays, an os ulnostyloideum is sometimes mistaken for an avulsion fracture of the styloid process. However, the distinction between these is extremely difficult. It is alleged that the os ulnostyloideum has a close relationship with or is synonymous with the os triquetrum secundarium.
Os centrale
The os carpi centrale (also briefly os centrale) is, where present, located on the dorsal side of the wrist between the scaphoid, the trapezoid and capitate, radially to the deep fossa of the capitate. The bone is present in almost every human embryo of 17–49 mm length, but then usually fuses with the ulnar side of the scaphoid. Sometimes it fuses with the capitate or the trapezoid. The literature also refers to an os centrale at the palm of the carpus, but this existence is questioned.In most primates, including orangutans and gibbons, the os centrale is an independent bone that is attached to the scaphoid by strong ligaments. Conversely, in African apes and humans, the os centrale normally fuses to the scaphoid early in development. In chimpanzees, the bone fuses with the scaphoid first after birth, while in gibbons and orangutans this occurs first at older age. A good number of scholars have construed the scaphoid-centrale fusion as a functional adaptation to knuckle-walking, since a fused morphology would better cope with the increased shear stress on this joint during this kind of quadrupedal locomotion. The results from a simulation study have shown that fused scaphoid-centrales show lower stress values as compared to non fused morphologies, thus supporting a biomechanical explanation for the scaphoid-centrale fusion as a functional adaptation for knuckle-walking.
Ankle
Accessory bones at the ankle mainly include:
Os subtibiale, with a prevalence of approximately 1%. It is a secondary ossification center of the distal tibia that appears during the first year of life, and which in most people fuses with the shaft at approximately 15 years in females and approximately 17 years in males.
Os subfibulare, with a prevalence of approximately 0.2%.Os trigonum (further described below) may also be seen on an ankle X-ray.
Foot
Accessory navicular
An accessory navicular bone, also called os tibiale externum, occasionally develops in front of the ankle towards the inside of the foot. This bone may be present in approximately 2–21% of the general population and is usually asymptomatic. When it is symptomatic, surgery may be necessary.
The Geist classification divides the accessory navicular bones into three types.
Type 1: An os tibiale externum is a 2–3 mm sesamoid bone in the distal posterior tibialis tendon. Usually asymptomatic.
Type 2: Triangular or heart-shaped ossicle measuring up to 12 mm, which represents a secondary ossification center connected to the navicular tuberosity by a 1–2 mm layer of fibrocartilage or hyaline cartilage. Portions of the posterior tibialis tendon sometimes insert onto the accessory ossicle, which can cause dysfunction, and therefore, symptoms.
Type 3: A cornuate navicular bone represents an enlarged navicular tuberosity, which may represent a fused Type 2 accessory bone. Occasionally symptomatic due to bunion formation.
Os trigonum
The os trigonum or accessory talus represents a failure of fusion of the lateral tubercle of the posterior process of the talus bone. Is estimated to be present in 7–25% of adults. It can be mistaken for an avulsion fracture of lateral tubercle of talus (Shepherd fracture) or a fracture of the Stieda process. In most cases, Os Trigonum will go unnoticed, but with some ankle injuries it can get trapped between the heel and ankle bones which irritates the surrounding structures, leading to Os Trigonum Syndrome.
Less common accessory bones
Other locations
Neck
Nodules in the posterior margin of the nuchal ligament form bone tissue in approximately 11% of males and 3–5% in females after the third decade of life, and may then be regarded to be sesamoid bones.
Shoulder
An os acromiale forms when any of its four ossification centers fail to fuse. These four ossification centers are called (from tip to base) pre-acromion, meso-acromion, meta-acromion, and basi-acromion. In most cases, the first three fuse at 15–18 years, whereas the base part fuses to the scapular spine at 12 years. Such failure to fuse occurs in between 1% and 15% of cases. It rarely causes pain.
Vertebral column
An Oppenheimer ossicle is found in approximately 4% (range 1–7%) of individuals. It is associated with the facet joints of lumbar spines. It usually occurs as a single, unilateral ossicle at the inferior articular processes, but can also occur at the superior articular processes.
Knee
The fabella is present in 10% to 30% of individuals.
See also
Accessory muscle
== References == |
Trimalleolar fracture | A trimalleolar fracture is a fracture of the ankle that involves the lateral malleolus, the medial malleolus, and the distal posterior aspect of the tibia, which can be termed the posterior malleolus. The trauma is sometimes accompanied by ligament damage and dislocation.The three aforementioned parts of bone articulate with the talus bone of the foot. Strictly speaking, there are only two malleoli (medial and lateral), but the term trimalleolar is used nevertheless and as such is a misnomer. The trimalleolar fracture is also known as cotton fracture.
Treatment
Surgical repair using open reduction and internal fixation is generally required, and because there is no lateral restraint of the foot, the ankle cannot bear any weight while the bone knits. This typically takes six weeks in an otherwise healthy person, but can take as much as twelve weeks. Non-surgical treatment may sometimes be considered in cases where the patient has significant health problems or where the risk of surgery may be too great.
References
Further reading
Weber, Martin (2004). "Trimalleolar Fractures with Impaction of the Posteromedial Tibial Plafond: Implications for Talar Stability". Foot & Ankle International. 25 (10): 716–27. doi:10.1177/107110070402501005. PMID 15566703. S2CID 43182738.
Weber, Martin; Ganz, Reinhold (2003). "Malunion following Trimalleolar Fracture with Posterolateral Subluxation of the Talus — Reconstruction Including the Posterior Malleolus". Foot & Ankle International. 24 (4): 338–44. doi:10.1177/107110070302400406. PMID 12735377. S2CID 20888046.
Bucholz, R. W.; Henry, S; Henley, M. B. (1994). "Fixation with bioabsorbable screws for the treatment of fractures of the ankle". The Journal of Bone and Joint Surgery. 76 (3): 319–24. doi:10.2106/00004623-199403000-00001. PMID 8126036.
Haraguchi, Naoki; Haruyama, H; Toga, H; Kato, F (2006). "Pathoanatomy of Posterior Malleolar Fractures of the Ankle". The Journal of Bone and Joint Surgery. 88 (5): 1085–92. doi:10.2106/JBJS.E.00856. PMID 16651584.
Langenhuijsen, Johan F.; Heetveld, Martin J.; Ultee, Jan M.; Steller, E. Philip; Butzelaar, Rudi M. J. M. (2002). "Results of Ankle Fractures with Involvement of the Posterior Tibial Margin". The Journal of Trauma: Injury, Infection, and Critical Care. 53 (1): 55–60. doi:10.1097/00005373-200207000-00012. PMID 12131390.
Van Den Bekerom, Michel P. J.; Haverkamp, Daniel; Kloen, Peter (2009). "Biomechanical and Clinical Evaluation of Posterior Malleolar Fractures. A Systematic Review of the Literature". The Journal of Trauma: Injury, Infection, and Critical Care. 66 (1): 279–84. doi:10.1097/TA.0b013e318187eb16. PMID 19131839.
Helmy, Naeder; Meyer, Dominik C.; Vienne, Patrick; Espinosa, Norman (2012). "The Posterolateral Approach for the Treatment of Trimalleolar Fractures". Techniques in Foot & Ankle Surgery. 11 (4): 189–93. doi:10.1097/BTF.0b013e3182743f11.
Forberger, Jens; Sabandal, Philipp V.; Dietrich, Michael; Gralla, Jan; Lattmann, Thomas; Platz, Andreas (2009). "Posterolateral Approach to the Displaced Posterior Malleolus: Functional Outcome and Local Morbidity". Foot & Ankle International. 30 (4): 309–14. doi:10.3113/FAI.2009.0309. PMID 19356354. S2CID 34963028.
== External links == |
Endocardial fibroelastosis | Endocardial fibroelastosis (EFE) is a rare heart disorder usually occurring in children two years old and younger. It may also be considered a reaction to stress, not necessarily a specific disease.It should not be confused with endomyocardial fibrosis.
Signs and symptoms
EFE is characterized by a thickening of the innermost lining of the heart chambers (the endocardium) due to an increase in the amount of supporting connective tissue and elastic fibres. It is an uncommon cause of unexplained heart failure in infants and children, and is one component of HEC syndrome. Fibroelastosis is strongly seen as a primary cause of restrictive cardiomyopathy in children, along with cardiac amyloidosis, which is more commonly seen in progressive multiple myeloma patients and the elderly.
Cause
A review cites references to 31 different diseases and other stresses associated with the EFE reaction. These include infections, cardiomyopathies, immunologic diseases, congenital malformations, even electrocution by lightning strike. EFE has two distinct genetic forms, each having a different mode of inheritance. An X-linked recessive form, and an autosomal recessive form have both been observed.
Diagnosis
Treatment
The cause should be identified and, where possible, the treatment should be directed to that cause. A last resort form of treatment is heart transplant.
History
An infant with dilated, failing heart was no rarity on the pediatric wards of hospitals in the mid-twentieth century. On autopsy, most of these patients hearts showed the thickened endocardial layer noted above. This was thought to be a disease affecting both the heart muscle and the endocardium and it was given various names such as: idiopathic hypertrophy of the heart, endocardial sclerosis, cardiac enlargement of unknown cause, etc. Some of these hearts also had overt congenital anomalies, especially aortic stenosis and coarctation of the aorta.The term "endocardial fibroelastosis" was introduced by Weinberg and Himmelfarb in 1943. In their pathology laboratory they noted that usually the endocardium was pearly white or opaque instead of normally thin and transparent and microscopically showed a systematic layering of collagenous and elastic fibers. They felt their new term was more adequately descriptive, and, indeed it was quickly and widely adopted. Clinicians began applying it to any infant with a dilated, failing heart, in spite of the fact that the only way to definitively establish the presence of EFE was to see it at autopsy. EFE had quickly become the name of a disease, and it continues to be used by many physicians in this way, though many patients with identical symptoms do not have the endocardial reaction of EFE.In the latter decades of the twentieth century, new discoveries and new thinking about heart muscle disease gave rise to the term "cardiomyopathy". Many of the cases of infantile cardiac failure were accordingly called "primary cardiomyopathy" as well as "primary EFE", while those with identifiable congenital anomalies stressing the heart were called "secondary EFE". In 1957 Black-Schaffer proposed a unitary explanation that stress on the ventricle, of any kind, may trigger the endocardial reaction, so that all EFE could be thought of as secondary.Evidence gradually accumulated as to the role of infection as one such type of stress. The studies of Fruhling and colleagues in 1962 were critical. They followed a series of epidemics of Coxsackie virus infection in their part of France. After each epidemic there were increased numbers of cases with EFE coming to autopsy. On closer study there were cases of pure acute myocarditis, cases of mixed myocarditis and EFE, and cases where myocarditis had healed, leaving just EFE. They were able to culture Coxsackie virus from the tissues of many of the cases at all stages of this apparent progression. A similar progression from myocarditis to EFE was later observed at Johns Hopkins but no virology was done.Noren and colleagues at the University of Minnesota, acting on an idea floated at a pediatric meeting, were able to show a relation between exposure to maternal mumps in fetal life, EFE, and a positive skin test for mumps in infants. This brought on a large ongoing controversy and finally prompted a virologist colleague of theirs to inject embryonated eggs with mumps virus. The chicks at first showed the changes of myocarditis, about a year later, typical EFE, and transitional changes in between. Despite this, the controversy about the role of mumps continued as the actual incidence of EFE plummeted. The proponents of mumps as a cause pointed to this as the effect of the recent implementation of widespread mumps immunization.Evidence that viral infection may play a role as a cause or trigger of EFE was greatly reinforced by the study directed by Towbin in the virus laboratory of Texas Childrens Hospital. They applied the methods of todays genetics to old preserved specimens from autopsies of patients with EFE done well before mumps immunization began and found mumps genome in the tissues of over 80% of these patients. It seems undeniable that transplacental mumps infection had been in the past the major cause of EFE, and that immunization was indeed the cause of EFE having become rare.Non-infectious causes of EFE have also been studied, spurred by the opening of new avenues of genetics research. Now there are specific named genes associated with certain cardiomyopathies, some of which show the characteristic reaction of EFE. A typical example is Barth syndrome and the responsible gene, tafazzin.Developments in echocardiography, both the technology of the machines and the skill of the operators, have made it no longer necessary to see the endocardium at autopsy. EFE can now be found non-invasively by the recording of increased endocardial echos. Fetal echocardiography has shown that EFE can begin to accumulate as early as 14 weeks of gestation, and increase with incredible rapidity and even that it can be reversed if the stress can be removed early in fetal life.The North American Pediatric Cardiomyopathy Registry was founded in 2000 and has been supported since by the National Heart, Lung and Blood Institute. Because of the logic of the diagnostic tree, where EFE applies to many branches of the tree and thus cannot occupy a branch, it is not listed by the Registry as a cause but rather, "with EFE" is a modifier that can be applied to any cause.Thus, the past half-century has seen EFE evolve from a mysterious but frequently observed disease to a rare but much better understood reaction to many diseases and other stresses.
See also
Papillary fibroelastoma
References
== External links == |
Nail–patella syndrome | Nail–patella syndrome is a genetic disorder that results in small, poorly developed nails and kneecaps, but can also affect many other areas of the body, such as the elbows, chest, and hips. The name "nail–patella" can be very misleading because the syndrome often affects many other areas of the body, including even the production of certain proteins.: 666 Those affected by NPS may have one or more affected areas of the body, and its severity varies depending on the individual. It is also referred to as iliac horn syndrome, hereditary onychoosteodysplasia (HOOD syndrome), Fong disease or Turner–Kieser syndrome.Diagnosis of NPS can be made at birth but is common for it to remain undiagnosed for several generations. While there is no cure available for NPS, treatment is available and recommended.
Signs and symptoms
The skeletal structures of individuals who have this disorder may have pronounced deformities. As reported by several medical doctors, the following features are commonly found in people who with nail–patella syndrome:Bones and joints
Patellar involvement is present in approximately 90% of patients; however, patellar aplasia occurs in only 20%.
In instances in which the patellae are smaller or luxated, the knees may be unstable.
The elbows may have limited motion (e.g., limited pronation, supination, extension).
Subluxation of the radial head may occur.
Arthrodysplasia of the elbows is reported in approximately 90% of patients.
General hyperextension of the joints can be present.
Exostoses arising from the posterior aspect of the iliac bones ("iliac horns") are present in as many as 80% of patients; this finding is considered pathognomonic for the syndrome.
Other reported bone changes include scoliosis, scapular hypoplasia, and the presence of cervical ribs.
Glaucoma is also closely associated with nail-patella, specifically open-angled glaucoma (OAG). Side affects may include frequent headaches, blurred vision, or total vision loss. This occurs gradually over time and symptoms may not be evident in children.Kidney issues may arise such as deposition of protein in the urine and nephritis. Proteinuria is usually the first sign of kidney involvement. It can reveal itself either rapidly or years after having asymptomatic deposition of protein in the urine, kidney failure occurs in around 5% of NPS patients. Hypothyroidism, irritable bowel syndrome, attention deficit hyperactivity disorder (ADHD), and thin tooth enamel are associated with NPS, but whether these are related or simply coincidences are unclear.
Genetics
Nail–patella syndrome is inherited via autosomal dominancy linked to aberrancy on human chromosome 9s q arm (the longer arm), 9q34. This autosomal dominancy means that only a single copy, instead of both, is sufficient for the disorder to be expressed in the offspring, meaning the chance of getting the disorder from an affected heterozygous parent is 50%. The frequency of the occurrence is 1/50,000. The disorder is linked to the ABO blood group locus.It is associated with random mutations in the LMX1B gene. Studies have been conducted and 83 mutations of this gene have been identified.
Diagnosis
The hallmark features of this syndrome are poorly developed fingernails, toenails, and patellae (kneecaps). Sometimes, this disease causes the affected person to have either no thumbnails or a small piece of a thumbnail on the edge of the thumb. The lack of development or complete absence of fingernails results from the loss of function mutations in the LMX1B gene. This mutation may cause a reduction in dorsalising signals, which then results in the failure to normally develop dorsal specific structures such as nails and patellae. Other common abnormalities include elbow deformities, abnormally shaped pelvic (hip) bones, and kidney disease.
Treatment
Treatment for NPS varies depending on the symptoms observed.
Perform screening for kidney disease and glaucoma, surgery, intensive physiotherapy, or genetic counseling.
ACE inhibitors are taken to treat proteinuria and hypertension in NPS patients.
Dialysis and kidney transplant.
Physical therapy, bracing and analgesics for joint pain.
See also
List of cutaneous conditions
List of radiographic findings associated with cutaneous conditions
References
External links
GeneReview/NCBI/NIH/UW entry on nail–patella syndrome |
Persistent generalized lymphadenopathy | Persistent generalized lymphadenopathy (PGL) is enlarged, painless, non-tender lymph nodes occurring in a couple of different areas for more than three to six months for which no other reason can be found. This condition frequently occurs in people in the latency period of HIV/AIDS.The lymphatic system is part of the immune surveillance system. Blood contains fluid and blood cells. The fluid, which may contain suspended foreign material such as bacteria and viruses, seeps through blood vessel walls into the tissues, where it bathes the body cells and exchanges substances with them. Some of this lymph fluid is then taken up by lymphatic vessels and passed back to the heart, where it is again mixed with the blood. On its way, the fluid passes through the lymph nodes, small nodular organs located throughout the body but concentrated in certain areas such as the armpits or groin. These lymph nodes are also known as glands or lymphoid tissue. If they detect something foreign passing through them, they enlarge. This is called lymphadenopathy or swollen glands. Usually this is localized (for example, an infected spot on the scalp will cause lymph nodes in the neck on that same side to swell). However, when two or more lymph node groups are involved, it is called generalized lymphadenopathy. Usually this is in response to significant systemic disease and will subside once the person has recovered. Sometimes it can persist long-term, even when no explanation for the lymphadenopathy can be found.PGL is often found in cases of autoimmune disease (where the body is attacking itself). These include diseases such as rheumatoid arthritis, lupus and sarcoidosis. Some forms of cancer will also cause PGL. Sometimes, despite exhaustive investigation, no cause for PGL is found. For the patient and the physician, this can continue to be a source of concern, but many adults have had PGL all their lives and suffered no ill effects. In others, the PGL may persist for a decade or more and then mysteriously subside. Children often have generalized lymphadenopathy of the head and neck, or even PGL, without the finding of a sinister cause. At puberty this usually disappears.The immune system of some people may be sensitized by exposure to a living exogenous irritant such as a bacterial or viral infection, which then results in PGL after the organism has been cleared from the body. In some cases the sensitization is caused by non-living exogenous irritants such as cyclic hydrocarbons (for example, resinous vapours) or pesticides and herbicides.
== References == |
Banki syndrome | Banki syndrome is a rare disorder in which two or more bones are fused. The symptoms may include: abnormality of the long bone of hand; short fingers or toes; permanent curving of the pinkie finger; fusion of wrist bones. The disorder has been reported in three generations of a single Hungarian family. First described by Z. Banki in a 1965 paper, it has been noted as being similar to Liebenberg syndrome, featuring lunatotriquetral fusion of the lunate bone with the triquetral bone, clinodactyly of the fingers, overall short metacarpals, and thin diaphysis of the longer bones, but unlike Liebenberg, no elbow dysplasia is observed.
Sources
== References == |
Trimethylaminuria | Trimethylaminuria (TMAU), also known as fish odor syndrome or fish malodor syndrome, is a rare metabolic disorder that causes a defect in the normal production of an enzyme named flavin-containing monooxygenase 3 (FMO3). When FMO3 is not working correctly or if not enough enzyme is produced, the body loses the ability to properly convert trimethylamine (TMA) from precursor compounds in food digestion into trimethylamine oxide (TMAO), through a process called N-oxidation. Trimethylamine then builds up and is released in the persons sweat, urine, and breath, giving off a strong fishy odor or strong body odor. Primary trimethylaminuria is caused by genetic mutations that affect the FMO3 function of the liver. A variant of TMAU (secondary trimethylaminuria or TMAU2) is an acquired form of TMAU where there is no genetic cause, yet excessive TMA is secreted. TMAU2 can be caused by a range of issues, including a precursor overload (ingesting too many precursors), hormonal issues related to menstrual cycles, liver damage, and liver and kidney failure. It is hypothesised that intestinal dysbiosis may cause temporary TMAU2 symptoms, however there is no direct evidence of this in a scientific study.
Metabolic pathway
Trimethylamine enters the body via the consumption of certain foods and supplements. When food is consumed that contains TMA and/or TMAO (predominately seafood; saltwater fish, shellfish, seaweed and kelp), TMAO is converted by bacteria in the lower gastrointestinal tract (gut) into TMA. Additionally, when a food substance, supplement or medicine containing a precursor (choline or carnitine) is ingested, bacteria in the gut convert a portion of those precursors to TMA. Moderate amounts of precursor are absorbed in the small intestine before reaching the gut, however if precursor rich food saturates the transport capacity of the intestine, excess precursor ends up in the gut. The proportion of precursor converted to TMA is related to the amount of specific bacteria in the gut.TMA in the gut is absorbed through the intestinal lining and enters the bloodstream, where it is filtered by the liver. The liver usually produces an abundance of the enzyme FMO3, which neutralises the TMA by oxidising it to odourless TMAO, and passes it through to the bladder. If FMO3 enzyme production is compromised, or there is too much TMA for the amount of enzyme, then TMA will continue to circulate in the bloodstream until enough enzyme is produced. While TMA is in the bloodstream, it is slowly exits the body via bodily fluids; urine, sweat, saliva, reproductive fluids and breath (See fluid balance for rates of fluid loss). TMA has no known interactions with any known internal or organ function.
Although lecithin, creatinine and betaine are technically precursors to TMA, studies have shown no significant effect on the production of excess TMA/TMAO in urinary analysis at normal dietary levels of consumption.
Symptoms and signs
Trimethylamine is most noticeable in urine, as it is captured, concentrated and released in intervals. Fishy smelling urine is a primary identifying symptom in infant children (Trimethylaminuria literally meaning "trimethylamine in urine").
Trimethylamine is also released in the persons sweat, reproductive fluids, and breath, and can give off a fishy odor when the concentration of trimethylamine is high enough to be detected. The intensity of the smell is directly correlated with the concentration of trimethylamine in the bloodstream.
Some people with trimethylaminuria report having a strong odor all the time, but when in a clinical setting most have only moderate to no smell, depending on diet and the severity of their FM03 mutation. In a study by Wise PM, of 115 identified tmau subjects, 0% had a smell detectable at a social distance and only 5% had some minor malodour when sniffing their palms. After a choline challenge load test (intentionally ingesting a TMA precursor) only 10% expressed a smell at a social distance, suggesting that those that produced odour had a more severe form of FMO3 impairment. Smell events are often sporadic and episodic in nature (based on diet over the previous 24 hours), making it often difficult to diagnose by smell alone.
Individuals with this condition do not have any physical symptoms, and they typically appear healthy.The condition seems to be more common in women than men, for unknown reasons. Scientists suspect that such female sex hormones as progesterone and estrogen aggravate the condition. According to several reports, the condition worsens around puberty. In women, symptoms may worsen just before and during menstrual periods, after taking oral contraceptives, and around menopause.The odor seems to vary depending on many known factors, including diet, hormonal changes, stress level, amount of sweat, other odors in the space, and the observers sense of smell.
Genetics
Most cases of trimethylaminuria appear to be inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. The parents of an individual with an autosomal recessive disorder are both carriers of one copy of the altered gene. Carriers may have mild symptoms of trimethylaminuria or experience temporary episodes of fish-like body odor.Mutations in the FMO3 gene, which is found on the long arm of chromosome 1, cause trimethylaminuria. The FMO3 gene makes an enzyme that breaks down nitrogen-containing compounds from the diet, including trimethylamine. These compounds are produced by bacteria in the intestine as they digest proteins from eggs, meat, soy, and other foods. Normally, the FMO3 enzyme converts fishy-smelling trimethylamine into trimethylamine N-oxide which has no odor. If the enzyme is missing or its activity is reduced because of a mutation in the FMO3 gene, trimethylamine is not broken down and instead builds up in the body. As the compound is released in a persons sweat, urine, and breath, it causes the strong odor characteristic of trimethylaminuria. Researchers believe that stress and diet also play a role in triggering symptoms.There are more than 40 known mutations associated with TMAU. Loss-of-function mutations, nonsense mutations, and missense mutations are three of the most common. Nonsense and missense mutations cause the most severe phenotypes.
Although FMO3 mutations account for most known cases of trimethylaminuria, some cases are caused by other factors. A fish-like body odor could result from an excess of certain proteins in the diet or from an increase in bacteria in the digestive system. A few cases of the disorder have been identified in adults with liver damage caused by hepatitis.
In 2007 the evolution of the FMO3 gene was studied, including the evolution of some mutations associated with TMAU.
Diagnosis
Measurement of urine for the ratio of trimethylamine to trimethylamine oxide is the standard screening test. A blood test is available to provide genetic analysis. The prominent enzyme responsible for TMA N-oxygenation is coded by the FMO3 gene.
False positives can occur in the following conditions, where elevated TMA can be present in the urine without any underlying TMAU:
Urinary tract infection
Bacterial vaginosis
Cervical cancer
Advanced liver or kidney diseaseA similar foul-smelling odor of the urine has also been associated with colonization of the urinary tract with a bacterium called Aerococcus urinae, especially in children.Olfactory reference syndrome is a condition where there is a persistent false belief and preoccupation with the idea of emitting an abnormal body odor. According to McNiven at a canadian genetics clinic, 83% of referrals for genetic testing for TMAU were deemed likely to instead have ORS. Findings found that the use of “fecal/sewage” as a description, and the use of multiple descriptors of the smell, and incorrect locations of smell origin effectively differentiated ORS from TMAU. In the literature on body odour identification, emphasis is frequently placed on multiple consultations to reduce the risk of misdiagnosis, and also asking the individual to have a reliable confidant accompany them to the consultation who can confirm the reality of the reported symptom. ORS patients are unable to provide such confidants as they have no objective odor.A fecal smell (fecal body odour) is often a self reported symptom associated with TMAU, however there is no recorded evidence of fecal body odour present in any study related to TMAU. Cashman JR found that 53% of TMAU and 59% of non-TMAU subjects suffered from regular halitosis, dental plaque on the back of the tongue, which produced on average "200-600 ppb of sulfurous/fecal smelling volatile sulfur compounds (i.e., VSC: hydrogen sulfide; methylmercaptan; dimethylsulfide) with each exhalation, creating a “malodorous cloud” in their vicinity. It is likely that halitosis, ORS or in severe cases, a bowel obstruction leading to fecal vomiting may be the cause.
There is the possibility that someone may suffer from both Trimethylaminuria and ORS-like paranoia, due to the potential lack of ability to smell the odour oneself and the worry that it generates. It is recommended to organise reliable confidants, colleagues, friends or relatives ("smell buddies") to work with the sufferer to discretely inform them if they are presenting an odour.
Treatment
There is no known permanent cure or treatment for primary trimethylaminuria, only mitigation of the effects. For secondary trimethylaminuria, it depends on the cause; for precursor overload, reducing the intake of TMA and its precursors will end symptoms. For TMAU caused by hypothetical gut dysbiosis, clinical review by a doctor, a plant based diet and reduced precursor intake should return gut flora to a healthy state.Primary TMAU sufferers generally have some residual FMO3 activity in the liver which processes TMA, however this happens relatively slowly. According to a study by Al-Waiz M TMA filters through to the bladder at half the rate of TMAO, and a healthy functioning person passes 99% of TMAO in urine within 24 hours. Therefore its estimated that the majority of TMA would be filtered out within 48 hours if no additional TMA or precursor is ingested, regardless of liver function.
The metabolic and clinical manifestations of TMAU are generally regarded as benign, as there is no associated organ dysfunction. This designation, and the fact that the condition is often unrecognised by doctors, misdiagnosed and can have important ramifications including missed or delayed diagnosis.Affected individuals experience shame and embarrassment, fail to maintain relationships, avoid contact with people who comment on their condition, and are obsessive about masking the odour with hygiene products and even smoking. The malodorous aspect can have serious and destructive effects on schooling, personal life, career and relationships, resulting in social isolation, low self-esteem, depression, paranoid behaviour, and suicide. Delayed diagnosis, body odour and the lack of cure may lead to psychosocial issues. When the condition is suspected or known to occur in a family, genetic testing can be helpful in identifying the specific individuals who have or carry the disorder.Ways of reducing the fishy odor may include:
Avoiding all seafood, including fish, shellfish, kelp, seaweed. Seafood contains TMAO, which is converted to TMA in the stomach, and will directly raise TMA levels in the person.
Avoiding red meat (beef, lamb and pork), liver, offal, and foods and supplements that contain carnitine. A study performed by Wang Z found that when comparing diets where the main protein source was red meat, white meat and non-meat protein sources, consumption of red meat increased the production of TMAO, whereas white meat and non-meat protein diets generated only low to negligible amounts TMAO. This study indicates that red meat is a major driver of TMA production by altering the balance of microbiota in the stomach due to the carnitine found in red meat. A further study by Crimarco A found that a 8 week plant based diet significantly reduced TMAO production, and further, that after switching the diet to include animal based protein, TMAO production was less than the participants who had only been given an animal protein based diet. The findings suggest that the microbiome in the gut is modified by a plant based diet, and for a time a person will lack the bacteria required to convert choline and carnitine into TMA at the same rate of a animal protein based diet.
Reducing the intake of fish, red meat, white meat, offal, egg yolks, legumes, beans, whey products, and other foods and supplements that contain high levels of choline. Choline is an essential nutrient so complete elimination of choline is unadvised. As above, white meat (chicken, turkey) and plant based products may be fine to consume if red meat is predominantly avoided. Note, while raw ingredients like soybeans have a relatively high choline content, some processed products like soy sauce, soy milk and tofu have low choline content, due to dilution of ingredients, small serving size, or removal as a byproduct during the manufacturing process. Its best to check the choline content of food and the portion size for a better understanding of how much choline is being consumed.
Vitamin B2 at 50 mg per day in combination with diet resolved smell issues for 2 children with TMAU. B2 was found to increase residual FMO3 performance.
Taking low doses of antibiotics such as neomycin and metronidazole in order to reduce the amount of bacteria in the gut, although this is not recommended as a long term solution due to antibiotic resistance and other side effects.
Using slightly acidic detergent and body washes with a pH between 5.5 and 6.5Additionally, at least one study has suggested that daily intake of the supplements activated charcoal and copper chlorophyllin may temporarily improve the quality of life of individuals afflicted with TMAU by helping their bodies to oxidize and convert TMA to the odorless N-oxide (TMAO) metabolite. Study participants experienced subjective reduction in odor as well as objective reduction in TMA and increase in TMAO concentration measured in their urine. The study found that:
85% of test participants experienced complete loss of detectable "fishy" odor
10% experienced some reduction in detectable odor
5% did not experience any detectable odor reduction
History
The first clinical case of TMAU was described in 1970.
Notable media
In 2014, singer/songwriter Cassie Graves was first featured in the Daily Mail, the Daily Mirror, and The Metro UK newspapers in both print and Online, giving an interview about her experiences with Trimethylaminuria. The article was later repurposed in media across the globe, most notably by HuffPost.In 2016, Graves was then featured in Princess Productions Medical Mysteries on UKs Channel 5, which went on a journey to find an official diagnosis for the condition, and again sparked a global media interest in the condition.
References
External links
This article incorporates public domain text from The U.S. National Library of Medicine and The National Human Genome Research Institute |
X-linked complicated corpus callosum dysgenesis | X-linked complicated corpus callosum dysgenesis is a genetic disorder characterized by dysplasia, hypoplasia or agenesis of the corpus callosum alongside variable intellectual disability and spastic paraplegia. Only 13 cases (all male) have been described in medical literature. Transmission is X-linked recessive. It is the mildest subtype of L1 syndrome.This condition differs from other L1 syndromes due to the fact that neither hydrocephalus, adducted thumbs, or speech difficulties are common in patients with the condition.
Genetics
This condition is caused by X-linked recessive mutations in the L1CAM gene, located in the long arm of the X chromosome. Mutations involved in the milder variants of L1 syndrome (including X-linked complicated corpus callosum dysgenesis) usually work by changing the L1 protein structure.
Cases
The following list comprises all cases of X-linked complicated corpus callosum dysgenesis described in medical literature (from OMIM):
1964: Menkes et al. describes 5 males from 4 sibships of a 2-generation American family. The males (all infants) had partial corpus callosum agenesis, severe intellectual disabilities, developmental delays, and epilepsy. The disorder first manifested right after birth, with recurrent seizures occurring hours after it. Out of these 5 babies, 3 had died. Post-mortem examination of one of the dead infants revealed chemical and anatomical abnormalities.
1983: Kaplan et al. describes 2 males from a 2-generation Canadian family. The proband was a 2 year old male, the first-born child of healthy, non-consanguineous Ashkenazi Jewish parents in their mid-20s, his pregnancy was uneventful (besides slight vaginal bleeding experienced by the mother sometime during her first three months of pregnancy). He was noted to have unilateral congenital ptosis, clinodactyly affecting the index and ring fingers, bilateral thumb adduction, and upper limb weakness at birth, with symptoms of Hirschsprungs disease showing 24 hours after he was born. He was psychomotorly delayed. CT scans showed brain growth delay, corpus callosum agenesis, and a hypoplastic inferior vermis and cerebellum. Electroencephalograms gave abnormal results. He was born weighing 3.09 kilograms, being 49 cm long, and with a head circumference of 33.5 cm. The second case was his 24-year-old maternal uncle. He was psychomotorly delayed like his nephew, and he noted to have pectus excavatum and speckled irises only. CT scans showed only corpus callosum agenesis. His head circumference at the time was 52 cm. Chromosomal analysis done on the proband child, his mother and his uncle was normal. Family history on the mothers family only revealed a distant third-cousin with Hirschsprungs disease, her two other brothers were normal, and she went on to have a normal female pregnancy.
1992: Kang et al. describes 4 male children each from 4 different sibships belonging to an ethnic Chinese Taiwanese family, constituting the first case report of X-linked complicated corpus callosum dysgenesis in China. Said children had microcephaly, spasticity, intellectual disabilities, hydrocephalus, and facial dysmorphisms. Some of them had an interhemispheric cyst.
2006: Basel-Vanagaite et al. describes 2 Israeli Jewish brothers who both had partial corpus callosum agenesis alongside mild intellectual disability. One of the siblings had bilateral congenital radial head dislocation and Hirschsprungs disease. Genetic testing revealed a missense mutation (p.P240L) in exon 7 of the L1CAM gene.
== References == |
Epidermolytic hyperkeratosis | Epidermolytic ichthyosis (EI), also known as bullous epidermis ichthyosis (BEI), epidermolytic hyperkeratosis (EHK), bullous congenital ichthyosiform erythroderma (BCIE), bullous ichthyosiform erythroderma: 482 or bullous congenital ichthyosiform erythroderma Brocq, is a rare and severe form of ichthyosis this skin disease affects around 1 in 300,000 people.
The condition is caused by a genetic mutation, so it cannot be completely cured without some form of gene therapy.
While some research has been done into possible gene therapy treatments, the work hasnt yet been successfully developed to the stage where it can be routinely given to patients.
The condition involves the clumping of keratin filaments.: 562
Presentation
Epidermolytic hyperkeratosis is a skin disorder that is present at birth. Affected babies may have very red skin (erythroderma) and severe blisters. Because newborns with this disorder are missing the protection provided by normal skin, they are at risk of becoming dehydrated and developing infections in the skin or throughout the body (sepsis).
As affected individuals get older, blistering is less frequent, erythroderma becomes less evident, and the skin becomes thick (hyperkeratotic), especially over joints, on areas of skin that come into contact with each other, or on the scalp or neck. This thickened skin is usually darker than normal. Bacteria can grow in the thick skin, often causing a distinct odor.
Epidermolytic hyperkeratosis can be categorized into two types :-
People with PS-type epidermolytic hyperkeratosis have thick skin on the palms of their hands and soles of their feet (palmoplantar or palm/sole hyperkeratosis) in addition to other areas of the body.
People with the other type, NPS-type, do not have extensive palmoplantar hyperkeratosis, but do have hyperkeratosis on other areas of the body.Epidermolytic hyperkeratosis is part of a group of conditions called ichthyoses, which refers to the scaly skin seen in individuals with related disorders. However, in epidermolytic hyperkeratosis, the skin is thick but not scaly as in some of the other conditions in the group.
http://ghr.nlm.nih.gov/condition/epidermolytic-hyperkeratosis
Genetics
It is possible to classify epidermolytic hyperkeratosis based upon palm and sole hyperkeratosis.This is a dominant genetic condition caused by mutations in the genes encoding the proteins keratin 1 or keratin 10.
Keratin 1 is associated with the variants affecting the palms and soles.
Keratin 10 is associated with the variants in which these are unaffected.
Diagnosis
The condition can be diagnosed via exam that reveals; generalized redness; thick, generally dark, scales that tend to form parallel rows of spines or ridges, especially near large joints; the skin is fragile and blisters easily following trauma; extent of blistering and amount of scale is variable.
Treatment
Oral retinoids have proven effective in treating this disorder. Depending on the side effects they may improve the quality of life. Examples are etretinate, acitretin, isotretinoin
Gene therapy
Gene therapy is really the only true therapy on the horizon for sufferers of EHK.
Over the past 10 years since the first EHK mouse model was developed, many ideas have been discussed about how best to cure EHK. Back as far as 1994 researchers were discussing new promising ideas such as topical lotions that would deliver ribozymes in a liposome cream. Ribozymes are a small piece of synthetic RNA which can digest RNA molecules. When cells make a protein from a gene on a chromosome sitting in the nucleus, the gene is first transcribed as a piece of RNA. This RNA is then translated into a protein. Ribozymes can be designed to destroy RNA molecules with specific sequences. In theory, this will stop the production of the protein encoded by the mutant alleles of the gene.
Successful gene therapy solutions have been recently achieved on mouse models by Jiang Chen M.D., a post-doctoral fellow in the laboratory of Dennis Roop, Ph.D., in the Center for Cutaneous Molecular Biology at Baylor College of Medicine. In 1998 they developed an inducible mouse model for epidermolysis hyperkeratosis which is viable, because the expression of a mutant K10 allele can be restricted to a focal area of the skin. "Once the mutant K10 allele is activated in epidermal stem cells by topical application of an inducer, these stem cells continuously give rise to defective progeny that form hyperkeratotic lesions which persist for the life of the mouse. It was observed that partial suppression of the mutant K10 gene may be sufficient to eliminate the disorder."
To test this observation, Dr. Chen and his team of researchers developed siRNAs that target the mutant K10 gene products for degradation, without affecting normal K10 gene products. Dr. Chen observed that under these conditions, an efficient knock-down of mutant, but not normal, K10 genes could be achieved. The results allowed the normal K10 genes to function properly building healthy skin tissues. He claims that these results may prove to be a very vital step forward in forging a novel gene therapy and possible permanent corrective therapy for this debilitating skin disorder.
Next steps
The challenge has always been how to deliver the siRNA using a topical method or retroviral vectors and ex vivo gene transfer. In 2011/12 a team at Northwestern University claim to have solved the topical delivery of siRNA dilemma. Personalized siRNA can be delivered in a commercial moisturizer or phosphate-buffered saline, and do not require barrier disruption or transfection agents, such as liposomes, peptides, or viruses. "Topical application of nucleic acids offers many potential therapeutic advantages for suppressing genes in the skin, and potentially for systemic gene delivery. However, the epidermal barrier typically precludes entry of gene-suppressing therapy unless the barrier is disrupted. We now show that spherical nucleic acid nanoparticle conjugates (SNA-NCs), gold cores surrounded by a dense shell of highly oriented, covalently immobilized siRNA, freely penetrate almost 100% of keratinocytes in vitro, mouse skin, and human epidermis within hours after application."
This new discovery may soon offer hope to all suffering from mono-genetic diseases such as EHK. This may lead to promising personalized, topically delivered gene therapy of cutaneous tumors, skin inflammation, and dominant negative genetic skin disorders.
UPDATE: OCTOBER 2014
As of late, Paller reports "we are using a new nanotechnology-based technique called spherical nucleic acids (SNAs) to suppress the production of the abnormal keratin 10 gene that is the most common change leading to epidermolytic ichthyosis. We continue to screen candidate SNAs to find a few that clearly suppress the abnormal keratin 10 gene much more than the normal keratin 10 gene. In the meantime, we have developed several tools towards this effort, which can also be used by other researchers. Most recently weve developed a special lentivirus reporter construct in which we can see through changes in fluorescence whether or not our SNA works."
Dr. Paller and her team recently received more good news with regard to progressing their research. "We just received a grant from the National Institutes of Health (NIH) to continue this effort based on our preliminary data collected with FIRSTs funding support. FIRST has been instrumental in furthering our research efforts related to ichthyosis," she said.
Maintenance
Until gene therapy solutions finally become reality, EHK sufferers must treat their fragile skin carefully. Most have learned that taking regular extended baths allows patients to care for their fragile skin and keep it manageable. Baths that include sea salt seem to improve the process of softening and removing the thickened skin.
Ointments like Petroleum Jelly, Aveeno, and other barrier type ointment help hold the moisture in the skin after a bath.
See also
Hyperkeratosis
Ichthyosis
Ichthyosis bullosa of Siemens
Isotretinoin (Accutane)
List of cutaneous conditions
List of cutaneous conditions caused by mutations in keratins
List of verrucous carcinoma subtypes
Nonbullous ichthyosiform erythroderma
References
== External links == |
Ankle flare | A "flare" is a spreading area of redness or flush. It is the second reaction in the triple response to injury and is due to dilatation of the arteriole. When this flare occurs around the ankle, it is called an ankle flare. The condition is also known as a malleolar flare, in reference to the malleolus, the bony prominence on each side of the ankle.
Ankle flares are often caused by venous ulcer, due to deep vein thrombosis or varicose veins. It is considered to be an early sign of advanced venous disease. Treatment involves management of the underlying condition, along with supportive care.
See also
Corona phlebectatica
== References == |
Ischemic fasciitis | Ischemic fasciities (IF), also termed atypical decubital fibroplasia or decubital ischemic fasciitis, is a rare pseudosarcomatous (i.e. easily mistaken for a sarcoma) tumor. It was first described by E. A. Montgomery et al. in 1992. This tumor typically forms in the subcutaneous tissues (i.e. lower most tissue layer of the skin) that overlie bony protuberances such as a hip in individuals who are debilitated and bed-ridden.Microscopically, IF lesions consist of proliferating, atypical fibroblasts and/or myofibroblasts. The lesions were initially regarded as non-neoplastic proliferation responses of these cell types to long-term tissue pressure or trauma. More recently, however, the World Health Organization, 2020, defined IF lesions as neoplasms, i.e. tissue growths which are uncoordinated with that of the normal surrounding tissue and persist in growing even if the original trigger for their development is removed. The Organization formally classified IF lesions as belonging to the category of benign fibroblastic and myofibroblastic tumors.The treatment of choice for these often disfiguring, uncomfortable, and/or painful IF tumors is generally conservative, local surgical excision. It is critically important that these benign tumors be distinguished from other fasciitis tumors as well as certain sarcomas which can be highly invasive and/or malignant and therefor require far more aggressive treatment.
Presentation
In the original study of IF, individuals diagnosed with the disorder were women (16 cases) or men (12 cases) age 15 to 95 years; In a more recent study, diagnosed individuals were women (15 cases) or men (29 cases) aged 23–96 years old. Most individuals in these two studies were in their 8th or 9th decade when diagnosed with IF and, overall, had a relatively long history of being invalided, immobilized, and/or bed-ridden due to other disorders such as severe osteoarthritis, rheumatoid arthritis, chronic renal failure, chronic obstructive pulmonary disease, cancer, or dementia. In the study of 44 individuals, however, an appreciable number of patients did not have a history of debilitation. Some individuals reported that they had prior trauma in the areas where their lesions developed.Individuals present with a painless or painful and sometimes disabling slowly growing mass that is ill-defined, located in deep subcutaneous tissues, and, rarely, has spread into an adjacent skeletal muscle or tendon. The masses vary from 1.3 to 10 cm in maximum diameter. In the study of 44 cases, 76.7% of the tumors were located around the base of a hip (11 cases), shoulder (7 cases), or greater trochanter of the femur; 4 were in a hip joint, 4 in a thigh, 3 in the iliac crest, 2 in a buttock, and 1 each in the lumbar region, scapular region, or a deltoid muscle; in the remaining cases, ~11.2% of the tumors were on the chest wall away from the shoulders and ~11.2% were on the back. Typically, the tumors reside over boney protuberances which, it is thought, provide the mechanical pressures that cause poor blood flow to nearby subcutaneous tissues, aberrant wound healing in these tissues, and thereby the development of IF.
Pathology
On gross examination, IF tumors are typically white-yellow masses with central necrosis (i.e. areas of dead or dying cells), and areas containing cysts and/or old, dried hemorrhages. The tumors are often poorly circumscribed, have an infiltrative appearance, may be multinodular, and lie in subcutaneous tissue but may also involve the dermal layer of the skin and/or the reticular dermis. Microscopic histopathological studies of IF tissues report the characteristic presence of a distinct zonal appearance, i.e. the presence of central zones of fibrinoid necrosis and areas of cyst-laden necrosis in a hypocellular background surrounding by a zone of granulation tissue (i.e. connective tissue containing microscopic blood vessels) populated by atypical, swollen fibroblasts, myofibroblasts, and/or macrophages.Immunohistochemistry analyses of IF tumors often show the presence of fibroblasts, fibroblast-like cells, and or other types of cells that in a percentage of cases express smooth muscle actin proteins, CD68 protein,. desmin protein, vimentin protein, and collagen type IV protein, but not keratin, S100, calponin, or CD34 proteins. The finding that a tumors cells have some of these patterns of protein expression can help support the diagnosis of IF.
Gene and chromosome abnormalities
A single case of IF was found to have tumor cells bearing chromosomal translocations between chromosomes 1 and 2 and/or chromosomes 7 and 19. While further studies are needed to confirm these finding and to conduct further gene and chromosome analyses, these results support the notion that IF tumors are neoplasms rather than purely reactive lesions.
Diagnosis
IF tumors have features which overlap other types of fasciitis disorders such as proliferative fasciitis and nodular fasciitis. However, the age, history of debilitation, tumor location over boney protuberances, and tumor histopathology of having two distinctly different zones tend to distinguish IF from these two as well as the following tumors. Decubitus ulcers, i.e. common bed sores, differ from IF in typically having extensive ulcerations of the skin and histopathological evidence of acute inflammation as determined by the presence of various types of white blood cells. IF has also been mistaken for epithelioid sarcoma and elastofibroma dorsi. IF differs form epithelioid sarcoma by its clinical presentation, typical tumor cell morphology, i.e. round cells with atypical nuclei and eosinophilic cytoplasm, and complete or relative lack of necrotic areas. Elastofibroma dorsi is distinguished from IF by its abundant content of elastic fibers.
Treatment
IF tumors are commonly treated by surgical excision although in rare cases these tumors have recurred at the site of their removal. Recurrent tumors have been treated by repeated surgical excisions. Since IF tumors have not been reported to metastasize and no deaths have been attributed to it, long-term clinical observation without surgical intervention is a reasonable alternative to surgery, particularly for IF tumors that are neither uncomfortable, painful, or disfiguring.
== References == |
Poikiloderma of Civatte | Poikiloderma of Civatte is a cutaneous condition and refers to reticulated red to red-brown skin patches with telangiectasias. It is identifiable as a reddish-brown discoloration on the side of the neck, usually on both sides. It is more common in lighter-skinned individuals, in females rather than in males and more often affects middle-aged to elderly women.
This disease is basically a change of the skin due to dilation of the blood vessels in the neck. "Civatte" was the French dermatologist who first identified it in the 1920s.
See also
Cutis rhomboidalis nuchae
List of cutaneous conditions
Poikiloderma
Poikiloderma vasculare atrophicans
References
== External links == |
Harrington rod | The Harrington rod (or Harrington implant) is a stainless steel surgical device. Historically, this rod was implanted along the spinal column to treat, among other conditions, a lateral or coronal-plane curvature of the spine, or scoliosis. Up to one million people had Harrington rods implanted for scoliosis between the early 1960s and the late 1990s.
History
The Harrington implant was developed in 1953 by Paul Harrington, a professor of orthopedic surgery at Baylor College of Medicine in Houston, Texas.Harrington rods were intended to provide a means to reduce the curvature and to provide more stability to a spinal fusion. Before the Harrington rod was invented, scoliosis patients had their spines fused without any instrumentation to support it; such fusions required many months in plaster casts, and large curvatures could progress despite fusion.
Purpose
Harrington rod instrumentation was used to treat instability and deformity of the spine. Instability occurs when the spine no longer maintains its normal shape during movement. Such instability results in nerve damage, spinal deformities, and disabling pain. Spinal deformities may be caused by birth defects, fractures, marfan syndrome, neurofibromatosis, neuromuscular diseases, severe injuries, and tumors. By far, the most common use for the Harrington rod was in the treatment of scoliosis, for which it was invented.
Description
The device itself was a stainless steel distraction rod fitted with hooks at both ends and a ratchet and was implanted through an extensive posterior spinal approach, the hooks being secured onto the vertebral laminae. It was used at the beginning without performing a spinal fusion but early results proved fusion as part of the procedure was mandatory, as movement of the unfused spine would cause the metal to fatigue and eventually break. The procedure required the use of a postoperative plaster cast or bracing until vertebral fusion had occurred.
Flatback syndrome
Flatback syndrome is a problem that develops in some patients treated with Harrington rod instrumentation, where the rod extends down into lower part of the lumbar spine. Because the Harrington cannot follow the natural lordosis of the lower back (i.e. the backwaist curve), the spine is straightened out into an unnatural position. At first, the unfused spinal segments compensate for the straightening effects, but eventually the discs degenerate and wear down. The patient then develops back pain, has difficulty standing upright, and experiences limitations when walking. Eventually, the problem requires surgery to realign the spine.
As exemplified by Pecina and Dapic in the European Spine Journal (February 2007), flatback syndrome is not inevitable and does not happen to every person with a low Harrington rod instrumented fusion – there are many people who have had Harrington rods for decades with no adverse effects.
References
External links
Medscape – Modern Posterior Thoracic Instrumentation
20-year follow-up of Harrington instrumentation in the treatment of severe Idiopathic Scoliosis, Pecina & Dapic, European Spine Journal Vol 16 No 2 Feb 2007 (subscription only) |
Interdigitating dendritic cell sarcoma | Interdigitating dendritic cell sarcoma is a form of malignant histiocytosis affecting dendritic cells.
It can present in the spleen. It can also present in the duodenum.
References
== External links == |
Atrial tachycardia | Atrial tachycardia is a type of heart rhythm problem in which the hearts electrical impulse comes from an ectopic pacemaker (that is, an abnormally located cardiac pacemaker) in the upper chambers (atria) of the heart, rather than from the sinoatrial node, the normal origin of the hearts electrical activity.
As with any other form of tachycardia (rapid heart beat), the underlying mechanism can be either the rapid discharge of an abnormal focus, the presence of a ring of cardiac tissue that gives rise to a circle movement (reentry), or a triggered rapid rhythm due to other pathological circumstances (as would be the case with some drug toxicities, such as digoxin toxicity).
Classification
Forms of atrial tachycardia (ATach) include multifocal atrial tachycardia (MAT), focal atrial tachycardia and atrial flutter. Paroxysmal atrial tachycardia (PAT) is an episode of arrhythmia that begins and ends abruptly.
Etiology
Atrial tachycardia tends to occur in individuals with structural heart disease, with or without heart failure, and ischemic coronary artery disease. However, focal atrial tachycardia often occurs in healthy individuals without structural heart disease. Other possible etiologies are listed below:
Hypoxia
Pulmonary disease
Ischemic heart disease
Stimulants: cocaine, caffeine, chocolate, ephedra
Alcohol
Metabolic disturbances
Digoxin toxicity
Heightened sympathetic toneA study noted 10 to 15% of patients presenting for supraventricular tachycardia ablation had atrial tachycardia.
Diagnosis
Electrocardiographic features include:
Atrial rate: 100 to 250 BPM
Ventricular conduction can be variable
Irregular or irregularly irregular in the setting of variable AV block
Regular if 1 to 1, 2 to 1, or 4 to 1 AV block
P wave morphology
Unifocal, but similar in morphology to each other
Might be inverted
Differs from normal sinus P wave
May exhibit either long RP or short PR intervals
Rhythm may be paroxysmal or sustained
May demonstrate an increase in the rate at initiation (e.g., "warm up," or "rev up")
May demonstrate a decrease in the rate at termination (e.g., "cool down")
Treatment
Initial management of focal atrial tachycardia should focus on addressing underlying causes: treating acute illness, cessation of stimulants, stress reduction, appropriately managing digoxin toxicity, or chronic disease management. The ventricular rate is controllable with the use of beta blockers or calcium channel blockers. If atrial tachyarrhythmia persists and the patient is symptomatic, the patient may benefit from class IA, IC, or class III antiarrhythmics. Catheter ablation of focal atrial tachycardia may be appropriate in patients failing medical therapy.
Epidemiology
A European study of young males applying for pilot licenses demonstrated that 0.34% had asymptomatic atrial tachycardia and 0.46% had symptomatic atrial tachycardia.
References
== External links == |
Amputation | Amputation is the removal of a limb by trauma, medical illness, or surgery. As a surgical measure, it is used to control pain or a disease process in the affected limb, such as malignancy or gangrene. In some cases, it is carried out on individuals as a preventive surgery for such problems. A special case is that of congenital amputation, a congenital disorder, where fetal limbs have been cut off by constrictive bands. In some countries, amputation is currently used to punish people who commit crimes. Amputation has also been used as a tactic in war and acts of terrorism; it may also occur as a war injury. In some cultures and religions, minor amputations or mutilations are considered a ritual accomplishment. When done by a person, the person executing the amputation is an amputator.In the US, the majority of new amputations occur due to complications of the vascular system (the blood vessels), especially from diabetes. Between 1988 and 1996, there were an average of 133,735 hospital discharges for amputation per year in the US. In 2005, just in the US, there were 1.6 million amputees. In 2013, the US had 2.1 million amputees. Approximately 185,000 amputations occur in the United States each year. In 2009, hospital costs associated with amputation totaled more than $8.3 billion. There will be an estimated 3.6 million people in the US living with limb loss by 2025.
Types
Leg
Lower limb amputations can be divided into two broad categories: minor and major amputations. Minor amputations generally refer to the amputation of digits. Major amputations are commonly below-knee- or above-knee amputations. Common partial foot amputations include the Chopart, Lisfranc, and ray amputations.
Common forms of ankle disarticulations include Pyrogoff, Boyd, and Syme amputations. A less common major amputation is the Van Nes rotation, or rotationplasty, i.e. the turning around and reattachment of the foot to allow the ankle joint to take over the function of the knee.
Types of amputations include:
partial foot amputation
amputation of the lower limb distal to the ankle joint
ankle disarticulation
amputation of the lower limb at the ankle joint
trans-tibial amputation
amputation of the lower limb between the knee joint and the ankle joint, commonly referred to as a below-knee amputation
knee disarticulation
amputation of the lower limb at the knee joint
trans-femoral amputation
amputation of the lower limb between the hip joint and the knee joint, commonly referred to an above-knee amputation
hip disarticulation
amputation of the lower limb at the hip joint
trans-pelvic disarticulation
amputation of the whole lower limb together with all or part of the pelvis, also known as a hemipelvectomy or hindquarter amputation
Arm
Types of upper extremity amputations include:
partial hand amputation
wrist disarticulation
trans-radial amputation, commonly referred to as below-elbow or forearm amputation
elbow disarticulation
trans-humeral amputation, commonly referred to as above-elbow amputation
shoulder disarticulation
forequarter amputationA variant of the trans-radial amputation is the Krukenberg procedure in which the radius and ulna are used to create a stump capable of a pincer action.
Other
Facial amputations include but are not limited to:
amputation of the ears
amputation of the nose (rhinotomy)
amputation of the tongue (glossectomy).
amputation of the eyes (enucleation).
amputation of the teeth (dental avulsion). Removal of teeth, mainly incisors, is or was practiced by some cultures for ritual purposes (for instance in the Iberomaurusian culture of Neolithic North Africa).
Breasts:
amputation of the breasts (mastectomy).
Genitals:
amputation of the testicles (castration).
amputation of the penis (penectomy).
amputation of the foreskin (circumcision).
amputation of the clitoris (clitoridectomy).Hemicorporectomy, or amputation at the waist, and decapitation, or amputation at the neck, are the most radical amputations.
Genital modification and mutilation may involve amputating tissue, although not necessarily as a result of injury or disease.
Self-amputation
In some rare cases when a person has become trapped in a deserted place, with no means of communication or hope of rescue, the victim has amputated his or her own limb. The most notable case of this is Aron Ralston, a hiker who amputated his own right forearm after it was pinned by a boulder in a hiking accident and he was unable to free himself for over five days.Body integrity identity disorder is a psychological condition in which an individual feels compelled to remove one or more of their body parts, usually a limb. In some cases, that individual may take drastic measures to remove the offending appendages, either by causing irreparable damage to the limb so that medical intervention cannot save the limb, or by causing the limb to be severed.
Causes
Circulatory disorders
Diabetic vasculopathy
Sepsis with peripheral necrosis
Peripheral artery disease which can lead to gangrene
A severe deep vein thrombosis (phlegmasia cerulea dolens) can cause compartment syndrome and gangrene
Neoplasm
Cancerous bone or soft tissue tumors (e.g. osteosarcoma, chondrosarcoma, fibrosarcoma, epithelioid sarcoma, Ewings sarcoma, synovial sarcoma, sacrococcygeal teratoma, liposarcoma), melanoma
Trauma
Severe limb injuries in which the limb cannot be saved or efforts to save the limb fail.
Traumatic amputation (an unexpected amputation that occurs at the scene of an accident, where the limb is partially or entirely severed as a direct result of the accident, for example, a finger that is severed from the blade of a table saw)
Amputation in utero (Amniotic band)
Congenital anomalies
Deformities of digits and/or limbs (e.g., proximal femoral focal deficiency, Fibular hemimelia)
Extra digits and/or limbs (e.g., polydactyly)
Infection
Bone infection (osteomyelitis) and/or diabetic foot infections
Gangrene
Trench foot
Necrosis
Meningococcal meningitis
Streptococcus
Vibrio vulnificus
Necrotizing fasciitis
Gas gangrene
Legionella
Influenza A Virus
Animal bites
Sepsis
Bubonic plague
Frostbite
Frostbite is a cold-related injury occurring when an area (typically a limb or other extremity) is exposed to extreme low temperatures, causing the freezing of the skin or other tissues. Its pathophysiology involves the formation of ice crystals upon freezing and blood clots upon thawing, leading to cell damage and cell death. Treatment of severe frostbite may require surgical amputation of the affected tissue or limb; if there is deep injury autoamputation may occur.
Athletic performance
Sometimes professional athletes may choose to have a non-essential digit amputated to relieve chronic pain and impaired performance.
Australian Rules footballer Daniel Chick elected to have his left ring finger amputated as chronic pain and injury was limiting his performance.
Rugby union player Jone Tawake also had a finger removed.
National Football League safety Ronnie Lott had the tip of his little finger removed after it was damaged in the 1985 NFL season.
Criminal penalty
According to Quran 5:38, the punishment for stealing is the amputation of the hand. Under Sharia law, after repeated offense, the foot may also be cut off. This is still in practice today in countries like Brunei, the United Arab Emirates, Iran, Saudi Arabia, Yemen, and 11 states of Northern Nigeria.
The United States considers amputation to be more severe than other punishments but less than death penalty, expressed in the double jeopardy clause: "nor shall any person be subject for the same offence to be twice put in jeopardy of life or limb...". Thomas Jefferson proposed a bill penalizing various crimes with amputation, such as "if a man, by castration, if a woman, by cutting thro the cartilage of her nose a hole of one half inch diameter at the least" and "cutting out or disabling the tongue, slitting or cutting off a nose, lip or ear, branding, or otherwise, shall be maimed or disfigured in like sort: or if that cannot be for want of the same part, then as nearly as may be in some other part of at least equal value and estimation in the opinion of a jury". That bill is not a current law, so it either did not gain enough approval to become law, or it has since been repealed.
As of 2021, this form of punishment is controversial, as most modern cultures consider it to be morally abhorrent, as it has the effect of permanently disabling a person and constitutes torture. It is thus seen as a grossly disproportional for crimes less than those such as murder.
Surgery
Method
The first step is ligating the supplying artery and vein, to prevent hemorrhage (bleeding). The muscles are transected, and finally, the bone is sawed through with an oscillating saw. Sharp and rough edges of bones are filed, skin and muscle flaps are then transposed over the stump, occasionally with the insertion of elements to attach a prosthesis.
Distal stabilisation of muscles is recommended. This allows effective muscle contraction which reduces atrophy, allows functional use of the stump and maintains soft tissue coverage of the remnant bone. The preferred stabilisation technique is myodesis where the muscle is attached to the bone or its periosteum. In joint disarticulation amputations tenodesis may be used where the muscle tendon is attached to the bone. Muscles should be attached under similar tension to normal physiological conditions.An experimental technique known as the "Ewing amputation" aims to improve post-amputation proprioception.In 1920, Dr. Janos Ertl, Sr. of Hungary, developed the Ertl procedure in order to return a high number of amputees to the work force. The Ertl technique, an osteomyoplastic procedure for transtibial amputation, can be used to create a highly functional residual limb. Creation of a tibiofibular bone bridge provides a stable, broad tibiofibular articulation that may be capable of some distal weight bearing. Several different modified techniques and fibular bridge fixation methods have been used; however, no current evidence exists regarding comparison of the different techniques.
Post-operative management
A 2019 Cochrane systematic review aimed to determine whether rigid dressings were more effective than soft dressings in helping wounds heal following transtibial (below the knee) amputations. Due to the limited and very low certainty evidence available, the authors concluded that it was uncertain what the benefits and harms were for each dressing type. They recommended that clinicians consider the pros and cons of each dressing type on a case-by-case basis e.g. rigid dressings may potentially benefit patients who have a high risk of falls and soft dressings may potentially benefit patients who have poor skin integrity.A 2017 review found that the use of rigid removable dressings (RRDs) in trans-tibial amputations, rather than soft bandaging, improved healing time, reduced edema, prevented knee flexion contractures and reduced complications, including further amputation, from external trauma such as falls onto the stump.Post-operative management, in addition to wound healing, should consider maintenance of limb strength, joint range, edema management, preservation of the intact limb (if applicable) and stump desensitization.
Trauma
Traumatic amputation is the partial or total avulsion of a part of a body during a serious accident, like traffic, labor, or combat.Traumatic amputation of a human limb, either partial or total, creates the immediate danger of death from blood loss.Orthopedic surgeons often assess the severity of different injuries using the Mangled Extremity Severity Score. Given different clinical and situational factors, they can predict the likelihood of amputation. This is especially useful for emergency physicians to quickly evaluate patients and decide on consultations.
Causes
Traumatic amputation is uncommon in humans (1 per 20,804 population per year). Loss of limb usually happens immediately during the accident, but sometimes a few days later after medical complications. Statistically, the most common causes of traumatic amputations are:
Vehicle accidents (cars, motorcycles, bicycles, trains, etc.)
Labor accidents (equipment, instruments, cylinders, chainsaws, press machines, meat machines, wood machines, etc.)
Agricultural accidents, with machines and mower equipment
Electric shock hazards
Firearms, bladed weapons, explosives
Violent rupture of ship rope or industry wire rope
Ring traction (ring amputation, de-gloving injuries)
Building doors and car doors
Animal attacks
Gas cylinder explosions
Other rare accidents
Treatment
The development of the science of microsurgery over the last 40 years has provided several treatment options for a traumatic amputation, depending on the patients specific trauma and clinical situation:
1st choice: Surgical amputation - break - prosthesis
2nd choice: Surgical amputation - transplantation of other tissue - plastic reconstruction.
3rd choice: Replantation - reconnection - revascularisation of amputated limb, by microscope (after 1969)
4th choice: Transplantation of cadaveric hand (after 2000)
Epidemiology
In the United States in 1999, there were 14,420 non-fatal traumatic amputations according to the American Statistical Association. Of these, 4,435 occurred as a result of traffic and transportation accidents and 9,985 were due to labor accidents. Of all traumatic amputations, the distribution percentage is 30.75% for traffic accidents and 69.24% for labor accidents.
The population of the United States in 1999 was about 300,000,000, so the conclusion is that there is one amputation per 20,804 persons per year. In the group of labor amputations, 53% occurred in laborers and technicians, 30% in production and service workers, 16% in silviculture and fishery workers.
A study found that in 2010, 22.8% of patients undergoing amputation of a lower extremity in the United States were readmitted to the hospital within 30 days.
Prevention
Methods in preventing amputation, limb-sparing techniques, depend on the problems that might cause amputations to be necessary. Chronic infections, often caused by diabetes or decubitus ulcers in bedridden patients, are common causes of infections that lead to gangrene, which would then necessitate amputation.There are two key challenges: first, many patients have impaired circulation in their extremities, and second, they have difficulty curing infections in limbs with poor blood circulation.Crush injuries where there is extensive tissue damage and poor circulation also benefit from hyperbaric oxygen therapy (HBOT). The high level of oxygenation and revascularization speed up recovery times and prevent infections.A study found that the patented method called Circulator Boot achieved significant results in prevention of amputation in patients with diabetes and arteriosclerosis. Another study found it also effective for healing limb ulcers caused by peripheral vascular disease. The boot checks the heart rhythm and compresses the limb between heartbeats; the compression helps cure the wounds in the walls of veins and arteries, and helps to push the blood back to the heart.For victims of trauma, advances in microsurgery in the 1970s have made replantations of severed body parts possible.
The establishment of laws, rules, and guidelines, and employment of modern equipment help protect people from traumatic amputations.
Prognosis
The individual may experience psychological trauma and emotional discomfort. The stump will remain an area of reduced mechanical stability. Limb loss can present significant or even drastic practical limitations.A large proportion of amputees (50–80%) experience the phenomenon of phantom limbs; they feel body parts that are no longer there. These limbs can itch, ache, burn, feel tense, dry or wet, locked in or trapped or they can feel as if they are moving. Some scientists believe it has to do with a kind of neural map that the brain has of the body, which sends information to the rest of the brain about limbs regardless of their existence. Phantom sensations and phantom pain may also occur after the removal of body parts other than the limbs, e.g. after amputation of the breast, extraction of a tooth (phantom tooth pain) or removal of an eye (phantom eye syndrome).
A similar phenomenon is unexplained sensation in a body part unrelated to the amputated limb. It has been hypothesized that the portion of the brain responsible for processing stimulation from amputated limbs, being deprived of input, expands into the surrounding brain, (Phantoms in the Brain: V.S. Ramachandran and Sandra Blakeslee) such that an individual who has had an arm amputated will experience unexplained pressure or movement on his face or head.
In many cases, the phantom limb aids in adaptation to a prosthesis, as it permits the person to experience proprioception of the prosthetic limb. To support improved resistance or usability, comfort or healing, some type of stump socks may be worn instead of or as part of wearing a prosthesis.Another side effect can be heterotopic ossification, especially when a bone injury is combined with a head injury. The brain signals the bone to grow instead of scar tissue to form, and nodules and other growth can interfere with prosthetics and sometimes require further operations. This type of injury has been especially common among soldiers wounded by improvised explosive devices in the Iraq War.Due to technological advances in prosthetics, many amputees live active lives with little restriction. Organizations such as the Challenged Athletes Foundation have been developed to give amputees the opportunity to be involved in athletics and adaptive sports such as amputee soccer.Nearly half of the individuals who have an amputation due to vascular disease will die within 5 years, usually secondary to the extensive co-morbidities rather than due to direct consequences of amputation. This is higher than the five year mortality rates for breast cancer, colon cancer, and prostate cancer. Of persons with diabetes who have a lower extremity amputation, up to 55% will require amputation of the second leg within two to three years.
Etymology
The word amputation is borrowed from Latin amputātus, past participle of amputāre "to prune back (a plant), prune away, remove by cutting (unwanted parts or features), cut off (a branch, limb, body part)," from am-, assimilated variant of amb- "about, around" + putāre "to prune, make clean or tidy, scour (wool)". The English word "Poes" was first applied to surgery in the 17th century, possibly first in Peter Lowes A discourse of the Whole Art of Chirurgerie (published in either 1597 or 1612); his work was derived from 16th-century French texts and early English writers also used the words "extirpation" (16th-century French texts tended to use extirper), "disarticulation", and "dismemberment" (from the Old French desmembrer and a more common term before the 17th century for limb loss or removal), or simply "cutting", but by the end of the 17th century "amputation" had come to dominate as the accepted medical term.
Notable cases
Patch Adams
Rick Allen
Douglas Bader
Carl Brashear
Lisa Bufano
Tammy Duckworth
Terry Fox
Pete Gray
Shaquem Griffin
Robert David Hall
Bethany Hamilton
Hugh Herr
Frida Kahlo
Aimee Mullins
Oscar Pistorius
Amy Purdy
Aron Ralston
Hans-Ulrich Rudel
Alex Zanardi
Ronnie Lott
Hari Budha Magar
Kalamandalam Sankaran Embranthiri
See also
Acrotomophilia
Adapted automobile
Flail limb
Robotic prosthesis control
References
Further reading
Miller, Brian Craig. Empty Sleeves: Amputation in the Civil War South (University of Georgia Press, 2015). xviii, 257 pp.
== External links == |
Seckel syndrome | Seckel syndrome, or microcephalic primordial dwarfism (also known as bird-headed dwarfism, Harpers syndrome, Virchow–Seckel dwarfism and bird-headed dwarf of Seckel) is an extremely rare congenital nanosomic disorder. Inheritance is autosomal recessive. It is characterized by intrauterine growth restriction and postnatal dwarfism with a small head, narrow bird-like face with a beak-like nose, large eyes with down-slanting palpebral fissures, receding mandible and intellectual disability.
A mouse model has been developed. This mouse model is characterized by a severe deficiency of ATR protein. These mice have high levels of replicative stress and DNA damage. Adult Seckel mice display accelerated ageing. These findings are consistent with the DNA damage theory of aging.
Symptoms and signs
Symptoms include:
intellectual disability (more than half of the patients have an IQ below 50)
microcephaly
sometimes pancytopenia (low blood counts)
cryptorchidism in males
low birth weight
dislocations of pelvis and elbow
unusually large eyes
blindness or visual impairment
large, low-set ears
small chin due to receded lower jaw
Genetics
It is believed to be caused by defects of genes on chromosome 3 and 18. One form of Seckel syndrome can be caused by mutation in the gene encoding the ataxia telangiectasia and Rad3-related protein (ATR) which maps to chromosome 3q22.1-q24. This gene is central in the cells DNA damage response and repair mechanism.
Types include:
Diagnosis
Treatment
History
The syndrome was named after German-American physician Helmut Paul George Seckel (1900–1960). The synonym Harpers syndrome was named after Rita G. Harper.
See also
Koo-Koo the Bird Girl
References
External links
Seckels syndrome at Who Named It? |
White superficial onychomycosis | White superficial onychomycosis is an infection of the nail plate by fungus, primarily affecting the surface of the nail.: 305
See also
Onychomycosis
Skin lesion
== References == |
Loeys–Dietz syndrome | Loeys–Dietz syndrome (LDS) is an autosomal dominant genetic connective tissue disorder. It has features similar to Marfan syndrome and Ehlers–Danlos syndrome. The disorder is marked by aneurysms in the aorta, often in children, and the aorta may also undergo sudden dissection in the weakened layers of the wall of the aorta. Aneurysms and dissections also can occur in arteries other than the aorta. Because aneurysms in children tend to rupture early, children are at greater risk for dying if the syndrome is not identified. Surgery to repair aortic aneurysms is essential for treatment.
There are five types of the syndrome, labelled types I through V, which are distinguished by their genetic cause. Type 1, Type 2, Type 3, Type 4 and Type 5 are caused by mutations in TGFBR1, TGFBR2, SMAD3, TGFB2, and TGFB3 respectively. These five genes encoding transforming growth factors play a role in cell signaling that promotes growth and development of the bodys tissues. Mutations of these genes cause production of proteins without function. The skin cells for individuals with Loeys–Dietz syndrome are not able to produce collagen, the protein that allows skin cells to be strong and elastic. This causes these individuals to be susceptible to different tears in the skin such as hernias. Although the disorder has an autosomal pattern of inheritance, this disorder results from a new gene mutation in 75% of cases and occurs in people with no history of the disorder in their family. In other cases it is inherited from one affected parent.Loeys–Dietz syndrome was identified and characterized by pediatric geneticists Bart Loeys and Harry "Hal" Dietz at Johns Hopkins University in 2005.
Signs and symptoms
There is considerable variability in the phenotype of Loeys–Dietz syndrome, from mild features to severe systemic abnormalities. The primary manifestations of Loeys–Dietz syndrome are arterial tortuosity (winding course of blood vessels), widely spaced eyes (hypertelorism), wide or split uvula, and aneurysms at the aortic root. Other features may include cleft palate and a blue/gray appearance of the white of the eyes. Cardiac defects and club foot may be noted at birth.There is overlap in the manifestations of Loeys–Dietz and Marfan syndromes, including increased risk of ascending aortic aneurysm and aortic dissection, abnormally long limbs and fingers, and dural ectasia (a gradual stretching and weakening of the dura mater that can cause abdominal and leg pain). Findings of hypertelorism (widely spaced eyes), bifid or split uvula, and skin findings such as easy bruising or abnormal scars may distinguish Loeys–Dietz from Marfan syndrome.Affected individuals often develop immune system related problems such as allergies to food, asthma, hay fever, and inflammatory disorders such as eczema or inflammatory bowel disease.Findings of Loeys–Dietz syndrome may include:
Skeletal/spinal malformations: craniosynostosis, Scoliosis, spinal instability and spondylolisthesis, Kyphosis
Sternal abnormalities: pectus excavatum, pectus carinatum
Contractures of fingers and toes (camptodactyly)
Long fingers and lax joints
Weakened or missing eye muscles (strabismus)
Club foot
Premature fusion of the skull bones (craniosynostosis)
Joint hypermobility
Congenital heart problems including patent ductus arteriosus (connection between the aorta and the lung circulation) and atrial septal defect (connection between heart chambers)
Translucency of the skin with velvety texture
Abnormal junction of the brain and medulla (Arnold–Chiari malformation)
Bicuspid aortic valves
Criss-crossed pulmonary arteries
Cause
Types (old nomenclature)
Several genetic causes of Loeys–Dietz syndrome have been identified. A de novo mutation in TGFB3, a ligand of the TGF β pathway, was identified in an individual with a syndrome presenting partially overlapping symptoms with Marfan Syndrome and Loeys–Dietz Syndrome.
Diagnosis
Diagnosis involves consideration of physical features and genetic testing. Presence of split uvula is a differentiating characteristic from Marfan Syndrome, as well as the severity of the heart defects. Loeys–Dietz Syndrome patients have more severe heart involvement and it is advised that they be treated for enlarged aorta earlier due to the increased risk of early rupture in Loeys–Dietz patients. Because different people express different combinations of symptoms and the syndrome was first identified in 2005, many doctors may not be aware of its existence.
Treatment
As there is no known cure, Loeys–Dietz syndrome is a lifelong condition. Due to the high risk of death from aortic aneurysm rupture, patients should be followed closely to monitor aneurysm formation, which can then be corrected with vascular surgery. Previous research in laboratory mice has suggested that the angiotensin II receptor antagonist losartan, which appears to block TGF-beta activity, can slow or halt the formation of aortic aneurysms in Marfan syndrome. A large clinical trial sponsored by the National Institutes of Health is currently underway to explore the use of losartan to prevent aneurysms in Marfan syndrome patients. Both Marfan syndrome and Loeys–Dietz syndrome are associated with increased TGF-beta signaling in the vessel wall. Therefore, losartan also holds promise for the treatment of Loeys–Dietz syndrome. In those patients in which losartan is not halting the growth of the aorta, irbesartan has been shown to work and is currently also being studied and prescribed for some patients with this condition.If an increased heart rate is present, a cardioselective beta-1 blocker, with or without losartan, is sometimes prescribed to reduce the heart rate to prevent any extra pressure on the tissue of the aorta. Likewise, strenuous physical activity is discouraged in patients, especially weight lifting and contact sports.
Epidemiology
The incidence of Loeys–Dietz syndrome is unknown; however, Type 1 and 2 appear to be the most common.
References
Further reading
Bertoli-Avella, A. M; Gillis, E; Morisaki, H; Verhagen, J. M. A; De Graaf, B. M; Van De Beek, G; Gallo, E; Kruithof, B. P. T; Venselaar, H; Myers, L. A; Laga, S; Doyle, A. J; Oswald, G; Van Cappellen, G. W. A; Yamanaka, I; Van Der Helm, R. M; Beverloo, B; De Klein, A; Pardo, L; Lammens, M; Evers, C; Devriendt, K; Dumoulein, M; Timmermans, J; Bruggenwirth, H. T; Verheijen, F; Rodrigus, I; Baynam, G; Kempers, M; et al. (2015). "Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections". Journal of the American College of Cardiology. 65 (13): 1324–1336. doi:10.1016/j.jacc.2015.01.040. PMC 4380321. PMID 25835445.
External links
orphan.net LDS-Syndrome |
Saccharopinuria | Saccharopinuria (an excess of saccharopine in the urine), also called saccharopinemia, saccharopine dehydrogenase deficiency or alpha-aminoadipic semialdehyde synthase deficiency, is a variant form of hyperlysinemia. It is caused by a partial deficiency of the enzyme saccharopine dehydrogenase, which plays a secondary role in the lysine metabolic pathway. Inheritance is thought to be autosomal recessive, but this cannot be established as individuals affected by saccharopinuria typically have only a 40% reduction in functional enzyme.
See also
Hyperlysinemia
References
External links
Saccharopinuria; Alpha-aminoadipic semialdehyde synthase deficiency at NIHs Office of Rare Diseases |
Choroid plexus cyst | Choroid plexus cysts (CPCs) are cysts that occur within choroid plexus of the brain. They are the most common type of intraventricular cyst, occurring in 1% of all pregnancies.It is believed that many adults have one or more tiny CPCs. The fetal brain may create these cysts as a normal part of development. They are temporary and usually are gone by the 32nd week of pregnancy.CPCs are a rare cause of intermittent hydrocephalus. This is caused by a blockage of foramina within the ventricular drainage system of the central nervous system (CNS), which can lead to expansion of the ventricles, compressing the brain (the cranial cavity cannot expand to accommodate the increase in fluid volume) and possibly causing damage.
Pathology
The brain contains pockets or spaces called ventricles with a spongy layer of cells and blood vessels called the choroid plexus. This is in the middle of the fetal brain. The choroid plexus has the important function of producing cerebrospinal fluid. The fluid produced by the cells of the choroid plexus fills the ventricles and then flows around the brain and the spinal cord to provide a cushion of fluid around these structures.CPCs can form within this structure and come from fluid trapped within this spongy layer of cells, much like a soap bubble or a blister. CPCs are often called "soft signs" or fetal ultrasound "markers" because some studies have found a weak association between CPCs and fetal chromosome abnormalities.Choroid plexus cysts are usually asymptomatic and disappears by 26 to 28 weeks of pregnancy. However, large cysts can cause hydrocephalus.
Genetic causes
There is a possible association between ultrasound-detected fetal CPCs and Trisomy 18. It is not correlated to the presence of Trisomy 21 (Down syndrome). Therefore, genetic counseling is often recommended to provide more information about fetal CPCs, to answer questions and concerns, and to outline available options such as amniocentesis or a blood test from the mother.Generally the risks are very low if there are no other risk factors. If no additional abnormalities are detected by a thorough "level II" ultrasound, the likelihood the fetus has trisomy 18 is very low.A meta-analysis of 8 studies between 1990 and 2000 with choroid plexus cysts that were identified in second-trimester (an incidence of 1.2%). The incidence of the cysts in women younger than 35 was 1% (n=1017). The study found no cases of trisomy 18 in fetuses with cysts whose mother was younger than 35. The study concluded that "there is no evidence that detection of isolated choroid plexus cyst in women who are <35 years of age increases the risk of trisomy 18".Other factors which may have a bearing on the babys chances of developing chromosome problems include:
mothers age at the expected date of delivery
the results of serum screening; XAFP triple testing or quad screening
evidence of other "fetal findings" seen at the time of the ultrasound that may suggest a chromosome problem
References
Further reading
Lun, Melody P.; Monuki, Edwin S.; Lehtinen, Maria K. (2015). "Development and functions of the choroid plexus–cerebrospinal fluid system". Nature Reviews Neuroscience. 16 (8): 445–457. doi:10.1038/nrn3921. PMC 4629451. PMID 26174708.
Rochon, Meredith; Eddleman, Keith (March 2004). "Controversial ultrasound findings". Obstetrics and Gynecology Clinics of North America. 31 (1): 61–99. doi:10.1016/S0889-8545(03)00123-2. PMID 15062448.
McKinney, Alexander M. (2017). "Choroid Plexus: Normal Locations and Appearances". Atlas of Normal Imaging Variations of the Brain, Skull, and Craniocervical Vasculature. Springer International Publishing. pp. 177–237. doi:10.1007/978-3-319-39790-0_11. ISBN 978-3-319-39790-0.
Aktürk, Erhan; Güler, Aşkın Evren (26 March 2020). "Review of fetal choroid plexus cysts: A cross-sectional study on 9244 pregnant women". Journal of Surgery and Medicine. doi:10.28982/josam.706887.
DeRoo, TR; Harris, RD; Sargent, SK; Denholm, TA; Crow, HC (December 1988). "Fetal choroid plexus cysts: prevalence, clinical significance, and sonographic appearance". American Journal of Roentgenology. 151 (6): 1179–1181. doi:10.2214/ajr.151.6.1179. PMID 3055893.
Chitkara, Usha; Cogswell, Carolyn; Norton, Karen; Wilkins, Isabelle A.; Mehalek, Karen; Berkowitz, Richard L. (August 1988). "Choroid Plexus Cysts in the Fetus: A Benign Anatomic Variant or Pathologic Entity? Report of 41 Cases and Review of the Literature". Obstetrics & Gynecology. 72 (2): 185–189. PMID 3292976. |
Myositis | Myositis is a rare disease that involves inflammation of the muscles. This can present with a variety of symptoms such as skin involvement (i.e., rashes), muscle weakness, and other organ involvement. You can also have systemic symptoms such as weight loss, fatigue, and low fever.
Causes
Injury, medicines, infection, or an autoimmune disorder can lead to myositis. It can also be idiopathic.
Injury - A mild form of myositis can occur with hard exercise. A more severe form of muscle injury, called rhabdomyolysis, is also associated with myositis. This is a condition where injury to your muscles causes them to quickly break down.
Medicines - A variety of different medicines can cause myositis. One of the most common drug types that can cause myositis is statins. Statins are drugs that are used to help lower high cholesterol. One of the most common side effects of statin therapy is muscle pain. Rarely, statin therapy can lead to myositis.
Infection - The most common infectious cause of myositis is viral infections, such as the common cold. Viruses, such as COVID-19, are also shown to be a rare cause of myositis.
Autoimmune - Normally, if you get an infection, your immune system attacks the bacteria/virus that is making you sick. In autoimmune diseases, your immune system gets confused and instead starts attacking your body. In the case of myositis, your immune system attacks your muscles. The three main types of autoimmune myositis are dermatomyositis, polymyositis, and inclusion body myositis. Other autoimmune diseases, such as systemic lupus erythematosus, can also cause myositis-like symptoms.
Diagnosis
There are various tools that can be used to help diagnose myositis. The most common ones are: physical exam, electromyography, magnetic resonance imaging, muscle biopsy, and blood tests.
The first thing your doctor will likely do is perform a physical exam. They will look for various things such as muscle weakness and rashes.
Another possible test is an electromyography (EMG). This is a test that inserts tiny needles into your muscles. This allows a physician to look at your muscles’ response to various electrical nerve signals and evaluate which muscles potentially have myositis.
Magnetic resonance imaging (MRI) is also useful. This is a test that uses a big magnet to create images on a computer. This allows a physician to examine your muscles. It is painless.
Muscle biopsies are the most reliable tests for diagnosing myositis. It will tell your doctor for certain if you have myositis or not.
There are also a variety of blood tests available that help in the diagnoses of myositis. Your doctor may look for elevation of creatine kinase in blood, which is indicative of muscle inflammation. Certain autoantibodies (antibodies that target your muscle cells) can also be found in the blood that can indicate that myositis is caused by an autoimmune disease. Some specific examples of autoantibodies are Anti-Jo-1, Anti-HMGCR, Anti-TIF1, etc.
Treatment
Treatment for myositis depends on the underlying cause. For myositis that is caused by a viral infection, no treatment is typically needed. If it is caused by a bacterial infection, antibiotics can be used. If myositis is being caused by a medication, it is important to stop that medication.There are a variety of treatment options available if myositis is caused by an autoimmune disease. Glucocorticoids are often the first choice for treatment. This drug works to weaken your immune system so that your immune system is not able to attack your muscles. This is a type of steroid and can cause a wide array of side effects such as mood changes, increased hunger, trouble sleeping, etc. Another treatment option is a steroid-sparing immunosuppressive agent. This works to also weaken your immune system, but does not cause the side effects that the steroids do. Yet another treatment option is a class of drugs called biologics. Also, intravenous immunoglobulins (IVIg) has also been shown to be effective in the treatment of myositis caused by an autoimmune disease.
See also
Myopathy (muscle disease)
Myalgia (muscle pain)
Masticatory muscle myositis (a disease in dogs)
Perimyositis
References
External links
Myositis: NIH
Myositis Association https://www.myositis.org |
Alström syndrome | Alström syndrome (AS), also called Alström–Hallgren syndrome, is a very rare autosomal recessive genetic disorder characterised by childhood obesity and multiple organ dysfunction. Symptoms include early-onset type 2 diabetes, cone-rod dystrophy resulting in blindness, sensorineural hearing loss and dilated cardiomyopathy. Endocrine disorders typically also occur, such as hypergonadotrophic hypogonadism and hypothyroidism, as well as acanthosis nigricans resulting from hyperinsulinemia. Developmental delay is seen in almost half of people with Alström syndrome.It is caused by mutations in the gene ALMS1, which is involved in the formation of cellular cilia, making Alström syndrome a ciliopathy. At least 239 disease-causing mutations in ALMS1 have been described as of 2015. Alström syndrome is sometimes confused with Bardet–Biedl syndrome, another ciliopathy which has similar symptoms, but Bardet–Biedl syndrome tends to have later onset in its symptoms, includes polydactyly and is caused by mutations in BBS genes.There is no cure for Alström syndrome. Treatments target the individual symptoms and can include diet, corrective lenses, hearing aids, medications for diabetes and heart issues and dialysis and transplantation in the case of kidney or liver failure. Prognosis varies depending on the specific combination of symptoms, but individuals with Alström syndrome rarely live beyond 50.At least 900 cases have been reported. Prevalence is fewer than 1 in 1,000,000 individuals in the general population, but the disorder is much more common in Acadians, both in Nova Scotia and Louisiana. It was first described by Swedish psychiatrist Carl-Henry Alström and his three associates, B. Hallgren, I. B. Nilsson and H. Asander, in 1959.
Signs and symptoms
Symptoms for Alström syndrome generally appear during infancy with great variability in age. Some of the symptoms include:
Heart failure (dilated cardiomyopathy) in over 60% of cases, usually within the first few weeks after birth, but sometimes the onset is in adolescence or adulthood.
Light sensitivity and vision problems (cone-rod dystrophy) in all cases, usually within 15 months of birth and progressively worsening until about 20 years of age
Delays in early, developmental milestones in 50% of cases, learning disabilities in about 30% of cases
Obesity in 100% of cases, apparent by 5 years of age but often apparent in infancy (Alström infants usually have normal birth weights, and by adolescence, weights tend to be in the high-normal to normal range.)
Nystagmus (usually affects the children), one of the first symptoms to occur which causes involuntary rapid eye movement.
Mild to moderate bilateral sensorineural hearing loss.
Type 2 diabetes usually occurs in early childhood.
Hyperinsulinemia/insulin resistance—development of high level of insulin in blood.
Hypertriglyceridemia
Steatosis (fatty liver) and elevated transaminases (liver enzymes) often develop in childhood and can progress in some patients to cirrhosis and liver failure.
Endocrine dysfunctions may occur where the patient may experience an under or over active thyroid gland, weak growth hormone, increased androgen in females and low testosterone in males.
Slowly progressive kidney failure can occur in the second to fourth decade of life.
Cause
Alström syndrome is caused by a mutation in the ALMS1 gene, located on the short arm of chromosome 2 (2p13.2). The gene mutation is inherited as an autosomal recessive trait. This means both parents have to pass a defective copy of the ALMS1 gene in order for their child to have the syndrome, even though the parents may not show signs or symptoms of the condition.The ALMS1 gene contains instructions to encode a specific protein known as ALMS1. The protein then is involved in ciliary function, cell cycle control and intracellular transport. In addition, the protein is expressed in all organ tissues of the body. It has a role in the proper function, maintenance and formation of cilia, which are found in all types of cells in the body. At least 239 disease-causing mutations in ALMS1 have been described as of 2015. Most of these mutations have led to the production of a dysfunctional version of the ALSM1 protein which are present in tissues, but at low levels.
Diagnosis
It is possible to clinically detect Alström syndrome in infancy, but more frequently, it is detected much later, as doctors tend to detect symptoms as separate problems. Currently, Alström syndrome is often diagnosed clinically, since genetic testing is costly and only available on a limited basis.A physical examination would be needed to properly diagnose the patient. Certain physical characteristics can determine if the patient has some type of genetic disorder. Usually, a geneticist would perform the physical examination by measuring the distance around the head, distance between the eyes and the length of arms and legs. In addition, examinations for the nervous system or the eyes may be performed. Various imaging studies like computerized tomography scans (CT), Magnetic Resonance Imaging (MRI) or X-rays are used to see the structures within the body.Family and personal medical history are required. Information about the health of an individual is crucial because it provides traces to a genetic diagnosis.Laboratory tests, particularly genetic testing, are performed to diagnose genetic disorders. Some of the types of genetic testing are molecular, biochemical and chromosomal. Other laboratory tests performed may measure levels of certain substances in urine and blood that can also help suggest a diagnosis.
Related disorders
Recent findings in genetic research have suggested that a large number of genetic disorders, both genetic syndromes and genetic diseases, that were not previously identified in the medical literature as related, may be, in fact, highly related in the genetypical root cause of the widely varying, phenotypically-observed disorders. Thus, Alstrom syndrome is a ciliopathy. Other known ciliopathies include primary ciliary dyskinesia, Bardet–Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Meckel–Gruber syndrome and some forms of retinal degeneration.
Diagnostic criteria
Marshall JD et al. provided a comprehensive guidance for diagnostic criteria in their 2007 publication.Birth – 2 years:
Minimum diagnosis requires 2 major criteria or 1 major and 2 minor criteria.
Major criteria are:
ALMS1 mutation in 1 allele and/or family history of Alström syndrome
Vision pathology (nystagmus, photophobia).Minor criteria are:
Obesity
Dilated cardiomyopathy with congestive heart failure.Other variable supportive evidence:
Recurrent pulmonary infections, normal digits, delayed developmental milestones.
At 3–14 years of age:
2 major criteria or 1 major and 3 minor criteria.
Major criteria are:
ALMS1 mutation in 1 allele and/or family history of Alström syndrome,
Vision pathology (nystagmus, photophobia, diminished acuity). If old enough for testing: cone dystrophy by ERG.Minor criteria:
Obesity and/or insulin resistance and/or Type 2 Diabetes
History of dilated cardiomyopathy with congestive heart failure
Hearing loss
Liver dysfunction
Kidney failure
Advanced bone ageVariable supportive evidence:
Recurrent pulmonary infections, normal digits, delayed developmental milestones, hyperlipidemia, scoliosis, flat wide feet
hypothyroidism, hypertension, recurrent urinary tract infection, growth hormone deficiency.
Presentation 15 years – adulthood:
2 major and 2 minor criteria or 1 major and 4 minor criteria.
Major criteria are:
ALMS1 mutation in 1 allele and/or family history of Alström syndrome.
Vision pathology (history of nystagmus in infancy/childhood, legal blindness, cone and rod dystrophy by ERG).Minor criteria:
Obesity and/or insulin resistance and/or Type 2 Diabetes
History of dilated cardiomyopathy with congestive heart failure.
Hearing loss
Hepatic dysfunction
Renal failure
Short stature
Males: hypogonadism, Females: irregular menses and/or hyperandrogenismOther supportive features:
Recurrent pulmonary infections, normal digits, history of developmental delay, hyperlipidemia, scoliosis, flat wide feet,
hypothyroidism, hypertension, recurrent urinary tract infections/urinary dysfunction, growth hormone deficiency, alopecia.
Prevention
Prevention for Alström syndrome is considered to be harder compared to other diseases/syndromes because it is an inherited condition. However, there are other options that are available for parents with a family history of Alström syndrome. Genetic testing and counseling are available where individuals are able to meet with a genetic counselor to discuss risks of having the children with the disease. The genetic counselor may also help determine whether individuals carry the defective ALSM1 gene before the individuals conceive a child. Some of the tests the genetic counselors perform include chorionic villus sampling (CVS), preimplantation genetic diagnosis (PGD) and amniocentesis. With PGD, the embryos are tested for the ALSM1 gene and only the embryos that are not affected may be chosen for implantation via in vitro fertilization.
Treatment
There is no cure for Alström syndrome; however, there are treatment aims to reduce the symptoms and prevent further complications. Some of these treatment aims include:
Corrective lenses: tinted lenses that help with the sensitivity from bright lights. The patients may have to adapt to reading in Braille, use adaptive equipment, mobility aids and adaptive computing skills.
Education: patients with Alström syndrome who have intellectual disabilities must have access to education. They must be able to receive free and appropriate education. Some Alström syndrome patients are educated in normal classrooms. Other patients have to take special education classes or attend to specialized schools that are prepared to teach children with disabilities. Staff members from schools have to consult with patients parents or caregivers in order to design an education plan based on the childs needs. In addition, the school may document the progress of the child in order to confirm that the childs needs are being met.
Hearing aids: the battery-operated devices are available in three styles: behind the ear, in the ear and inside the ear canal. Behind the ear aims for mild-to-profound hearing loss. In the ear aims for mild to severe hearing loss. Lastly, the canal device is aimed for mild to moderately severe hearing loss. Patients that have severe hearing loss may benefit from a cochlear implant.
Diet: an appropriate and healthy diet is necessary for individuals with Alström syndrome because it could potentially decreases chances of obesity or diabetes.
Occupational therapy: the therapist helps the child learn skills to help him or her perform basic daily tasks like eating, getting dressed and communicating with others.
Physical Activity: exercising reduces chances of being obese and helping control blood sugar levels.
Dialysis: helps restore filtering function. With hemodialysis, a patients blood circulates into an external filter and clean. The filtered blood is then returned into the body. With peritoneal dialysis, fluid containing dextrose is introduced into the abdomen by a tube. The solution then absorbs the wastes into the body and is then removed.
Transplantation: patients that endure a kidney failure may undergo a kidney transplantation.
Surgery: if the patient endures severe scoliosis or kyphosis, surgery may be required.
Medication
Antibiotics: patients with lung problems will be prescribed antibiotics because they are more prone to infections like bronchitis.
Oral diabetes medications: are taken by mouth to treat diabetes. Can be taken combined into a single pill, which may be more effective and convenient for people with diabetes. It is usually taken once or twice daily before meals. Some of these medications includes:
Meglitinides (repaglinide and nateglinide): taken to stimulate the cells found in the pancreas to release insulin. These drugs are taken by mouth daily before each meal and could cause a drop in blood sugar.
Metformin (biguanide): decreases the amount blood sugar being released by the liver and by stimulating the cells within muscles to take up blood sugar. Taken twice daily.
Thiazolidinediones (rosiglitazone and pioglitazone): taken to help insulin work more efficiently in muscle and fat cells causing the liver to release less glucose. Is associated with heart failure.
Dipeptidyl peptidase IV (DPP-4) inhibitors (sitagliptin): helps with improving blood sugar levels by decreasing the action of an enzyme breaking down GLP-1 (lowers the blood sugar level).
Injected diabetes medicine: taken by an injection into the fat below the skin. Sometimes referred as subcutaneous injections. Some of these medications include the following:
Pramlintide (Symlin): is an Amylin agonist. It acts centrally (via the brain) to reduce food intake and blood sugar. It is most commonly used at mealtimes by people with type 1 and type 2 diabetes.
Exenatide (Byetta): synthetic form of exendin-4 ( a GLP-1 receptor agonist that increases secretion of insulin, decreases the secretion of glucagon from the pancreas and reduces food intake).
Cholesterol-lowering medications: is necessary when cholesterol levels are high. HMG-CoA reductase inhibitors, also called "statins," effectively lower levels of low-density lipoprotein, cholesterol and triglycerides. High-dose nicotinic acid (niacin) may also reduce cholesterol levels.
Heart medications: Angiotensin-converting enzyme (ACE) inhibitors, diuretics, digoxin and beta-blockers may help with the management of cardiomyopathy and heart failure.
Prognosis
A prognosis for Alström syndrome is complicated because it widely varies. Any person that has the syndrome have different set of disorders. Permanent blindness, deafness and type 2 diabetes may occur. Liver and kidney failure can progressively get worse. The life expectancy is usually reduced and the patients rarely live past 50 years old.
Research
The Jackson Laboratory in Bar Harbor, Maine, USA with the University of Southampton, UK isolated the single gene (ALMS1) responsible for Alström syndrome.Research was conducted in 2014 on Alström syndrome patients regarding degeneration and plasticity of the optic pathway. The functional and structural changes have been investigated on the optic pathway in Alström syndrome by using magnetic resonance imaging to provide better insight on the underlying pathogenic mechanisms. Eleven patients with the syndrome (mean age of 23 years, 5 females, 6 males) underwent a brain MRI. The protocol also included conventional sequences, resting-state functional MRI and diffusion tensor imaging. Results found that patients with Alström syndrome had occipital regions with decreased white matter volume as well as decreased gray matter volume sparing the occipital poles. The diffused fractional anisotropy decreased and the radial diffusivity increased while mean and axial diffusivities were normal. Lastly, the reduced connectivity in the medial visual network was strikingly sparing the occipital poles. The conclusion of the research was that the protean occipital brain changes in patients with Alström syndrome. They are likely to reflect coexistence of diffuse primary myelin derangement, anterograde trans-synaptic degeneration and complex cortical reorganization that affect the posterior and anterior visual cortex.
References
Further reading
Marshall JD, Beck S, Maffei P, Naggert JK (2007). "Alström syndrome". Eur. J. Hum. Genet. 15 (12): 1193–202. doi:10.1038/sj.ejhg.5201933. PMID 17940554.
== External links == |
Staphylococcal infection | A staphylococcal infection or staph infection is an infection caused by members of the Staphylococcus genus of bacteria.
These bacteria commonly inhabit the skin and nose where they are innocuous, but may enter the body through cuts or abrasions which may be nearly invisible. Once inside the body, the bacteria may spread to a number of body systems and organs, including the heart, where the toxins produced by the bacteria may cause cardiac arrest. Once the bacterium has been identified as the cause of the illness, treatment is often in the form of antibiotics and, where possible, drainage of the infected area. However, many strains of this bacterium have become antibiotic resistant; for those with these kinds of infection, the bodys own immune system is the only defense against the disease. If that system is weakened or compromised, the disease may progress rapidly. Anyone can contract staph, but pregnant women, children, and people with chronic diseases or who are immuno-deficient are often more susceptible to contracting an infection.
Types
Other infections include:
Closed-space infections of the fingertips, known as paronychia.
Suspected involvement in atopic dermatitis (eczema), including related clinical trials.
Coagulase-positive
The main coagulase-positive staphylococcus is Staphylococcus aureus, although not all strains of Staphylococcus aureus are coagulase positive. These bacteria can survive on dry surfaces, increasing the chance of transmission. S. aureus is also implicated in toxic shock syndrome; during the 1980s some tampons allowed the rapid growth of S. aureus, which released toxins that were absorbed into the bloodstream. Any S. aureus infection can cause the staphylococcal scalded skin syndrome, a cutaneous reaction to exotoxin absorbed into the bloodstream. It can also cause a type of septicaemia called pyaemia. The infection can be life-threatening. Problematically, methicillin-resistant Staphylococcus aureus (MRSA) has become a major cause of hospital-acquired infections. MRSA has also been recognized with increasing frequency in community-acquired infections. The symptoms of a Staph Infection include a collection of pus, such as a boil or furuncle, or abscess. The area is typically tender or painful and may be reddened or swollen.
Coagulase-negative
S. epidermidis, a coagulase-negative staphylococcus species, is a commensal of the skin, but can cause severe infections in immune-suppressed patients and those with central venous catheters.
S. saprophyticus, another coagulase-negative species that is part of the normal vaginal flora, is predominantly implicated in uncomplicated lower genitourinary tract infections in young sexually active women.
Other staphylococcal species have been implicated in human infections, notably S. lugdunensis, S. schleiferi, and S. caprae.
Causes
Staph infections have a multitude of different causes, such as:
Open wounds – This is by far the biggest cause of staph infection. Any open wound, even ones as small as a paper cut, are vulnerable to being infected. Staph bacteria will enter the body through any open wound, so it is important to properly treat, disinfect, and bandage any wounds.
Contact with infected persons or surfaces – Staph infections are very contagious when in contact with a person that is already infected. A person with staph infection is contagious until the bacteria are completely out of their body, and any wounds from the infection are healed. It is common to see the spread of staph in contact sports; i.e. wrestling, through contact in locker rooms, or by sharing any equipment.
Weakened immune system – Anyone with a weakened immune system for any reason can be more easily affected by staph bacteria, because their bodies are unable to defend against infectious bacteria as well.
Unwashed linens – Staph bacteria are very resistant under harsh conditions, and they will cling to objects where they can create a niche. Unwashed bath towels, blanket, bed sheets, and clothes can create a great environment for these bacteria to grow. This is important to recognize, because every single day people use linens in their daily lives.
Infection after surgery – Hospitals are a very common place for staph bacteria to contaminate. This becomes problematic when people are in surgery, because in some cases staph can be introduced to a persons body when an incision is opened.
Invasive devices – Medical devices that have any connection to organs to the outside of the body are very problematic, because they allow an easy open pathway into the body. Examples of these devices are; catheters, dialysis tubing, feeding tubes, breathing tubes, etc.
Signs and symptoms
Staph infection is typically characterized by redness, pus, swelling, and tenderness in areas of the infection. But, each type of skin infection caused by staph bacteria is different.
A few common skin infections caused by staph bacteria are:
Boils – Boils are the most common type of staph infection, they are pockets of white pus that start where a hair follicle or oil gland is. The boil is tender and red where the infection is located on the skin.
Impetigo – Impetigo is most prominent among children, and is usually located around their mouth, nose, hands, and feet. It shows up like a rash of painful blisters, will eventually produce pus that is yellowish in color.
Cellulitis – Cellulitis is also rash-like; the skin that is infected will be red, swollen, and usually warm to the touch. Cellulitis commonly infects the lower legs, but can also, less commonly, affect the face and arms.
Staphylococcus scalded skin syndrome – Staphylococcus scalded skin syndrome is caused by toxins produced when a staph infection gets too severe. It is characterized by a fever, rash, and blisters.
Methicillin-resistant Staphylococcus aureus (MRSA) – MRSA is one of the most common antibiotic-resistant strains of staph bacteria. It is more difficult to treat than other staph infections. MRSA causes rashes, boils, sores, and other abscesses.
Treatment
Treatment for staph infection varies depending on the type and severity of infection. Common treatments are antibiotics, topical creams, and drainage/cleaning of infectious wounds.
Etymology
The generic name Staphylococcus is derived from the Greek word "staphyle", meaning bunch of grapes, and "kokkos", meaning granule. The bacteria, when seen under a microscope, appear like a branch of grapes or nuts.
Epidemiology
Staphylococcus bacteria is one of the leading community-acquired bacteria. According to the CDC, after a push from hospitals to better prevent staph infections, the percentage of people affected has dropped dramatically. However, staph infections are still prominent and a cause for concern among healthcare professionals, especially new antibiotic-resistant strains. In the U.S., the incidence of staph infection is around 38.2 to 45.7 per 100,000 person-years, whereas other First World countries have an average incidence rate of 10 to 30 per 100,000 person-years.
References
== External links == |
Sirenomelia | Sirenomelia, also called mermaid syndrome, is a rare congenital deformity in which the legs are fused together, giving the appearance of a mermaids tail, hence the nickname.
Classification
Sirenomelia is classified by the skeletal structure of the lower limb, ranging from class I, where all bones are present and only the soft tissues are fused, to class VII where the only bone present is a fused femur.It has also been classified as an expanded part of the VACTERL association and as a form of caudal regression syndrome.
Presentation
Sirenomelia is mainly characterized by the fusion of both legs with rotation of the fibula. It may include the absence of the lower spine, as well as abnormalities of the pelvis and renal organs. It was previously thought to be a severe form of sacral agensis/caudal regression syndrome, but more recent research confirms that these two conditions are not related. NORD has a separate report on caudal regression syndrome. In general, the more severe cases of limb fusion correlate with more severe dysplasia in the pelvis. Rather than the two iliac arteries present in fetuses with complete renal agenesis, fetuses with sirenomelia display no branching of the abdominal aorta, which is always absent.Associated defects recorded in cases of sirenomelia include neural tube defects (rachischisis, anencephaly, and spina bifida), holoprosencephaly, hypoplastic left heart syndrome, other heart defects, esophageal atresia, omphalocele, intestinal malrotation, persistent cloaca, and other limb defects (most commonly absence of the radius).
Causes
The ultimate cause of sirenomelia is a subject of debate. The first hypothesis of its origin was developed in 1927 and proposed that a lack of blood supply to the lower limbs during their development is responsible for the defect. This "vascular steal" hypothesis was developed in response to the observed absence or severe underdevelopment of the aorta below the umbilical artery, which "steals" the blood supply from the lower limbs. Other hypotheses involve an insult to the embryo between 28 and 32 days affecting the caudal mesoderm, a teratogen exposure affecting the neural tube during neurulation, and a defect in the twinning process that either stops the process of caudal differentiation or generates a second primitive streak.Maternal diabetes mellitus has been associated with caudal regression syndrome and sirenomelia, although a few sources question this association. Prenatal cocaine exposure has also been suggested as an association with sirenomelia.
Genetics
In animal models, several genes have been found to cause or be associated with sirenomelia. The srn (siren) gene is observed to cause hindlimb fusion in homozygous mice. Mice with knockouts or mutations in both tsg1 and bmp7 will also have hindlimb fusion.
Diagnosis
Though obvious at birth, sirenomelia can be diagnosed as early as 14 weeks gestation on prenatal ultrasound. When there is low amniotic fluid around the fetus (oligohydramnios), the diagnosis is more difficult.
Prognosis
Sirenomelia is usually fatal. Many pregnancies with a sirenomelic fetus spontaneously miscarry. One-third to one-half of infants are stillborn, with all but a few dying in the neonatal period.In cases of monoamniotic twins where one is affected, the twin with sirenomelia is protected from Potter sequence (particularly pulmonary hypoplasia and abnormal facies) by the normal twins production of amniotic fluid.
Epidemiology
This condition is found in approximately one out of every 100,000 live births; studies produce rates from 1 in 68,741 to 1 in 97,807. It is 100 to 150 times more likely in identical (monozygotic) twins than in singletons or fraternal twins. Sirenomelia is not associated with any ethnic background, but fetuses with sirenomelia are more likely to be male.
Etymology
The word sirenomelia derives from the ancient Greek word seirēn, referring to the mythological Sirens, who were sometimes depicted as mermaids, and melos, meaning "limb".
History
Sirenomelia was first reported in 1542. In 1927, Otto Kampmeier discovered the association between sirenomelia and single umbilical artery.
Notable individuals
Only a few individuals who had some functioning kidney tissue have survived the neonatal period.
Tiffany Yorks
Tiffany Yorks of Clearwater, Florida (May 7, 1988 – February 24, 2016) underwent successful surgery in order to separate her legs before she was a year old. She was the longest-surviving sirenomelia patient to date. She had mobility issues due to her fragile leg bones, and compensated by using crutches or a wheelchair. She died on February 24, 2016, at the age of 27.
Shiloh Pepin
Shiloh Jade Pepin (August 4, 1999 – October 23, 2009) was born in Kennebunkport, Maine, United States with her lower extremities fused, no bladder, no uterus, no rectum, only 6 inches of large intestine, no vagina, only one quarter of a kidney and one ovary. Her parents initially anticipated she could expect only a few months of life. At age 4 months, her natural kidney failed, and she began dialysis. A kidney transplant at age 2 lasted a number of years, and in 2007 a second kidney transplant was successful. She attended Consolidated Elementary School. She remained hopeful about her disease and joked often and lived her life happily, despite her challenges, as seen in her TLC documentary in "Extraordinary People: Mermaid Girl". Shiloh and her family were debating surgery because of the risks involved, even though it would improve her quality of life. Many people who have this condition undergo surgery when they are young, but Shiloh was already 8 years old in the documentary and had not undergone surgery. Shiloh was the only one of the three survivors of sirenomelia without surgery for separation of the conjoined legs. She died of pneumonia on October 23, 2009, at Maine Medical Center in Portland, Maine, at the age of 10; having appeared on the Oprah Winfrey Show on September 22, 2009. Shiloh gained a following of admirers by documenting her condition on TV, Facebook, and the Internet.
Milagros Cerrón
Milagros Cerrón Arauco (April 27, 2004 – October 24, 2019) was born in Huancayo, Peru. Although most of Milagros internal organs, including her heart and lungs, were in perfect condition, she was born with serious internal defects, including a deformed left kidney and a very small right one located very low in her body. In addition, her digestive, urinary tracts and genitals shared a single tube.
This birth defect occurs during the gastrulation week (week 3) of embryonic development. Gastrulation establishes the three germ layers: ectoderm, mesoderm and endoderm. It seems that complications such as defects in the urogenital system as mentioned above can be possibly due to malformations in the intermediate mesoderm.
A four-hour operation to insert silicone bags between her legs to stretch the skin was successfully completed on February 8, 2005. A successful operation to separate her legs to just above the knee took place May 31, 2005, in a "Solidarity Hospital" in the district of Surquillo in Lima. The procedure, however, was so intensive that she became traumatized to the degree of losing her ability to form proper speech patterns, leaving her nearly mute. It is not known if this was a physiological or psychological condition. However, at Milagros second birthday, her mother reported that she knew more than 50 words. A second operation to complete the separation up to the groin took place on September 7, 2006.Her doctor Luis Rubio said he was pleased with the progress Milagros had made, but cautioned that she still needed 10 to 15 years of rehabilitation and more operations before she could lead a normal life, particularly reconstructive surgery to rebuild her rudimentary anus, urethra and genitalia.
Milagros parents are from a poor village in Perus Andes Mountains; the Solidarity Hospital had given a job to her father Ricardo Cerrón so that the family could remain in Lima, while the City of Lima pledged to pay for many of the operations.She died on October 24, 2019, at the age of 15.
== References == |
Delirium tremens | Delirium tremens (DTs) is a rapid onset of confusion usually caused by withdrawal from alcohol. When it occurs, it is often three days into the withdrawal symptoms and lasts for two to three days. Physical effects may include shaking, shivering, irregular heart rate, and sweating. People may also hallucinate. Occasionally, a very high body temperature or seizures may result in death. Alcohol is one of the most dangerous drugs to withdraw from.Delirium tremens typically only occurs in people with a high intake of alcohol for more than a month. A similar syndrome may occur with benzodiazepine and barbiturate withdrawal. Withdrawal from stimulants such as cocaine do not have major medical complications. In a person with delirium tremens it is important to rule out other associated problems such as electrolyte abnormalities, pancreatitis, and alcoholic hepatitis.Prevention is by treating withdrawal symptoms. If delirium tremens occurs, aggressive treatment improves outcomes. Treatment in a quiet intensive care unit with sufficient light is often recommended. Benzodiazepines are the medication of choice with diazepam, lorazepam, chlordiazepoxide, and oxazepam all commonly used. They should be given until a person is lightly sleeping. The antipsychotic haloperidol may also be used. The vitamin thiamine is recommended. Mortality without treatment is between 15% and 40%. Currently death occurs in about 1% to 4% of cases.About half of people with alcoholism will develop withdrawal symptoms upon reducing their use. Of these, 3% to 5% develop DTs or have seizures.The name delirium tremens was first used in 1813; however, the symptoms were well described since the 1700s. The word "delirium" is Latin for "going off the furrow," a plowing metaphor. It is also called the shaking frenzy and Saunders-Sutton syndrome. There are numerous nicknames for the condition, including "the DTs" and "seeing pink elephants" (see below).
Signs and symptoms
The main symptoms of delirium tremens are nightmares, agitation, global confusion, disorientation, visual and auditory hallucinations, tactile hallucinations, fever, high blood pressure, heavy sweating, and other signs of autonomic hyperactivity (fast heart rate and high blood pressure). These symptoms may appear suddenly but typically develop two to three days after the stopping of heavy drinking, being worst on the fourth or fifth day.These symptoms are characteristically worse at night. In general, DT is considered the most severe manifestation of alcohol withdrawal and occurs 3–10 days following the last drink.Other common symptoms include intense perceptual disturbance such as visions of insects, snakes, or rats. These may be hallucinations or illusions related to the environment, e.g., patterns on the wallpaper or in the peripheral vision that the patient falsely perceives as a resemblance to the morphology of an insect, and are also associated with tactile hallucinations such as sensations of something crawling on the subject—a phenomenon known as formication. Delirium tremens usually includes extremely intense feelings of "impending doom". Severe anxiety and feelings of imminent death are common DT symptoms.DT can sometimes be associated with severe, uncontrollable tremors of the extremities and secondary symptoms such as anxiety, panic attacks, and paranoia. Confusion is often noticeable to onlookers as those with DT will have trouble forming simple sentences or making basic logical calculations.DT should be distinguished from alcoholic hallucinosis, the latter of which occurs in approximately 20% of hospitalized alcoholics and does not carry a risk of significant mortality. In contrast, DT occurs in 5–10% of alcoholics and carries up to 15% mortality with treatment and up to 35% mortality without treatment.
Causes
Delirium tremens is mainly caused by a long period of drinking being stopped abruptly. Withdrawal leads to a biochemical regulation cascade.Delirium tremens is most common in people who are in alcohol withdrawal, especially in those who drink the equivalent of 7 to 8 US pints (3 to 4 L) of beer or 1 US pint (0.5 L) of distilled beverage daily. Delirium tremens commonly affects those with a history of habitual alcohol use or alcoholism that has existed for more than 10 years.
Pathophysiology
Delirium tremens is a component of alcohol withdrawal hypothesized to be the result of compensatory changes in response to chronic heavy alcohol use. Alcohol positively allosterically modulates the binding of GABA, enhancing its effect and resulting in inhibition of neurons projecting into the nucleus accumbens, as well as inhibiting NMDA receptors. This combined with desensitization of alpha-2 adrenergic receptors, results in a homeostatic upregulation of these systems in chronic alcohol use.When alcohol use ceases, the unregulated mechanisms result in hyperexcitability of neurons as natural GABAergic systems are down-regulated and excitatory glutamatergic systems are unregulated. This combined with increased noradrenergic activity results in the symptoms of delirium tremens.
Diagnosis
Diagnosis is mainly based on symptoms. In a person with delirium tremens it is important to rule out other associated problems such as electrolyte abnormalities, pancreatitis, and alcoholic hepatitis.
Treatment
Delirium tremens due to alcohol withdrawal can be treated with benzodiazepines. High doses may be necessary to prevent death. Amounts given are based on the symptoms. Typically the person is kept sedated with benzodiazepines, such as diazepam, lorazepam, chlordiazepoxide, or oxazepam.
In some cases antipsychotics, such as haloperidol may also be used. Older drugs such as paraldehyde and clomethiazole were formerly the traditional treatment but have now largely been superseded by the benzodiazepines.Acamprosate is occasionally used in addition to other treatments, and is then carried on into long-term use to reduce the risk of relapse. If status epilepticus occurs it is treated in the usual way.It can also be helpful to provide a well lit room as people often have hallucinations.Alcoholic beverages can also be prescribed as a treatment for delirium tremens, but this practice is not universally supported.High doses of thiamine often by the intravenous route is also recommended.
Society and culture
Nicknames for delirium tremens include "the DTs", "the shakes", "the oopizootics", "barrel-fever", "the blue horrors", "bottleache", "bats", "the drunken horrors", "seeing pink elephants", "gallon distemper", "quart mania", "heebie jeebies", "pink spiders", and "riding the ghost train", as well as "ork orks", "the zoots", "the 750 itch", and "pint paralysis". Another nickname is "the Brooklyn Boys", found in Eugene ONeills one-act play Hughie set in Times Square in the 1920s.English author George Eliot provides a case involving delirium tremens in her novel Middlemarch (1871–72). Alcoholic scoundrel John Raffles, both an abusive stepfather of Joshua Riggs and blackmailing nemesis of financier Nicholas Bulstrode, dies, whose "death was due to delirium tremens" while at Peter Featherstones Stone Court property. Housekeeper Mrs. Abel provides Raffles final night of care per Bulstrodes instruction whose directions given to Abel stand adverse to Dr. Tertius Lydgates orders.
"Remember, if he calls for liquors of any sort, not to give it to him." (Lydgate to Bulstrode). "...he gave directions to Bulstrode as to the doses, and the point at which they should cease. He insisted on the risk of not ceasing, and repeated his order that no alcohol should be given.
(Bulstrode reflecting): "The thought was, that he had not told Mrs. Abel when the dose of opium must cease. ... He walked up-stairs, candle in hand, not knowing whether he should straitaway enter his own room and go to bed, or turn to the patients room and rectify his omission. ... He turned to his own room. Before he had quite undressed, Mrs. Abel rapped at his door ...If you please sir, should I have no brandy nor nothing to give the poor creetur? ...When I nursed my poor master, Mr. Robisson, I had to give him port-wine and brandy constant, and a big glass at a time, added Mrs. Abel with a touch of remonstrance in her tone. ...a key was thrust through the inch of doorway, and Mr. Bulstrode said huskily, That is the key of the wine-cooler. You will find plenty of brandy there."
French writer Émile Zolas novel The Drinking Den (LAssommoir) includes a character – Coupeau, the main character Gervaises husband – who has delirium tremens by the end of the book.
American writer Mark Twain describes an episode of delirium tremens in his book The Adventures of Huckleberry Finn (1884). In chapter 6, Huck states about his father, "After supper pap took the jug, and said he had enough whisky there for two drunks and one delirium tremens. That was always his word." Subsequently, Pap Finn runs around with hallucinations of snakes and chases Huck around their cabin with a knife in an attempt to kill him, thinking Huck is the "Angel of Death".
One of the characters in Joseph Conrads novel Lord Jim experiences "DTs of the worst kind" with symptoms that include seeing millions of pink frogs.
English author M. R. James mentions delirium tremens in his 1904 ghost story "Oh, Whistle, and Ill Come to You, My Lad". Professor Parkins while staying at the Globe Inn when in coastal Burnstow to "improve his game" of golf, despite being "a convinced disbeliever in what is called the supernatural", when face to face with an entity in his "double-bed room" during the storys climax, is heard "uttering cry upon cry at the utmost pitch of his voice" though later "was somehow cleared of the ready suspicion of delirium tremens".
In the 1945 film The Lost Weekend, Ray Milland won the Academy Award for Best Actor for his depiction of a character who experiences delirium tremens after being hospitalized, hallucinating that he saw a bat fly in and eat a mouse poking through a wall.Writer Jack Kerouac details his experiences with delirium tremens in his book Big Sur.The M*A*S*H TV series episode "Bottoms Up" (season 9, episode 15) featured a side story about a nurse (Cpt. Helen Whitfield) who was found to be drinking heavily off-duty. By the culmination of the episode, after a confrontation by Maj. Margaret Houlihan, the character swears off alcohol and presumably quits immediately. At mealtime, roughly 48 hours later, Whitfield becomes hysterical upon being served food in the Mess tent, claiming that things are crawling onto her from it. Margaret and Col. Sherman Potter subdue her. Potter, having recognized the symptoms of delirium tremens orders 5 ml of paraldehyde from a witnessing nurse.
During the filming of the 1975 film Monty Python and the Holy Grail, Graham Chapman developed delirium tremens due to the lack of alcohol on the set. It was particularly bad during the filming of the bridge of death scene where Chapman was visibly shaking, sweating and could not cross the bridge. His fellow Pythons were astonished as Chapman was an accomplished mountaineer.
The Belgian beer "Delirium Tremens," introduced in 1988, is a direct reference and also uses a pink elephant as its logo to highlight one of the symptoms of delirium tremens.In the 1995 film Leaving Las Vegas, Nicolas Cage plays a suicidal alcoholic who rids himself of all his possessions and travels to Las Vegas to drink himself to death. During his travels, he experiences delirium tremens on a couch after waking up from a binge and crawls in pain to the refrigerator for more vodka. Cages performance as Ben Sanderson in the film won the Academy Award for Best Actor in 1996.
Russian composer Modest Mussorgsky (1839-1881) died of delirium tremens.
See also
Alcohol dementia
Alcohol detoxification
Delusional parasitosis
Excited delirium
On the wagon
References
External links
Why Does Alcohol Cause the Shakes? | Alcohol Withdrawal Syndrome Tremors | Dr Peter MCcann MCC, MBBS | Castle Craig Hospital |
Thyrotoxicosis factitia | Thyrotoxicosis factitia (alimentary thyrotoxicosis, exogenous thyrotoxicosis) refers to a condition of thyrotoxicosis caused by the ingestion of exogenous thyroid hormone. It can be the result of mistaken ingestion of excess drug, such as levothyroxine and triiodothyronine, or as a symptom of Munchausen syndrome. It is an uncommon form of hyperthyroidism.
Patients present with hyperthyroidism and may be mistaken for Graves’ disease, if TSH receptor positive, or thyroiditis because of absent uptake on a thyroid radionuclide uptake scan due to suppression of thyroid function by exogenous thyroid hormones. Ingestion of thyroid hormone also suppresses thyroglobulin levels helping to differentiate thyrotoxicosis factitia from other causes of hyperthyroidism, in which serum thyroglobulin is elevated. Caution, however, should be exercised in interpreting thyroglobulin results without thyroglobulin antibodies, since thyroglobulin antibodies commonly interfere in thyroglobulin immunoassays causing false positive and negative results which may lead to clinical misdirection. In such cases, increased faecal thyroxine levels in thyrotoxicosis factitia may help differentiate it from other causes of hyperthyroidism.
See also
Foodborne illness
Liothyronine
References
== External links == |
Trichilemmoma | Trichilemmoma (also known as "tricholemmoma") is a benign cutaneous neoplasm that shows differentiation toward cells of the outer root sheath.: 673 The lesion is often seen in the face and neck region. Multifocal occurrence is associated with Cowden syndrome, in which hamartomatous intestinal polyposis is seen in conjunction with multiple tricholemmoma lesions.
Additional images
See also
Cowden syndrome
Trichilemmal carcinoma
List of cutaneous conditions
List of cutaneous neoplasms associated with systemic syndromes
References
== External links == |
Pneumomediastinum | Pneumomediastinum (from Greek pneuma – "air", also known as mediastinal emphysema) is pneumatosis (abnormal presence of air or other gas) in the mediastinum. First described in 1819 by René Laennec, the condition can result from physical trauma or other situations that lead to air escaping from the lungs, airways, or bowel into the chest cavity.
In underwater divers it is usually the result of pulmonary barotrauma.
Signs and symptoms
The main symptom is usually severe central chest pain. Other symptoms include laboured breathing, voice distortion (as with helium) and subcutaneous emphysema, specifically affecting the face, neck, and chest. Pneumomediastinum can also be characterized by the shortness of breath that is typical of a respiratory system problem. It is often recognized on auscultation by a "crunching" sound timed with the cardiac cycle (Hammans crunch).
Pneumomediastinum may also present with symptoms mimicking cardiac tamponade as a result of the increased intrapulmonary pressure on venous flow to the heart.
Cause
It is most commonly caused by:
Esophageal rupture, for example in Boerhaave syndrome
Asthma or other conditions leading to alveolar rupture
Bowel rupture, where air in the abdominal cavity tracts up into the chest.It has also been associated with:
Mycoplasma pneumoniae pneumonia
obesityIt can be induced to assist thoracoscopic surgery.It can be caused by a pulmonary barotrauma induced by a person moving from a higher to a lower pressure environment, such as when a scuba or surface-supplied diver, a free-diver after lung-packing, or an airplane passenger ascends. In the case of scuba and surface supplied divers, the diver breathes gas at ambient pressure, and if this is not able to escape freely during ascent, the pressure difference will cause it to expand, and may rupture the lung tissues (pulmonary barotrauma), and escape to a variety of places, one of which can be the mediastinum. A diver with symptoms of mediastinal emphysema may also have any combination of arterial gas embolism, pneumothorax and subcutaneous or pulmonary interstitial emphysema. Factors which may prevent free escape of the compressed breathing gas include holding the breath or respiratory obstructions such as cysts, mucus plugs, or scar tissue.In rare cases, pneumomediastinum may also arise as a result of blunt chest trauma (e.g. car accidents, fights, over pressure of breathing apparatus), while still evolving in the same fashion as the spontaneous form.Pneumomediastinum is most commonly seen in otherwise healthy young male patients and may not be prefaced by a relevant medical history of similar ailments.
Diagnosis
Pneumomediastinum is uncommon and occurs when air leaks into the mediastinum. The diagnosis can be confirmed via chest X-ray showing a radiolucent outline around the heart and mediastinum or via CT scanning of the thorax.
Treatment
The tissues in the mediastinum will slowly resorb the air in the cavity so most pneumomediastinums are treated conservatively. Breathing high flow oxygen will increase the absorption of the air.
If the air is under pressure and compressing the heart, a needle may be inserted into the cavity, releasing the air.
Surgery may be needed to repair the hole in the trachea, esophagus or bowel.If there is lung collapse, it is imperative the affected individual lies on the side of the collapse. Although painful, this allows full inflation of the unaffected lung.
References
External links
00964 at CHORUS |
Gumma (pathology) | A gumma (plural gummata or gummas) is a soft, non-cancerous growth resulting from the tertiary stage of syphilis (and yaws). It is a form of granuloma. Gummas are most commonly found in the liver (gumma hepatis), but can also be found in brain, heart, skin, bone, testis, and other tissues, leading to a variety of potential problems including neurological disorders or heart valve disease.
Presentation
Gummas have a firm, necrotic center surrounded by inflamed tissue, which forms an amorphous proteinaceous mass. The center may become partly hyalinized.
These central regions begin to die through coagulative necrosis, though they also retain some of the structural characteristics of previously normal tissues, enabling a distinction from the granulomas of tuberculosis where caseous necrosis obliterates preexisting structures. Other histological features of gummas include an intervening zone containing epithelioid cells with indistinct borders and multinucleated giant cells, and a peripheral zone of fibroblasts and capillaries. Infiltration of lymphocytes and plasma cells can be seen in the peripheral zone as well. With time, gummas eventually undergo fibrous degeneration, leaving behind an irregular scar or a round fibrous nodule.It is restricted to necrosis involving spirochaetal infections that cause syphilis. Growths that have the appearance of gummas are described as gummatous.
Pathology
In syphilis, the gumma is caused by a reaction to spirochaete bacteria in the tissue.
It appears to be the human bodys way to slow down the action of this bacteria; it is a unique immune response that develops in humans after the immune system fails to kill off syphilis.
Epidemiology
The formation of gummata is rare in developed countries, but common in areas that lack adequate medical treatment.Syphilitic gummas are found in most but not all cases of tertiary syphilis, and can occur either singly or in groups. Gummatous lesions are usually associated with long-term syphilitic infection; however, such lesions can also be a symptom of benign late syphilis.
References
== External links == |
Chromhidrosis | Chromhidrosis is a rare condition characterized by the secretion of colored sweat. It is caused by the deposition of lipofuscin in the sweat glands. Cases of red, blue, green, yellow, pink, and black sweat have been reported.
Usually, chromhidrosis affects the apocrine glands, mainly on the face and underarms. A limited number of treatment options exist, including regular application of capsaicin cream, and prolonged relief may be provided by botulinum toxin treatment. Chromogenic pigments produced by bacteria (Corynebacterium in particular) are implicated in this condition, but their exact role still requires careful microbiological elucidation.
Chromhidrosis of the eccrine glands is rare; it occurs mainly after the ingestion of certain dyes or drugs.
See also
List of cutaneous conditions
References
Further reading
Schwarz, T; Neumann, R; Duschet, P; Brückler, B; Klein, W; Oppolzer, G; Bardach, H; Gschnait, F (1989). "Apokrine Chromhidrose" [Apocrine chromhidrosis]. Der Hautarzt (in German). 40 (2): 106–9. PMID 2714985.
Marksjr, J (1989). "Treatment of apocrine chromhidrosis with topical capsaicin". Journal of the American Academy of Dermatology. 21 (2 Pt 2): 418–20. doi:10.1016/S0190-9622(89)80050-7. PMID 2474015.
Bartels, Eva (2008). "Farbkodierte Dopplersonographie der Vertebralarterien. Vergleich mit der konventionellen Duplexsonographie" [Color coded Doppler sonography of the vertebral arteries. Comparison with conventional duplex sonography]. Ultraschall in der Medizin. 13 (2): 59–66. doi:10.1055/s-2007-1005277. PMID 1604294.
== External links == |
Deaf-mute | Deaf-mute is a term which was used historically to identify a person who was either deaf and used sign language or both deaf and could not speak. The term continues to be used to refer to deaf people who cannot speak an oral language or have some degree of speaking ability, but choose not to speak because of the negative or unwanted attention atypical voices sometimes attract. Such people communicate using sign language. Some consider it to be a derogatory term if used outside its historical context; the preferred term today is simply "deaf".
Historical usage of "deaf-mute" and other terms
United Kingdom
In 19th century British English "mute" and "dumb" meant "non-speaking", and were not pejorative terms. For example, in 1889 Queen Victoria instigated the Royal Commission on The Blind, the Deaf and Dumb etc.in the United Kingdom. The intention was to examine contemporary education and employment of blind or deaf people, with a view to improving conditions for them. The Oxford English Dictionary states that the North American pejorative usage of the word to imply stupidity was first noted in the UK in 1928. According to the OED, "deaf-mute" was coined in the early 19th century as a medical term for an inability to speak as a consequence of deafness. There is no mention of offensiveness of this term in the UK.
North America
The primary definition of "dumb" in Websters Dictionary is "lacking intelligence" or "stupid". Its second definition of the word is "lacking the ability to speak ... now often offensive". Websters definition of "mute", on the other hand, gives the adjectival meaning as "unable to speak", whereas one of its usages as a noun is "a person who cannot speak ... sometimes offensive".In informal American English the terms "mute" and "dumb" are sometimes used to refer to other hearing people in jest, to chide, or to invoke an image of someone who refuses to employ common sense or who is unreliable. In the past deaf-mute was used to describe deaf people who used sign language, but in modern times, the term is frequently viewed today as offensive and inaccurate. From antiquity (as noted in the Code of Hammurabi) until recent times, the terms "deaf-mute" and "deaf and dumb" were sometimes considered analogous to "stupid" by some hearing people. The simple identity of "deaf" has been embraced by the community of signing deaf people since the foundations of public deaf education in the 18th century and remains the preferred term of reference or identity for many years. Within the deaf community there are some who prefer the term "Deaf" (upper-case D) to "deaf" (lower-case) as a description of their status and identity.
Jewish law
Classification as a deaf-mute has a particular importance in Jewish law. Because historically it was thought impossible to teach or communicate with them, deaf-mutes were not moral agents, and therefore were unable to own real estate, act as witnesses, or be punished for any crime. However, today when techniques for educating deaf people are known, they are no longer classed as such.
Deaf-mute people in history
The Ottoman Sultans used people referred to as "congenital deaf-mutes" (called in Turkish dilsiz or bizeban, i.e. "mute" or "without tongue") in their own personal service from the 15th century to the end of the Ottoman Empire. Due to their nature, they were often entrusted with confidential and delicate missions, including executions.
Deaf-muteness in art and literature
Stephen Kings novel The Stand features a main character named Nick Andros who is referred to as "deaf-mute." Though deaf people almost always have a voice, King interpreted the term literally and made Nick unable to vocalize. However, he could read lips and make himself clearly understood by pantomiming and in writing.
The phrase is used in The Catcher in the Rye to indicate someone who does not speak his mind, and hears nothing, in effect becoming isolated from the world.
Chief Bromden, in One Flew Over the Cuckoos Nest, is believed by all to be deaf and mute, but in fact he can hear and speak; he does not let anyone know this because, as he grew up, he was not spoken to (making him "deaf") and ignored (making him "mute").
The character Singer in the novel The Heart Is a Lonely Hunter, written in 1940, is referred to as "deaf-mute" throughout.
In the classic Zorro stories, television series, etc. Zorros aid Bernardo, a mute, pretends that he can also not hear, in order to get information to aid his master in his fight for justice.
In the early 87th Precinct novels written by Ed McBain, Teddy Carella, the wife of Detective Steve Carella, was referred to as a "deaf-mute," but in later books, McBain stopped using the term. In the foreword to a reprinted edition of "The Con Man", originally published in 1957, McBain says, "A reader pointed out to me two or three years ago that this expression was now considered derogatory. Out the window it went, and Teddy is now speech-and-hearing impaired."
== References == |
Obstructive sleep apnea | Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder and is characterized by recurrent episodes of complete or partial obstruction of the upper airway leading to reduced or absent breathing during sleep. These episodes are termed "apneas" with complete or near-complete cessation of breathing, or "hypopneas" when the reduction in breathing is partial. In either case, a fall in blood oxygen saturation, a disruption in sleep, or both may result. A high frequency of apneas or hypopneas during sleep may interfere with restorative sleep, which – in combination with disturbances in blood oxygenation – is thought to contribute to negative consequences to health and quality of life. The terms obstructive sleep apnea syndrome (OSAS) or obstructive sleep apnea–hypopnea syndrome (OSAHS) may be used to refer to OSA when it is associated with symptoms during the daytime (e.g. excessive daytime sleepiness, decreased cognitive function).Most individuals with OSA are unaware of disturbances in breathing while sleeping, even after awakening. A bed partner or family member may observe an individual snoring or appear to stop breathing, gasp, or choke while sleeping. Individuals who live or sleep alone are often unaware of the condition. Symptoms may be present for years or even decades without identification, during which time the individual may become conditioned to the daytime sleepiness, headaches and fatigue associated with significant levels of sleep disturbance. Obstructive sleep apnea has been associated with neurocognitive morbidity, as well as a link between snoring and neurocognitive disorders.
Classification
In the third edition of the International Classification of Sleep Disorders (ICSD-3), Obstructive Sleep Apnea is classified amongst the Sleep-Related Breathing Disorders and is divided in two categories, namely adult OSA and pediatric OSA. Obstructive Sleep Apnea is differentiated from central sleep apnea (CSA), which is characterized by episodes of reduction or cessation in breathing attributable to decreased effort, rather than upper airway obstruction. The respiratory effort must then be assessed in order to correctly classify the apnea as obstructive given the specificity of the diaphragmatic activity in this condition: the inspiratory effort is continued or increased through the entire episode of absent airflow. When hypopneas are present alongside apneas, the term Obstructive Sleep Apnea-Hypopnea is used and when it is associated with daytime sleepiness and other daytime symptoms, it is called Obstructive Sleep Apnea-Hypopnea Syndrome. To be categorized as obstructive, the hypopnea must meet one or more of the following symptoms: (1) snoring during the event, (2) increased oronasal flow flattening, or (3) thoraco-abdominal paradoxical respiration during the event. If none of them are present during the event, then it is categorized as central hypopnea.
Signs and symptoms
Common symptoms of OSA syndrome include unexplained daytime sleepiness, restless sleep, and loud snoring (with periods of silence followed by gasps). Less common symptoms are morning headaches; insomnia; trouble concentrating; mood changes such as irritability, anxiety, and depression; forgetfulness; increased heart rate or blood pressure; decreased sex drive; unexplained weight gain; increased urinary frequency or nocturia; frequent heartburn or gastroesophageal reflux; and heavy night sweats.Many people experience episodes of OSA for only a short period. This can be the result of an upper respiratory infection that causes nasal congestion, along with swelling of the throat, or tonsillitis that temporarily produces very enlarged tonsils. The Epstein-Barr virus, for example, is known to be able to dramatically increase the size of lymphoid tissue during acute infection, and OSA is fairly common in acute cases of severe infectious mononucleosis. Temporary spells of OSA syndrome may also occur in individuals who are under the influence of a drug (such as alcohol) that may relax their body tone excessively and interfere with normal arousal from sleep mechanisms.
Adults
The hallmark symptom of OSA syndrome in adults is excessive daytime sleepiness. Typically, an adult or adolescent with severe long-standing OSA will fall asleep for very brief periods in the course of usual daytime activities if given an opportunity to sit or rest. This behavior may be quite dramatic, sometimes occurring during conversations with others at social gatherings.The hypoxia (absence of oxygen supply) related to OSA may cause changes in the neurons of the hippocampus and the right frontal cortex. Research using neuro-imaging revealed evidence of hippocampal atrophy in people with OSA. They found that OSA can cause problems in mentally manipulating non-verbal information, in executive functions and working memory. This repeated brain hypoxia is also considered to be a cause of Alzheimers disease.Diagnosis of obstructive sleep apnea is significantly more common among people in relationships, who are alerted to their condition by being informed by their sleeping partner since individuals with obstructive sleep apnea are often unaware of the condition. There is a stigma associated with loud snoring, and it is not considered a feminine trait. Consequently, females are less likely to be told by their partners that they snore, or to admit it to themselves or doctors. Furthermore, CPAP (Continuous Positive Airway Pressure) machines are also perceived negatively by females, and less likely to be utilized to their full extent in this group.
Children
Although this so-called "hypersomnolence" (excessive sleepiness) may also occur in children, it is not at all typical of young children with sleep apnea. Toddlers and young children with severe OSA instead ordinarily behave as if "over-tired" or "hyperactive"; and usually appear to have behavioral problems like irritability, and a deficit in attention. Adults and children with very severe OSA also differ in typical body habitus. Adults are generally heavy, with particularly short and heavy necks. Young children, on the other hand, are generally not only thin but may have "failure to thrive", where growth is reduced. Poor growth occurs for two reasons: the work of breathing is intense enough that calories are burned at high rates even at rest, and the nose and throat are so obstructed that eating is both tasteless and physically uncomfortable. OSA in children, unlike adults, is often caused by obstructive tonsils and adenoids and may sometimes be cured with tonsillectomy and adenoidectomy.This problem can also be caused by excessive weight in children. In this case, the symptoms are more like the symptoms adults feel such as restlessness, exhaustion, etc. If adenotonsillar hypertrophy remains the most common cause of OSA in children, obesity can also play a role in the pathophysiology of upper airway obstruction during sleep which can lead to OSA, making obese children more likely to develop the condition. The recent epidemic increase of obesity prevalence has thus contributed to changes in the prevalence and in the characteristics of pediatric OSA, the severity of OSA being proportional to the degree of obesity. Obesity leads to the narrowing of upper airway structure due to fatty infiltration and fat deposits in the anterior neck region and cervical structures. Alongside with the additional weight loading on the respiratory system, it increases the risk of pharyngeal collapsibility while reducing the intrathoracic volume and diaphragm excursion. Moreover, excessive daytime sleepiness resulting from sleep fragmentation can decrease physical activity and thus lead to weight gain (by sedentary habits or increased food intake to overcome somnolence). The obesity-related obstruction of upper airway structure has led some authors to distinguish between two types of OSA in children: type I is associated with marked lymphadenoid hypertrophy without obesity and type II is first associated with obesity and with milder upper airway lymphadenoid hyperplasia. The two types of OSA in children can results in different morbidities and consequences. Studies have shown that weight loss in obese adolescents can reduce sleep apnea and thus the symptoms of OSA.
Pathophysiology
The transition from wakefulness to sleep (either REM sleep or NREM sleep) is associated with a reduction in upper-airway muscle tone. During REM sleep, muscle tone of the throat and neck, as well as that of the vast majority of skeletal muscles, are almost completely relaxed. This allows the tongue and soft palate/oropharynx to relax, reducing airway patency and potentially impeding or completely obstructing the flow of air into the lungs during inspiration, resulting in reduced respiratory ventilation. If reductions in ventilation are associated with sufficiently low blood-oxygen levels or with sufficiently high breathing efforts against an obstructed airway, neurological mechanisms may trigger a sudden interruption of sleep, called a neurological arousal. This arousal can cause an individual to gasp for air and awaken. These arousals rarely result in complete awakening but can have a significant negative effect on the restorative quality of sleep. In significant cases of OSA, one consequence is sleep deprivation resulting from the repetitive disruption and recovery of sleep activity. This sleep interruption in Stage 3 (also called slow-wave sleep), and in REM sleep, can interfere with normal growth patterns, healing and immune response, especially in children and young adults.
The fundamental cause of OSA is a blocked upper airway, usually behind the tongue and epiglottis, whereby the otherwise patent airway, in an erect and awake patient, collapses when the patient is lying on his or her back and loses muscle tone upon entering deep sleep.
At the beginning of sleep, a patient is in light sleep and there is no tone loss of throat muscles. Airflow is laminar and soundless. As the upper airway collapse progresses, the obstruction becomes increasingly apparent by the initiation of noisy breathing as air turbulence increases, followed by gradually louder snoring as a Venturi effect forms through the ever-narrowing air passage.
The patients blood-oxygen saturation gradually falls until cessation of sleep noises, signifying total airway obstruction of airflow, which may last for several minutes.
Eventually, the patient must at least partially awaken from deep sleep into light sleep, automatically regaining general muscle tone. This switch from deep to light to deep sleep can be recorded using ECT monitors.
In light sleep, muscle tone is near normal, the airway spontaneously opens, normal noiseless breathing resumes and blood-oxygen saturation rises. Eventually, the patient reenters deep sleep, upper airway tone is again lost, the patient enters the various levels of noisy breathing and the airway blockage returns.
The cycle of muscle-tone loss and restoration coinciding with periods of deep and light sleep repeats throughout the patients period of sleep.
The number of apnoea and hypopnoea episodes during any given hour is counted and given a score. If a patient has an average of five or more episodes per hour, mild OSA may be confirmed. An average of 30 or more episodes per hour indicates severe OSA.
Pathophysiological models
The causes of spontaneous upper-airway blockage are strongly debated by clinical professionals. The areas of thought are divided mostly into three medical groups.
Some pulmonologists and neurologists believe the risk factors to be:
Advanced age, although OSA occurs in neonates, as with Pierre Robin syndrome, and in all age groups of people.
Brain injury (temporary or permanent), although this does not account for the 99% of OSA patients who have normal brains and normal lives.
Decreased muscle tone caused by drugs or alcohol, or caused by neurological disorders. This also would not account for the majority of people with OSA.
Long-term snoring, which is postulated to potentially induce local nerve lesions in the soft tissues of the pharynx. Snoring may produce traumatic vibrations that may give rise to nerve injuries in the upper airway muscles, further contributing to OSA.
Increased soft tissue around the airway, often resulting from obesity, though not seen in all patients with OSA.Some otorhinolaryngologists believe the risk factors to be structural features that give rise to a narrowed airway, such as enlarged tonsils, an enlarged posterior tongue or fat deposits in the neck. Further factors leading to OSA can be impaired nasal breathing, floppy soft palate or a collapsible epiglottis.
Some oral and maxillofacial surgeons believe the risk factors to be a number of primary forms of mandibular hypoplasia, which offers a primary anatomical basis to the development of OSA through glossoptosis. Some maxillofacial surgeons who offer orthognathic surgery for treatment of OSA believe that their treatments offer superior guarantees of cure of OSA.
Risk factors
Obesity
It is well known that children, adolescents or adults with OSA are often obese. Obese people show an increase in neck fat tissue which potentiate respiratory obstruction during sleep.However, people of all ages and sex with normal body mass indices (BMIs) can also demonstrate OSA – and these people do not have significant measures of subdermal or intra neck fat as shown on DEXA scans. It is speculated that they may have increased muscle mass, or alternatively have a tendency to decreased muscle tone potentiating airway collapse during sleep.However, loss of muscle tone is a key feature of deep sleep anyway, and whilst obesity seems a common association, it is not an invariable state of OSA.
Sleeping supine (on ones back) is also represented as a risk factor for OSA. Clearly, gravity and loss of tongue and throat tone as a person enters deep sleep are clear and obvious factors contributing to OSA developing. But this explanation is also confounded by the presence of neck obesity.
Use of CPAP definitively primarily expands a collapsed upper airway, allowing for nasal breathing – and positive use of CPAP would prove that airway collapse is the cause of OSA.
Throat lesions, particularly enlarged tonsils, are well recognized as aggravators of OSA, and removal may provide full or partial or semi-permanent relief from OSA, which also indicates that enlarged tonsils may play a role in the pathogenesis of OSA.
Age
Old age is often accompanied by muscular and neurological loss of muscle tone of the upper airway. Decreased muscle tone is also temporarily caused by chemical depressants; alcoholic drinks and sedative medications being the most common. Permanent premature muscular tonal loss in the upper airway may be precipitated by traumatic brain injury, neuromuscular disorders, or poor adherence to chemical and or speech therapy treatments.
Muscle tone
Individuals with decreased muscle tone and increased soft tissue around the airway, and structural features that give rise to a narrowed airway are at high risk for OSA. Men, in which the anatomy is typified by increased mass in the torso and neck, are at increased risk of developing sleep apnea, especially through middle age and later. Typically, women experience this condition less frequently and to a lesser degree than do men, owing partially to physiology, but possibly also to differential levels of progesterone. Prevalence in post-menopausal women approaches that of men in the same age range. Women are at greater risk for developing OSA during pregnancy.
Medication and lifestyle
Lifestyle factors such as smoking may also increase the chances of developing OSA as the chemical irritants in smoke tend to inflame the soft tissue of the upper airway and promote fluid retention, both of which can result in narrowing of the upper airway. Cigarettes may also have an impact due to a decline of blood nicotine levels, which alters sleep stability. Smokers thus show a higher risk to develop OSA, but the effect of cigarettes on increased OSA is reversible with the cessation of smoking. Children exposed to cigarette smoke may also develop OSA as the lymphadenoid tissue will proliferate excessively in contact with the irritants. An individual may also experience or exacerbate OSA with the consumption of alcohol, sedatives, or any other medication that increases sleepiness as most of these drugs are also muscle relaxants. Allergic rhinitis and asthma have also been shown to be implicated in the increased prevalence of adenotonsillar hypertrophy and OSA.
Genetic
OSA also appears to have a genetic component; those with a family history of it are more likely to develop it themselves.
Craniofacial syndromes
Of substantial recent interest is the idea that there is a general human tendency towards developing short lower jaws (neoteny) is a major cause of OSA through a combined condition called glossoptosis. The posterior “normal” tongue is displaced backwards by a smaller “abnormal” anterior tongue and lower jaw. In much the same way, a narrow upper jaw will also contribute to OSA due to its relation to airway volume. A more narrow upper jaw results in more narrow nasal passages and a more narrow throat, this also appears to be why so many OSA patients experience nasal congestion especially while lying down.
Maxillofacial surgeons see many effects of small lower jaws, including crowded teeth, malocclusions, as well as OSA – all of which are treatable by surgical operations that increase and normalise jaw size. Operations such as custom BIMAX, GenioPaully, and IMDO (in adolescence) offer a valid medical option that replaces all traditional forms of OSA treatment – including CPAP, Mandibular Advancement Splints, tonsillectomy and UPPP. There are patterns of unusual facial features that occur in recognizable syndromes. Some of these craniofacial syndromes are genetic, others are from unknown causes. In many craniofacial syndromes, the features that are unusual involve the nose, mouth, and jaw, or resting muscle tone, and put the individual at risk for OSA syndrome.
Down syndrome is one such syndrome. In this chromosomal abnormality, several features combine to make the presence of obstructive sleep apnea more likely. The specific features of Down syndrome that predispose to obstructive sleep apnea include relatively low muscle tone, narrow nasopharynx, and large tongue. Obesity and enlarged tonsils and adenoids, conditions that occur commonly in the western population, are much more likely to be obstructive in a person with these features than without them. Obstructive sleep apnea does occur even more frequently in people with Down syndrome than in the general population. A little over 50% of all people with Down syndrome experience obstructive sleep apnea, and some physicians advocate routine testing of this group.In other craniofacial syndromes, the abnormal feature may actually improve the airway, but its correction may put the person at risk for obstructive sleep apnea after surgery when it is modified. Cleft palate syndromes are such an example. During the newborn period, all humans are obligate nasal breathers. The palate is both the roof of the mouth and the floor of the nose. Having an open palate may make feeding difficult, but generally, does not interfere with breathing, in fact, if the nose is very obstructed, then an open palate may relieve breathing. There are a number of clefting syndromes in which the open palate is not the only abnormal feature; additionally, there is a narrow nasal passage – which may not be obvious. In such individuals, closure of the cleft palate – whether by surgery or by a temporary oral appliance – can cause the onset of obstruction.
Skeletal advancement in an effort to physically increase the pharyngeal airspace is often an option for craniofacial patients with upper airway obstruction and small lower jaws (mandibles). These syndromes include Treacher Collins syndrome and Pierre Robin sequence. Mandibular advancement surgery is one of the modifications needed to improve the airway, others may include reduction of the tongue, tonsillectomy or modified uvulopalatoplasty.
Post-operative complication
OSA can also occur as a serious post-operative complication that seems to be most frequently associated with pharyngeal flap surgery as compared to other procedures for the treatment of velopharyngeal inadequacy (VPI). In OSA, recurrent interruptions of respiration during sleep are associated with temporary airway obstruction. Following pharyngeal flap surgery, depending on size and position, the flap itself may have an "obturator" or obstructive effect within the pharynx during sleep, blocking ports of airflow and hindering effective respiration. There have been documented instances of severe airway obstruction, and reports of post-operative OSA continues to increase as healthcare professionals (i.e. physicians, speech language pathologists) become more educated about this possible dangerous condition. Subsequently, in clinical practice, concerns of OSA have matched or exceeded interest in speech outcomes following pharyngeal flap surgery.The surgical treatment for velopalatal insufficiency may cause obstructive sleep apnea syndrome. When velopalatal insufficiency is present, air leaks into the nasopharynx even when the soft palate should close off the nose. A simple test for this condition can be made by placing a tiny mirror on the nose, and asking the subject to say "P". This p sound, a plosive, is normally produced with the nasal airway closes off – all air comes out of the pursed lips, none from the nose. If it is impossible to say the sound without fogging a nasal mirror, there is an air leak – reasonable evidence of poor palatal closure. Speech is often unclear due to inability to pronounce certain sounds. One of the surgical treatments for velopalatal insufficiency involves tailoring the tissue from the back of the throat and using it to purposefully cause partial obstruction of the opening of the nasopharynx. This may actually cause OSA syndrome in susceptible individuals, particularly in the days following surgery, when swelling occurs (see below: Special Situation: Anesthesia and Surgery).Finally, patients with OSA are at an increased risk of many perioperative complications when they are present for surgery, even if the planned procedure is not on the head and neck. Guidelines intended to reduce the risk of perioperative complications have been published.
Consequences
There are 3 levels of consequences: physiologic, intermediate and clinical. The physiologic consequences contain hypoxia, sleep fragmentation, autonomic nervous system dysregulation or hyperoxia. The intermediate results regroup inflammation, pulmonary vasoconstriction, general metabolic dysfunction, oxidation of proteins and lipids or increased adiposity. The clinical repercussions are composed by pulmonary hypertension, accidents, obesity, diabetes, different heart diseases or hypertension.
In children
Obstructive sleep apnea is the most common Sleep-Disordered Breathing (SDB) and affects up to 11% of children born at term – it is even more common (3 to 6 times more) in children born pre-term. As a SDB, OSA in children can lead to several adverse consequences, also in the long-term with consequences lasting into adulthood. The implications of OSA in children are complex and cover a large scope of consequences: when it is left untreated, OSA can lead to morbidity affecting many different domains of life (organs, body systems, behavioral disturbance, depression, decreased quality of life, etc.). Therefore, nocturnal symptoms indicating the presence of OSA (e.g. snoring, gasping, restless sleep and excessive energy used to breathe during sleep) are associated with daytime symptoms such as concentration and learning difficulties and irritability, neurocognitive development impairment, decreased school performance and behavioral difficulties. For example, SDB such as OSA contributes to hyperactive behavior that can lead to the diagnosis and treatment of attention deficit hyperactivity disorder (ADHD). However, once the SDB is treated, the hyperactive behavior can improve, and the treatment can be stopped. Obesity also has an impact on the consequences of OSA and lead to different manifestations or severity. Studies have shown that, contrary to adults, children with obstructive sleep-disordered breathing are able to maintain cerebral oxygenation. However, the condition still has effects on the brain and can lead to adverse neurocognitive and behavioral sequelae. It is particularly concerning as those consequences happen while the brain is still developing. The degree to which the sleep is disturbed and fragmented has been significantly linked to the severity of the consequences, the latter having the possibility to decrease once the sleep is improved. It is more the disruption of sleep processes than the total amount of sleep the child experience that generates the adverse consequences on the childs daytime functioning; it contributes to the hyperactivity for example.Children with OSA may experience learning and memory deficits and OSA has also been linked to lowered childhood IQ scores.
Neurocognitive and behavioral consequences
Nocturnal sleep fragmentation has been linked to neurocognitive impairments, therefore, the identification of SDB such as OSA is crucial in children, those impairments having the possibility to be reversible with the appropriate treatment for the sleep disorder. The neurocognitive and behavioral dysfunctions commonly present in children with OSA include the following: hyperactivity, impulsivity, aggressive behaviors, low social and communication abilities and reduced adaptive skills.
Children with OSA commonly show cognitive deficits, resulting in attention and concentration difficulties, as well as lower academic performance and IQ. Poor academic performances have been linked to OSA and suggested to result from cortical and sympathetic arousals and hypoxemia which affects memory consolidation. A study with Indian children affected by OSA has shown poor school grades, including mathematics, science, language and physical education. This study allowed to see the overall impact of OSA on learning abilities associated with language or numeracy skills, and physical development. It has been suggested that the deficits in academic performance related to OSA could be mediated through reduced executive functions or language skills, those domains contributing highly to learning abilities and behavior. The deficits in school performance can nevertheless be improved if adenotonsillectomy is performed on children to treat the OSA. It is thus crucial to identify the OSA for children with school difficulties; many cases remaining unnoticed.As studies have shown that learning skills and behaviors can be improved if the OSA is treated, the neurocognitive and behavioral deficits are thus at least partly reversible. This reversible dimension has been postulated to be negatively correlated to the duration of the symptoms, which would mean that the longer the OSA is left untreated, the less reversible are the consequences.
Somatic and metabolic consequences
Similarly to adults, OSA in children is linked to a higher risk for cardiovascular morbidities, due to increased sympathetic activity and impaired cardiac autonomic control. Amongst the cardiovascular dysfunctions resulting from OSA, we can find systemic hypertension and blood pressure dysregulation (elevated blood pressure, or variability of the blood pressure for example). The variability of the blood pressure has been shown to be correlated with the severity of the symptoms such as the frequency of the apnea and hypopnea. Pulmonary hypertension is also common amongst the cardiovascular problems resulting from OSA. Children with obstructive sleep-disordered breathing also show a faster heart rate during wakefulness and during sleep.In adult patients, OSA has been shown to be associated with insulin resistance. In children, metabolic consequences of OSA are complicated to assess as they can also be associated to puberty and obesity (if present). However, when OSA is associated with obesity, the interaction of the two conditions can lead to metabolic disturbances such as insulin resistance and altered lipidemia, liver disease, abdominal adiposity and metabolic syndrome. Obesity interact with those effects.
Nocturnal enuresis
Children with OSA also show a higher risk for nocturnal enuresis and it is hypothesized to be caused by an excessive production of urine, impaired performance of the bladder and urethra or an inability to suppress the nocturnal bladder contraction, due to a failure to arouse. The risk for nocturnal enuresis increases with the severity of the sleep-disordered breathing: the more respiratory events per hour of sleep, the higher is the risk for nocturnal enuresis. Obesity may also play a role as it is associated with OSA and with nocturnal diuresis (due to unhealthy diet). The interaction between OSA and obesity might thus result in nocturnal enuresis. Considering the high prevalence of nocturnal enuresis amongst children with sleep-disordered breathing, it is important to consider the latter in the differential diagnosis of nocturnal enuresis as the treatment of the sleep disorder might have a favourable therapeutic effect on the enuresis. For example, an adenotonsillectomy performed to reduce OSA has a positive impact on nocturnal enuresis. A study has shown that this surgery has 60–75% chance to resolve the nocturnal enuresis completely, and 80–85% chance to reduce its symptoms alongside others symptoms of OSA.
Other consequences
Contrary to adults, excessive daytime sleepiness (EDS) is not the most commonly reported symptoms in children with OSA. However, using objective questionnaires, it is possible to notice that the frequency of EDS in children is higher than what is reported by the parents or caretakers (40–50%). And the risk for EDS is even increased when OSA is associated with obesity.Due to all the consequences and symptoms |
Obstructive sleep apnea | it generates, OSA in children lead to a significant decrease in the quality of life, the decrease being even higher when obesity is present. The quality of life can however be improved with the treatment of OSA. SBD have also been linked to a higher rate of internalizing disorders such as anxiety and depression. Indeed, depressive symptoms have shown to be higher in children with OSA, especially in males. Once again, the severity of depressive symptoms is positively correlated with the severity of the SBD. It also interacts with obesity as obese children have higher risk to show depressive symptoms and obesity can cause OSA. The link can also go the other way around with the depression inducing obesity (due to overeating) which worsens the OSA. Adenotonsillectomy can decrease the intensity of the depressive symptoms.Other consequences of a disturbed sleep in children with OSA comprise anhedonia increased fatigue and decreased interest in daily activities, which in turn can affect the childs social relationships.
In adults
While there are some similarities between adults and children, OSA does not have the same consequences in both populations. Examples of similarities are the snoring – which is the most common complaint in both pediatric OSA and OSA in adults – variability of blood pressure and cardiovascular morbidities. A major difference is the excessive daytime sleepiness (EDS) which is commonly reported in adult OSA, while it is not very common in pediatric OSA. Nevertheless, OSA in adults also implies a large scope of adverse and serious consequences, the latter leading to higher mortality amongst OSA patients. Those consequences are even worsened by common morbidities such as obesity.
Neurocognitive consequences
Similarly to children, OSA affects cognitive functions in adults. Meta-analysis have shown that the most common cognitive impairments happen in the domains of attention, verbal and visual delayed long-term memory, visuospatial/constructional abilities and executive functions, such as mental flexibility. The executive functioning – mainly dominated by the prefrontal cortex – being significantly impaired in patients with OSA, it is believed that the prefrontal region and its connectivity are affected by sleep disorders.Regarding memory deficits, verbal memory is significantly impaired as patients show difficulties in recalling verbal information immediately as well as with a delay. While meta-analysis have shown no deficits in retention of information for patients with OSA, those impairment in verbal memory may be linked to problems in encoding information. This deficit in encoding of information is also noticed in visuo-spatial memory; however, the visual memory seems to be intact in OSA patients.The cognitive impairments have been suggested to be resulting from sleep fragmentation and sleep deprivation, as well as the excessive daytime sleepiness associated with them. More precisely, attention and memory deficits seem to result from sleep fragmentation, while deficits in global cognitive function (executive function, psychomotor function, language abilities) are more related to hypoxia or hypercarbia which accompanies the obstructive events during sleep. However, no consistent correlation has been found between the degree of cognitive impairment and the severity of the sleep disturbance or hypoxia.
These impairments may improve with an effective treatment for OSA, such as continuous positive airway pressure (CPAP) therapy. Driving a motor vehicle is an example of a complex task that relies on drivers cognitive abilities, such as attention, reaction time and vigilance. Very brief moments of inattention called microsleep events could be an indicator for daytime vigilance impairment, although these may not be present in all drivers with obstructive sleep apnea.
Behavioral consequences
The hyperactivity and difficulties in emotional regulation found in pediatric patients (children) are not reported in adults. OSA in adults is nevertheless associated with personality changes and automatic behavior. The biggest impact of OSA is the excessive daytime sleepiness (EDS), reported in approximately 30% of OSA patients. EDS can be caused by the disturbance of sleep quality, the insufficient sleep duration or the sleep fragmentation and it is responsible for further complications as it may lead to depressive symptoms, impairments of social life and decreased effectiveness at work. Studies have shown that those consequences of EDS can be improved following a CPAP treatment.
Physiological and metabolic consequences
OSA in adults is associated with a higher risk for cardiovascular morbidities, diabetes, hypertension, coronary artery disease and stroke – OSA might have a role in the etiology of these conditions. Those conditions may lead to increased mortality that an appropriate treatment for OSA may reduce. OSA is often linked with hypertension as it induces an increase in sympathetic activity that can lead to the elevation of blood pressure. The OSA-related hypercapnia has been suggested to be related to this development of hypertension. Treating the OSA may prevent the development of hypertension.
The relationship between OSA and excess body weight is complex as obesity is more prevalent amongst OSA patients but can also be a risk factor for the development of OSA – it accounts for 58% of adult cases. Thus, both OSA and obesity (when present) may work synergistically and lead to hyperlipidemia, diabetes, insulin resistance and other symptoms of the metabolic syndrome. The metabolic syndrome itself is often associated with OSA: 74–85% of OSA patients are diagnosed with it. CPAP therapy can lead to an improvement of some of the cardiovascular component of the metabolic syndrome while weight loss is also recommended for its positive effects on OSA consequences and metabolic dysfunctions. An intervention comprising exercise and diet is thus effective for the treatment of OSA as it positively impacts the severity of both obesity symptoms and OSA symptoms.Individuals with Type 2 diabetes are often co-diagnosed with OSA, where Type 2 diabetes prevalence rates range between 15% to 30% within the OSA population. The relationship between OSA and Type 2 diabetes could possibly be explained by the fact that OSA-characteristic fragmented sleep and irregular hypoxemia leads to the dysregulated metabolism of glucose in the blood. In particular, many polysomnography studies showed that OSA left untreated worsens glycemic control in individuals with Type 2 diabetes. However, it is possible that the relationship between OSA and Type 2 diabetes is bidirectional since diabetes-related nerve dysfunction may affect the respiratory system and induce breathing disturbances during sleep.
Psychological consequences
Sleep is of major importance for psychological and emotional health. As it is greatly impaired in OSA, this condition is associated with mood disorders and several psychological outcomes, especially depression and anxiety. Therefore, psychological disorders are commonly observed in OSA patients who show a higher prevalence of psychological distress, mostly due to the impaired sleep quality and structure and the repeated episodes of hypoxia. The presence of psychological disorders may also worsen the sleep disorders which implies that the psychopathology may either be a factor or a consequence of the OSA. The adverse consequences of OSA such as cardiovascular comorbidities and metabolic disturbances also play a role on the development of mental disorders, and patients with chronic condition have also been reported to have higher risk to experience depression. In OSA patients with psychiatric disorders, it is crucial to treat the OSA as it may reduce the psychiatric symptoms.Some cases of OSA are caused by nasal obstruction which has also been related to psychological problems due to an altered ratio of calcium and magnesium in brain cells. Nasal obstruction can thus aggravate the psychological health of OSA patients. Nasal surgery for those patients might decrease the OSA severity and improve the psychological symptoms.
Other consequences
Untreated OSA also leads to a decreased quality of life, difficulties in social functioning, occupational problems and accidents and a greatly increased rate of vehicle accidents. Those serious outcomes of OSA are mostly related to the excessive daytime sleepiness resulting from the sleep fragmentation and highlight the need to provide the patients with appropriate treatment. Effective treatment majorly improves those adverse consequences, including quality of life.OSA patients also frequently report pain disorders such as headache or fibromyalgia, OSA patients showing an increased pain intensity alongside a decreased pain tolerance.
Diagnosis
In a systematic review of published evidence, the United States Preventive Services Task Force in 2017 concluded that there was uncertainty about the accuracy or clinical utility of all potential screening tools for OSA, and recommended that current evidence is insufficient to assess the balance of benefits and harms of screening for OSA in asymptomatic adults.The diagnosis of OSA syndrome is made when the patient shows recurrent episodes of partial or complete collapse of the upper airway during sleep resulting in apneas or hypopneas, respectively. Criteria defining an apnea or a hypopnea vary. The American Academy of Sleep Medicine (AASM) defines an apnea as a reduction in airflow of ≥ 90% lasting at least 10 seconds. A hypopnea is defined as a reduction in airflow of ≥ 30% lasting at least 10 seconds and associated with a ≥ 4% decrease in pulse oxygenation, or as a ≥ 30% reduction in airflow lasting at least 10 seconds and associated either with a ≥ 3% decrease in pulse oxygenation or with an arousal.To define the severity of the condition, the Apnea-Hypopnea Index (AHI) or the Respiratory Disturbance Index (RDI) are used. While the AHI measures the mean number of apneas and hypopneas per hour of sleep, the RDI adds to this measure the respiratory effort-related arousals (RERAs). The OSA syndrome is thus diagnosed if the AHI is > 5 episodes per hour and results in daytime sleepiness and fatigue or when the RDI is ≥ 15 independently of the symptoms. According to the American Association of Sleep Medicine, daytime sleepiness is determined as mild, moderate and severe depending on its impact on social life. Daytime sleepiness can be assessed with the Epworth Sleepiness Scale (ESS), a self-reported questionnaire on the propensity to fall asleep or doze off during daytime. Screening tools for OSA itself comprise the STOP questionnaire, the Berlin questionnaire and the STOP-BANG questionnaire which has been reported as being a very powerful tool to detect OSA.
Criteria
According to the International Classification of Sleep Disorders, there are 4 types of criteria. The first one concerns sleep – excessive sleepiness, nonrestorative sleep, fatigue or insomnia symptoms. The second and third criteria are about respiration – waking with breath holding, gasping, or choking; snoring, breathing interruptions or both during sleep. The last criterion revolved around medical issues as hypertension, coronary artery disease, stroke, heart failure, atrial fibrillation, type 2 diabetes mellitus, mood disorder or cognitive impairment. Two levels of severity are distinguished, the first one is determined by a polysomnography or home sleep apnea test demonstrating 5 or more predominantly obstructive respiratory events per hour of sleep and the higher levels are determined by 15 or more events. If the events are present less than 5 times per hour, no obstructive sleep apnea is diagnosed.A considerable night-to-night variability further complicates diagnosis of OSA. In unclear cases, multiple testing might be required to achieve an accurate diagnosis.
Polysomnography
Nighttime in-laboratory Level 1 polysomnography (PSG) is the gold standard test for diagnosis. Patients are monitored with EEG leads, pulse oximetry, temperature and pressure sensors to detect nasal and oral airflow, respiratory impedance plethysmography or similar resistance belts around the chest and abdomen to detect motion, an ECG lead, and EMG sensors to detect muscle contraction in the chin, chest, and legs. A hypopnea can be based on one of two criteria. It can either be a reduction in airflow of at least 30% for more than 10 seconds associated with at least 4% oxygen desaturation or a reduction in airflow of at least 30% for more than 10 seconds associated with at least 3% oxygen desaturation or an arousal from sleep on EEG.An "event" can be either an apnea, characterized by complete cessation of airflow for at least 10 seconds, or a hypopnea in which airflow decreases by 50 percent for 10 seconds or decreases by 30 percent if there is an associated decrease in the oxygen saturation or an arousal from sleep. To grade the severity of sleep apnea, the number of events per hour is reported as the apnea-hypopnea index (AHI). An AHI of less than 5 is considered normal. An AHI of 5–15 is mild; 15–30 is moderate, and more than 30 events per hour characterizes severe sleep apnea.
Home oximetry
In patients who are at high likelihood of having OSA, a randomized controlled trial found that home oximetry (a non-invasive method of monitoring blood oxygenation) may be adequate and easier to obtain than formal polysomnography. High probability patients were identified by an Epworth Sleepiness Scale (ESS) score of 10 or greater and a Sleep Apnea Clinical Score (SACS) of 15 or greater. Home oximetry, however, does not measure apneic events or respiratory event-related arousals and thus does not produce an AHI value.
Treatment
The treatment of OSAS depends upon the level of obstruction, if the obstruction is at nose or epiglottis a surgery could be required depending on the condition. Numerous treatment options are used in obstructive sleep apnea. Avoiding alcohol and smoking is recommended, as is avoiding medications that relax the central nervous system (for example, sedatives and muscle relaxants). Weight loss is recommended in those who are overweight. Continuous positive airway pressure (CPAP) and mandibular advancement devices are often used and found to be equally effective. Physical training, even without weight loss, improves sleep apnea. There is insufficient evidence to support widespread use of medications. In selected patients, e.g. with tonsillar hyperplasia tonsillectomy is recommended. In patients failing CPAP and oral appliances, surgical treatment with conservative uvulopalatopharyngoplasty (UPPP) as salvage surgery is recommended. Randomized controlled studies of the efficacy of UPPP are published, showing effect on nocturnal respiration and excessive daytime sleepiness, and a systematic Meta-analysis.
Physical intervention
The most widely used current therapeutic intervention is positive airway pressure whereby a breathing machine pumps a controlled stream of air through a mask worn over the nose, mouth, or both. The additional pressure holds open the relaxed muscles. There are several variants:
Continuous positive airway pressure (CPAP) is effective for both moderate and severe disease. It is the most common treatment for obstructive sleep apnea.
Variable positive airway pressure (VPAP) (also known as bilevel (BiPAP or BPAP)) uses an electronic circuit to monitor the patients breathing and provides two different pressures, a higher one during inhalation and a lower pressure during exhalation. This system is more expensive and is sometimes used with patients who have other coexisting respiratory problems or who find breathing out against an increased pressure to be uncomfortable or disruptive to their sleep.
Nasal EPAP, which is a bandage-like device placed over the nostrils that utilizes a persons own breathing to create positive airway pressure to prevent obstructed breathing.
Automatic positive airway pressure, also known as "Auto CPAP", incorporates pressure sensors and monitors the persons breathing.
A 5% reduction in weight among those with moderate to severe OSA may decrease symptoms similarly to CPAP.Encouraging people with moderate to severe OSA to use CPAP devices can be challenging as their use often requires a behavioural change in sleeping habits. 8% of people who use CPAP devices stop using them after the first night, and 50% of people with moderate to severe OSA stop using their devices in the first year. Educational initiatives and supportive interventions to help improve compliance with CPAP therapy have been shown to improve the length of time people who need CPAP therapy use their devices.Oral appliances or splints are often preferred but may not be as effective as CPAP. This device is a mouthguard similar to those used in sports to protect the teeth. It is designed to hold the lower jaw slightly down and forward relative to the natural, relaxed position. This position holds the tongue farther away from the back of the airway and may be enough to relieve apnea or improve breathing.
Many people benefit from sleeping at a 30-degree elevation of the upper body or higher, as if in a recliner. Doing so helps prevent the gravitational collapse of the airway. Sleeping on a side as opposed to sleeping on the back is also recommended.Some studies have suggested that playing a wind instrument may reduce snoring and apnea incidents. This may be especially true of double reed instruments.
Rapid Palatal Expansion
In children, orthodontic treatment to expand the volume of the nasal airway, such as nonsurgical Rapid Palatal expansion is common.
Since the palatal suture is fused in adults, regular RPE using tooth-borne expanders cannot be performed. Mini-implant assisted rapid palatal expansion (MARPE) has been recently developed as a non-surgical option for the transverse expansion of the maxilla in adults. This method increases the volume of the nasal cavity and nasopharynx, leading to increased airflow and reduced respiratory arousals during sleep. Changes are permanent with minimal complications.
Surgery
Surgical treatments to modify airway anatomy, known as sleep surgery, are varied and must be tailored to the specific airway obstruction needs of a patient. Surgery is not considered a first line treatment for obstructive sleep apnea in adults. There are prospective, randomized, comparative clinical trials, and also a systematic Meta-analysis, showing evidence that conservative uvulopalatopharyngoplasty (UPPP) with or without tonsillectomy is effective in selected patients failing conservative treatment. For those with obstructive sleep apnea unable or unwilling to comply with first line treatment, the surgical intervention has to be adapted to an individuals specific anatomy and physiology, personal preference and disease severity. Uvulopalatopharyngoplasty with or without is the most common surgery for patients with obstructive sleep apnea. Studies have shown that treatment effect of tonsillectomy increases with tonsil size. However, there is little randomized clinical trial evidence for other types of sleep surgery.There are a number of different operations that may be performed including:
Septoplasty is a corrective surgical procedure for Nasal septum deviation in which the nasal septum is straightened.
Tonsillectomy or adenoidectomy in an attempt to increase the size of the airway.
Removal or reduction of parts of the soft palate and some or all of the uvula, such as uvulopalatopharyngoplasty (UPPP) or laser-assisted uvulopalatoplasty (LAUP). Modern variants of this procedure sometimes use radiofrequency waves to heat and remove tissue.
Turbinectomy is a surgical procedure in which all or some of the turbinate bones are removed to relieve nasal obstruction.
Reduction of the tongue base, either with laser excision or radiofrequency ablation.
Genioglossus advancement, in which a small portion of the lower jaw that attaches to the tongue is moved forward, to pull the tongue away from the back of the airway.
Hyoid suspension, in which the hyoid bone in the neck, another attachment point for tongue muscles, is pulled forward in front of the larynx.
Maxillomandibular advancementIn the morbidly obese, a major loss of weight (such as what occurs after bariatric surgery) can sometimes cure the condition.
OSA in children is often due to enlarged tonsils and adenoids because the lymphoid tissue grows fast during young age. Surgical removal of enlarged tonsils (tonsillectomy) and the adenoid (adenoidectomy) are currently first line treatment among children with OSA. The operation is a common procedure but in the most extreme cases, children with severe OSA requires special precautions before, surgery (see "Surgery and obstructive sleep apnea syndrome" below). In some countries, a milder surgical procedure called tonsillotomy is used to remove the protruding tonsillar tissue, a method associated with less pain and lower risk of postoperative hemorrhage.
Neurostimulation
For patients who cannot use a continuous positive airway pressure device, the U.S. Food and Drug Administration in 2014 granted pre-market approval for an upper airway stimulation system that senses respiration and delivers mild electrical stimulation to the hypoglossal nerve in order to increase muscle tone at the back of the tongue so it will not collapse over the airway. The device includes a handheld patient controller to allow it to be switched on before sleep and is powered by an implantable pulse generator, similar to one used for cardiac rhythm management. Approval for this active implantable neuromodulation device was preceded by a clinical trial whose results were published in the New England Journal of Medicine.
Radiofrequency ablation
Radiofrequency ablation (RFA), which is conceptually analogous in some ways to surgery, uses low frequency (300 kHz to 1 MHz) radio wave energy to target tissue, causing coagulative necrosis. RFA achieves its effects at 40 °C to 70 °C unlike other electrosurgical devices which require 400 °C to 600 °C for efficacy.Subsequent evaluations of safety and efficacy have led to the recognition of RFA by the American Academy of Otolaryngology as a somnoplasty treatment option in selected situations for mild to moderate OSA, but the evidence was judged insufficient for routine adoption by the American College of Physicians.RFA has some potential advantages in carefully selected medical settings, such as intolerance to the CPAP device. For example, when adherence is defined as greater than four hours of nightly use, 46% to 83% of patients with obstructive sleep apnea are non-adherent with CPAP for a variety of reasons, including discomfort while sleeping.
RFA is usually performed in an outpatient setting, using either local anesthetics or conscious sedation anesthesia, the procedure itself typically lasting under 3 minutes. The targeted tissue, such as tongue or palate, is usually approached through the mouth without the need for incisions, although occasionally the target is approached through the neck using assisted imaging. If the tongue is being targeted, this can be done from either dorsal or ventral side. Complications include ulceration, infection, nerve weakness or numbness and swelling. These complications occur in less than 1% of procedures.
Medications
Evidence is insufficient to support the use of medications to treat obstructive sleep apnea. This includes the use of fluoxetine, paroxetine, acetazolamide, and tryptophan among others.Recent studies are trying to investigate cannabinoids as a treatment for OSA, especially dronabinol which is a synthetic form of THC (delta-9-tetrahydrocannabinol). Cannabis is known to influence sleep, for example it can reduce sleep onset latency, however, results are not consistent. Studies about dronabinol have shown positive impact on the OSA, as they observed a reduced AHI (Apnea-Hypopnea Index) and an increased self-reported sleepiness (the objective sleepiness being unaffected). However, more evidence are needed as many effects of those substances remain unknown, especially the effects of a long-term intake. The effect on sleepiness and weight gain are particularly of concern. Because of uncertainty about its effects and a lack of consistent evidence, the American Academy of Sleep Medicine does not approve the use of medical cannabis for the treatment of OSA.
Oral appliances / functional orthopedic appliances
Evidence to support oral appliances/functional orthopedic appliances in children is insufficient with very low evidence of effect. However, the oral appliances/functional orthopedic appliances may be considered in specified cases as an auxiliary in the treatment of children who have craniofacial anomalies which are risk factors of apnea.
Prognosis
Stroke and other cardiovascular diseases are related to OSA, and those under the age of 70 have an increased risk of early death. Persons with sleep apnea have a 30% higher risk of heart attack or death than those unaffected. In severe and prolonged cases, increased in pulmonary pressures are transmitted to the right side of the heart. This can result in a severe form of congestive heart failure known as cor pulmonale. Diastolic function of the heart also becomes affected. Elevated arterial pressure (i.e., hypertension) can be a consequence of OSA syndrome. When hypertension is caused by OSA, it is distinctive in that, unlike most cases (so-called essential hypertension), the readings do not drop significantly when the individual is sleeping (non-dipper) or even increase (inverted dipper).Without treatment, the sleep deprivation and lack of oxygen caused by sleep apnea increases health risks such as cardiovascular disease, aortic disease (e.g. aortic aneurysm), high blood pressure, stroke, diabetes, clinical depression, weight gain, obesity, and even death.
OSA is associated with cognitive impairment, including deficits in inductive and deductive reasoning, attention, vigilance, learning, executive functions, and episodic and working memory. OSA is associated with increased risk for developing mild cognitive impairment and dementia, and has been associated with neuroanatomical changes (reductions in volumes of the hippocampus, and gray matter volume of the frontal and parietal lobes) which can however be at least in part reversed with CPAP treatment.
Epidemiology
Until the 1990s, little was known regarding the frequency of OSA. A recent meta-analysis of 24 epidemiological studies on the prevalence of OSA in the general population aged 18 and older revealed that for ≥ 5 apnea events per hour, OSA prevalence ranged from 9% to 38%, specifically ranging from 13% to 33% in men and 6% to 19% in women, while in the population aged 65 and older, OSA prevalence was as high as 84%, including 90% in men and 78% in women. Nevertheless, for ≥ 15 apnea events per hour, OSA prevalence ranged from 6% to 17%, and almost 49% prevalence in the older population aged 65 and older. Moreover, a higher BMI is also linked to a higher prevalence of OSA, where a 10% increase in body weight led to a 6-fold risk of OSA in obese men and women.However, OSA is underdiagnosed as it is not always accompanied by daytime sleepiness which can leave the sleep-disordered breathing unnoticed. The prevalence of OSA with daytime sleepiness is thus estimated to affect 3% to 7% of men and 2% to 5% of women, and the disease is common in both developed and developing countries. OSA prevalence increases with age and is most commonly diagnosed in individuals over 65 years old, with estimations ranging from 22.1% to 83.6%. The prevalence has drastically increased the past decades mainly explained by the obesity epidemic currently observed.Men are more affected by OSA than women, but the phenomenology differs between both genders. Snoring and witnessed apnea are more frequent among men but insomnia for example is more frequent among women. The OSA frequency increase with age for the women. The mortality is higher for women.Some studies report that it is more frequent among the Hispanic and African American population than among the white population.If studied carefully in a sleep lab by polysomnography (formal "sleep study"), it is believed that approximately 1 in 5 American adults would have at least mild OSA.
Research
Neurostimulation is currently being studied as a method of treatment; an implanted hypoglossal nerve stimulation system received European CE Mark (Conformité Européenne) approval in March 2012. Also being studied are exercises of the muscles around the mouth and throat through activities such as playing the didgeridoo.
See also
== References == |
Brachycephaly | Brachycephaly (derived from the Ancient Greek βραχύς, short and κεφαλή, head) is the shape of a skull shorter than typical for its species. It is perceived as a desirable trait in some domesticated dog and cat breeds, notably the pug and Persian, and can be normal or abnormal in other animal species. In humans, the cephalic disorder is known as flat head syndrome, and results from premature fusion of the coronal sutures, or from external deformation. The coronal suture is the fibrous joint that unites the frontal bone with the two parietal bones of the skull. The parietal bones form the top and sides of the skull. This feature can be seen in Down syndrome.
In anthropology, human populations have been characterized as either dolichocephalic (long-headed), mesaticephalic (moderate-headed), or brachycephalic (short-headed). The usefulness of the cephalic index was questioned by Giuseppe Sergi, who argued that cranial morphology provided a better means to model racial ancestry.There are also cases of brachycephaly associated with plagiocephaly. Brachycephaly with plagiocephaly is positional and has become more prevalent since the "Back to Sleep" campaign. The Back to Sleep campaign began in 1994 as a way to educate parents about ways to reduce the risk for sudden infant death syndrome (SIDS). The campaign was named for its recommendation to place healthy babies on their backs to sleep. Placing babies on their backs to sleep reduces the risk for SIDS, also known as "cot death" or "crib death." This campaign has been successful in promoting infant back sleeping and other risk-reduction strategies to parents, family members, child care providers, health professionals, and all other caregivers of infants, at a cost of increasing the incidence of this deformation of the head. It is considered a cosmetic problem. Many pediatricians remain unaware of the issue and possible treatments. Treatments include regular prone repositioning of babies ("tummy time").
Brachycephaly as a desired trait
Brachycephaly also describes a developmentally normal type of skull with a high cephalic index, such as in snub-nosed breeds of dog such as pugs, Shih Tzus, and bulldogs or cats such as the Persian, Exotic and Himalayan. The term is from Greek roots meaning short and head. While being a desirable trait of specific cat and dog breeds, the production and breeding of brachycephalic animals is technically considered as an animal abuse in some legislations. This arises from the fact that animals with significantly shortened skulls frequently develop brachycephalic airway obstructive syndrome, causing them to have difficulties when breathing, suffering from hyperthermia due to insufficient cooling abilities and frequent infections of the cornea and lacrimal glands. Breeding of animals that will have significantly worsened life quality due to anatomical abnormalities is clearly stated to be illegal in some European countries, yet the production of such breeds is still very frequent. Apart from these, brachycephalic pups and kittens also have high prenatal mortality. Attention should be paid to breed standards which promote increased brachycephaly in cats which has the potential to negatively impact their welfare, and potential buyers of brachycephalic cat breeds should be made aware of the risks of their conformation.
Diagnosis
Treatment
Brachycephaly can be corrected with a cranial remolding orthoses (helmet) which provide painless total contact over the prominent areas of the skull and leave voids over the flattened areas to provide a pathway for more symmetrical skull growth. Treatment generally takes 3–4 months, but varies depending on the infants age and severity of the cranial asymmetry.
However, studies by scientists in the Netherlands have found there was no significant difference over time between infants treated with helmets and infants left untreated. All parents of infants treated with helmets confirmed negative side effects including skin irritation and sweating.
This study focused only on patients with mild to moderate cases, the participation rate was only 21%, and there was a 73% reporting of fitting issues, calling into question the validity of the study. Incorrectly fit devices cannot be expected to yield results. Additionally, independent published research that examined the effectiveness of helmet therapy concludes that as many as 95% of patients demonstrate an improvement in head shape symmetry following helmet therapy, and the American Orthotics and Prosthetics Association (AOPA) has serious concerns about the relevance and validity of this study.
See also
Artificial cranial deformation
Cephalic index
Craniosynostosis
Dolichocephaly
Plagiocephaly
Safe to Sleep
References
External links
NINDS – Cephalic Disorders Overview
Brachycephalic Official Website
[1] |
Extramammary Pagets disease | Extramammary Pagets Disease (EMPD) is a rare and slow-growing malignancy which occurs within the epithelium and accounts for 6.5% of all Pagets disease. The clinical presentation of this disease is similar to the characteristics of mammary Pagets disease (MPD). However, unlike MPD, which occurs in large lactiferous ducts and then extends into the epidermis, EMPD originates in glandular regions rich in apocrine secretions outside the mammary glands. EMPD incidence is increasing by 3.2% every year, affecting hormonally-targeted tissues such as the vulva and scrotum. In women, 81.3% of EMPD cases are related to the vulva, while for men, 43.2% of the manifestations present at the scrotum.The disease can be classified as being either primary or secondary depending on the presence or absence of associated malignancies. EMPD presents with typical symptoms such as scaly, erythematous, eczematous lesions accompanied by itchiness. In addition to this, 10% of patients are often asymptomatic. As a consequence, EMPD has high rates of misdiagnoses and delayed diagnoses. There are a variety of treatment options available, but most are unsuccessful. If caught early and treated, prognosis is generally good.
Presentation
Patients with EMPD present with typical symptoms, similar to MPD, such as severe itchiness (also called pruritus), rash, plaque formation, burning sensation, pain and tenderness. These symptoms are often confused for dermatitis or eczema. 10% of patients are asymptomatic resulting in delayed diagnosis. In rare cases bleeding can also be seen.
Disease of the vulva
Vulvar Pagets disease affect women and presents as erythematous (red), eczematous lesions. It is itchy and sometimes pain can be associated with the affected area. The lesion is clearly separated from normal skin in most cases, and sometimes scattered areas of white scale can be present, giving a "strawberries and cream" appearance.Involvement may be extensive including the perianal region, genitocrural, and inguinal folds. Clinical examination should determine the presence of periurethral and perianal lesions. In these cases an involvement of the skin by a noncutaneous internal neoplasm may occur.
Pathophysiology
EMPD occurs due to an invasion of the epidermis by Paget cells. The cause of the disease is still under debate with recent research indicating that the disease may be associated with Toker cells.
Disease of the vulva
Originates from local organs such as the Bartholin gland, the urethra, or the rectum. Predilection towards postmenopausal women.
Metastatic disease
Metastasis of Paget cells from the epidermis to distant regions is a multistep process that involves:
Invasion of local lymph nodes and venous system
Movement out from lymph nodes and venous system
Proliferation at new siteProtein molecules HER2 and mTOR expressed in Paget cells are responsible for providing characteristics of proliferation and survival.
Diagnosis
Due to the rarity of EMPD and lack of clinical knowledge, the disease is not very commonly diagnosed. Patients are often misdiagnosed with eczema or dermatitis and a delay of 2 years is expected from the onset of symptoms before a definitive diagnosis has been reached.It is important to include that the lesion is associated with another cancer. A biopsy will establish the diagnosis. Punch biopsies are not effective in differentially diagnosing for EMPD and as a result, excisional biopsies of the affected area are taken [XX]. A positive test result for EMPD shows increased numbers of large polygonal cells with a pale bluish cytoplasm, large nucleus and nucleolus, infiltrating the epidermal layer. These neoplastic cells can be found singly scattered or can appear in groups called nests.Paget cells contain mucin and cytokeratins which can be used in the diagnosis of EMPD [8] MUC5A2 is found in EMPD of the vulvar and male genitalia regions whereas MUC2 is expressed in perianal EMPD. Loss of MUC5A2 can indicate an invasive spread. Immunohistochemistry (IHC) can be used to determine whether EMPD is either primary or secondary. Primary EMPD tests positive for CK7 but negative for CK20, whereas secondary is positive for both. Lack of positivity for hormone receptors and HER2 protein is overexpressed meaning that the cells are dividing rapidly and can be indicate an aggressive and more recurrent disease.
Classification
Primary EMPD is of cutaneous origins and is found within the epidermis or the underlying apocrine glands. Although it is limited to the epithelium, it has potential to spread and progress into an invasive tumour, metastasising to the local lymph nodes and distant organs. This form of EMPD is not associated with an adenocarcinoma.The secondary form results due to an underlying adenocarcinoma spreading to the epidermis. Similar to the primary form, if secondary EMPD invades the dermis, the neoplastic cells can metastasise to the lymph nodes and in some cases, the dermis.According to the Wilkinson and Brown subclassification system, there are three subtypes for each classification.
Treatment
Many chemotherapy treatments have been used, however the results are not desirable as prognosis remains to be poor. Surgery remains to be the preferred treatment of choice. Wide local excision with a 3 cm margin and intra-operative frozen sections are suggested, due to high risk of local extension despite normal appearing tissue. In cases where Paget cells have invaded the dermis and metastasized, complete removal is often unsuccessful. Recurrence is a common result. Lymphadenoectomy is often performed for infiltrative cases. In lieu of surgery, radiotherapy is also an option and is especially preferred for elderly patients or for inoperable cases where the tumour size is too large. This form of treatment is also considered as possible adjuvant therapy following excision to combat the high recurrence rate. However, there are side effects of radiotherapy, including but not limited to: vulvitis, post-radiation atrophy of mucus membranes, vaginal stenosis and sexual dysfunction.Laser therapy and photodynamic therapies were also used in the past, but it was discovered the carbon dioxide laser did not penetrate deep enough and both treatment modalities resulted in high recurrence rates.Topical chemotherapy treatments are effective, with imiquimod showing promising results. However, overall survival begins to decline 10 months following treatment with chemotherapy. Patients with metastatic EMPD only survive for a median of 1.5 years, and have a 7% 5-year survival rate.
Prognosis
Prognosis is generally good, but factors such as depth of invasion and duration of disease need to be considered. In primary EMPD, if invasion of the underlying tissue is non-existent or even minimal, treatment options are more likely to be effective, however, if there are signs that the disease has metastasised, the prognosis is usually poor.
Epidemiology
EMPD is most prevalent in Caucasian women and Asian men over the age of 60. The invasive form occurs in 5–25% of all EMPD patients and 17–30% of the cases involve an underlying adenocarcinoma. 10-20% of EMPD is of the secondary form. Approximately 10% of patients develop invasive adenocarcinoma that may progress to metastatic disease.The disease affects regions that are rich in apocrine secretions. 65% EMPD occurs at the vulva, followed by 15% at perianal areas and 14% at the male genitalia. In terms of the vulva, the labia majora is the site that is most often involved, followed by labia minora, clitoris and perineum. EMPD originating at the vulva can spread to the upper vaginal mucosa and cervix. Other areas where EMPD can be found, although very rarely, include: the axillae, eyelids, external auditory canal, umbilical region, trunk and extremities.
History
The first case of Pagets disease was described by James Paget in 1874. Radcliffe Crocker, in 1889, then described EMPD following an observation of a patient with urinary carcinoma affecting the penis and scrotum, showing symptoms that were almost identical to MPD as described by Paget. Later in 1893, Darier and Coulillaud described the perianal location of EMPD.
References
External links
Definition at cancer.org |
Eiken syndrome | Eiken syndrome is a rare autosomal bone dysplasia with a skeletal phenotype which has been described in a unique consanguineous family, where it segregates as a recessive trait.
References
Further reading
Duchatelet, Sabine; Ostergaard, Elsebet; Cortes, Dina; Lemainque, Arnaud; Julier, Cécile (2005). "Recessive mutations in PTHR1 cause contrasting skeletal dysplasias in Eiken and Blomstrand syndromes". Human Molecular Genetics. Oxford Journals. 14 (1): 1–5. doi:10.1093/hmg/ddi001. PMID 15525660.
Eiken M, Prag J, Petersen K, Kaufmann H: - A new familial skeletal dysplasia with severely retarded ossification and abnormal modeling of bones especially of the epiphyses, the hands, and feet. Eur J Pediatr 1984, 141:231-235.
== External links == |
Blounts disease | Blounts disease (or Blount disease) is a growth disorder of the tibia (shin bone) which causes the lower leg to angle inward, resembling a bowleg. It is also known as "tibia vara".
Description and risk factors
Blount disease is a growth disorder of the shin bone which causes the lower leg to angle inward, resembling a bowleg. It can present in boys under 4-years in both legs, or in adolescents usually on one side. Causes are thought to be genetic and environmental, like obesity, African-American lineage, and early walkers.
Etymology
Blount disease is named after Walter Putnam Blount (1900–1992), an American pediatric orthopedic surgeon, who described it in 1937. It has also been known as Mau-Nilsonne Syndrome, after C. Mau and H. Nilsonne, who published early case reports of the condition. it is today considered an acquired disease of the proximal tibial metaphysis rather than an epiphyseal dysplasia or osteochondrosis.
Diagnosis
Differential Diagnosis
Lower extremity deformities in Rickets can closely mimic those produced by Blounts disease. To differentiate between Rickets and Blounts disease it is important to correlate the clinical picture with laboratory findings such as calcium, phosphorus and alkaline phosphatase. Besides the X-ray appearance. Bone deformities in Rickets have a reasonable likelihood to correct over time, while this is not the case with Blounts disease. Nevertheless, both disorders may need surgical intervention in the form of bone osteotomy or more commonly guided growth surgery. Osteochondrodysplasias or genetic bone diseases can cause lower extremity deformities similar to Blounts disease. The clinical appearance and the characteristic radiographic are important to confirm the diagnosis.
Treatment
Children who develop severe bowing before the age of 3 may be treated with knee ankle foot orthoses. However, bracing may fail, or bowing may not be detected until the child is older. Bracing should be started by 3 years of age. In some cases, surgery may be performed.Blount disease is one of the 8 severe comorbidities of severe obesity (BMI >35), which are an indication for bariatric surgery in children per a 2019 policy statement of the American Academy of Pediatrics.
The other severe comorbidities are: obstructive sleep apnea (Apnea-Hypopnea Index > .5), Type2 Diabetes mellitus, idiopathic intracranial hypertension (IIH), nonalcoholic steatohepatitis, SCFE, GERD, and hypertension.
References
External links
Dakshina Murthy T S. S; Alessandro De Leucio. Blount Disease Treasure Island (FL): StatPearls Publishing; 2022 Jan-. |
Symbrachydactyly | Symbrachydactyly is a congenital abnormality, characterized by limb anomalies consisting of brachydactyly, cutaneous syndactyly and global hypoplasia of the hand or foot. In many cases, bones will be missing from the fingers and some fingers or toes may be missing altogether. The ends of the hand may have "nubbins"—small stumps of soft tissue where the finger would have developed, which may have tiny residual nails.No clear statistics are available regarding the incidence rate for symbrachydactyly. This may be due, in part, to the wide variety of definitions and classifications that are used in diagnosis.In most cases, children born with symbrachydactyly are able to adapt to their physical limitations and experience a fully functional life with no treatment. Most children with this condition can use their hands well enough to do all the usual things children do. Possible treatment includes surgery or a routine of regularly stretching the fingers.
Cause
The cause of symbrachydactyly is unknown. One possible cause might be an interruption of the blood supply to the developing arm at four to six weeks of pregnancy. There is no link to anything the mother did or did not do during pregnancy. There is also no increased risk of having another child with the same condition or that the child will pass the condition on to his or her children.
Treatment
Most children with symbrachydactyly have excellent function in daily activities. Due to the length of their arm, they do not qualify for most artificial limbs. However, some adaptive prosthetics and equipment for sports and leisure activities may be helpful when the child is older. Children who demonstrate some functional movement in their remaining fingers and within the palm are evaluated for possible surgery such as toe transfers.
See also
Hypodactylia
Poland anomaly
References
External links
Treatment options for symbrachydactyly |
Parastremmatic dwarfism | Parastremmatic dwarfism is a rare bone disease that features severe dwarfism, thoracic kyphosis (a type of scoliosis that affects the upper back), a distortion and twisting of the limbs, contractures of the large joints, malformations of the vertebrae and pelvis, and incontinence. The disease was first reported in 1970 by Leonard Langer and associates; they used the term parastremmatic from the Greek parastremma, or distorted limbs, to describe it. On X-rays, the disease is distinguished by a "flocky" or lace-like appearance to the bones. The disease is congenital, which means it is apparent at birth. It is caused by a mutation in the TRPV4 gene, located on chromosome 12 in humans. The disease is inherited in an autosomal dominant manner.
Presentation
Parastremmatic dwarfism is apparent at birth, with affected infants usually being described as "stiff", or as "twisted dwarfs" when the skeletal deformities and appearance of dwarfism further present themselves. Skeletal deformities usually develop in the sixth to twelfth month of an infants life. The deformities may be attributed to osteomalacia, a lack of bone mineralization.Parastremmatic Dwarfism is further characterised by short stature, bowing of extremeties and further neuroskeletal dysplasia.
Genetics
Parastremmatic dwarfism is caused by a missense mutation (where one amino acid is replaced by another in a gene sequence) in the TRPV4 gene, located on the long arm of human chromosome 12, at 12q24.11. The mutation is in exon 11 of the gene, and is labelled R594H; this means that the codon (the code for an amino acid molecule) for arginine was erroneously substituted by a codon for histidine at position 594 in that exon. This same mutation in the TRVP4 gene is known to cause the Kozlowski type of spondylometaphyseal dysplasia.Parastremmatic dwarfism is inherited in an autosomal dominant manner, which means that the defective gene responsible for the disease is located on an autosome (chromosome 12 is an autosome), and one copy of the defective gene is sufficient to cause the disorder when inherited from a parent who also has the disorder.Parastremmatic Dwarfism results from mutations within the N-ankyrin domain of TRPV4, which has been identified to be involved in regulation of the TRPV4 calcium ion channel. This influx of calicum may be responsible for neuronal cell death, as well as affecting levels of circulating growth hormones.Parastremmatic Dwarfism is a very rare disorder, and as of 2011, only 5 people were diagnosed worldwide. As such, functional analysis has proved elusive at this time.
Diagnosis
Treatment
References
== External links == |
Necrophilia | Necrophilia, also known as necrophilism, necrolagnia, necrocoitus, necrochlesis, and thanatophilia, is sexual attraction towards or a sexual act involving corpses. It is classified as a paraphilia by the World Health Organization (WHO) in its International Classification of Diseases (ICD) diagnostic manual, as well as by the American Psychiatric Association in its Diagnostic and Statistical Manual (DSM).
Origins of term
Various terms for the crime of corpse-violation animate sixteenth- through nineteenth-century works on law and legal medicine. The plural term "nécrophiles" was coined by Belgian physician Joseph Guislain in his lecture series, Leçons Orales Sur Les Phrénopathies, given around 1850, about the contemporary necrophiliac François Bertrand:
It is within the category of the destructive madmen [aliénés destructeurs] that one needs to situate certain patients to whom I would like to give the name of necrophiliacs [nécrophiles]. The alienists have adopted, as a new form, the case of Sergeant Bertrand, the disinterrer of cadavers on whom all the newspapers have recently reported. However, dont think that we are dealing here with a form of phrenopathy which appears for the first time. The ancients, in speaking about lycanthropy, have cited examples to which one can more or less relate the case which has just now attracted the public attention so strongly.
Psychiatrist Bénédict Morel popularised the term about a decade later when discussing Bertrand.
History
In the ancient world, sailors returning corpses to their home country were often accused of necrophilia. Singular accounts of necrophilia in history are sporadic, though written records suggest the practice was present within Ancient Egypt. Herodotus writes in The Histories that, to discourage intercourse with a corpse, ancient Egyptians left deceased beautiful women to decay for "three or four days" before giving them to the embalmers. Herodotus also alluded to suggestions that the Greek tyrant Periander had defiled the corpse of his wife, employing a metaphor: "Periander baked his bread in a cold oven." Acts of necrophilia are depicted on ceramics from the Moche culture, which reigned in northern Peru from the first to eighth century CE. A common theme in these artifacts is the masturbation of a male skeleton by a living woman. Hittite law from the 16th century BC through to the 13th century BC explicitly permitted sex with the dead. In what is now Northeast China, the ethnic Xianbei emperor Murong Xi (385–407) of the Later Yan state had intercourse with the corpse of his beloved empress Fu Xunying, after the latter was already cold and put into the coffin.In Renaissance Italy, following the reputed moral collapse brought about by the Black Death and before the Roman Inquisition of the Counter-Reformation, literature was replete with sexual references; these include necrophilia, as in the epic poem Orlando Innamorato by Matteo Maria Boiardo, first published in 1483. In a notorious modern example, American serial killer Jeffrey Dahmer was a necrophiliac. Dahmer wanted to create a sex slave who would mindlessly consent to whatever he wanted. When his attempts failed, and his male victim died, he would keep the corpse until it decomposed beyond recognition, masturbating and performing sexual intercourse on the body. He would perform sexual activities before and after murdering his victims. Dahmer explained that he only killed his victims because he did not want them to leave.
More modern necrophiliacs include Scottish serial killer Dennis Nilsen, and English David Fuller, who is considered the worst offender of this kind in English legal history.Havelock Ellis, in his 1903 volume of Studies of the Psychology of Sex, believed that necrophilia was related to algolagnia, in that both involve the transformation of a supposed negative emotion, such as anger, fear, disgust, or grief, into sexual desire.
Classification
In the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), recurrent, intense sexual interest in corpses can be diagnosed under Other Specified Paraphilic Disorder (necrophilia) when it causes marked distress or impairment in important areas of functioning.Forensic Psychologist Anil Aggrawal introduced a ten tier classification of necrophiliacs based on increasing severity of disorder.
Additionally, criminologist Lee Mellors typology of homicidal necrophiliacs consists of eight categories (A–H) and is based on the combination of two behavioural axes: destructive (offender mutilates the corpse for sexual reasons) – preservative (offender does not), and cold (offender used the corpse sexually two hours or more after death) – warm (offender used the corpse sexually less than two hours after death). This renders four categories (A-D) to which Mellor adds an additional four (E-H):
Category A (cold/destructive), e.g. Ted Bundy, Jeffrey Dahmer
Category B (cold/preservative), e.g. Gary Ridgway, Dennis Nilsen, Carl Tanzler
Category C (warm/destructive) e.g. Andrei Chikatilo, Joseph Vacher
Category D (warm/preservative) e.g. Robert Yates, Earle Nelson
Category E (dabblers) e.g. Richard Ramirez, Mark Dixie
Category F (catathymic — impulsively and explosively lashing out)
Category G (exclusive necromutilophiles) e.g. Robert Napper, Peter Sutcliffe
Category H (sexual cannibals & vampires) e.g. Albert Fish, Peter KürtenDabblers have transitory opportunistic sexual relations with corpses, but do not prefer them. Catathymic necrophiliacs commit postmortem sex acts only while in a sudden impulsive state. Exclusive necromutilophiles derive pleasure purely from mutilating the corpse, while sexual cannibals and vampires are sexually aroused by eating human body parts. Category A, C, and F offenders may also cannibalise or drink the blood of their victims.
Research
Humans
Necrophilia is often assumed to be rare, but no data for its prevalence in the general population exists. Some necrophiliacs only fantasise about the act, without carrying it out. In 1958, Klaf and Brown commented that, although rarely described, necrophiliac fantasies may occur more often than is generally supposed.Rosman and Resnick (1989) reviewed 123 cases of necrophilia. The sample was divided into genuine necrophiliacs, who had a persistent attraction to corpses, and pseudo-necrophiliacs, who acted out of opportunity, sadism, or transient interest. Of the total, 92% were male and 8% were female. 57% of the genuine necrophiliacs had occupational access to corpses, with morgue attendants, hospital orderly, and cemetery employees being the most common jobs. The researchers theorised that either of the following situations could be antecedents to necrophilia:
The necrophiliac develops poor self-esteem, perhaps due in part to a significant loss;
(a) They are very fearful of rejection by others and they desire a sexual partner who is incapable of rejecting them; and/or
(b) They are fearful of the dead, and transform their fear—by means of reaction formation—into a desire.
They develop an exciting fantasy of sex with a corpse, sometimes after exposure to a corpse.
Motives
The most common motive for necrophiliacs is the possession of a partner who is unable to resist or reject them. However, in the past, necrophiliacs have expressed having more than one motive.The authors reported that of their sample of 34 genuine necrophiliacs:
68% were motivated by a desire for a non-resisting and non-rejecting partner
21% were motivated by a want for a reunion with a lost partner
15% were motivated by sexual attraction to dead people
15% were motivated by a desire for comfort or to overcome feelings of isolation
12% were motivated by a desire to remedy low self-esteem by expressing power over a corpseLesser common motives include:
Unavailability of a living partner
Compensation for a fear of women
Belief that sex with a living woman is a mortal sin
Need to achieve a feeling of total control over a sexual partner
Compliance with a command hallucination
Performance of a series of destructive acts
Expression of polymorphous perverse sexual desires
Need to perform limitless sexual activityIQ data was limited, but not abnormally low. About half of the sample had a personality disorder, and 11% of true necrophiliacs were psychotic. Rosman and Resnick concluded that their data challenged the conventional view of necrophiliacs as generally psychotic, mentally deficient, or unable to obtain a consenting partner.
Other animals
Necrophilia has been observed in mammals, birds, reptiles and frogs. In 1960, Robert Dickerman described necrophilia in ground squirrels, which he termed "Davian behaviour" in reference to a limerick about a necrophiliac miner named Dave. The label is still used for necrophilia in animals. Certain species of arachnids and insects practice sexual cannibalism, where the female cannibalises her male mate before, during, or after copulation.
Kees Moeliker made an observation while he was sitting in his office at the Natural History Museum Rotterdam, when he heard the distinctive thud of a bird hitting the glass facade of the building. Upon inspection, he discovered a drake (male) mallard lying dead outside the building. Next to the downed bird, a second drake mallard was standing close by. As Moeliker observed the couple, the living drake pecked at the corpse of the dead one for a few minutes then mounted the corpse and began copulating with it. The act of necrophilia lasted for about 75 minutes, in which time, according to Moeliker, the living drake took two short breaks before resuming with copulating behaviour. Moeliker surmised that at the time of the collision with the window the two mallards were engaged in a common pattern in duck behaviour called "attempted rape flight". "When one died the other one just went for it and didnt get any negative feedback – well, didnt get any feedback," according to Moeliker. Necrophilia had previously only been reported in heterosexual mallard pairs.In a short paper known as "Sexual Habits of the Adélie Penguin", deemed too shocking for contemporary publication, George Murray Levick described "little hooligan bands" of penguins mating with dead females in the Cape Adare rookery, the largest group of Adélie penguins, in 1911 and 1912. This is nowadays ascribed to lack of experience of young penguins; a dead female, with eyes half-closed, closely resembles a compliant female. A gentoo penguin was observed attempting to have intercourse with a dead penguin in 1921.A male New Zealand sea lion was once observed attempting to copulate with a dead female New Zealand fur seal in the wild. The sea lion nudged the seal repeatedly, then mounted her and made several pelvic thrusts. Approximately ten minutes later, the sea lion became disturbed by the researchers presence, dragged the corpse of the seal into the water, and swam away while holding it. A male sea otter was observed holding a female sea otter underwater until she drowned before repeatedly copulating with her carcass. Several months later, the same sea otter was again observed copulating with the carcass of a different female. Copulation with a dead female pilot whale by a captive male pilot whale has been observed, and possible sexual behaviour between two male humpback whales, one dead, has also been reported.In 1983, a male rock dove was observed to be copulating with the corpse of a dove that shortly before had its head crushed by a car. In 2001, a researcher laid out sand martin corpses to attract flocks of other sand martins. In each of six trials, 1–5 individuals from flocks of 50–500 were observed attempting to copulate with the dead sand martins. This occurred one to two months after the breeding season; since copulation outside the breeding season is uncommon among birds, the researcher speculated that the lack of resistance by the corpses stimulated the behaviour. Charles Brown observed at least ten cliff swallows attempt to copulate with a road-killed cliff swallow in the space of 15 minutes. He commented, "This isnt the first time Ive seen cliff swallows do this; the bright orange rump sticking up seems to be all the stimulus these birds need." Necrophilia has also been reported in the European swallow, grey-backed sparrow-lark, Starks lark, and the snow goose. A Norwegian television report showed a male hybrid between a black grouse and western capercaillie kill a male black grouse before attempting to copulate with it. In 2015, due to work done by the University of Washington, it was found that crows would commit necrophilia on dead crow corpses in about 4% of encounters with corpses.
Necrophilia has been documented in various lizard species, including Ameiva ameiva, the leopard lizard, and Holbrookia maculata. There are two reports of necrophilic behaviour in the sleepy lizard (Tiliqua rugosa). In one, the partner of a male lizard got caught in fencing wire and died. The male continued to display courtship behaviour towards his partner two days after her death. This lizards necrophilia was believed to stem from its strong monogamous bond. In one study of black and white tegu lizards, two different males were observed attempting to court and copulate with a single female corpse on two consecutive days. On the first day, the corpse was freshly dead, but by the second day it was bloating and emitting a strong putrid odor. The researcher attributed the behaviour to sex pheromones still acting on the carcass.Male garter snakes often copulate with dead females. One case has been reported in the Bothrops jararaca snake with a dead South American rattlesnake. The prairie rattlesnake (Crotalus viridis) and Helicops carinicauda snake have both been seen attempting to mate with decapitated females, presumably attracted by still-active sex pheromones. Male crayfish sometimes copulate with dead crayfish of either sex, and in one observation with a dead crayfish of a different species.In anurans, it has been observed in the foothill yellow-legged frog, the yellow fire-bellied toad, the common frog, the Oregon spotted frog, the common Asian Toad, Dendropsophus columbianus, and Rhinella jimi. The film Cane Toads: An Unnatural History shows a male toad copulating with a female toad that had been run over by a car for eight hours. Necrophilic amplexus in frogs may occur because males will mount any pliable object the size of an adult female. If the mounted object is a live frog not appropriate for mating, it will vibrate its body or vocalise a call to be released. Dead frogs cannot do this, so they may be held for hours. The Amazonian frog Rhinella proboscidea sometimes practices what has been termed "functional necrophilia": a male grasps the corpse of a dead female and squeezes it until its oocytes are ejected before fertilising them.
Treatment
Treatment for necrophilia is similar to that prescribed for most paraphilias. Besides advocating treatment of the associated psychopathology, there is little known on the treatment of necrophilia. There has not been a sufficient number of necrophiliacs to establish any effective treatments. However, based on the available data, clinicians are suggested to:
Determine whether or not a patient has necrophilia
Treat any psychopathology that is associated with necrophilia
Establish psycho-therapeutic rapport
Provide male patients with heightened sex drives with anti-androgens
Help patients find a normal sexual relationship
Help divert the necrophilic fantasies to a living object via desensitization
Case studies
Jeffrey Dahmer
Serial killer Jeffrey Dahmer (1960–1994) was known to perform oral sex or masturbate, or both, upon the corpses of his victims before dismembering them. In unguarded, taped interviews with his defense attorney, Wendy Patrickus, Jeffrey Dahmer explicitly stated that he had sex with his victims before and after their deaths. He explained that he wanted to remain with the person as long as possible, preserving some of his victims selected organs, skeletal tissue and bones.
Ted Bundy
Ted Bundy (1946–1989) was an American serial killer who raped and murdered at least 30 young women during the 1970s. He also confessed to participating in necrophilic acts, claiming to have chosen secluded disposal sites for his victims bodies specifically for post-mortem sexual intercourse.
Karen Greenlee
In 1987, Karen Greenlee gave a detailed interview called “The Unrepentant Necrophile” for Jim Mortons (edited by Adam Parafrey) book Apocalypse Culture. In this interview, she stated that she had a preference for younger men and was attracted to the smell of blood and death. She considered necrophilia an addiction. The interview was held in her apartment, which was apparently a small studio filled with books, necrophilic drawings, and satanic adornments. She also had written a confession letter in which she claimed to have abused 20–40 male corpses.
Dennis Nilsen
Dennis Nilsen (1945–2018) was a Scottish serial killer who had developed an association between death and intimacy, later finding posing as a corpse a source of sexual arousal. In 1978, Nilsen committed his first murder and had intercourse with the victims corpse, keeping the body for months before disposal. Nilsen was reported to have sexually abused the corpses of various victims until his arrest.
Legality
Australia
Necrophilia is not explicitly mentioned in Australian law; however, under the Crimes Act 1900 – Sect 81C, penalised for misconduct with regard to corpses is any person who:(a) indecently interferes with any dead human body, or
(b) improperly interferes with, or offers any indignity to, any dead human body or human remains (whether buried or not), and
shall be liable to imprisonment for two years.
Brazil
Article 212 of the Brazilian Penal Code (federal Decree-Law No 2.848) states as follows:
Art. 212 – To abuse a cadaver or its ashes:Penalty: detention, from 1 to 3 years, plus fine.
Although sex with a corpse is not explicitly mentioned, a person who has sex with a corpse may be convicted of a crime under the above Article. The legal asset protected by such Article is not the corpses objective honour, but the feeling of good memories, respect, and veneration that living people keep about the deceased person: these persons are considered passive subjects of the corpses violation.
India
Section 297 of the Indian Penal Code entitled "Trespassing on burial places, etc.", states as follows:
Whoever, with the intention of wounding the feelings of any person, or of insulting the religion of any person, or with the knowledge that the feelings of any person are likely to be wounded, or that the religion of any person is likely to be insulted thereby,
commits any trespass in any place of worship or on any place of sculpture, or any place set apart from the performance of funeral rites or as a depository for the remains of the dead, or offers any indignity to any human corpse, or causes disturbance to any persons assembled for the performance of funeral ceremonies, shall be punished with imprisonment of either description for a term which may extend to one year, or with fine, or with both.
Although sex with a corpse is not explicitly mentioned, a person who has sex with a corpse may be convicted under the above section. Section 377 of the Indian Penal Code can also be invoked.
Philippines
There are no laws which explicitly prohibit sexual acts on corpses. The closest applicable law is the provision in the Revised Penal Code which only criminalizes "defamation to blacken the memory of one who is dead". There were at least efforts to introduce bills criminalizing sexual acts on corpses during the 15th Congress; one by which penalizes sexual acts of males of corpses of women, and another which covers sexual intercourse, anal sex, and oral sex done on corpses. Both proposals penalizes the act with fine and imprisonment.
New Zealand
Under Section 150 of the New Zealand Crimes Act 1961, it is an offence for there to be "misconduct in respect to human remains". Subsection (b) elaborates that this applies if someone "improperly or indecently interferes with or offers indignity to any dead human body or human remains, whether buried or not". This statute is therefore applicable to sex with corpses and carries a potential two-year prison sentence, although there is no relevant case law.
South Africa
Section 14 of the Criminal Law (Sexual Offences and Related Matters) Amendment Act, 2007 prohibits the commission of a sexual act with a corpse. Until codified by the act it was a common law offence.
Sweden
Section 16, § 10 of the Swedish Penal Code criminalises necrophilia, but it is not explicitly mentioned. Necrophilia falls under the regulations against abusing a corpse or grave (Brott mot griftefrid), which carries a maximum sentence of two years in prison. One person has been convicted of necrophilia. He was sentenced to psychiatric care for that and other crimes, including arson.
United Kingdom
Sexual penetration of a corpse was made illegal under the Sexual Offences Act 2003, carrying a maximum sentence of two years imprisonment. Prior to 2003, necrophilia was not illegal; however, exposing a naked corpse in public was classed as a public nuisance (R v. Clark [1883] 15 Cox 171).
United States
There is no federal legislation specifically barring sex with a corpse. Multiple states have their own laws:
See also
Incidents of necrophilia
Necrophilia in popular culture
Vulnerability and care theory of love
Death during consensual sex
Somnophilia
Paraphilias
Footnotes
Sources
Aggrawal, Anil (2010). Necrophilia: Forensic and Medico-legal Aspects. Boca Raton, Florida: CRC Press. ISBN 978-1420089127.
Aggrawal, Anil (19 April 2016). Necrophilia: Forensic and Medico-legal Aspects. CRC Press. ISBN 978-1-4200-8913-4.
Finbow, Steve (2014). Grave Desire: A Cultural History of Necrophilia. Winchester, UK: Zero Books. ISBN 978-1-7827-9342-7.
Lee Mellor (2016) Homicide: A Forensic Psychology Casebook. CRC Press. ISBN 9781498731522.
Purcell, Catherine; Arrigo, Bruce A. (7 June 2006). The Psychology of Lust Murder: Paraphilia, Sexual Killing, and Serial Homicide. Elsevier. ISBN 978-0-08-046257-8.
West, Sarah G.; Resnick, Phillip J. (2017). "Necrophilia". Unusual and Rare Psychological Disorders: A Handbook for Clinical Practice and Research. Oxford University Press. ISBN 978-0-19-024586-3.
Further reading
Lisa Downing, Desiring the Dead: Necrophilia and Nineteenth-Century French Literature. Oxford: Legenda, 2003
Richard von Krafft-Ebing, Psychopathia Sexualis. New York: Stein & Day, 1965. Originally published in 1886.
In literature
Gabrielle Wittkop, The Necrophiliac, 1972
Barbara Gowdy, We So Seldom Look on Love, 1992
Frank OHara, Ode on Necrophilia, 1960
== External links == |
Eccrine nevus | An eccrine nevus is an extremely rare cutaneous condition that, histologically, is characterized by an increase in size or number of eccrine secretory coils.: 774
See also
Apocrine nevus
Nevus comedonicus
List of cutaneous conditions
References
== External links == |
Patellar tendinitis | Patellar tendinitis, also known as jumpers knee, is an overuse injury of the tendon that straightens the knee. Symptoms include pain in the front of the knee. Typically the pain and tenderness is at the lower part of the kneecap, though the upper part may also be affected. Generally there is no pain when the person is at rest. Complications may include patellar tendon rupture.Risk factors include being involved in athletics and being overweight. It is particularly common in athletes who are involved in jumping sports such as basketball and volleyball. The underlying mechanism involves small tears in the tendon connecting the kneecap with the shinbone. Diagnosis is generally based on symptoms and examination. Other conditions that can appear similar include infrapatellar bursitis, chondromalacia patella and patellofemoral syndrome.Treatment often involves resting the knee and physical therapy. Evidence for treatments, including rest, however is poor. Recovery can take between months and persist over years. It is relatively common with about 14% of athletes currently affected; however research reflects that more than half of athletes with this injury end their careers as a result. Males are more commonly affected than females. The term "jumpers knee" was coined in 1973.
Signs and symptoms
People report anterior knee pain, often with an aching quality. The symptom onset is insidious. Rarely is a discrete injury described. Usually, the problem is below the kneecap but it may also be above. Jumpers knee can be classified into 1 of 4 stages, as follows:Stage 1 – Pain only after activity, without functional impairment
Stage 2 – Pain during and after activity, although the person is still able to perform satisfactorily in his or her sport
Stage 3 – Prolonged pain during and after activity, with increasing difficulty in performing at a satisfactory level
Stage 4 – Complete tendon tear requiring surgical repair
It begins as inflammation in the patellar tendon where it attaches to the patella and may progress by tearing or degenerating the tendon. People present with an ache over the patella tendon. Most people are between 10 and 16 years old. Magnetic resonance imaging can reveal edema (increased T2 signal intensity) in the proximal aspect of the patellar tendon.
Causes
It is an overuse injury from repetitive overloading of the extensor mechanism of the knee. The microtears exceed the bodys healing mechanism unless the activity is stopped.Among the risk factors for patellar tendonitis are low ankle dorsiflexion, weak gluteal muscles, and muscle tightness, particularly in the calves, quadriceps muscle, and hamstrings.It may be associated with stiff ankle movement and ankle sprains.
Diagnosis
Diagnosis is generally based on symptoms and a physical examination. Ultrasound or magnetic resonance imaging may help clarify how severe the problem is.
Treatment
Evidence for treatment is poor. In the early stages rest, ice, compression, and elevation may be tried. Tentative evidence supports exercises involving eccentric muscle contractions of the quadriceps on a decline board. Specific exercises and stretches to strengthen the muscles and tendons may be recommended, e.g. cycling or swimming. Use of a strap for jumpers knee and suspension inlays for shoes may also reduce the problems. Corticosteroid injections and NSAIDs are generally recommended.
Procedures
Dry needling, sclerosing injections, platelet-rich plasma, extracorporeal shock wave treatment, and heat therapy have been tried.
Surgery
Surgery may be tried if other measures fail. This may involve removal of myxoid degeneration in the tendon. This is reserved for people with severe pain for 6–12 months despite conservative measures. Novel treatment modalities targeting the abnormal blood vessel growth which occurs in the condition are currently being investigated. Knee operations in most cases have no better effects than exercise programs.
Epidemiology
It is relatively common with about 14% of athletes currently affected. Males are more commonly affected than females.
References
== External links == |
Primary cutaneous immunocytoma | Primary cutaneous immunocytoma is a skin condition that represents a low grade B-cell lymphoma related to marginal zone B-cell lymphoma but with a predominance of cells having plasmacytic features.: 741
See also
Primary cutaneous marginal zone lymphoma
Skin lesion
== References == |
Orbital lymphoma | Orbital lymphoma is a common type of non-Hodgkin lymphoma that occurs near or on the eye. Common symptoms include decreased vision and uveitis. Orbital lymphoma can be diagnosed via a biopsy of the eye and is usually treated with radiotherapy or in combination with chemotherapy.
Types
There are two main types of intraocular lymphomas: primary central nervous system involvement (PCNSL) and primary central nervous system with ocular involvement (PCNSLO). The difference between PCNSL and PCNSLO is that PNSCL involves the central nervous system, while PCNSLO does not. 56-86% of orbital lymphomas are classified PCNSL and 15-25% are classified PCNSLO.PCNSLO is common in people who are severely immunosuppressed.
Symptoms of this form of ocular lymphoma include painless decreased vision, sensitivity to light, a red eye, and floaters. Diagnosis is difficult due to its gradual onset and the fact that the symptoms are the same as other diseases.
PCNSLO is usually bilateral, but sometimes grows unevenly. Like other metastatic tumors of the eye, it is usually confined to the choroid.
Signs and symptoms
Primary visible signs of ocular lymphoma include proptosis and a visible mass in the eye. Symptoms are due to mass effect.
Pathophysiology
Recent studies have detected the presence of viral DNA in ocular lymphoma cells. This implies that pathogens play a role in ocular lymphoma. Other studies have found that the aging population, the increasing number of immunosuppressive drugs, and the AIDS epidemic have also contributed to the increased incidence of Non-Hodgkin lymphomas.
Ocular MALT lymphomas may also be associated with Chlamydia psittaci, although whether or not this is the case is still debated.Follicular lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, B-cell chronic lymphocytic leukemia, peripheral T-cell lymphoma, and natural killer cell lymphoma have also been reported to affect the orbit.
Diagnosis
Classification
There are two types of ocular lymphomas: intraocular lymphomas and adnexal lymphomas. An intraocular lymphoma occurs within the eye, while an adnexal lymphoma occurs outside, but adjoined to the eye.
Treatment
Radiotherapy is the most effective treatment for local disease either as the sole treatment for low-grade lymphoma or in combination with chemotherapy for intermediate- and high-grade lymphoma. Radiotherapy dose in range of 30-45 Gy administered in fractions are advised in treating the local orbital lymphomas.
Epidemiology
Orbital lymphoma accounts for 55% of malignant orbital tumors in adults. In one study, this was 10% of patients presenting with orbital tumors or similar lesions. Orbital lymphoma is more prevalent in Asia and Europe than in the United States.Although intraocular lymphoma is rare, the number of cases per year is rising, affecting mainly people in their seventies and immunocompromised patients. A recent study has shown that ocular lymphoma is more prevalent in women than men.The survival rate is approximately 60% after 5 years.
References
== External links == |
Subacute sclerosing panencephalitis | Subacute sclerosing panencephalitis (SSPE)—also known as Dawson disease—is a rare form of chronic, progressive brain inflammation caused by slow infection with certain defective strains of hypermutated measles virus. The condition primarily affects children, teens, and young adults. It has been estimated that about 2 in 10,000 people who get measles will eventually develop SSPE. However, a 2016 study estimated that the rate for unvaccinated infants under 15 months was as high as 1 in 609. No cure for SSPE exists, and the condition is almost always fatal. SSPE should not be confused with acute disseminated encephalomyelitis, which can also be caused by the measles virus, but has a very different timing and course.SSPE is caused by the wild-type virus, not by vaccine strains.
Signs and symptoms
SSPE is characterized by a history of primary measles infection, followed by an asymptomatic period that lasts 7 years on average but can range from 1 month to 27 years. After the asymptomatic period, progressive neurological deterioration occurs, characterized by behavior change, intellectual problems, myoclonic seizures, blindness, ataxia, and eventually death.
Progression
Symptoms progress through the following 4 stages:
Stage 1: There may be personality changes, mood swings, or depression. Fever, headache, and memory loss may also be present. This stage may last up to 6 months.
Stage 2: This stage may involve jerking, muscle spasms, seizures, loss of vision, and dementia.
Stage 3: Jerking movements are replaced by writhing (twisting) movements and rigidity. At this stage, complications may result in blindness or death.
Stage 4: Progressive loss of consciousness into a persistent vegetative state, which may be preceded by or concomitant with paralysis, occurs in the final stage, during which breathing, heart rate, and blood pressure are affected. Death usually occurs as a result of fever, heart failure, or the brain’s inability to control the autonomic nervous system.
Pathogenesis
A large number of nucleocapsids are produced in the neurons and the glial cells. In these cells the viral genes that encode envelope proteins have restricted expression. As a result, infectious particles like the M protein are not produced, and the virus is able to survive persistently without evoking an immune response. Eventually the infection will lead to SSPE.
Diagnosis
According to the Merck Manual: "SSPE is suspected in young patients with dementia and neuromuscular irritability. EEG, CT or MRI, CSF examination, and measles serologic testing are done. EEG shows periodic complexes with high-voltage diphasic waves occurring synchronously throughout the recording. CT or MRI may show cortical atrophy or white matter lesions. CSF examination usually reveals normal pressure, cell count, and total protein content; however, CSF globulin is almost always elevated, constituting up to 20 to 60% of CSF protein. Serum and CSF contain elevated levels of measles virus antibodies. Anti-measles IgG appears to increase as the disease progresses.
If test results are inconclusive, brain biopsy may be needed."
Treatment
If the diagnosis is made during stage 1 it may be possible to treat the disease with oral isoprinosine (Inosiplex) and intraventricular interferon alfa, but the response to these drugs varies from patient to patient, and the only accepted treatments are supportive measures such as anticonvulsants. Following onset of stage 2, the disease is invariably fatal.
Prognosis
In the classic presentation of the disease death occurs in 1 to 3 years, but faster and slower progressions can occur. Faster deterioration in cases of acute fulminant SSPE leads to death within 3 months of diagnosis. Although the prognosis is bleak for SSPE past stage 1, there is a 5% spontaneous remission rate—this may be either a full remission that may last many years or an improvement in condition giving a longer progression period or at least a longer period with the less severe symptoms.
Epidemiology
SSPE is a rare condition, although there is still relatively high incidence in Asia and the Middle East. However, the number of reported cases is declining since the introduction of the measles vaccine—eradication of the measles virus prevents the SSPE mutation and therefore the progression of the disease or even the initial infection itself.
References
Further reading
Bonthius D, Stanek N, Grose C (2000). "Subacute sclerosing panencephalitis, a measles complication, in an internationally adopted child". Emerg Infect Dis. 6 (4): 377–81. doi:10.3201/eid0604.000409. PMC 2640885. PMID 10905971.
External links
23-273l. at Merck Manual of Diagnosis and Therapy Home Edition
subacute_panencephalitis at NINDS
PubMed Health: Subacute sclerosing panencephalitis Archived 2014-08-08 at the Wayback Machine
synd/1889 at Who Named It? |
Speech disorder | Speech disorders or speech impairments are a type of communication disorder in which normal speech is disrupted. This can mean stuttering, lisps, etc. Someone who is unable to speak due to a speech disorder is considered mute. Speech is a complex process that requires precise timing, nerve and muscle control, and as a result is susceptible to impairments. Speech disorders affect roughly 11.5% of the US population, and may be caused by a stroke, an accident or birth defect.
Classification
Classifying speech into normal and disordered is more problematic than it first seems. By strict classification, only 5% to 10% of the population has a completely normal manner of speaking (with respect to all parameters) and healthy voice; all others have one disorder or another.
There are three different levels of classification when determining the magnitude and type of a speech disorder and the proper treatment or therapy:
Sounds the patient can produce
Phonemic – can be produced easily; used meaningfully and constructively
Phonetic – produced only upon request; not used consistently, meaningfully, or constructively; not used in connected speech
Stimulate sounds
Easily stimulated
Stimulate after demonstration and probing (i.e. with a tongue depressor)
Cannot produce the sound
Cannot be produced voluntarily
No production ever observed
Types of disorder
Apraxia of speech may result from stroke or progressive illness, and involves inconsistent production of speech sounds and rearranging of sounds in a word ("potato" may become "topato" and next "totapo"). Production of words becomes more difficult with effort, but common phrases may sometimes be spoken spontaneously without effort.
Cluttering, a speech and fluency disorder characterized primarily by a rapid rate of speech, which makes speech difficult to understand.
Developmental verbal dyspraxia also known as childhood apraxia of speech.
Dysarthria is a weakness or paralysis of speech muscles caused by damage to the nerves or brain. Dysarthria is often caused by strokes, Parkinsons disease, ALS, head or neck injuries, surgical accident, or cerebral palsy.
Aphasia
Dysprosody is an extremely rare neurological speech disorder. It is characterized by alterations in intensity, in the timing of utterance segments, and in rhythm, cadence, and intonation of words. The changes to the duration, the fundamental frequency, and the intensity of tonic and atonic syllables of the sentences spoken, deprive an individuals particular speech of its characteristics. The cause of dysprosody is usually associated with neurological pathologies such as brain vascular accidents, cranioencephalic traumatisms, and brain tumors.
Muteness is the complete inability to speak.
Speech sound disorders involve difficulty in producing specific speech sounds (most often certain consonants, such as /s/ or /r/), and are subdivided into articulation disorders (also called phonetic disorders) and phonemic disorders. Articulation disorders are characterized by difficulty learning to produce sounds physically. Phonemic disorders are characterized by difficulty in learning the sound distinctions of a language, so that one sound may be used in place of many. However, it is not uncommon for a single person to have a mixed speech sound disorder with both phonemic and phonetic components.
Stuttering (AKA “Dysphemia”) affects approximately 1% of the adult population.
Voice disorders are impairments, often physical, that involve the function of the larynx or vocal resonance.
Causes
In most cases the cause is unknown. However, there are various known causes of speech impairments, such as hearing loss, neurological disorders, brain injury, an increase in mental strain, constant bullying, intellectual disability, substance use disorder, physical impairments such as cleft lip and palate, and vocal abuse or misuse.
Treatment
Many of these types of disorders can be treated by speech therapy, but others require medical attention by a doctor in phoniatrics. Other treatments include correction of organic conditions and psychotherapy.In the United States, school-age children with a speech disorder are often placed in special education programs. Children who struggle to learn to talk often experience persistent communication difficulties in addition to academic struggles. More than 700,000 of the students served in the public schools special education programs in the 2000–2001 school year were categorized as having a speech or language impairment. This estimate does not include children who have speech and language impairments secondary to other conditions such as deafness". Many school districts provide the students with speech therapy during school hours, although extended day and summer services may be appropriate under certain circumstances.
Patients will be treated in teams, depending on the type of disorder they have. A team can include speech–language pathologists, specialists, family doctors, teachers, and family members.
Social effects
Having a speech disorder can have negative social effects, especially among young children. Those with a speech disorder can be targets of bullying because of their disorder. The bullying can result in decreased self-esteem.
Language disorders
Language disorders are usually considered distinct from speech disorders, although they are often used synonymously.
Speech disorders refer to problems in producing the sounds of speech or with the quality of voice, where language disorders are usually an impairment of either understanding words or being able to use words and do not have to do with speech production.
See also
References
== External links == |
Pulmonary-renal syndrome | Pulmonary-renal syndrome (PRS) is a rare medical syndrome in which respiratory failure involving bleeding in the lungs and kidney failure (glomerulonephritis) occur. PRS is associated with a high rate of morbidity and death. The term was first used by Goodpasture in 1919 to describe the association of respiratory and kidney failure.
Causes
Pulmonary-renal syndromes are most commonly caused by an underlying autoimmune disease. PRS is most commonly due to ANCA-associated vasculitides (e.g., granulomatosis with polyangiitis) or due to anti-basement membrane diseases (e.g., Goodpastures syndrome). Granulomatosis with polyangiitis usually presents with nasopharyngeal involvement as well, whereas Goodpastures will not. Microscopic polyangiitis is the most common cause of pulmonary-renal syndrome.Other causes include systemic lupus erythematosus, eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis, dermatomyositis, polymyositis, mixed connective tissue disease, poststreptococcal glomerulonephritis, rheumatoid arthritis, and systemic sclerosis. Less common causes also include IgA vasculitis and cryoglobulinemic vasculitis.
Other etiologies include toxic injury such as paraquat poisoning, infection with hantavirus, leptospirosis, or legionella, or vascular, as seen in nephrotic syndrome when a renal vein thrombosis embolizes to the lungs.
Diagnosis
Differential diagnosis
Cardiogenic shock can mimic a pulmonary renal syndrome and lead to coughing up blood due to pulmonary edema and kidney failure from inadequate blood flow.
Treatment
Treatment is primarily by corticosteroids and immunosuppressive medications like cyclophosphamide, methotrexate, and azathioprine. Plasmapheresis can be used in some circumstances.
== References == |
Subacute bacterial endocarditis | Subacute bacterial endocarditis, abbreviated SBE, is a type of endocarditis (more specifically, infective endocarditis). Subacute bacterial endocarditis can be considered a form of type III hypersensitivity.
Signs and symptoms
Among the signs of subacute bacterial endocarditis are:
Malaise
Weakness
Excessive sweat
Fever
Causes
It is usually caused by a form of Viridans group streptococcus bacteria that normally live in the mouth (Streptococcus mutans, mitis, sanguis or milleri).Other strains of streptococci can cause subacute endocarditis as well. These include streptococcus intermedius, which can cause
acute or subacute infection (about 15% of cases pertaining to infective endocarditis).Enterococci from urinary tract infections and coagulase negative staphylococci can also be causative agents.
Mechanism
The mechanism of subacute bacterial endocarditis could be due to malformed stenotic valves which in the company of bacteremia, become infected, via adhesion and subsequent colonization of the surface area. This causes an inflammatory response, with recruitment of matrix metalloproteinases, and destruction of collagen.Underlying structural valve disease is usually present in patients before developing subacute endocarditis, and is less likely to lead to septic emboli than is acute endocarditis, but subacute endocarditis has a relatively slow process of infection and, if left untreated, can worsen for up to one year before it is fatal. In cases of subacute bacterial endocarditis, the causative organism (streptococcus viridans) needs a previous heart valve disease to colonize. On the other hand, in cases of acute bacterial endocarditis, the organism can colonize on the healthy heart valve, causing the disease.
Diagnosis
Diagnosis of subacute bacterial endocarditis can be done by collecting three blood culture specimens over a 24-hour period for analysis, also it can usually be indicated by the existence of:
Oslers nodes
Roths spots
Nail clubbing
Treatment
The standard treatment is with a minimum of four weeks of high-dose intravenous penicillin with an aminoglycoside such as gentamicin.
The use of high-dose antibiotics is largely based upon animal models.Leo Loewe of Brooklyn Jewish Hospital was the first to successfully treat subacute bacterial endocarditis with penicillin. Loewe reported at the time seven cases of subacute bacterial endocarditis in 1944.
See also
Endocarditis
References
Further references
Goolsby, Mary Jo; Grubbs, Laurie (2011-04-28). Advanced Assessment: Interpreting Findings and Formulating Differential Diagnoses. F.A. Davis. ISBN 9780803625174.
Silverman, Sol; Eversole, Lewis R.; Truelove, Edmond L. (2002-01-01). Essentials of Oral Medicine. PMPH-USA. ISBN 9781550091465.
Kiefer, TL; Bashore, TM (2012). "Infective endocarditis: a comprehensive overview". Reviews in Cardiovascular Medicine. 13 (2–3): e105–20. PMID 23160159.
== External links == |
Peripheral ossifying fibroma | A peripheral ossifying fibroma, also known as ossifying fibrous epulis, is “a gingival nodule which is composed of a cellular fibroblastic connective tissue stroma which is associated with the formation of randomly dispersed foci of mineralised products, which consists of bone, cementum-like tissue, or a dystrophic calcification. The lesion is considered part of an ossifying fibroma, but that is usually considered to be a jaw tumor. Because of its overwhelming incidence on the gingiva, the condition is associated with two other diseases, though not because they occur together. Instead, the three are associated with each other because they appear frequently on gingiva: pyogenic granuloma and peripheral giant cell granuloma. Some researchers believe peripheral ossifying fibromas to be related to pyogenic fibromas and, in some instances, are the result of a pyogenic granuloma which has undergone fibrosis and calcification.
The term peripheral ossifying fibroma has been criticized as this lesion is not related to the ossifying fibroma of bone and is not a fibroma. This term is used in America, however in Britain, this lesion would be termed a fibrous epulis containing bone.
Signs and symptoms
The color of peripheral ossifying fibromas ranges from red to pink, and is frequently ulcerated. It can be sessile or pedunculated with the size usually being less than 2 cm. Weeks or months may pass by before it is seen and diagnosed.There is a gender difference with 66% of the disease occurring in females. The prevalence of peripheral ossifying fibromas is highest around 10 – 19 years of age. It appears only on the gingiva, more often on the maxilla rather than the mandible, and is frequently found in the area around incisors and canines. The adjacent teeth are usually not affected.Peripheral ossifying fibromas appear microscopically as a combination of a mineralized product and fibrous proliferation. The mineralized portion may be bone, cementum-like, or dystrophic calcifications. Additionally, highly developed bone or cementum is more likely to be present when the peripheral ossifying fibroma has existed for a longer period of time.
Diagnosis
Treatment
Treatment usually involves surgical removal of the lesion down to the bone. If there are any adjacent teeth, they are cleaned thoroughly to remove any possible source of irritation. Surgical methods can be traditional, Nd:YAG laser or QMR scalpel. Recurrence is around 16%, with some studies reporting up to 45%. It is unclear if the rate of recurrence is influenced by the surgical technique used.
References
== External links == |
Oculomotor apraxia | Oculomotor apraxia (OMA) is the absence or defect of controlled, voluntary, and purposeful eye movement. It was first described in 1952 by the American ophthalmologist David Glendenning Cogan. People with this condition have difficulty moving their eyes horizontally and moving them quickly. The main difficulty is in saccade initiation, but there is also impaired cancellation of the vestibulo-ocular reflex. Patients have to turn their head in order to compensate for the lack of eye movement initiation in order to follow an object or see objects in their peripheral vision, but they often exceed their target. There is controversy regarding whether OMA should be considered an apraxia, since apraxia is the inability to perform a learned or skilled motor action to command, and saccade initiation is neither a learned nor a skilled action.
Symptoms
Absence of fast phase nystagmus on horizontal optokinetic testing
Problems in nerve function involved in eye movement control, called neuropathy
Inability to visually follow objects
Head thrusts to compensate for the inability to accomplish voluntary horizontal gaze.
Related developmental problems
Even though OMA is not always associated with developmental issues, children with this condition often have hypotonia, decreased muscle tone, and show developmental delays. Some common delays are seen in speech, reading and motor development
Causes
OMA is a neurological condition. Although some brain imaging studies of people with OMA reveal a normal brain, some MRI studies have revealed unusual appearance of some brain areas, in particular the corpus callosum, cerebellum, and/or fourth ventricle. Oculomotor apraxia can be acquired or congenital. Sometimes no cause is found, in which case it is described as idiopathicA person may be born with the parts of the brain for eye movement control not working, or may manifest poor eye movement control in childhood. If any part of the brain that controls eye movement becomes damaged, then OMA may develop. One of the potential causes is bifrontal hemorrhages. In this case, OMA is associated with bilateral lesions of the frontal eye fields (FEF), located in the caudal middle frontal gyrus. The FEF control voluntary eye movements, including saccades, smooth pursuit and vergence. OMA can also be associated with bilateral hemorrhages in the parietal eye fields (PEF). The PEF surround the posterior, medial segment of the intraparietal sulcus. They have a role in reflexive saccades, and send information to the FEF. Since the FEF and PEF have complementary roles in voluntary and reflexive production of saccades, respectively, and they get inputs from different areas of the brain, only bilateral lesions to both the FEF and PEF will cause persistent OMA. Patients with either bilateral FEF or bilateral PEF damage (but not both FEF and PEF) have been shown to regain at least some voluntary saccadic initiation some time after their hemorrhages. Other causes of OMA include brain tumors and cardiovascular problems,.
Ataxia with oculomotor apraxia
A subgroup of genetically recessive ataxias associated with OMA has been identified, with an onset during childhood. These are ataxia with oculomotor apraxia type 1 (AOA1), ataxia with oculomotor apraxia 2 (AOA2), and ataxia telangiectasia. These are autosomal recessive disorders and the associated gene products are involved in DNA repair. Both horizontal and vertical eye movements are affected in these disorders. Although people with either type may have some mild cognitive problems, such as difficulty with concentration or performing multi-step activities, intellectual function is usually not affected.
Type 1
Ataxia-oculomotor apraxia type 1 (AOA1) usually has an onset of symptoms during childhood. It is an autosomal recessive cerebellar ataxia (ARCA) associated with hypoalbuminemia and hypercholesterolemia. Mutations in the gene APTX, which encodes for aprataxin, have been identified to be responsible for AOA1. Elevated creatine kinase is occasionally present, in addition to a sensorimotor axonal neuropathy, as shown by nerve conduction velocity studies. In addition, MRI studies have shown cerebellar atrophy, mild brainstem atrophy, and, in advanced cases, cortical atrophyThe aprataxin protein APTX can remove obstructive termini from DNA strand breaks that interfere with DNA repair. APTX is recruited to DNA single-strand breaks by XRCC1 protein, where it functions as a nick sensor to scan the single-strand breaks for 5’-AMP obstructive termini that are intermediates in failed DNA ligase reactions. The removal of these obstructions allows DNA repair of the break to be completed. It is not yet clear which specific single-strand breaks are the neurodegenerative agents in AOA1 patients that lack functional aprataxin protein. However single-strand breaks with 5’-AMP termini appear to be the most likely candidate lesion.
Type 2
Ataxia-oculomotor apraxia type 2 (AOA2), also known as spinocerebellar ataxia with axonal neuropathy type 2, has its onset during adolescence. It is characterized by cerebellar atrophy and peripheral neuropathy. Sufferers of Type 2 have high amounts of another protein called alpha-fetoprotein (AFP), and may also have high amounts of the protein creatine phosphokinase (CPK). Mutations in the SETX gene are the cause of the disease. AOA2 shows cerebellar atrophy, loss of Purkinje cells, and demyelination. In particular, there is a failure of the cerebrocerebellar circuit in AOA2 that has been shown to be responsible for the weaker coordination of complex cognitive functions such as working memory, executive functions, speech, and sequence learning. Although there is no sign of mental retardation or severe dementia, even after long disease duration, research on families with possible AOA2 have shown mild cognitive impairment as indexed by the Mini-Mental State Examination (MMSE) and the Mattis Dementia Rating Scale. These impairments appear to be mostly due to a deficit in initiation and concept subtests,.
Ataxia telangiectasia
Telangiectasias are widened blood vessels that can develop anywhere on the skin, mucous membranes, whites of the eyes, and even in the brain. Telangiectasias are associated with multiple systemic signs, the most serious of which are unusual sensitivity to ionizing radiation, excessive chromosomal breakage, and a deficiency in the immune system. Ataxia telangiectasia results from defects in the ataxia telangiectasia mutated gene, which can cause abnormal cell death in various places of the body, including brain areas related to coordinated movement of the eyes. Patients with ataxia telangiectasia have prolonged vertical and horizontal saccade latencies and hypometric saccades, and, although not all, some patients show head thrusts,.
Diagnosis
== References == |
Haemophilia | Haemophilia, or hemophilia (from Ancient Greek αἷμα (haîma) blood, and φιλία (philía) love of), is a mostly inherited genetic disorder that impairs the bodys ability to make blood clots, a process needed to stop bleeding. This results in people bleeding for a longer time after an injury, easy bruising, and an increased risk of bleeding inside joints or the brain. Those with a mild case of the disease may have symptoms only after an accident or during surgery. Bleeding into a joint can result in permanent damage while bleeding in the brain can result in long term headaches, seizures, or a decreased level of consciousness.There are two main types of haemophilia: haemophilia A, which occurs due to low amounts of clotting factor VIII, and haemophilia B, which occurs due to low levels of clotting factor IX. They are typically inherited from ones parents through an X chromosome carrying a nonfunctional gene. Rarely a new mutation may occur during early development or haemophilia may develop later in life due to antibodies forming against a clotting factor. Other types include haemophilia C, which occurs due to low levels of factor XI, Von Willebrand disease, which occur due to low level of a substance called von Willebrand factor in their blood, and parahaemophilia, which occurs due to low levels of factor V. Acquired haemophilia is associated with cancers, autoimmune disorders, and pregnancy. Diagnosis is by testing the blood for its ability to clot and its levels of clotting factors.Prevention may occur by removing an egg, fertilizing it, and testing the embryo before transferring it to the uterus. Human embryos in research can be regarded as the technical object/process. Missing blood clotting factors are replaced to treat haemophilia. This may be done on a regular basis or during bleeding episodes. Replacement may take place at home or in hospital. The clotting factors are made either from human blood or by recombinant methods. Up to 20% of people develop antibodies to the clotting factors which makes treatment more difficult. The medication desmopressin may be used in those with mild haemophilia A. Studies of gene therapy are in early human trials.Haemophilia A affects about 1 in 5,000–10,000, while haemophilia B affects about 1 in 40,000, males at birth. As haemophilia A and B are both X-linked recessive disorders, females are rarely severely affected. Some females with a nonfunctional gene on one of the X chromosomes may be mildly symptomatic. Haemophilia C occurs equally in both sexes and is mostly found in Ashkenazi Jews. In the 1800s haemophilia B was common within the royal families of Europe. The difference between haemophilia A and B was determined in 1952.
Signs and symptoms
Characteristic symptoms vary with severity. In general symptoms are internal or external bleeding episodes, which are called "bleeds". People with more severe haemophilia experience more severe and more frequent bleeds, while people with mild haemophilia usually experience more minor symptoms except after surgery or serious trauma. In cases of moderate haemophilia symptoms are variable which manifest along a spectrum between severe and mild forms.In both haemophilia A and B, there is spontaneous bleeding but a normal bleeding time, normal prothrombin time, normal thrombin time, but prolonged partial thromboplastin time. Internal bleeding is common in people with severe haemophilia and some individuals with moderate haemophilia. The most characteristic type of internal bleed is a joint bleed where blood enters into the joint spaces. This is most common with severe haemophiliacs and can occur spontaneously (without evident trauma). If not treated promptly, joint bleeds can lead to permanent joint damage and disfigurement. Bleeding into soft tissues such as muscles and subcutaneous tissues is less severe but can lead to damage and requires treatment.Children with mild to moderate haemophilia may not have any signs or symptoms at birth, especially if they do not undergo circumcision. Their first symptoms are often frequent and large bruises and haematomas from frequent bumps and falls as they learn to walk. Swelling and bruising from bleeding in the joints, soft tissue, and muscles may also occur. Children with mild haemophilia may not have noticeable symptoms for many years. Often, the first sign in very mild haemophiliacs is heavy bleeding from a dental procedure, an accident, or surgery. Females who are carriers usually have enough clotting factors from their one normal gene to prevent serious bleeding problems, though some may present as mild haemophiliacs.
Complications
Severe complications are much more common in cases of severe and moderate haemophilia. Complications may arise from the disease itself or from its treatment:
Deep internal bleeding, e.g. deep-muscle bleeding, leading to swelling, numbness or pain of a limb.
Joint damage from haemarthrosis (haemophilic arthropathy), potentially with severe pain, disfigurement, and even destruction of the joint and development of debilitating arthritis.
Transfusion transmitted infection from blood transfusions that are given as treatment.
Adverse reactions to clotting factor treatment, including the development of an immune inhibitor which renders factor replacement less effective.
Intracranial haemorrhage is a serious medical emergency caused by the buildup of pressure inside the skull. It can cause disorientation, nausea, loss of consciousness, brain damage, and death.Haemophilic arthropathy is characterized by chronic proliferative synovitis and cartilage destruction. If an intra-articular bleed is not drained early, it may cause apoptosis of chondrocytes and affect the synthesis of proteoglycans. The hypertrophied and fragile synovial lining while attempting to eliminate excessive blood may be more likely to easily rebleed, leading to a vicious cycle of hemarthrosis-synovitis-hemarthrosis. In addition, iron deposition in the synovium may induce an inflammatory response activating the immune system and stimulating angiogenesis, resulting in cartilage and bone destruction.
Genetics
Typically, females possess two X-chromosomes, and males have one X and one Y-chromosome. Since the mutations causing the disease are X-linked recessive, a female carrying the defect on one of her X-chromosomes may not be affected by it, as the equivalent dominant allele on her other chromosome should express itself to produce the necessary clotting factors, due to X inactivation. Therefore, heterozygous females are just carriers of this genetic disposition. However, the Y-chromosome in the male has no gene for factors VIII or IX. If the genes responsible for production of factor VIII or factor IX present on a males X-chromosome are deficient there is no equivalent on the Y-chromosome to cancel it out, so the deficient gene is not masked and the disorder will develop.Since a male receives his single X-chromosome from his mother, the son of a healthy female silently carrying the deficient gene will have a 50% chance of inheriting that gene from her and with it the disease; and if his mother is affected with haemophilia, he will have a 100% chance of being a haemophiliac. In contrast, for a female to inherit the disease, she must receive two deficient X-chromosomes, one from her mother and the other from her father (who must therefore be a haemophiliac himself). Hence, haemophilia is expressed far more commonly among males than females, while females, who must have two deficient X-chromosomes in order to have haemophilia, are far more likely to be silent carriers, survive childhood and to submit each of her genetic children to an at least 50% risk of receiving the deficient gene. However, it is possible for female carriers to become mild haemophiliacs due to lyonisation (inactivation) of the X-chromosomes. Haemophiliac daughters are more common than they once were, as improved treatments for the disease have allowed more haemophiliac males to survive to adulthood and become parents. Adult females may experience menorrhagia (heavy periods) due to the bleeding tendency. The pattern of inheritance is criss-cross type. This type of pattern is also seen in colour blindness.A mother who is a carrier has a 50% chance of passing the faulty X-chromosome to her daughter, while an affected father will always pass on the affected gene to his daughters. A son cannot inherit the defective gene from his father. Genetic testing and genetic counselling is recommended for families with haemophilia. Prenatal testing, such as amniocentesis, is available to pregnant women who may be carriers of the condition.As with all genetic disorders, it is also possible for a human to acquire it spontaneously through mutation, rather than inheriting it, because of a new mutation in one of their parents gametes. Spontaneous mutations account for about 33% of all cases of haemophilia A. About 30% of cases of haemophilia B are the result of a spontaneous gene mutation.
If a female gives birth to a haemophiliac son, either the female is a carrier for the blood disorder or the haemophilia was the result of a spontaneous mutation. Until modern direct DNA testing, however, it was impossible to determine if a female with only healthy children was a carrier or not.If a male has the disease and has children with a female who is not a carrier, his daughters will be carriers of haemophilia. His sons, however, will not be affected with the disease. The disease is X-linked and the father cannot pass haemophilia through the Y-chromosome. Males with the disorder are then no more likely to pass on the gene to their children than carrier females, though all daughters they sire will be carriers and all sons they father will not have haemophilia (unless the mother is a carrier).
Severity
There are numerous different mutations which cause each type of haemophilia. Due to differences in changes to the genes involved, people with haemophilia often have some level of active clotting factor. Individuals with less than 1% active factor are classified as having severe haemophilia, those with 1–5% active factor have moderate haemophilia, and those with mild haemophilia have between 5% and 40% of normal levels of active clotting factor.
Diagnosis
Haemophilia can be diagnosed before, during or after birth if there is a family history of the condition. Several options are available to parents. If there is no family history of haemophilia, it is usually only diagnosed when a child begins to walk or crawl. They may experience joint bleeds or easy bruising.Mild haemophilia may only be discovered later, usually after an injury or a dental or surgical procedure.
Before pregnancy
Genetic testing and counselling are available to help determine the risk of passing the condition onto a child. This may involve testing a sample of tissue or blood to look for signs of the genetic mutation that causes haemophilia.
During pregnancy
A pregnant woman with a history of haemophilia in her family can test for the haemophilia gene. Such tests include:
chorionic villus sampling (CVS): a small sample of the placenta is removed from the womb and tested for the haemophilia gene, usually during weeks 11–14 of pregnancy
amniocentesis: a sample of amniotic fluid is taken for testing, usually during weeks 15–20 of pregnancyThere is a small risk of these procedures causing problems such as miscarriage or premature labour, so the woman may discuss this with the doctor in charge of her care.
After birth
If haemophilia is suspected after a child has been born, a blood test can usually confirm the diagnosis. Blood from the umbilical cord can be tested at birth if theres a family history of haemophilia. A blood test will also be able to identify whether a child has haemophilia A or B, and how severe it is.
Classification
There are several types of haemophilia: haemophilia A, haemophilia B, haemophilia C, parahaemophilia, acquired haemophilia A, and acquired haemophilia B.Haemophilia A is a recessive X-linked genetic disorder resulting in a deficiency of functional clotting Factor VIII. Haemophilia B is also a recessive X-linked genetic disorder involving a lack of functional clotting Factor IX. Haemophilia C is an autosomal genetic disorder involving a lack of functional clotting Factor XI. Haemophilia C is not completely recessive, as heterozygous individuals also show increased bleeding.The type of haemophilia known as parahaemophilia is a mild and rare form and is due to a deficiency in factor V. This type can be inherited or acquired.A non-genetic form of haemophilia is caused by autoantibodies against factor VIII and so is known as acquired haemophilia A. It is a rare but potentially life-threatening bleeding disorder caused by the development of autoantibodies (inhibitors) directed against plasma coagulation factors. Acquired haemophilia can be associated with cancers, autoimmune disorders and following childbirth.
Management
There is no long-term cure. Treatment and prevention of bleeding episodes is done primarily by replacing the missing blood clotting factors.
Clotting factors
Clotting factors are usually not needed in mild haemophilia. In moderate haemophilia clotting factors are typically only needed when bleeding occurs or to prevent bleeding with certain events. In severe haemophilia preventive use is often recommended two or three times a week and may continue for life. Rapid treatment of bleeding episodes decreases damage to the body.Factor VIII is used in haemophilia A and factor IX in haemophilia B. Factor replacement can be either isolated from human blood serum, recombinant, or a combination of the two. Some people develop antibodies (inhibitors) against the replacement factors given to them, so the amount of the factor has to be increased or non-human replacement products must be given, such as porcine factor VIII.If a person becomes refractory to replacement coagulation factor as a result of high levels of circulating inhibitors, this may be partially overcome with recombinant human factor VIII.In early 2008, the US Food and Drug Administration (FDA) approved an anti-haemophilic drug completely free of albumin, which made it the first anti-haemophilic drug in the US to use an entirely synthetic purification process. Since 1993 recombinant factor products (which are typically cultured in Chinese hamster ovary (CHO) tissue culture cells and involve little, if any human plasma products) have been available and have been widely used in wealthier western countries. While recombinant clotting factor products offer higher purity and safety, they are, like concentrate, extremely expensive, and not generally available in the developing world. In many cases, factor products of any sort are difficult to obtain in developing countries.Clotting factors are either given preventively or on-demand. Preventive use involves the infusion of clotting factor on a regular schedule in order to keep clotting levels sufficiently high to prevent spontaneous bleeding episodes. On-demand (or episodic) treatment involves treating bleeding episodes once they arise. In 2007, a trial comparing on-demand treatment of boys (< 30 months) with haemophilia A with prophylactic treatment (infusions of 25 IU/kg body weight of Factor VIII every other day) in respect to its effect on the prevention of joint-diseases. When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group had a normal index joint-structure on MRI. Preventative treatment, however, resulted in average costs of $300,000 per year. The author of an editorial published in the same issue of the NEJM supports the idea that prophylactic treatment not only is more effective than on demand treatment but also suggests that starting after the first serious joint-related haemorrhage may be more cost effective than waiting until the fixed age to begin. Most haemophiliacs in third world countries have limited or no access to commercial blood clotting factor products.
Other
Desmopressin (DDAVP) may be used in those with mild haemophilia A. Tranexamic acid or epsilon aminocaproic acid may be given along with clotting factors to prevent breakdown of clots.Pain medicines, steroids, and physical therapy may be used to reduce pain and swelling in an affected joint. In those with severe hemophilia A already receiving FVIII, emicizumab may provide some benefit. Different treatments are used to help those with an acquired form of hemophilia in addition to the normal clotting factors. Often the most effective treatment is corticosteroids which remove the auto-antibodies in half of people. As a secondary route of treatment, cyclophosphamide and cyclosporine are used and are proven effective for those who did not respond to the steroid treatments. In rare cases a third route or treatment is used, high doses of intravenous immunoglobulin or immunosorbent that works to help control bleeding instead of battling the auto-antibodies.
Contraindications
Anticoagulants such as heparin and warfarin are contraindicated for people with haemophilia as these can aggravate clotting difficulties. Also contraindicated are those drugs which have "blood thinning" side effects. For instance, medicines which contain aspirin, ibuprofen, or naproxen sodium should not be taken because they are well known to have the side effect of prolonged bleeding.Also contraindicated are activities with a high likelihood of trauma, such as motorcycling and skateboarding. Popular sports with very high rates of physical contact and injuries such as American football, hockey, boxing, wrestling, and rugby should be avoided by people with haemophilia. Other active sports like soccer, baseball, and basketball also have a high rate of injuries, but have overall less contact and should be undertaken cautiously and only in consultation with a doctor.
Prognosis
Like most aspects of the disorder, life expectancy varies with severity and adequate treatment. People with severe haemophilia who do not receive adequate, modern treatment have greatly shortened lifespans and often do not reach maturity. Prior to the 1960s when effective treatment became available, average life expectancy was only 11 years. By the 1980s the life span of the average haemophiliac receiving appropriate treatment was 50–60 years. Today with appropriate treatment, males with haemophilia typically have a near normal quality of life with an average lifespan approximately 10 years shorter than an unaffected male.Since the 1980s the primary leading cause of death of people with severe haemophilia has shifted from haemorrhage to HIV/AIDS acquired through treatment with contaminated blood products. The second leading cause of death related to severe haemophilia complications is intracranial haemorrhage which today accounts for one third of all deaths of people with haemophilia. Two other major causes of death include hepatitis infections causing cirrhosis and obstruction of air or blood flow due to soft tissue haemorrhage.
Epidemiology
Haemophilia frequency is about 1 instance in every 10,000 births (or 1 in 5,000 male births) for haemophilia A and 1 in 50,000 births for haemophilia B. About 18,000 people in the United States have haemophilia. Each year in the US, about 400 babies are born with the disorder. Haemophilia usually occurs in males and less often in females. It is estimated that about 2,500 Canadians have haemophilia A, and about 500 Canadians have haemophilia B.
History
Scientific discovery
The excessive bleeding was known to ancient people. The Talmud instructs that a boy must not be circumcised if he had two brothers who died due to complications arising from their circumcisions, and Maimonides says that this excluded paternal half-brothers. This may have been due to a concern about hemophilia. The first medical professional to describe the disease was Arab surgeon Al-Zahrawi, also known as Abulcasis. In the tenth century he described families whose males died of bleeding after only minor traumas. While many other such descriptive and practical references to the disease appear throughout historical writings, scientific analysis did not begin until the start of the nineteenth century.In 1803, John Conrad Otto, a Philadelphian physician, wrote an account about "a hemorrhagic disposition existing in certain families" in which he called the affected males "bleeders". He recognised that the disorder was hereditary and that it affected mostly males and was passed down by healthy females. His paper was the second paper to describe important characteristics of an X-linked genetic disorder (the first paper being a description of colour blindness by John Dalton who studied his own family). Otto was able to trace the disease back to a woman who settled near Plymouth, New Hampshire, in 1720. The idea that affected males could pass the trait onto their unaffected daughters was not described until 1813 when John F. Hay, published an account in The New England Journal of Medicine.In 1924, a Finnish doctor discovered a hereditary bleeding disorder similar to haemophilia localised in Åland, southwest of Finland. This bleeding disorder is called "Von Willebrand Disease".
The term "haemophilia" is derived from the term "haemorrhaphilia" which was used in a description of the condition written by Friedrich Hopff in 1828, while he was a student at the University of Zurich. In 1937, Patek and Taylor, two doctors from Harvard, discovered anti-haemophilic globulin. In 1947, Pavlosky, a doctor from Buenos Aires, found haemophilia A and haemophilia B to be separate diseases by doing a lab test. This test was done by transferring the blood of one haemophiliac to another haemophiliac. The fact that this corrected the clotting problem showed that there was more than one form of haemophilia.
European royalty
Haemophilia has featured prominently in European royalty and thus is sometimes known as the royal disease. Queen Victoria passed the mutation for haemophilia B to her son Leopold and, through two of her daughters, Alice and Beatrice, to various royals across the continent, including the royal families of Spain, Germany, and Russia. In Russia, Tsarevich Alexei, the son and heir of Tsar Nicholas II, famously had haemophilia, which he had inherited from his mother, Empress Alexandra, one of Queen Victorias granddaughters. The haemophilia of Alexei would result in the rise to prominence of the Russian mystic Grigori Rasputin, at the imperial court.It was claimed that Rasputin was successful at treating Tsarevich Alexeis haemophilia. At the time, a common treatment administered by professional doctors was to use aspirin, which worsened rather than lessened the problem. It is believed that, by simply advising against the medical treatment, Rasputin could bring visible and significant improvement to the condition of Tsarevich Alexei.In Spain, Queen Victorias youngest daughter, Princess Beatrice, had a daughter Victoria Eugenie of Battenberg, who later became Queen of Spain. Two of her sons were haemophiliacs and both died from minor car accidents. Her eldest son, Prince Alfonso of Spain, Prince of Asturias, died at the age of 31 from internal bleeding after his car hit a telephone booth. Her youngest son, Infante Gonzalo, died at age 19 from abdominal bleeding following a minor car accident in which he and his sister hit a wall while avoiding a cyclist. Neither appeared injured or sought immediate medical care and Gonzalo died two days later from internal bleeding.
Treatment
The method for the production of an antihaemophilic factor was discovered by Judith Graham Pool from Stanford University in 1964, and approved for commercial use in 1971 in the United States under the name Cryoprecipitated AHF. Together with the development of a system for transportation and storage of human plasma in 1965, this was the first time an efficient treatment for haemophilia became available.
Blood contamination
Up until late 1985 many people with haemophilia received clotting factor products that posed a risk of HIV and hepatitis C infection. The plasma used to create the products was not screened or tested, nor had most of the products been subject to any form of viral inactivation.Tens of thousands worldwide were infected as a result of contaminated factor products including more than 10,000 people in the United States, 3,500 British, 1,400 Japanese, 700 Canadians, 250 Irish, and 115 Iraqis.Infection via the tainted factor products had mostly stopped by 1986 by which time viral inactivation methods had largely been put into place, although some products were shown to still be dangerous in 1987.
Research
Gene therapy
In those with severe haemophilia, gene therapy may reduce symptoms to those that a person with mild or moderate haemophilia might have. The best results have been found in haemophilia B. In 2016 early stage human research was ongoing with a few sites recruiting participants. In 2017 a gene therapy trial on nine people with haemophilia A reported that high doses did better than low doses. It is not currently an accepted treatment for haemophilia.In July 2022 results of a gene therapy candidate for haemophilia B called FLT180 were announced, it works using an adeno-associated virus (AAV) to restore the clotting factor IX (FIX) protein, normal levels of the protein were observed with low doses of the therapy but immunosuppression was necessitated to decrease the risk of vector-related immune responses.
See also
Coagulopathy
Purpura secondary to clotting disorders
Von Willebrand disease
World Federation of Hemophilia
References
External links
Haemophilia at Curlie
World Federation of Hemophilia |
Ulegyria | Ulegyria is a diagnosis used to describe a specific type of cortical scarring in the deep regions of the sulcus that leads to distortion of the gyri. Ulegyria is identified by its characteristic "mushroom-shaped" gyri, in which scarring causes shrinkage and atrophy in the deep sulcal regions while the surface gyri are spared. This condition is most often caused by hypoxic-ischemic brain injury in the perinatal period. The effects of ulegyria can range in severity, although it is most commonly associated with cerebral palsy, mental retardation and epilepsy. N.C. Bresler was the first to view ulegyria in 1899 and described this abnormal morphology in the brain as “mushroom-gyri." Although ulegyria was first identified in 1899, there is still limited information known or reported about the condition.
Anatomy
The physical features of ulegyria consist of small radial scars which occupy the cortical sulci. Overall, the physical structure of affected areas in the brain is described as a “mushroom”-like shape in which the gyri are unusually large and the sulci become wider deeper in the cortex. N.C. Bresler, the first person to view a brain with ulegyria in 1899, coined the phrase mushroom gyri. He also named the disorder, basing it off the Latin root ule, meaning scar. This mushroom-like structure is the result of the lower parts of the ulegyria-affected area being more prone to deterioration, while the upper gyri are usually spared. However, the entire affected area shrinks and presents brown coloration as a result of ulegyria. In addition, “islands” of neurons that are relatively unaffected can exist between ulegyria affected neurons. Ulegyria can develop bilaterally or unilaterally, though the former is more commonly diagnosed.Ulegyria can affect many parts of the brain including the cerebral cortex, parasagittal areas and posterior regions of the brain, such as the parietal and occipital lobes. These areas are situated either near artery rich regions or near a major cerebral artery. For instance, specifically in neonatal children, ulegyria-affected areas are found near the posterior cerebral artery or near the artery rich region between the middle and posterior regions of the brain, often referred to as watershed regions.Neurons affected by ulegyria exhibit properties that differ from normally functioning neurons. For instance, ulegyria affected neurons experience gliosis in which glial cells, specifically astrocytes, build up near and around neurons. Ulegyria affected neurons also display decreases in their white matter content, showing signs of sclerosis, which is characterized by the deterioration of myelin in neurons. However, in regions of grey matter, large dense aggregates of myelin are present. Ulegyria affected neurons also display metabolic disorders which could be linked to the disease phenylketonuria and disruptions in the urea cycle. Hypoglycemia and hypoxia are also thought to accompany the symptoms of ulegyria-affected neurons as well.
Causes
Ulegyria develops as a result of a brain injury called cerebral ischemia surrounding the time of an infants birth. Oftentimes, fetal hypoxic-ischemic brain injuries occur as a result of a pregnancy complications such as placental abruption, cord accident, or cardiovascular stress due to a difficult delivery. A lack of oxygen to the brain contributes to the formation of lesions usually near the three main cerebral arteries, located near the parietal lobe and occipital lobes of the brain. The cause of perinatal brain injuries includes:
1. cerebral ischemia
2. cerebral hemorrhage
3. ascending intrauterine infections.Some risk factors for perinatal brain injuries include: low birth weight, preterm birth, poor perinatal cardiorespiratory fitness, and artificial ventilation.
Cerebral ischemia
Cerebral ischemia occurs when the brain is not receiving adequate oxygen to continue normal functions. When this occurs, the body makes restoring oxygenated blood flow to life-sustaining organs a priority. The brain alters the diameter of major blood vessels to redistribute blood to key organs such as the brain, heart, and adrenal glands. If sympathetic nervous system activation does not produce any improvement, oxygen levels will continue to fall and disruptions to metabolism, other cellular processes, and overall functioning will ensue.
Another serious result of inefficient blood flow is that cells do not receive adequate amounts of glucose. An immediate effect of low intracellular glucose is reduced ATP production in the cell. This effectively inactivates the Na-K pump, leading to the uptake of calcium ions by the cell. Continued influx of calcium serves to constitutively activate downstream effectors, including lipases, proteases, and endonucleases, whose actions eventually destroy the cell skeleton. Intracellular calcium concentrations are increased further due to the opening of glutamate-regulated ion channels. Ischemia causes anoxic cell depolarizations and it is this increase in membrane potential at the presynaptic cell that triggers the release of glutamate, an excitatory neurotransmitter.Glucose deprivation in the brain for any amount of time has the potential to pose serious consequences, and the amount of time the brain spends under these anoxic conditions is directly related to accumulation of irreversible damage to protein biosynthesis pathways. Protein synthesis all over the body is severely inhibited and essentially comes to a standstill while the brain is suffering from acute oxygen deprivation. Once oxygen sufficiently saturates the tissues again, protein biosynthesis returns to normal in non-vulnerable areas but remains at below normal levels in other areas. Insufficient protein synthesis in the brain is especially troubling in the fetal brain given the amount of growth and development that normally occurs. Areas particularly vulnerable to the damaging effects of hypoxic episodes include: the superior brainstem, the cerebellum, white matter and subcortical structures supplied by the branches of deep and superficial penetrating blood vessels. Vulnerable areas where protein synthesis is interrupted usually indicate impending cell death in neurons. When oxygen levels return, oxygen radicals, nitric oxide and an imbalance of neurotransmitters cause further damage and lead to cellular death through apoptosis. Neuron cell death is responsible for gliosis and results in the mushroom appearance of areas and is characteristic of ulegyria.
Cerebral hemorrhage
A cerebral hemorrhage is the result of immature blood vessels of a brain lesion bursting. The germinal matrix is a part of the brain that normally disappears as the fetal brain develops but during this process it is not unusual for changes in vessel volume to cause a vessel to burst. According to recent microscopic studies, the most common location for a cerebral hemorrhage is where the medullary veins drain to the terminal vein in the sub-ependymal region. It has been hypothesized that because pre-term babies dont have fully developed sympathetic nervous systems, they cannot react as well to low oxygen saturation levels caused by the cerebral hemorrhage. Although babies born at full-term are still susceptible to this, they are likely to respond better and thus, tend to have better outcomes in response to low-oxygen events.
Ascending intrauterine infections
Recent research has found a connection between intrauterine infections and inflammation in the mother and an increased likelihood of perinatal brain damage in the fetus. This study suggested that intrauterine infections in the mother could affect glial cells and toll-like receptors (TLRs) which are important in moderating the inflammatory response in the fetal brain. When glial cells and TLRs are negatively affected they are not able to react to developing inflammation in the brain as well. The connection between ascending intrauterine infections and perinatal brain damage is a developing research theory but a more detailed explanation of the connection is not yet known.
Signs and symptoms
Ulegyria was found in about 1/3 of patients with defects caused by circulatory disease in the perinatal period. Most clinical observations of the condition report mental retardation, cerebral palsy, and seizures as the main defects. However, milder cases have been reported in which patients that exhibit ulegyria develop relatively normally. The main movement disorders associated with ulegyria that are classified as cerebral palsy are choreoathetosis, dystonia, and ataxia. It is suspected that ulegyria leads to epilepsy because malformation of the cortex obstructs the differentiation of neurons, glial cells, and synapses. Parietal-occipital lobe epilepsy, which is often synonymous with posterior cortex epilepsy (PCE), is the form of the disease seen in most cases involving ulegyria. This type of epilepsy is very rare, making up about 5% of all reports of epilepsy. This form of the disease involves symptoms that would be expected from damage to the parietal and occipital lobes: seizures with visual hallucinations, visuospatial dysfunction, tingling, numbness, pain, and a burning sensation. In addition to ulegyria, tumors and cortical dysplasia constitute the major causes of PCE. Most of the epilepsy seen in conjunction with ulegyria is classified as medically refractory, meaning it is not responsive to treatment. Patients usually present symptoms of epilepsy at an early age. The severity of epilepsy has been shown to depend on this age of onset as well as the quantity of cortical lesions; earlier onset of epilepsy and a larger extent of lesions tends to mean more severe seizures.
Similar conditions
Ulegyria is often confused with a similar distortion of the cortex known as polymicrogyria. Polymicrogyria is characterized by excessive folding of the surface gyri and a thickening of the cerebral cortex, rather than the sulcal scarring that is typical of ulegyria. In addition to morphological differences, the period in which polmicrogyria and ulegyria emerge is also different. Polymicrogyria typically forms while the embryos central nervous system is maturing. Ulegyria is acquired later in development during the perinatal period after neuronal migration has already occurred. It is also suspected that polymicrogyra is genetically linked, whereas ulegyria is caused by environmental factors—namely lack of oxygen.Polymicrogyria can lead to similar conditions that are linked to ulegyria such as mental retardation, cerebral palsy, and epilepsy. It has been observed that patients with polymicrogyria are not receptive to epilepsy surgery. However, responses of patients with ulegyria to similar surgeries are still not fully known, which makes distinction of these two disorders significant. In vivo neuroimaging techniques, namely MRI, have been instrumental in making this distinction. An MRI image of ulegyria is identified by mushroom shaped gyri, deformities in white matter, and localization mainly in the posterior cerebral region. Polymicrogyria is typically recognized by a scalloped appearance at the bordering region between grey and white matter. Although these distinctions have been made with many patients, there is still some difficulty in defining distinct boundaries between these two similar conditions.
Detection
Primarily, the main method of detecting ulegyria is through the use of MRI screening for epilepsy. Normally an MRI of an ulegyria affected region will reveal groups of deteriorated neurons with gliosis present. In addition, unaffected gyri are also present in especially bilateral watershed regions indicating delayed effects of perinatal hypoxic damage. However, there are three main criteria for diagnosing ulegyria using MRI in addition to the features mentioned above:
1.The presence of a poorly demarcated lesion
2. Atrophy and thinning of the cortex resulting in the characteristic “mushroom” like shape of ulegyria.
3. Presence of white matter signal abnormalities as a result of FLAIR signaling (fluid attenuated inversion recovery).Another sign of ulegyria that is visible on an MRI scan is the presence of a widened subarachnoid space, signifying cortex atrophy. FLAIR signaling can help visualize the depths of the parietal-occipital sulci, which also allows ulegyria-affected gyri to be identified. Though there is still confusion in differentiating ulegyria and polymicrogyria in patients, MRI allows for the proper identification in the majority of the cases. In addition, most of the current research regarding ulegyria is focused on improving this identification. Furthermore, MRI can diagnose whether ulegyria presence is unilateral or bilateral. Electroencephalography, EEG, can also be used to screen for ulegyria, though MRI is still preferred. This is mainly done for epilepsy patients as abnormalities in EEG recordings indicate the presence of ulegyria in the area of the brain being tested. For example, when EEG tests in epileptic patients show deviations in the frontal and central-parietal regions, ulegyria can be considered to be present in that area.
Treatment
Presently, there is no well-defined treatment for ulegyria mainly because of the irreversible ischaemic damage done to neurons of an affected area. However, conditions associated with ulegyria, such as epilepsy and cerebral palsy, can be treated using the appropriate treatment. For instance, seizures caused by epilepsy, due to the presence of ulegyria in the occipital lobe, can be controlled using antiepileptic drugs in some patients. In other patients, such as those who suffer from ulegyria in the posterior cortex, drugs are not effective and surgery of the area causing epilepsy is needed. These treatments treat only the conditions but have no effect on the condition of ulegyria itself.
== References == |
Hypogonadotropic hypogonadism | Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis (HPG axis). Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (GnRH), while pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary. GnRH is the central regulator in reproductive function and sexual development via the HPG axis. GnRH is released by GnRH neurons, which are hypothalamic neuroendocrine cells, into the hypophyseal portal system acting on gonadotrophs in the anterior pituitary.
The release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology. LH acts on Leydig cells in the male testes and theca cells in the female. FSH acts on Sertoli cells in the male and follicular cells in the female. Combined this causes the secretion of gonadal sex steroids and the initiation of folliculogenesis and spermatogenesis. The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH.
GnRH neurons lack sex steroid receptors and mediators such as kisspeptin stimulate GnRH neurons for pulsatile secretion of GnRH.
Types
There are two subtypes of HH, congenital HH (CHH) and acquired HH (AHH). CHH is due to genetic abnormalities resulting in non-functional GnRH secreting neurons or gonadotropic cell dysfunction in the anterior pituitary. CHH is divided into 2 subtypes depending on the condition of the olfactory system, anosmic HH (Kallman syndrome) and normosmic HH.
AHH is an acquired form of the disease often occurring after sexual maturation and is not related to genetic defects.
Pathogenesis
CHH is a type of HH resulting from the abnormal migration of GnRH neurons during embryonic development. GnRH neurons are derived from the olfactory placode and migrate into the central nervous system (CNS) during embryonic development. Embryonic migration can be affected by several gene mutations including but not limited to, KAL1, fibroblast growth factor (FGF8), sex determining region Y-Box 10 (SOX10), GNRHR, GNRH1 and KISS1R. Kallmann syndrome results in a loss of smell (anosmia) and is associated with KAL1 mutations. The KAL1 gene encodes anosmin-1, an extracellular adhesion molecule that plays a role in GnRH neuronal migration and adhesion.
Mutated KAL1 genes leads to ill GnRH neuronal migration as well as olfactory neuron disorder causing anosmia and non-functional GnRH releasing neurons. Mutations of KAL1 are mostly nucleotide insertion or deletion causing frame shifts in the translation of anosmin-1 resulting in a faulty protein.
Inactivating mutations in the genes encoding GNRH1 or its receptor will result in the failure of the HPG axis and give rise to normosmic CHH.
Inactivating mutations of KISS1 or KISS1R causes normosmic CHH in humans.
This is because KISS1 is the mediator for the feedback loop in the HPG axis allowing low levels of sex steroid to stimulate GnRH secretion from the hypothalamus.CHH is a genetically heterogenous disorder with cases reported as being X-linked, recessive and autosomally inherited.
The prevalence has been estimated to be 1/4000 to 1/10000 in males and 2 to 5 times less frequent in females. The prevalence difference between male and females is unknown, and is likely to be underreported for females.Acquired hypogonadotropic hypogonadism (AHH) is a postnatal onset of a GnRH releasing disorder and/or pituitary gonadotroph cell disorder.
There are many causes of AHH, mostly due to structural or functional abnormalities involving the HPG axis such as sarcoidosis, lymphocytic hypophysitis, pituitary adenomas, craniopharyngiomas and other CNS tumours. Most of these patients have multiple pituitary hormone deficiencies. Hyperprolactinaemia is the most common cause of AHH. It is a well-established cause of infertility in both male and female mammals. Prolactin inhibits GnRH neurons and therefore inhibits the subsequent release of LH, FSH and sex steroids. The mechanism of prolactin induced inhibition of GnRH release is poorly understood.
It is suspected that the prolactin receptor is expressed on a small subset of GnRH neurons in mice and thus has a direct inhibitory effect on GnRH release. There is evidence to suggest indirect inhibition of GnRH neurons mediated by other neurotransmitters such as dopamine, opioid, neuropeptide Y and γ-aminobutyric acid.
Drug usage of glucocorticoids and opioid analgesics in high dosages can lead to the inhibition of GnRH synthesis.
Opioid receptors reside in the hypothalamus and when bound to opioids they decrease the normal pulsatile secretion of GnRH and therefore result in HH.
Chronic treatment with supraphysiological doses of glucocorticoids results in a marked decrease in testosterone without an increase of LH levels, suggestive of a central mechanism of induced HH.
Diagnosis
The clinical presentation of HH depend on the time of onset as well as the severity of the defect.
Diagnostic tests to measure GnRH levels are difficult. This is because GnRH is confined within hypophyseal portal system and has a short half-life of 2–4 minutes.
GnRH levels are thus checked indirectly via LH and FSH levels which will be totally or partially absent in HH. Exogenous GnRH can be used as a diagnostic tool. If the patient has hypothalamic GnRH deficiency, LH and FSH will gradually appear in response to the exogenous GnRH but in pituitary cases of HH, a minimal response will be generated.
Typically, CHH is diagnosed in adolescence due to a lack of pubertal development, but it can be possible to diagnose in male neonates. Clinical presentations of CHH involve an absence of puberty by 18 years of age, poorly developed secondary sexual characteristics, or infertility.In men with CHH, serum levels of inhibin B are typically very low as inhibin B is a marker of Sertoli cell number.
For females, CHH is most commonly revealed by primary amenorrhea. Breast development is variable and pubic hair may or may not be present.
CHH can be diagnosed in the male neonate with cryptorchidism (maldescended testes) and a micropenis as signs of GnRH deficiency.
There are no clear signs of CHH in female neonates.
Another clinical sign of CHH, more specifically Kallmann syndrome, is a lack of a sense of smell due to the altered migration of GnRH neurons on the olfactory placode. Kallmann syndrome can also be shown through MRI imaging with irregular morphology or aplasia of the olfactory bulb and olfactory sulci. Anterior pituitary function must be normal for all other axes in CHH as it is an isolated disorder.
Testing anterior pituitary function is helpful to identify if the HH is due to hyperprolactinemia.
Management
The goal for HH therapy is to induce pubertal development, sexual function, fertility, bone health, and psychological wellbeing.
Testosterone therapy for males and estradiol therapy for females is used to improve genital development, develop secondary sexual characteristics, allow for the growth and closure of the epiphyseal plate, as well as improving sexual function.
This therapy does not restore fertility as gonadotropins are required for spermatogenesis and folliculogenesis. If fertility is desired, pulsatile GnRH therapy or gonadotropin therapy is necessary.Gonadotropin therapy involves the use of human chorionic gonadotropin (hCG) and FSH. In the male, hCG stimulates Leydig cells to produce testosterone so that plasma and testicular levels increase. With the increased levels of testosterone, sexual activity, libido and overall wellbeing should improve.
Administration of FSH is required to induce spermatogenesis by acting on Sertoli cells. FSH is required for maintaining the production of high numbers of good quality sperm. Gonadotropin therapy in HH men usually is able to generate enough sperm for fertility to occur, however sperm count is still lower than normal.In the female, the goal for gonadotropin therapy is to obtain ovulation. This is obtained with FSH treatment followed by hCG or LH to trigger ovulation. FSH will stimulate granulosa cells for follicular maturation while LH will act on luteal cells to produce steroids aiding follicular maturation and preparing the endometrium for pregnancy.For hyperprolactinaemia-caused AHH, dopamine agonists are used to improve GnRH secretion. Dopamine binds to D2 receptors on lactotrophs within the anterior pituitary.
This results in the inhibition of secretion of prolactin resulting in less direct and indirect inhibition of GnRH secretion.In up to 10–20% of cases, patients can exhibit sustained fertility and steroid production after therapy, resulting in hypogonadotropic hypogonadism reversal. The mechanism for this reversal is unknown but there is believed to be some neuronal plasticity within GnRH releasing cells.
See also
Androgens and estrogens
GnRH and gonadotropins (FSH and LH)
Hypergonadotropic hypogonadism
Hypothalamic–pituitary–gonadal axis
Isolated hypogonadotropic hypogonadism
References
== External links == |
Pseudopseudohypoparathyroidism | Pseudopseudohypoparathyroidism (PPHP) is an inherited disorder, named for its similarity to pseudohypoparathyroidism in presentation. It is more properly Albright hereditary osteodystrophy although without resistance of parathyroid hormone as frequently seen in that affliction. The term Pseudopseudohypoparathyroidism is used to describe a condition where the individual has the phenotypic appearance of Pseudohypoparathyroidism type 1a, but has (unexpected for the phenotype) normal labs including calcium and PTH.It can be considered a variant of Albright hereditary osteodystrophy, or Pseudohypoparathyroidism type 1A, as they present with the same constellation of signs and symptoms, including short stature, brachydactyly, subcutaneous calcification, and obesity.
Presentation
Pseudopseudohypoparathyroidism can be best understood by comparing it to other conditions:
Hormone resistance is not present in Pseudopseudohypoparathyroidism. Short stature may be present. Obesity is less common in Pseudopseudohypoparathyroidism than in Pseudohypoparathyroidism. Osteoma cutis may be present.
Genetics
A male with Pseudohypoparathyroidism has a 50% chance of passing on the defective GNAS gene to his children, although in an imprinted, inactive form. Any of his children receiving this gene will have Pseudopseudohypoparathyroidism. Any of his daughters that have Pseudopseudohypoparathyroidism may in turn pass along Pseudohypoparathyroidism 1A to her children as the imprinting pattern on the inherited paternal gene will be changed to the maternal pattern in the mothers ovum during meiosis. The gene will be reactivated in any children who inherit it.Pseudopseudohypoparathyroidism and pseudohypoparathyroidism both involve the same GNAS gene, but Pseudopseudohypoparathyroidism has normal calcium homeostasis because of the normal maternal allele in the kidney.
Pathophysiology
The GNAS1 gene involved in both Pseudohypoparathyroidism type 1a and Pseudopseudohypoparathyroidism is greatly affected by imprinting. When a father who has Pseudohypoparathyroidism undergoes spermatogenesis, imprinting of the GNAS1 gene inactivates both copies of his genes: one will be Functional and the other will be defective. Tissues in the body will re-activate different copies of the GNAS1 gene selectively; the kidneys will selectively activate the (functional) maternal copy while keeping the (defective) paternally-derived gene imprinted and inactive, even in normal individuals. Since the maternally-derived GNAS1 gene is functional, renal handling of calcium and phosphate is normal, and homeostasis is maintained in Pseudopseudohypoparathyroidism. However, the rest of the tissues will instead selectively display the defective gene, resulting in haploinsufficiency of the GNAS1 product in most tissues, and giving the phenotype of Pseudohypoparathyroidism type 1a. As a result, there is also a normal response of urinary cAMP to PTH, and normal serum PTH.
Diagnosis
The diagnosis is based on the presence of the Albright hereditary osteodystrophy pseudotype but without the PTH resistance. Blood tests including calcium, phosphate, and PTH will exclude other forms of Pseudohypoparathyroidism. X-rays may reveal a short fourth metacarpal. Genetic testing can confirm the diagnosis by showing GNAS gene mutation.
Treatment
Treatments focuses on symptoms, with genetic counseling recommended.
History
It was characterized in 1952 by Fuller Albright as "pseudo-pseudohypoparathyroidism" (with hyphen).
See also
Antidisestablishmentarianism
Floccinaucinihilipilification
GNAS complex locus
Honorificabilitudinitatibus
Longest word in English
Longest words
Parathyroid hormone
Pneumonoultramicroscopicsilicovolcanoconiosis
Supercalifragilisticexpialidocious
References
== External links == |
Scapular fracture | A scapular fracture is a fracture of the scapula, the shoulder blade. The scapula is sturdy and located in a protected place, so it rarely breaks. When it does, it is an indication that the individual was subjected to a considerable amount of force and that severe chest trauma may be present. High-speed vehicle accidents are the most common cause. This could be anywhere from a car accident, motorcycle crash, or high speed bicycle crash but falls and blows to the area can also be responsible for the injury. Signs and symptoms are similar to those of other fractures: they include pain, tenderness, and reduced motion of the affected area although symptoms can take a couple of days to appear. Imaging techniques such as X-ray are used to diagnose scapular fracture, but the injury may not be noticed in part because it is so frequently accompanied by other, severe injuries that demand attention. The injuries that usually accompany scapular fracture generally have the greatest impact on the patients outcome. However, the injury can also occur by itself; when it does, it does not present a significant threat to life. Treatment involves pain control and immobilizing the affected area, and, later, physical therapy.
Signs and symptoms
As with other types of fractures, scapular fracture may be associated with pain localized to the area of the fracture, tenderness, swelling, and crepitus (the crunching sound of bone ends grinding together). Since scapular fractures impair the motion of the shoulder, a person with a scapular fracture has a reduced ability to move the shoulder joint. Signs and symptoms may be masked by other injuries that accompany the scapular fracture.
Causes
Usually, it takes a large amount of energy to fracture the scapula; the force may be indirect but is more often direct. The scapula is fractured as the result of significant blunt trauma, as occurs in vehicle collisions. About three quarters of cases are caused by high-speed car and motorcycle collisions. Falls and blows to the shoulder area can also cause the injury. Crushing injuries (as may occur in railroad or forestry accidents) and sports injuries (as may occur in horseback riding, mountain biking, bmxing or skiing) can also fracture the scapula. Scapular fracture can result from electrical shocks and from seizures: muscles pulling in different directions contract powerfully at the same time. In cardiopulmonary resuscitation, the chest is compressed significantly; scapular fracture may occur as a complication of this technique.
Anatomy
The scapula has a body, neck, and spine; any of these may be fractured. The most commonly injured areas are the scapular body, spine, neck, and glenoid rim; the scapular body or neck is injured in about 80% of cases. Fractures that occur in the body may be vertical, horizontal, or comminuted (involving multiple fragments). Those that occur in the neck are usually parallel to the glenoid fossa. When they occur in the glenoid fossa, fractures are usually small chips out of the bone or extensions of fractures occurring in the scapular neck.The scapula is protected from the front by the ribcage and chest, and from the back it is protected by a thick layer of muscles. Also, the scapula is able to move, so traumatic forces exerted on it are dissipated, not absorbed by the bone. Thus a large amount of force is required to fracture it.
Diagnosis
Most fractures of the scapula can be seen on a chest X-ray; however, they may be missed during examination of the film. Serious associated injuries may distract from the scapular injury, and diagnosis is often delayed. Computed tomography may also be used. Scapular fractures can be detected in the standard chest and shoulder radiographs that are given to patients who have had significant physical trauma, but much of the scapula is hidden by the ribs on standard chest X-rays. Therefore, if scapular injury is suspected, more specific images of the scapular area can be taken.
Classification
Body fractures
Described based upon anatomic location
Neck fractures
Coracoid process fractures
Acromion fractures
Glenoid fossa fractures
Described by the Ideberg classification
Treatment
Treatment involves pain medication and immobilization at first; later, physical therapy is used. Ice over the affected area may increase comfort. Movement exercises are begun within at least a week of the injury; with these, fractures with little or no displacement heal without problems. Over 90% of scapular fractures are not significantly displaced; therefore, most of these fractures are best managed without surgery. Fractures of the scapular body with displacement may heal with malunion, but even this may not interfere with movement of the affected shoulder. However, displaced fractures in the scapular processes or in the glenoid do interfere with movement in the affected shoulder if they are not realigned properly. Therefore, while most scapular fractures are managed without surgery, surgical reduction is required for fractures in the neck or glenoid; otherwise motion of the shoulder may be impaired.
Epidemiology
Scapular fracture is present in about 1% of cases of blunt trauma and 3–5% of shoulder injuries. An estimated 0.4–1% of bone fractures are scapular fractures.The injury is associated with other injuries 80–90% of the time. Scapular fracture is associated with pulmonary contusion more than 50% of the time. Thus when the scapula is fractured, other injuries such as abdominal and chest trauma are automatically suspected. People with scapular fractures often also have injuries of the ribs, lung, and shoulder. Pneumothorax (an accumulation of air in the space outside the lung), clavicle fractures, and injuries to the blood vessels are among the most commonly associated injuries. The forces involved in scapular fracture can also cause tracheobronchial rupture, a tear in the airways. Fractures that occur in the scapular body are the type most likely to be accompanied by other injuries; other bony and soft tissue injuries accompany these fractures 80–95% of the time. Associated injuries can be serious and potentially deadly, and usually it is the associated injuries, rather than the scapular fracture, that have the greatest effect on the outcome. Scapular fractures can also occur by themselves; when they do, the death rate (mortality) is not significantly increased.The mean age of people affected is 35–45 years.
Notes
References
Wiedemann E, Euler E, Pfeifer K (2000). "Scapular fractures". In Wulker N, Mansat M, Fu FH (eds.). Shoulder Surgery: An Illustrated Textbook. Martin Dunitz. pp. 504–510. ISBN 1-85317-563-3.
External links
American Academy of Orthopaedic Surgeons (2007). Fracture of the shoulder blade (scapula). Retrieved on 2008-08-03. |
Acromicric dysplasia | Acromicric dysplasia is an extremely rare inherited disorder characterized by abnormally short hands and feet, growth retardation and delayed bone maturation leading to short stature. Most cases have occurred randomly for no apparent reason (sporadically). However, autosomal dominant inheritance has not been ruled out.
The disorder is different (but similar to) from other syndromic entities such as geleophysic dysplasia, Weill-Marchesani syndrome, and Myhre syndrome.
Genetics
This condition has been associated with mutations in the Fibrillin 1 (FBN1) gene.Mutations in this gene have also been associated with stiff skin syndrome, Marfan syndrome and its variant Marfanoid–progeroid–lipodystrophy syndrome, autosomal dominant Weill-Marchesani syndrome, isolated ectopia lentis, MASS phenotype, and Shprintzen-Goldberg syndrome.
References
External links
GeneReview/NIH/UW entry on Geleophysic Dysplasia |
Primary cutaneous histoplasmosis | Primary cutaneous histoplasmosis is a rare skin condition, reported on the penis, characterized by a chancre-type lesion with regional adenopathy.: 316
See also
Histoplasmosis
== References == |
Pelvic floor dysfunction | Pelvic floor dysfunction is a term used for a variety of disorders that occur when pelvic floor muscles and ligaments are impaired. The condition affects up to 50 percent of women who have given birth. Although this condition predominantly affects women, up to 16 percent of men are affected as well. Symptoms can include pelvic pain, pressure, pain during sex, urinary incontinence (UI), overactive bladder, bowel incontinence, incomplete emptying of feces, constipation, myofascial pelvic pain and pelvic organ prolapse. When pelvic organ prolapse occurs, there may be visible organ protrusion or a lump felt in the vagina or anus.Common treatments for pelvic floor dysfunction are surgery, medication, physical therapy and lifestyle modifications.
Epidemiology
Pelvic floor dysfunction is defined as a herniation of the pelvic organs through the pelvic organ walls and pelvic floor. The condition is widespread, affecting up to 50 percent of women at some point in their lifetime. About 11 percent of women will undergo surgery for urinary incontinence or pelvic organ prolapse by age 80. Women who experience pelvic floor dysfunction are more likely to report issues with arousal combined with dyspareunia. For women, there is a 20.5% risk for having a surgical intervention related to stress urinary incontinence. The literature suggests that white women are at increased risk for stress urinary incontinence.Though pelvic floor dysfunction is thought to more commonly affect women, 16% of men have been identified with pelvic floor dysfunction. Pelvic floor dysfunction and its multiple consequences, including urinary incontinence, is a concerning health issue becoming more evident as the population of advancing age individuals rises.
Causes
Mechanistically, the causes of pelvic floor dysfunction are two-fold: widening of the pelvic floor hiatus and descent of pelvic floor below the pubococcygeal line, with specific organ prolapse, graded relative to the hiatus. People with an inherited deficiency in their collagen type may be more likely to develop pelvic floor dysfunction. Additionally, people with congenitally weak connective tissue and fascia are at an increased risk for stress urinary incontinence and pelvic organ prolapse. Recent literature demonstrates that defects in endopelvic fascia and compromised levator ani muscle function have been categorized as important etiologic factors in the development of pelvic floor dysfunction. Some circumstances are clearly associated with collagen defects. These include vaginally delivering a child, being post-menopausal, and being of advanced age.Some lifestyle behaviors can lead to pelvic floor dysfunction. This includes avoiding urinating or bowel movements, obesity, use of muscle relaxants or narcotics, and use of antihistamines or anticholinergics. Using muscle relaxants or narcotics can lead to increased smooth and skeletal muscle relaxation, potentially related to urinary incontinence. Antihistamines and anticholinergics have additive effects that lead to urinary hesitancy and retention, ultimately leading to pelvic floor dysfunction. Urinary incontinence can also affect athletes, especially those in sports that require high impact such as jumping. Gymnasts, for example, report a high prevalence of urinary incontinence. Studies show that athletes in sports requiring high spinal stability may also have this condition, as the activation of abdominal wall muscles can cause urinary alterations during activities. In some cases, sexual abuse can also be associated with chronic pelvic pain and pelvic floor dysfunction.Pelvic floor dysfunction can result after pelvic radiation, as well as other treatments for gynecological cancers.
Diagnosis
Pelvic floor dysfunction can be assessed with a strong clinical history and physical exam, though imaging is often needed for diagnosis. As part of the clinical history, a healthcare provider may ask about obstetric history, including how many pregnancies and deliveries, what mode of delivery and if there were any complications during delivery. Providers will also ask about presence and severity of symptoms such as pelvic pain or pressure, problems with urination or defecation, painful sex, or sexual dysfunction. The physical exam may include both examination with a speculum to visualize the cervix and check for inflammation, as well as manual examination with the providers fingers to assess for pain and strength of pelvic floor muscle contraction.Imaging provides a more complete picture of the type and severity of pelvic floor dysfunction than history and physical exam alone. Historically, fluoroscopy with defecography and cystography were used. More recently, MRI has been used to complement and sometimes replace fluoroscopic assessment of the disorder. This technique is less invasive, and allows for less radiation exposure and increased patient comfort, though an enema is required the evening before the procedure. Both fluoroscopy and MRI assess the pelvic floor at rest and during maximum strain using coronal and sagittal views.When grading individual organ prolapse for severity, the rectum, bladder and uterus are individually assessed. Prolapse of the rectum is referred to as a rectocele, bladder prolapse through the anterior vaginal wall is called a cystocele, and prolapse of the small bowel is an enterocele. To assess the degree of dysfunction, three measurements are taken into account. First, an anatomic landmark known as the pubococcygeal line must be determined, which is a straight line connecting the inferior margin of the pubic symphysis at the midline with the junction of the first and second coccygeal elements on a sagittal image. After this, the location of the Puborectalis muscle sling is assessed, and a perpendicular line between the pubococcygeal line and muscle sling is drawn. This line provides a reference point for the measurement of pelvic floor descent. Descent greater than 2 cm below this line is considered mild and descent greater than 6 cm is considered severe. Lastly, a line from the pubic symphysis to the puborectalis muscle sling is drawn, which is a measurement of the pelvic floor hiatus. Measurements greater than 6 cm are considered mild, and greater than 10 cm severe. The degree of organ prolapse is assessed relative to the hiatus.
The grading for organ prolapse relative to the hiatus is more strict. Any descent below the hiatus is considered abnormal, and descent greater than 4 cm is considered severe.Ultrasound can also be used to diagnose pelvic floor dysfunction. Transabdominal, transvaginal, transperineal and endoanal ultrasound (EUS) are important tools for diagnosing pelvic floor dysfunction. For EUS, an ultrasound probe is inserted into the anal canal and can be used to visualize and assess the anatomy and function the pelvic floor. Ultrasound is easily accessible and noninvasive, however it may compress certain structures, does not produce high quality images and cannot be used to visualize the entire pelvic floor.
Treatment
There are several approaches to treatment of pelvic floor dysfunction, and often several approaches are used in combination.
Physical therapy
Pelvic floor muscle (PFM) training is vital for treating different types of pelvic floor dysfunction. Two common problems are uterine prolapse and urinary incontinence both of which stem from muscle weakness. Pelvic floor muscle therapy is the first-line of treatment for urinary incontinence and thus should be considered before more invasive procedures such as surgery. Being able to control the pelvic floor muscles is vital for a well functioning pelvic floor. Without the ability to control the pelvic floor muscles, pelvic floor training cannot be done successfully. Pelvic floor muscle therapy strengthens the muscles of the pelvic floor through repeated contractions of varying strength. Through vaginal palpation exams and the use of biofeedback, the tightening, lifting, and squeezing actions of these muscles can be determined. Biofeedback can be used to treat urinary incontinence as it records contractions of the pelvic floor muscles and can help patients become aware of the use of their muscles. PFM training can also increase female sexual satisfaction by improving sexual function and the ability to orgasm.In addition, abdominal muscle training has been shown to improve pelvic floor muscle function. By increasing abdominal muscle strength and control, a person may have an easier time activating the pelvic floor muscles in sync with the abdominal muscles. Many physiotherapists are specially trained to address the muscle weaknesses associated with pelvic floor dysfunction and can effectively treat pelvic floor dysfunction through strengthening exercises. Overall, physical therapy can significantly improve the quality of life of those with pelvic floor dysfunction by relieving symptoms.
Medication
Overactive bladder can be treated with medications, including those in the class of antimuscarinics and beta 3 agonists. Antimuscarinics are the most commonly used, however, beta 3 agonists can be used for those that are unable to take antimuscarinics due to side effects or other reasons.
Devices
A pessary is a plastic or silicone device that may be used for women with pelvic organ prolapse. This treatment is useful for individuals who do not want to have surgery or are unable to have surgery due risk of the procedure. Some pessaries have a knob that can also treat urinary incontinence. To be effective, pessaries must be fit by a medical provider and the largest device that fits comfortably should be used.
Lifestyle modifications
Treatment for pelvic floor dysfunction, especially the symptom of urinary incontinence, is essential, but so is prevention. Patients are usually encouraged to change their lifestyles; interventions such as reducing body weight, limiting the use of stimulants, quitting smoking, limiting strenuous efforts, preventing constipation and increasing physical activity can help prevent pelvic floor dysfunction. For those that already have diagnosed pelvic floor dysfunction, symptoms can be eased by physical activity, especially abdominal exercises and pelvic floor exercises (Kegels) that strengthen the pelvic floor. Symptoms of urinary incontinence can also be reduced by making dietary changes such as limiting intake of acidic and spicy foods, alcohol and caffeine.
Surgery
Surgery is performed when desired by the patient or when less invasive treatments, such as lifestyle modification and physical therapy, are not effective. There are various procedures used to address prolapse. Cystoceles are treated with a surgical procedure known as a Burch colposuspension, with the goal of suspending the prolapsed urethra so that the urethrovesical junction and proximal urethra are replaced in the pelvic cavity. Uterine prolapse is treated with hysterectomy and uterosacral suspension. With enteroceles, the prolapsed small bowel is elevated into the pelvis cavity and the rectovaginal fascia is reapproximated. Rectoceles, in which the anterior wall of the rectum protrudes into the posterior wall of the vagina, require posterior colporrhaphy, also known as repair of the vaginal wall. Though pelvic floor dysfunction is more common in women, there are also proven methods to assist men. In severe cases of pelvic floor dysfunction causing urinary incontinence, a radical prostatectomy followed by postoperative pelvic floor muscle therapy is an option.
== References == |
Myoclonic dystonia | Myoclonic dystonia or Myoclonus dystonia syndrome is a rare movement disorder that induces spontaneous muscle contraction causing abnormal posture. The prevalence of myoclonus dystonia has not been reported, however, this disorder falls under the umbrella of movement disorders which affect thousands worldwide. Myoclonus dystonia results from mutations in the SGCE gene coding for an integral membrane protein found in both neurons and muscle fibers. Those suffering from this disease exhibit symptoms of rapid, jerky movements of the upper limbs (myoclonus), as well as distortion of the bodys orientation due to simultaneous activation of agonist and antagonist muscles (dystonia).
Myoclonus dystonia is caused by loss-of-function-mutations in the epsilon sarcoglycan gene (SGCE). The disease is dominantly inherited, however SGCE is an imprinted gene, so only the paternal allele is expressed. Therefore, children suffering from this disease inherit the mutation from the father. If the mutated allele is inherited from the mother, the child is not likely to exhibit symptoms.
While no cure has been found for myoclonus dystonia, treatment options are available to those suffering from the disease. Ethanol often ameliorates the symptoms well, and so the syndrome is also called "Alcohol-responsive dystonia". Alcohol may be substituted by benzodiazepines, such as clonazepam, which work through the same mechanism. Deep brain stimulation (DBS) is another viable option that can alleviate symptoms without the unwanted side effects of medications, and has been successful in treating other movement disorders.
Signs and symptoms
Myoclonus dystonia is characterized by two primary features: myoclonus and dystonia. For the majority of individuals with myoclonus dystonia, the myoclonus component of the disorder is often the primary and most disabling feature in comparison to the dystonia component. The symptoms of myoclonus dystonia vary substantially in severity.
Myoclonus
Myoclonus is characterized by rapid contractions that affect the upper body including the neck, torso and arms, but may also affect the legs. These movements are stimulated by various factors including stress, noise, caffeine, and physical stimuli. Myoclonus can be characterized in multiple ways including neurological basis, muscular activity, and by stimuli. Myoclonus can be positive or negative; positive myoclonus results from brief spurts of muscle activity and negative myoclonus occurs when there is a lack of any muscular activity. Myoclonus is usually classified physiologically to optimize treatment. Myoclonus is a precursor effect to myoclonus dystonia and most commonly begins in childhood or adolescence.Myoclonus is classified as cortical, subcortical, peripheral or spinal. Cortical myoclonus is the most common of these four and affects the upper limbs and face. Myoclonus dystonia has been characterized under subcortical origin, specifically under nonsegmented myoclonus or brainstem myoclonus. Symptoms within this classification include the startle response and reticular reflex myoclonus. Sudden stimuli like noise or touch to areas around the head or chest cause the startle response which will go up the brain stem and down the spinal cord causing jerk-like movements. Hyperekplexia is a heightened brainstem response where an affected person will continue to elicit the same response to a repeated stimuli. In contrast, reticular reflex myoclonus occurs spontaneously to stimuli applied to distal limbs. Spinal myoclonus is caused by defects in spinal organization or connections, and peripheral myoclonus has symptoms of rhythmic jerks due to a neuron-the most common being the hemifacial spasm.
Dystonia
Dystonia is a response to simultaneous contraction of agonist and antagonist muscles seen as twisting and contorting that affect posture and stance. Other symptoms can include tremors and muscle spasms due to various interactions of muscle, contractions and movement. Dystonia can be either primary or secondary with the latter being more common. Primary dystonia or "pure" dystonia is only physiological in origin. Secondary dystonia has multiple origins that are physiological, pathological or neurological.
Myoclonus dystonia
Myoclonus dystonia includes the rapid contractions of myoclonus alongside the abnormal postures classified under dystonia, as well as neurological and psychiatric issues. This disease typically begins during childhood with symptoms of myoclonus and slight dystonia, most commonly cervical dystonia or writers cramp. Dystonia symptoms tend to not get exaggerated over the course of the disease and is rarely the only associated symptom, while the myoclonus symptoms can become more severe. Psychiatric issues are clinically diagnosed with the aforementioned symptoms and include depression, anxiety, personality disorders and addiction. Obsessive-compulsive disorder is associated with myoclonus dystonia as both have been found to have a commonality on chromosome 7 in various studies.Neurological symptoms are relatively common in those with myoclonus dystonia. Any neurological abnormalities will not normally be present in those affected at a young age. Neurological testing has been performed to determine the origins of these symptoms and multiple parts of the brain have been pinpointed including the brainstem, neocortex, pallidum, and thalamus. These cause various effects in those diagnosed with myoclonus dystonia including changes in posture and tremors, and very rarely dementia and ataxia.
Cause
The majority of myoclonus dystonia cases are the result of a mutation in the epsilon sarcoglycan gene (SGCE). This gene is found on chromosome 7, with its specific cytogenic location being 7q21.3. The 70,985 bp SGCE gene encodes the protein epsilon (ε)-sarcoglycan. The five proteins that make up the sarcoglycan family function as integral membrane proteins that anchor the cytoskeleton of cells to the extracellular matrix. Epsilon sarcoglycan is a membrane protein that can be found in the liver, lungs, kidney, and spleen, but is most prevalent in muscle and neuronal cells. Its prevalence in both muscle fibers and the synapses of neurons suggest why symptoms of both myoclonus and dystonia appear from the improperly functioning protein. Recessive mutations in the other sarcoglycans also result in muscular disorders, further supporting that mutations in the SGCE gene cause myoclonus dystonia.Epsilon sarcoglycan itself is part of the dystrophin-associated protein (DAP) complex that binds the sarcolemma of muscle cells to the extracellular connective tissue. The purpose is to reduce the mechanical force on the sarcolemma as a result of muscle contraction. In addition to myoclonus dystonia, problems associated with a dysfunctional DAP complex include Duchenne muscular dystrophy.Upwards of 65 mutations of the SGCE gene are thought to cause myoclonus dystonia. The majority of the mutations lead to a truncated protein product that results in the loss-of-function of the epsilon sarcoglycan protein. The dysfunctional protein is ultimately recycled by the cell by degradation mediated by the proteasome, resulting in significant shortages of the integral membrane protein in both neurons and muscle fibers.
The mutant allele is inherited in a dominant fashion—that is the mutation can be inherited if one parent has that allele. However, genomic imprinting occurs on the mothers allele, so only the fathers allele is expressed. Therefore, inheriting a mutated, paternal allele of the SGCE gene will result in the expression of the dysfunctional epsilon sarcoglycan protein. Offspring will not produce a mutant protein product in 95% of cases where the mother passes on a mutation in the SGCE gene.While SGCE gene mutations are the central cause of myoclonus dystonia, there have been separate cases where individuals and families present symptoms akin to myoclonus dystonia but lack the mutations at this locus. Base-pair deletions of the DYT1 gene, missense mutations in the DRD2 gene, maternal uniparental disomy, and chromosome 18 linkage have all been associated in rare cases myoclonus dystonia where the SGCE gene is unaffected.
Treatment
To date, there is no single, universal treatment that has been found to cure myoclonus dystonia. However, there are several treatment methods that have been found to be effective for helping to reduce the symptoms associated with the syndrome.
Medications
Many drugs used to treat myoclonus dystonia do not have a significant impact individually, but when combined, can work on different brain mechanisms to best alleviate symptoms. The method of treatment used depends on the severity of the symptoms presented in the individual, and whether the underlying cause of the syndrome is known.
Benzodiazepines
Benzodiazepines such as clonazepam improve tremors caused by the myoclonus aspect of this syndrome by binding allosterically to GABAA ionotropic receptors, causing an influx of chloride ions that produce an inhibitory effect that can calm myoclonic jerks.
Antiepileptics
Antiepileptics like valproate must act upon GABA receptors and manipulate ionic conductance to reduce tremors and spasms in myoclonus dystonia. GABA neurons that fire rapidly and affect the motor cortex are blocked by antiepileptics in addition to changes in sodium and calcium concentrations that can excite the neuron. Different antiepileptics vary in sufficiency to control ionic conductance and can also produce seizures or myoclonus symptoms in some patients. Another agent that has been used is zonisamide.
Anticholinergics
Anticholinergics like benzatropine alleviate dystonia symptoms by blocking the activity of acetylcholine. Acetylcholine is involved in the pathophysiology of dystonia within the basal ganglia, although its exact role has not been determined. Acetylcholine is involved with dopamine and glutamate pathways in the basal ganglia, in addition to presynaptic muscarinic receptors which are involved in motor control. Acetylcholine is usually overactive in dystonia patients and blocking of this neurotransmitter would reduce contortion of the upper body, but can produce side effects of drowsiness, confusion and memory issues in adults.
Botulinum toxin
Botulinum toxin injections also act upon acetylcholine to reduce dystonia symptoms. The neurotoxin is active in presynaptic terminals and blocks exocytosis of acetylcholine into the synaptic cleft which reduces muscle activity. Botulinum may also have a role in inhibiting glutamate and changing muscle movement. Studies have also shown possible axon transport of this neurotoxin as well as its function as a pain reliever without effect on overactive muscle movement in myoclonus dystonia patients.
Alcohol
Consumption of alcohol has also been found to be an effective agent for temporarily easing the severity of the tremors associated with myoclonus dystonia. Alcohol causes an increase in GABA transmission between interneurons and Purkinje cells. This then reduces the transmission of glutamate at granule cell-Purkinje cell synapses, which decreases muscle movements. This treatment only alleviates the strength of the tremors for a short duration and does not change how often tremors will occur. Doctors inform patients of risks associated with the use of alcohol for myoclonus dystonia due to the high susceptibility for excessive alcohol use and dependency. Alcohol use disorder itself causes tremors in the hands and degeneration of the Purkinje cells and other parts of the cerebral cortex, counteracting alcohols original corrective effects.
Deep brain stimulation
Deep brain stimulation (DBS) has been found to be an effective and safe treatment for myoclonus dystonia patients, whose severe and debilitating symptoms are resistant to drug treatments. Electrical stimulation within the brain is a common treatment for many movement disorders because of the ability to excite or inhibit neurons within the brain. Deep brain stimulation patients have electrodes inserted into the brain and then an electrical signal is sent from an external source to elicit a response. The frequency and intensity of this signal can be changed to monitor the effects on neuronal activity using voltage recordings or neuroimaging, like functional MRIs. By re-positioning the electrodes in different areas or changing the size or timing of the stimulus, varying effects can be seen on the patient depending on the origin of the disorder.In one study, five patients with genetically determined epsilon sarcoglycan protein deficiency underwent deep brain stimulation of the internal pallidum. Each patients movement and disability symptoms were assessed before and after treatment using the Burke-Fahn-Marsden Dystonia Rating Scale and the Unified Myoclonus Rating Scale. Upon completion of the surgery, both the myoclonus and dystonia symptoms of the disorder had decreased by 70%, with no report of unfavorable side effects. Therefore, deep brain stimulation has been shown to effectively improve both myoclonus and dystonia, unlike many drug treatments which may improve one or the other.Other studies examined the effects of DBS to both the ventrointermediate nucleus of the thalamus, Vim, and the globus pallidus interna, GPi. Following deep brain stimulation of GPi and Vim, the Unified Myoclonus Rating Scale disability score improved 61-66%. In addition, the Dystomia Rating Scale score improved by 45-48%. While there was no significant difference in improvement between GPi-Vim stimulation and GPi stimulation, GPi-Vim stimulation was significantly more effective than Vim deep brain stimulation alone. Overall, Deep brain stimulation shows promise as a viable treatment for myoclonus dystonia.Although myoclonus and dystonia are present in myoclonus dystonia patients, optimum treatment for myoclonus dystonia differs from the treatment for myoclonus or dystonia alone. Myoclonus improved significantly more than dystonia when Deep brain stimulation was applied. In addition, myoclonus improved regardless of whether Deep brain stimulation was applied to GPi or Vim. However, GPi stimulation was more effective at reducing the symptoms of dystonia than Vim stimulation.
References
== External links == |
Kasabach–Merritt syndrome | Kasabach–Merritt syndrome, also known as hemangioma with thrombocytopenia, is a rare disease, usually of infants, in which a vascular tumor leads to decreased platelet counts and sometimes other bleeding problems, which can be life-threatening. It is also known as hemangioma thrombocytopenia syndrome. It is named after Haig Haigouni Kasabach and Katharine Krom Merritt, the two pediatricians who first described the condition in 1940.
Signs and symptoms
Initially a vascular lesion is usually noted on the skin which can be firm and hard (indurated). Areas of tiny red dots (petechiae) can appear around the lesion or on other parts of the body. If the vascular lesion is internal, these petechiae and bruising can be seen on the skin. Bruising and spontaneous bleeding can also occur. The tumors are not hemangiomas. They usually present in young infants, less than three months of age, but have also been reported in the toddler age group. These tumors occur in the extremities, chest, neck, abdomen and pelvis. They infiltrate across tissue and can be aggravated by interventions, infection and trauma. When the tumors associated with KMP are internal such as in the chest or abdomen, they can cause significant illness and can be life-threatening due to bleeding. Internal lesions can take a longer time to diagnose.
Pathophysiology
Kasabach–Merritt syndrome is usually caused by a hemangioendothelioma or other vascular tumor, often present at birth. Although these tumors are relatively common, they only rarely cause Kasabach–Merritt syndrome.When these tumors are large or are growing rapidly, sometimes they can trap platelets, causing severe thrombocytopenia. The combination of vascular tumor and consumptive thrombocytopenia defines Kasabach–Merritt syndrome. Tumors can be found in the trunk, upper and lower extremities, retroperitoneum, and in the cervical and facial areas.This consumptive coagulopathy also uses up clotting factors, such as fibrinogen which may worsen bleeding. The coagulopathy can progress to disseminated intravascular coagulation and even death. Hemolytic anemia secondary to microangiopathic destruction (physical damage) of the RBCs can be expressed as mild, moderate, or severe.
Diagnosis
The diagnostic workup is directed by the presenting signs and symptoms, and can involve:
blood counts, clotting studies, and other laboratory testing
imaging tests (ultrasound, CT scan, MRI, sometimes angiography, and rarely nuclear medicine scans)
Biopsy of the tumor is contraindicated due to risk of bleeding.Patients uniformly show severe thrombocytopenia, low fibrinogen levels, high fibrin degradation products (due to fibrinolysis), and microangiopathic hemolysis.
Management
Management of Kasabach–Merritt syndrome, particularly in severe cases, can be complex and require the joint effort of multiple subspecialists. This is a rare disease with no consensus treatment guidelines or large randomized controlled trials to guide therapy.
Supportive care
Patient with Kasabach–Merritt syndrome can be extremely ill and may need intensive care. They are at risk of bleeding complications including intracranial hemorrhage. The thrombocytopenia and coagulopathy are managed with platelet transfusions and fresh frozen plasma, although caution is needed due to the risk of fluid overload and heart failure from multiple transfusions. The possibility of disseminated intravascular coagulation, a dangerous and difficult-to-manage condition, is concerning. Anticoagulant and antiplatelet medications can be used after careful assessment of the risks and benefits.
Definitive treatment
Generally, treatment of the underlying vascular tumor results in resolution of Kasabach–Merritt syndrome. If complete surgical resection is feasible, it provides a good opportunity for cure (although it can be dangerous to operate on a vascular tumor in a patient prone to bleeding, even with appropriate surgical subspecialists involved).If surgery is not possible, various other techniques can be used to control the tumor:
embolization (by interventional radiology) can limit the tumors blood supply
external compression bandages can have similar effects
certain medications, including:
corticosteroids
alpha-interferon
chemotherapy (e.g. vincristine)
radiation therapy has been used, often successfully, but now is avoided whenever possible due to the risk of long-term adverse effects (e.g. risk for future cancer).
Prognosis
Kasabach–Merritt syndrome has a mortality rate of about 30%. For patients that survive the acute disease, supportive care may be required through a gradual recovery.Furthermore, patients may need care from a dermatologist or plastic surgeon for residual cosmetic lesions or an otolaryngologist for head & neck/airway involvement. On long-term followup, most patients have skin discoloration and/or mild disfiguration from the dormant tumor.
See also
List of cutaneous conditions
References
== External links == |
Dysostosis | A dysostosis is a disorder of the development of bone, in particular affecting ossification. Examples include craniofacial dysostosis, Klippel–Feil syndrome, and Rubinstein–Taybi syndrome.
It is one of the two categories of constitutional disorders of bone (the other being osteochondrodysplasia). When the disorder involves the joint between two bones, the term synostosis is often used.
References
== External links == |
Complex post-traumatic stress disorder | Complex post-traumatic stress disorder (C-PTSD; also known as complex trauma disorder) is a psychological disorder that is theorized to develop in response to exposure to a series of traumatic events in a context in which the individual perceives little or no chance of escape, and particularly where the exposure is prolonged or repetitive. It is not yet recognized by the American Psychiatric Association or the DSM-5 as a valid disorder, although was added to the eleventh revision of the International Classification of Diseases (ICD-11). In addition to the symptoms of post-traumatic stress disorder (PTSD), an individual with C-PTSD experiences emotional dysregulation, negative self-beliefs and feelings of shame, guilt or failure regarding the trauma, and interpersonal difficulties. C-PTSD relates to the trauma model of mental disorders and is associated with chronic sexual, psychological, and physical abuse or neglect, or chronic intimate partner violence, bullying, victims of kidnapping and hostage situations, indentured servants, victims of slavery and human trafficking, sweatshop workers, prisoners of war, concentration camp survivors, and prisoners kept in solitary confinement for a long period of time, or defectors from authoritarian religions. Situations involving captivity/entrapment (a situation lacking a viable escape route for the victim or a perception of such) can lead to C-PTSD-like symptoms, which can include prolonged feelings of terror, worthlessness, helplessness, and deformation of ones identity and sense of self.C-PTSD has also been referred to as Enduring Personality Change after Catastrophic Event (EPCACE) and/or Disorders of Extreme Stress - not otherwise specified (DESNOS)Some researchers believe that C-PTSD is distinct from, but similar to, PTSD, somatization disorder, dissociative identity disorder, and borderline personality disorder. Its main distinctions are a distortion of the persons core identity and significant emotional dysregulation. It was first described in 1992 by American psychiatrist and scholar Judith Lewis Herman in her book Trauma & Recovery and an accompanying article.
The disorder is included in the World Health Organizations (WHO) eleventh revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-11). The C-PTSD criteria has not yet gone through the private approval board of the American Psychiatric Association (APA) for inclusion in the Diagnostic and Statistical Manual of Mental Disorders (DSM). Complex PTSD is also recognized by the United States Department of Veterans Affairs (VA), Healthdirect Australia (HDA), and the British National Health Service (NHS).
Symptoms
Children and adolescents
The diagnosis of PTSD was originally developed for adults who had suffered from a single-event trauma, such as rape, or a traumatic experience during a war. However, the situation for many children is quite different. Children can suffer chronic trauma such as maltreatment, family violence, dysfunction, or a disruption in attachment to their primary caregiver. In many cases, it is the childs caregiver who causes the trauma. The diagnosis of PTSD does not take into account how the developmental stages of children may affect their symptoms and how trauma can affect a childs development.The term developmental trauma disorder (DTD) has been proposed as the childhood equivalent of C-PTSD. This developmental form of trauma places children at risk for developing psychiatric and medical disorders. Bessel van der Kolk explains DTD as numerous encounters with interpersonal trauma such as physical assault, sexual assault, violence or death. It can also be brought on by subjective events such as abandonment, betrayal, defeat or shame.Repeated traumatization during childhood leads to symptoms that differ from those described for PTSD. Cook and others describe symptoms and behavioral characteristics in seven domains:
Attachment – "problems with relationship boundaries, lack of trust, social isolation, difficulty perceiving and responding to others emotional states"
Biology – "sensory-motor developmental dysfunction, sensory-integration difficulties, somatization, and increased medical problems"
Affect or emotional regulation – "poor affect regulation, difficulty identifying and expressing emotions and internal states, and difficulties communicating needs, wants, and wishes"
Dissociation – "amnesia, depersonalization, discrete states of consciousness with discrete memories, affect, and functioning, and impaired memory for state-based events"
Behavioral control – "problems with impulse control, aggression, pathological self-soothing, and sleep problems"
Cognition – "difficulty regulating attention; problems with a variety of executive functions such as planning, judgement, initiation, use of materials, and self-monitoring; difficulty processing new information; difficulty focusing and completing tasks; poor object constancy; problems with cause-effect thinking; and language developmental problems such as a gap between receptive and expressive communication abilities."
Self-concept – "fragmented and disconnected autobiographical narrative, disturbed body image, low self-esteem, excessive shame, and negative internal working models of self".
Adults
Adults with C-PTSD have sometimes experienced prolonged interpersonal traumatization beginning in childhood, rather than, or as well as, in adulthood. These early injuries interrupt the development of a robust sense of self and of others. Because physical and emotional pain or neglect was often inflicted by attachment figures such as caregivers or older siblings, these individuals may develop a sense that they are fundamentally flawed and that others cannot be relied upon. This can become a pervasive way of relating to others in adult life, described as insecure attachment. This symptom is neither included in the diagnosis of dissociative disorder nor in that of PTSD in the current DSM-5 (2013). Individuals with Complex PTSD also demonstrate lasting personality disturbances with a significant risk of revictimization.Six clusters of symptoms have been suggested for diagnosis of C-PTSD:
Alterations in regulation of affect and impulses
Alterations in attention or consciousness
Alterations in self-perception
Alterations in relations with others
Somatization
Alterations in systems of meaningExperiences in these areas may include:: 199–122
Changes in emotional regulation, including experiences such as persistent dysphoria, chronic suicidal preoccupation, self-injury, explosive or extremely inhibited anger (may alternate), and compulsive or extremely inhibited sexuality (may alternate).
Variations in consciousness, such as amnesia or improved recall for traumatic events, episodes of dissociation, depersonalization/derealization, and reliving experiences (either in the form of intrusive PTSD symptoms or in ruminative preoccupation).
Changes in self-perception, such as a sense of helplessness or paralysis of initiative, shame, guilt and self-blame, a sense of defilement or stigma, and a sense of being completely different from other human beings (may include a sense of specialness, utter aloneness, a belief that no other person can understand, or a feeling of nonhuman identity).
Varied changes in perception of the perpetrators, such as a preoccupation with the relationship with a perpetrator (including a preoccupation with revenge), an unrealistic attribution of total power to a perpetrator (though the individuals assessment may be more realistic than the clinicians), idealization or paradoxical gratitude, a sense of a special or supernatural relationship with a perpetrator, and acceptance of a perpetrators belief system or rationalizations.
Alterations in relations with others, such as isolation and withdrawal, disruption in intimate relationships, a repeated search for a rescuer (may alternate with isolation and withdrawal), persistent distrust, and repeated failures of self-protection.
Changes in systems of meaning, such as a loss of sustaining faith and a sense of hopelessness and despair.
Diagnostics
C-PTSD was considered for inclusion in the DSM-IV but was not included when the DSM-IV was published in 1994. It was also not included in the DSM-5, though post-traumatic stress disorder continues to be listed as a disorder.
Differential diagnosis
Post-traumatic stress disorder
Post-traumatic stress disorder (PTSD) was included in the DSM-III (1980), mainly due to the relatively large numbers of American combat veterans of the Vietnam War who were seeking treatment for the lingering effects of combat stress. In the 1980s, various researchers and clinicians suggested that PTSD might also accurately describe the sequelae of such traumas as child sexual abuse and domestic abuse. However, it was soon suggested that PTSD failed to account for the cluster of symptoms that were often observed in cases of prolonged abuse, particularly that which was perpetrated against children by caregivers during multiple childhood and adolescent developmental stages. Such patients were often extremely difficult to treat with established methods.PTSD descriptions fail to capture some of the core characteristics of C-PTSD. These elements include captivity, psychological fragmentation, the loss of a sense of safety, trust, and self-worth, as well as the tendency to be revictimized. Most importantly, there is a loss of a coherent sense of self: this loss, and the ensuing symptom profile, most pointedly differentiates C-PTSD from PTSD.: 199–122 C-PTSD is also characterized by attachment disorder, particularly the pervasive insecure, or disorganized-type attachment. DSM-IV (1994) dissociative disorders and PTSD do not include insecure attachment in their criteria. As a consequence of this aspect of C-PTSD, when some adults with C-PTSD become parents and confront their own childrens attachment needs, they may have particular difficulty in responding sensitively especially to their infants and young childrens routine distress – such as during routine separations, despite these parents best intentions and efforts. Although the great majority of survivors do not abuse others, this difficulty in parenting may have adverse repercussions for their childrens social and emotional development if parents with this condition and their children do not receive appropriate treatment.Thus, a differentiation between the diagnostic category of C-PTSD and that of PTSD has been suggested. C-PTSD better describes the pervasive negative impact of chronic repetitive trauma than does PTSD alone. PTSD can exist alongside C-PTSD; however a sole diagnosis of PTSD often does not sufficiently encapsulate the breadth of symptoms experienced by those who have experienced prolonged traumatic experience, and therefore C-PTSD extends beyond the PTSD parameters.C-PTSD also differs from continuous traumatic stress disorder (CTSD), which was introduced into the trauma literature by Gill Straker (1987). It was originally used by South African clinicians to describe the effects of exposure to frequent, high levels of violence usually associated with civil conflict and political repression. The term is also applicable to the effects of exposure to contexts in which gang violence and crime are endemic as well as to the effects of ongoing exposure to life threats in high-risk occupations such as police, fire and emergency services.
Traumatic grief
Traumatic grief or complicated mourning are conditions where both trauma and grief coincide. There are conceptual links between trauma and bereavement since loss of a loved one is inherently traumatic. If a traumatic event was life-threatening, but did not result in a death, then it is more likely that the survivor will experience post-traumatic stress symptoms. If a person dies, and the survivor was close to the person who died, then it is more likely that symptoms of grief will also develop. When the death is of a loved one, and was sudden or violent, then both symptoms often coincide. This is likely in children exposed to community violence.For C-PTSD to manifest traumatic grief, the violence would occur under conditions of captivity, loss of control and disempowerment, coinciding with the death of a friend or loved one in life-threatening circumstances. This again is most likely for children and stepchildren who experience prolonged domestic or chronic community violence that ultimately results in the death of friends and loved ones. The phenomenon of the increased risk of violence and death of stepchildren is referred to as the Cinderella effect.
Borderline personality disorder
C-PTSD may share some symptoms with both PTSD and borderline personality disorder (BPD). However, there is enough evidence to also differentiate C-PTSD from borderline personality disorder.
It may help to understand the intersection of attachment theory with C-PTSD and BPD if one reads the following opinion of Bessel A. van der Kolk together with an understanding drawn from a description of BPD:
Uncontrollable disruptions or distortions of attachment bonds precede the development of post-traumatic stress syndromes. People seek increased attachment in the face of danger. Adults, as well as children, may develop strong emotional ties with people who intermittently harass, beat, and, threaten them. The persistence of these attachment bonds leads to confusion of pain and love. Trauma can be repeated on behavioural, emotional, physiologic, and neuroendocrinologic levels. Repetition on these different levels causes a large variety of individual and social suffering.
However, C-PTSD and BPD have been found by some researchers to be distinctive disorders with different features. Those with C-PTSD do not fear abandonment or have unstable patterns of relations; rather, they withdraw. There are distinct and notably large differences between BPD and C-PTSD and while there are some similarities – predominantly in terms of issues with attachment (though this plays out in different ways) and trouble regulating strong emotional affects – the disorders are different in nature.
While the individuals in the BPD reported many of the symptoms of PTSD and CPTSD, the BPD class was clearly distinct in its endorsement of symptoms unique to BPD. The RR ratios presented in Table 5 revealed that the following symptoms were highly indicative of placement in the BPD rather than the CPTSD class: (1) frantic efforts to avoid real or imagined abandonment, (2) unstable and intense interpersonal relationships characterized by alternating between extremes of idealization and devaluation, (3) markedly and persistently unstable self-image or sense of self, and (4) impulsiveness. Given the gravity of suicidal and self-injurious behaviors, it is important to note that there were also marked differences in the presence of suicidal and self-injurious behaviors with approximately 50% of individuals in the BPD class reporting this symptom but much fewer and an equivalent number doing so in the CPTSD and PTSD classes (14.3 and 16.7%, respectively). The only BPD symptom that individuals in the BPD class did not differ from the CPTSD class was chronic feelings of emptiness, suggesting that in this sample, this symptom is not specific to either BPD or CPTSD and does not discriminate between them.
Overall, the findings indicate that there are several ways in which complex PTSD and BPD differ, consistent with the proposed diagnostic formulation of CPTSD. BPD is characterized by fears of abandonment, unstable sense of self, unstable relationships with others, and impulsive and self-harming behaviors. In contrast, in CPTSD as in PTSD, there was little endorsement of items related to instability in self-representation or relationships. Self-concept is likely to be consistently negative and relational difficulties concern mostly avoidance of relationships and sense of alienation.
In addition, 25% of those diagnosed with BPD have no known history of childhood neglect or abuse and individuals are six times as likely to develop BPD if they have a relative who was so diagnosed compared to those who do not. One conclusion is that there is a genetic predisposition to BPD unrelated to trauma. Researchers conducting a longitudinal investigation of identical twins found that "genetic factors play a major role in individual differences of borderline personality disorder features in Western society." A 2014 study published in European Journal of Psychotraumatology was able to compare and contrast C-PTSD, PTSD, Borderline Personality Disorder and found that it could distinguish between individual cases of each and when it was co-morbid, arguing for a case of separate diagnoses for each. BPD may be confused with C-PTSD by some without proper knowledge of the two conditions because those with BPD also tend to have PTSD or to have some history of trauma.
In Trauma and Recovery, Herman expresses the additional concern that patients with C-PTSD frequently risk being misunderstood as inherently dependent, masochistic, or self-defeating, comparing this attitude to the historical misdiagnosis of female hysteria. However, those who develop C-PTSD do so as a result of the intensity of the traumatic bond – in which someone becomes tightly biolo-chemically bound to someone who abuses them and the responses they learned to survive, navigate and deal with the abuse they suffered then become automatic responses, imbedded in their personality over the years of trauma – a normal reaction to an abnormal situation.
Treatment
While standard evidence-based treatments may be effective for treating post traumatic stress disorder, treating complex PTSD often involves addressing interpersonal relational difficulties and a different set of symptoms which make it more challenging to treat. According to the United States Department of Veteran Affairs:
The current PTSD diagnosis often does not fully capture the severe psychological harm that occurs with prolonged, repeated trauma. People who experience chronic trauma often report additional symptoms alongside formal PTSD symptoms, such as changes in their self-concept and the way they adapt to stressful events.
The utility of PTSD-derived psychotherapies for assisting children with C-PTSD is uncertain. This area of diagnosis and treatment calls for caution in use of the category C-PTSD. Dr. Julian Ford and Dr. Bessel van der Kolk have suggested that C-PTSD may not be as useful a category for diagnosis and treatment of children as a proposed category of developmental trauma disorder (DTD).: 60 According to Courtois & Ford, for DTD to be diagnosed it requires a
history of exposure to early life developmentally adverse interpersonal trauma such as sexual abuse, physical abuse, violence, traumatic losses or other significant disruption or betrayal of the childs relationships with primary caregivers, which has been postulated as an etiological basis for complex traumatic stress disorders. Diagnosis, treatment planning and outcome are always relational.
Since C-PTSD or DTD in children is often caused by chronic maltreatment, neglect or abuse in a care-giving relationship the first element of the biopsychosocial system to address is that relationship. This invariably involves some sort of child protection agency. This both widens the range of support that can be given to the child but also the complexity of the situation, since the agencys statutory legal obligations may then need to be enforced.
A number of practical, therapeutic and ethical principles for assessment and intervention have been developed and explored in the field:: 67
Identifying and addressing threats to the childs or familys safety and stability are the first priority.
A relational bridge must be developed to engage, retain and maximize the benefit for the child and caregiver.
Diagnosis, treatment planning and outcome monitoring are always relational (and) strengths based.
All phases of treatment should aim to enhance self-regulation competencies.
Determining with whom, when and how to address traumatic memories.
Preventing and managing relational discontinuities and psychosocial crises.
Adults
Trauma recovery model
Judith Lewis Herman, in her book, Trauma and Recovery, proposed a complex trauma recovery model that occurs in three stages:
Establishing safety
Remembrance and mourning for what was lost
Reconnecting with community and more broadly, societyHerman believes recovery can only occur within a healing relationship and only if the survivor is empowered by that relationship. This healing relationship need not be romantic or sexual in the colloquial sense of "relationship", however, and can also include relationships with friends, co-workers, ones relatives or children, and the therapeutic relationship.Complex trauma means complex reactions and this leads to complex treatments. Hence, treatment for C-PTSD requires a multi-modal approach.It has been suggested that treatment for complex PTSD should differ from treatment for PTSD by focusing on problems that cause more functional impairment than the PTSD symptoms. These problems include emotional dysregulation, dissociation, and interpersonal problems. Six suggested core components of complex trauma treatment include:
Safety
Self-regulation
Self-reflective information processing
Traumatic experiences integration
Relational engagement
Positive affect enhancementThe above components can be conceptualized as a model with three phases. Every case will not be the same, but one can expect the first phase to consist of teaching adequate coping strategies and addressing safety concerns. The next phase would focus on decreasing avoidance of traumatic stimuli and applying coping skills learned in phase one. The care provider may also begin challenging assumptions about the trauma and introducing alternative narratives about the trauma. The final phase would consist of solidifying what has previously been learned and transferring these strategies to future stressful events.
Neuroscientific and trauma informed interventions
In practice, the forms of treatment and intervention varies from individual to individual since there is a wide spectrum of childhood experiences of developmental trauma and symptomatology and not all survivors respond positively, uniformly, to the same treatment. Therefore, treatment is generally tailored to the individual. Recent neuroscientific research has shed some light on the impact that severe childhood abuse and neglect (trauma) has on a childs developing brain, specifically as it relates to the development in brain structures, function and connectivity among children from infancy to adulthood. This understanding of the neurophysiological underpinning of complex trauma phenomena is what currently is referred to in the field of traumatology as trauma informed which has become the rationale which has influenced the development of new treatments specifically targeting those with childhood developmental trauma.
Dr. Martin Teicher, a Harvard psychiatrist and researcher, has suggested that the development of specific complex trauma related symptomatology (and in fact the development of many adult onset psychopathologies) may be connected to gender differences and at what stage of childhood development trauma, abuse or neglect occurred. For example, it is well established that the development of dissociative identity disorder among women is often associated with early childhood sexual abuse.
Use of evidence-based treatment and its limitations
One of the current challenges faced by many survivors of complex trauma (or developmental trauma disorder) is support for treatment since many of the current therapies are relatively expensive and not all forms of therapy or intervention are reimbursed by insurance companies who use evidence-based practice as a criteria for reimbursement. Cognitive behavioral therapy, prolonged exposure therapy and dialectical behavioral therapy are well established forms of evidence-based intervention. These treatments are approved and endorsed by the American Psychiatric Association, the American Psychological Association and the Veterans Administration.
While standard evidence-based treatments may be effective for treating standard post-traumatic stress disorder, treating complex PTSD often involves addressing interpersonal relational difficulties and a different set of symptoms which make it more challenging to treat. The United States Department of Veterans Affairs acknowledges,
the current PTSD diagnosis often does not fully capture the severe psychological harm that occurs with prolonged, repeated trauma. People who experience chronic trauma often report additional symptoms alongside formal PTSD symptoms, such as changes in their self-concept and the way they adapt to stressful events.
For example, "Limited evidence suggests that predominantly [Cognitive behavioral therapy] CBT [evidence-based] treatments are effective, but do not suffice to achieve satisfactory end states, especially in Complex PTSD populations."
Treatment challenges
It is widely acknowledged by those who work in the trauma field that there is no one single, standard, one size fits all treatment for complex PTSD. There is also no clear consensus regarding the best treatment among the greater mental health professional community which included clinical psychologists, social workers, licensed therapists MFTs) and psychiatrists. Although most trauma neuroscientifically informed practitioners understand the importance of utilizing a combination of both top down and bottom up interventions as well as including somatic interventions (sensorimotor psychotherapy or somatic experiencing or yoga) for the purposes of processing and integrating trauma memories.
Survivors with complex trauma often struggle to find a mental health professional who is properly trained in trauma informed practices. They can also be challenging to receive adequate treatment and services to treat a mental health condition which is not universally recognized or well understood by general practitioners.
Allistair and Hull echo the sentiment of many other trauma neuroscience researchers (including Bessel van der Kolk and Bruce D. Perry) who argue:
Complex presentations are often excluded from studies because they do not fit neatly into the simple nosological categorisations required for research power. This means that the most severe disorders are not studied adequately and patients most affected by early trauma are often not recognised by services. Both historically and currently, at the individual as well as the societal level, "dissociation from the acknowledgement of the severe impact of childhood abuse on the developing brain leads to inadequate provision of services. Assimilation into treatment models of the emerging affective neuroscience of adverse experience could help to redress the balance by shifting the focus from top-down regulation to bottom-up, body-based processing."
Complex post trauma stress disorder is a long term mental health condition which is often difficult and relatively expensive to treat and often requires several years of psychotherapy, modes of intervention and treatment by highly skilled, mental health professionals who specialize in trauma informed modalities designed to process and integrate childhood trauma memories for the purposes of mitigating symptoms and improving the survivors quality of life. Delaying therapy for people with complex PTSD, whether intentionally or not, can exacerbate the condition.
Recommended treatment modalities and interventions
There is no one treatment which has been designed specifically for use with the adult complex PTSD population (with the exception of component based psychotherapy ) there are many therapeutic interventions used by mental health professionals to treat PTSD. As of February 2017, the American Psychological Association PTSD Guideline Development Panel (GDP) strongly recommends the following for the treatment of PTSD:
Cognitive behavioral therapy (CBT) and trauma focused CBT
Cognitive processing therapy (CPT)
Cognitive therapy (CT)
Prolonged exposure therapy (PE)The American Psychological Association also conditionally recommends
Brief eclectic psychotherapy (BEP)
Eye movement desensitization and reprocessing (EMDR)
Narrative exposure therapy (NET)While these treatments have been recommended, there is still on-going debate regarding the best and most efficacious treatment for complex PTSD. Many commonly used treatments are considered complementary or alternative since there still is a lack of research to classify these approaches as evidenced based. Some of these additional interventions and modalities include:
biofeedback
dyadic resourcing (used with EMDR)
emotionally focused therapy
emotional freedom technique (EFT) or tapping
equine-assisted therapy
expressive arts therapy
internal family systems therapy
dialectical behavior therapy (DBT)
family systems therapy
group therapy
neurofeedback
psychodynamic therapy
sensorimotor psychotherapy
somatic experiencing
yoga, specifically trauma-sensitive yoga
Arguments against diagnosis
Though acceptance of the idea of complex PTSD has increased with mental health professionals, the fundamental research required for the proper validation of a new disorder is insufficient as of 2013. The disorder was proposed under the name DES-NOS (Disorder of Extreme Stress Not Otherwise Specified) for inclusion in the DSM-IV but was rejected by members of the Diagnostic and Statistical Manual of Mental Disorders (DSM) committee of the American Psychiatric Association for lack of sufficient diagnostic validity research. Chief among the stated limitations was a study which showed that 95% of individuals who could be diagnosed with the proposed DES-NOS were also diagnosable with PTSD, raising questions about the added usefulness of an additional disorder.Following the failure of DES-NOS to gain formal recognition in the DSM-IV, the concept was re-packaged for children and adolescents and given a new name, developmental trauma disorder. Supporters of DTD appealed to the developers of the DSM-5 to recognize DTD as a new disorder. Just as the developers of DSM-IV refused to included DES-NOS, the developers of DSM-5 refused to include DTD due to a perceived lack of sufficient research.
One of the main justifications offered for this proposed disorder has been that the current system of diagnosing PTSD plus comorbid disorders does not capture the wide array of symptoms in one diagnosis. Because individuals who suffered repeated and prolonged traumas often show PTSD plus other concurrent psychiatric disorders, some researchers have argued that a single broad disorder such as C-PTSD provides a better and more parsimonious diagnosis than the current system of PTSD plus concurrent disorders. Conversely, an article published in BioMed Central has posited there is no evidence that being labeled with a single disorder leads to better treatment than being labeled with PTSD plus concurrent disorders.Complex PTSD embraces a wider range of symptoms relative to PTSD, specifically emphasizing problems of emotional regulation, negative self-concept, and interpersonal problems. Diagnosing complex PTSD can imply that this wider range of symptoms is caused by traumatic experiences, rather than acknowledging any pre-existing experiences of trauma which could lead to a higher risk of experiencing future traumas. It also asserts that this wider range of symptoms and higher risk of traumatization are related by hidden confounder variables and there is no causal relationship between symptoms and trauma experiences.
In the diagnosis of PTSD, the definition of the stressor event is narrowly limited to life-threatening events, with the implication that these are typically sudden and unexpected events. Complex PTSD vastly widened the definition of potential stressor events by calling them adverse events, and deliberating dropping reference to life-threatening, so that experiences can be included such as neglect, emotional abuse, or living in a war zone without having specifically experienced life-threatening events. By broadening the stressor criterion, an article published by the Child and Youth Care Forum claims this has led to confusing differences between competing definitions of complex PTSD, undercutting the clear operationalization of symptoms seen as one of the successes of the DSM.There are |
Complex post-traumatic stress disorder | no known case reports with prospective repeated assessments to clearly demonstrate that the alleged symptoms followed the adverse events. Instead, supporters of complex PTSD have pushed for recognition of a disorder before conducting any of the prospective repeated assessments that are needed.
See also
References
Further reading
External links
Post-traumatic stress at Curlie
APA practice parameters for assessment and treatment for PTSD (Updated 2017) |
Copper toxicity | Copper toxicity (or Copperiedus) is a type of metal poisoning caused by an excess of copper in the body. Copperiedus could occur from consuming excess copper salts, but most commonly it is the result of the genetic condition Wilsons disease and Menkes disease, which are associated with mismanaged transport and storage of copper ions. Copper is essential to human health as it is a component of many proteins.
Chronic toxicity by copper is "rare". The suggested safe level of copper in drinking water for humans varies depending on the source, but tends to be pegged at 1.3 mg/L. So rare is the toxicity of copper that copper(II) sulfate is a routine reagent in undergraduate chemistry laboratories.
Signs and symptoms
Acute symptoms of copper poisoning by ingestion include vomiting, hematemesis (vomiting of blood), hypotension (low blood pressure), melena (black "tarry" feces), coma, jaundice (yellowish pigmentation of the skin), and gastrointestinal distress. Individuals with glucose-6-phosphate dehydrogenase deficiency may be at increased risk of hematologic effects of copper. Hemolytic anemia resulting from the treatment of burns with copper compounds is infrequent.Chronic (long-term) copper exposure can damage the liver and kidneys. Mammals have efficient mechanisms to regulate copper stores such that they are generally protected from excess dietary copper levels.Those same protection mechanisms can cause milder symptoms, which are often misdiagnosed as psychiatric disorders. There is a lot of research on the function of the Cu/Zn ratio in neurological, endocrinological, and psychological conditions. Many of the substances that protect us from excess copper perform important functions in our neurological and endocrine systems, leading to diagnostic difficulties. When they are used to bind copper in the plasma, to prevent it from being absorbed in the tissues, their own function may go unfulfilled. Such symptoms often include mood swings, irritability, depression, fatigue, excitation, difficulty focusing, and feeling out of control. To further complicate diagnosis, some symptoms of excess copper are similar to those of a copper deficit.
The U.S. Environmental Protection Agencys Maximum Contaminant Level (MCL) in drinking water is 1.3 milligrams per liter. The MCL for copper is based on the expectation that a lifetime of consuming copper in water at this level is without adverse effect (gastrointestinal). The US EPA lists copper as a micronutrient and a toxin. Toxicity in mammals includes a wide range of animals and effects such as liver cirrhosis, necrosis in kidneys and the brain, gastrointestinal distress, lesions, low blood pressure, and fetal mortality. The Occupational Safety and Health Administration (OSHA) has set a limit of 0.1 mg/m3 for copper fumes (vapor generated from heating copper) and 1 mg/m3 for copper dusts (fine metallic copper particles) and mists (aerosol of soluble copper) in workroom air during an eight-hour work shift, 40-hour work week. Toxicity to other species of plants and animals is noted to varying levels.
EPA cancer data
The EPA lists no evidence for human cancer incidence connected with copper, and lists animal evidence linking copper to cancer as "inadequate". Two studies in mice have shown no increased incidence of cancer. One of these used regular injections of copper compounds, including cupric oxide. One study of two strains of mice fed copper compounds found a varying increased incidence of reticulum cell sarcoma in males of one strain, but not the other (there was a slightly increased incidence in females of both strains). These results have not been repeated.
Pathophysiology
Indian childhood cirrhosis
One manifestation of copper toxicity, cirrhosis of the liver in children (Indian childhood cirrhosis), has been linked to boiling milk in copper cookware. The Merck Manual states that recent studies suggest that a genetic defect is associated with this particular cirrhosis.
Wilson disease
An inherited condition called Wilsons disease causes the body to retain copper, since it is not excreted by the liver into the bile. This disease, if untreated, can lead to brain and liver damage, and bis-choline tetrathiomolybdate is under investigation as a therapy against Wilsons disease.
Menkes disease
An X-linked recessive trait that is inherited named Menkes disease causes disruption of connective tissue due to mutations in genes. If severely affected the approximate span of life is three years. One treatment used to correct the mutation is copper-histidine treatment.
Alzheimers disease
Elevated free copper levels exist in Alzheimers disease, which has been hypothesized to be linked to inorganic copper consumption. Copper and zinc are known to bind to amyloid beta proteins in Alzheimers disease. This bound form is thought to mediate the production of reactive oxygen species in the brain.
Diagnosis
ICD-9-CM
ICD-9-CM code 985.8 Toxic effect of other specified metals includes acute & chronic copper poisoning (or other toxic effect) whether intentional, accidental, industrial etc.
In addition, it includes poisoning and toxic effects of other metals including tin, selenium, nickel, iron, heavy metals, thallium, silver, lithium, cobalt, aluminum and bismuth. Some poisonings, e.g. zinc phosphide, would/could also be included as well as under 989.4 Poisoning due to other pesticides, etc.
Excluded are toxic effects of mercury, arsenic, manganese, beryllium, antimony, cadmium, and chromium.
ICD-10-CM
SNOMED
Treatment
In cases of suspected copper poisoning, penicillamine is the drug of choice, and dimercaprol, a heavy metal chelating agent, is often administered. Vinegar is not recommended to be given, as it assists in solubilizing insoluble copper salts. The inflammatory symptoms are to be treated on general principles, as are the nervous ones. Treatment can also look like ozone oxidation for environmental toxicity problems, as well as removing sediment in water areas because sediment can be a home for toxicants to reside. There is some evidence that alpha-lipoic acid (ALA) may work as a milder chelator of tissue-bound copper. Alpha lipoic acid is also being researched for chelating other heavy metals, such as mercury.
Aquatic life
Too much copper in water may damage marine and freshwater organisms such as fish and molluscs. Fish species vary in their sensitivity to copper, with the LD50 for 96-h exposure to copper sulphate reported to be in the order of 58 mg per litre for Tilapia (Oreochromis niloticus) and 70 mg per litre for catfish (Clarias gariepinus) The chronic effect of sublethal concentrations of copper on fish and other creatures is damage to gills, liver, kidneys and the nervous system. It also interferes with the sense of smell in fish, thus preventing them from choosing good mates or finding their way to mating areas.Copper-based paint is a common marine antifouling agent. In the United States, copper-based paint replaced tributyltin, which was banned due to its toxicity, as a way for boats to control organic growth on their hulls. In 2011, Washington state became the first U.S. state to ban the use of copper-based paint for boating, although it only applied to recreational boats. California has also pursued initiatives to reduce the effect of copper leaching, with the U.S. EPA pursuing research.Copper is an essential elemental for metabolic processes in marine algae. It is required for electron transport in photosynthesis and by various enzyme systems. Too much copper can also affect phytoplankton or marine algae in both marine and freshwater ecosystems. It has been show to inhibit photosynthesis, disrupt electron transport in photosystem 2, reduce pigment concentrations, restrict growth, reduce reproduction, etc. The toxicity of copper is widely recognized and is used to help prevent algal blooms. The effect of copper is solely dependent on the free copper the water is receiving. Its determined by the relative solubility and the concentration of the copper binding ligands.
Studies have shown that copper concentrations are toxic when marine phytoplankton are confined to areas that are heavily impacted by anthropogenic emissions. Some of the studies have used a marine amphipod to show how Copper affects it. This particular study said that the juveniles were 4.5 more times sensitive to the toxins than the adults. Another study used 7 different algal species. They found that one species was more sensitive than the others, which was Synechococcus, and that another species was more sensitive in seawater, which wasThalassiosira weissflogii.One study used cyanobacteria, diatoms, coccolithophores, and dinoflagellates. This study showed that cyanobacteria was the most sensitive, diatoms were the least sensitive, and the coccolithophores and dinoflagellates were intermediate. They used copper ion in a buffer system and controlled it at different levels. They found that cyanobacteria reproduction rates were reduced while other algae had maximum reproduction rates. They found that Copper may influence seasonal successions of species.
Bacteria
Copper and copper alloys such as brass have been found to be toxic to bacteria via the oligodynamic effect. The exact mechanism of action is unknown, but common to other heavy metals. Viruses are less susceptible to this effect than bacteria. Associated applications include the use of brass doorknobs in hospitals, which have been found to self-disinfect after eight hours, and mineral sanitizers, in which copper can act as an algicide. Overuse of copper sulfate as an algicide has been speculated to have caused a copper poisoning epidemic on Great Palm Island in 1979.
== References == |
Seabathers eruption | Seabathers eruption is an itching dermatitis caused by a hypersensitivity reaction to the immature nematocysts of larval-stage thimble jellyfish (Linuche unguiculata), sea anemones (Edwardsiella lineata) and other larval cnidarians. The cause is sometimes attributed to "sea lice" or "sea ants", but sea lice (Caligidae) are crustacean parasites of fish only.It should not be confused with swimmers itch.
Symptoms and signs
Symptoms generally arise later after one takes a shower. It is unusual to notice the eruptions immediately. Symptoms can last from a few days up to two weeks, the shorter time being the norm.The reaction is identified by severe itching around small red papules 1mm to 1.5 cm in size located on areas of skin that were covered by water-permeable clothing or hair during ocean swimming. Initial swimmer exposure to the free-floating larvae produces no effects, as each organism possesses only a single undeveloped nematocyst which is inactive while suspended in seawater. However, due to their microscopic size and sticky bodies, large concentrations of larvae can become trapped in minute gaps between skin and clothing or hair. Once the swimmer leaves the ocean, the organisms stuck against the skin die and automatically discharge their nematocysts when crushed, dried out, or exposed to freshwater. This is why symptoms usually do not appear until the swimmer dries themselves in the sun or takes a freshwater shower without first removing the affected clothing.
Treatment
Treatment is symptomatic, with most affected using a topical anti-itch cream (diphenhydramine) and a cortisone solution (hydrocortisone).
Incidence
Seabathers eruption is common throughout the range of Linuche unguiculata in the Caribbean, Florida, Mexico, and Gulf States. Cases were first identified in Brazil in 2001. The closely related Linuche aquila, found anywhere between Malaysia, the Philippines and the east coast of Africa, is also known to cause the condition.Swimmers in Queensland, Australia, have reported seabathers eruption during the summer months of the year. Swimmers at the east-coast beaches of Auckland and the rest of the Hauraki Gulf in New Zealand can develop seabathers eruption, typically during summer.
References
== External links == |
Callosity | A callosity is another name for callus, a piece of skin that has become thickened as a result of repeated contact and friction.
Primates
All Old World monkeys, gibbons, and some chimpanzees have pads on their rears known as ischial callosities. Ischial relates to the ischium: it forms the lower and back part of the hip bone.
The pads enable the monkeys to sleep sitting upright on thin branches, beyond reach of predators, without falling.
The ischial callosities are one of the most distinctive pelvic features which separates Old World monkeys from New World monkeys.
Right whales
In whales, the term callosity refers to the rough, calcified skin patches found on the heads of the three species of right whales. These callosities are a characteristic feature of the whale genus Eubalaena; because they are found on the head of the whale and appear white against the dark background of the whales skin, they make it very easy to identify these species. The callosities themselves are grey; the white appearance is due to large colonies of whale lice, whale barnacles and parasitic worms which reside on them. Young whales and diseased individuals are often infested with a different species of cyamid, which gives an orange hue rather than white on these whales. Callosities arise naturally and are present even in late-term whale fetuses, although the work of lice digging into the surface of the skin may make them more jagged and hard over time.Callosities are found on the upper surface of the whales head, above the eyes, on the jawline and chin and surrounding the blowholes. Callosities form a unique pattern on every right whale and though callosities which are overgrown break off, the patterns do not change over a lifetime. This makes them a very useful tool for the purposes of photo-identification and conservation.The evolutionary significance of callosities is unknown. Male right whales have a higher density of callosities than females. Males have been observed scratching one another with their callosities and it has been suggested by Payne & Dorsey (1983) that they are a sexually dimorphic feature, used for intra-specific sexual aggression. That explanation is not entirely satisfactory, because it does not account for the appearance of callosities in females. It has been proposed that the barnacles attached to callosities are important in helping fend off attacks by orcas.
See also
Callus
Notes
References
Steudel, K (1981). "Functional Aspects of Primate Pelvic Structure: A Multivariate Approach" (PDF). American Journal of Physical Anthropology. 55 (3): 399–410. doi:10.1002/ajpa.1330550314. PMID 6791507. Archived from the original (PDF) on 2010-06-10. Retrieved 2009-07-19.
Callosities by Mason T. Weinrich in the Encyclopedia of Marine Mammals. ISBN 0-12-551340-2.
A Dictionary of Zoology 1999, Oxford University Press 1999
"On Butts and Baboons". Artsibasheva, A. http://monkeybuiznezz.wordpress.com/2012/09/27/on-butts-and-baboons/ |
Chorditis | Chorditis is the inflammation of vocal cords (vocal folds) usually as a result of voice abuse but sometimes because of cancer.
Types
Chorditis fibrinosa
Chorditis nodosa
Chorditis tuberosa
See also
Vocal fold nodule
References
== External links == |
Subcutaneous granuloma annulare | Subcutaneous granuloma annulare is a skin condition of unknown cause, most commonly affecting children, with girls affected twice as commonly as boys, characterized by skin lesions most often on the lower legs.: 704
See also
Granuloma annulare
Skin lesion
List of cutaneous conditions
References
== External links == |
Condylomata lata | Condylomata lata or condyloma latum, is a cutaneous condition characterized by wart-like lesions on the genitals. They are generally symptoms of the secondary phase of syphilis, caused by the spirochete, Treponema pallidum.Condylomata lata occurs in about one-third of secondary syphilis patients and is characterized by painless, mucosal, and warty erosions which are flat, velvety, moist and broad base in nature. They tend to develop in warm, moist sites of the genitals and perineum. These lesions hold a high accumulation of spirochetes and are highly infectious. Complete resolution of the lesions is spontaneous and occurs after a few days to many weeks, where it is either resolved completely or enters the tertiary phase, defined by a latent state.
See also
Chromobacteriosis infection
List of cutaneous conditions
== References == |
Baastrups sign | Baastrups sign is an orthopedic and radiographic disorder that often occurs in elderly humans. It is characterized by enlargement of the posterior spinous processes of the lumbar spine, with normal intervertebral disc height and neuroforamina. The reason it is referred to as kissing spine is because the posterior spinous processes kiss and touch one another as the individual goes into lumbar extension, for example when flat on their stomach. The condition has been seen in humans, canines, particularly with boxer breeds, and certain breeds of horses. This disorder is named after Christian Ingerslev Baastrup.
Diagnosis
The salient feature of the disorder is the exuberant osteophytosis that occurs at posterior lumbar spinous processes. Osteophytes are coarse calcifications at the edges of bone that form due to repetitive stress and trauma. There is also atrophy and fatty replacement of paraspinal musculature, which can be detected by CT or MRI.
Treatment
The malpositioning seen on radiography may not cause any symptoms at all. If there are related symptoms, however, therapeutic options include chiropractic care, physical therapy and nerve block injections. As a last resort, decompressive laminectomy may be attempted to relieve pain symptoms and remove the abnormally enlarged portions of bone.
References
== External links == |
Indian childhood cirrhosis | Indian childhood cirrhosis is a chronic liver disease of childhood characterised by cirrhosis of the liver associated with the deposition of copper in the liver. It primarily affects children of 1–3 years of age and has a genetic predisposition. It had a very high case fatality in the past, but has eventually become preventable, treatable and is now rare.It remains a part of the differential diagnosis of Wilsons disease.
See also
North American Indian childhood cirrhosis
References
Further reading
Nayak N.C.; Chitale A.R. (2013). "Indian childhood cirrhosis (ICC) & ICC-like diseases: The changing scenario of facts versus notions". Indian J. Med. Res. 137 (6): 1029–42. PMC 3734708. PMID 23852284. |
Vertebral artery dissection | Vertebral artery dissection (VAD) is a flap-like tear of the inner lining of the vertebral artery, which is located in the neck and supplies blood to the brain. After the tear, blood enters the arterial wall and forms a blood clot, thickening the artery wall and often impeding blood flow. The symptoms of vertebral artery dissection include head and neck pain and intermittent or permanent stroke symptoms such as difficulty speaking, impaired coordination and visual loss. It is usually diagnosed with a contrast-enhanced CT or MRI scan.Vertebral dissection may occur after physical trauma to the neck, such as a blunt injury (e.g. traffic collision), or strangulation, or after sudden neck movements, i.e. coughing, but may also happen spontaneously. 1–4% of spontaneous cases have a clear underlying connective tissue disorder affecting the blood vessels. Treatment is usually with either antiplatelet drugs such as aspirin or with anticoagulants such as heparin or warfarin.Vertebral artery dissection is less common than carotid artery dissection (dissection of the large arteries in the front of the neck). The two conditions together account for 10–25% of non-hemorrhagic strokes in young and middle-aged people. Over 75% recover completely or with minimal impact on functioning, with the remainder having more severe disability and a very small proportion (about 2%) dying from complications. It was first described in the 1970s by the Canadian neurologist C. Miller Fisher.
Classification
Vertebral artery dissection is one of the two types of dissection of the arteries in the neck. The other type, carotid artery dissection, involves the carotid arteries. Vertebral artery dissection is further classified as being either traumatic (caused by mechanical trauma to the neck) or spontaneous, and it may also be classified by the part of the artery involved: extracranial (the part outside the skull) and intracranial (the part inside the skull).
Signs and symptoms
Head pain occurs in 50–75% of all cases of vertebral artery dissection. It tends to be located at the back of the head, either on the affected side or in the middle, and develops gradually. It is either dull or pressure-like in character or throbbing. About half of those with VAD consider the headache distinct, while the remainder have had a similar headache before. It is suspected that VAD with headache as the only symptom is fairly common; 8% of all cases of vertebral and carotid dissection are diagnosed on the basis of pain alone.Obstruction of blood flow through the affected vessel may lead to dysfunction of part of the brain supplied by the artery. This happens in 77–96% of cases. This may be temporary ("transient ischemic attack") in 10–16% of cases, but many (67–85% of cases) end up with a permanent deficit or a stroke. The vertebral artery supplies the part of the brain that lies in the posterior fossa of the skull, and this type of stroke is therefore called a posterior circulation infarct. Problems may include difficulty speaking or swallowing (lateral medullary syndrome); this occurs in less than a fifth of cases and occurs due to dysfunction of the brainstem. Others may experience unsteadiness or lack of coordination due to involvement of the cerebellum, and still others may develop visual loss (on one side of the visual field) due to involvement of the visual cortex in the occipital lobe. In the event of involvement of the sympathetic tracts in the brainstem, a partial Horners syndrome may develop; this is the combination of a drooping eyelid, constricted pupil, and an apparently sunken eye on one side of the face.If the dissection of the artery extends to the part of the artery that lies inside the skull, subarachnoid hemorrhage may occur (1% of cases). This arises due to rupture of the artery and accumulation of blood in the subarachnoid space. It may be characterized by a different, usually severe headache; it may also cause a range of additional neurological symptoms.13–16% of all people with vertebral or carotid dissection have dissection in another cervical artery. It is therefore possible for the symptoms to occur on both sides, or for symptoms of carotid artery dissection to occur at the same time as those of vertebral artery dissection. Some give a figure of multiple vessel dissection as high as 30%.
Causes
The causes of vertebral artery dissection can be grouped under two main categories, spontaneous and traumatic.
Spontaneous
Spontaneous cases are considered to be caused by intrinsic factors that weaken the arterial wall. Only a very small proportion (1–4%) have a clear underlying connective tissue disorder, such as Ehlers–Danlos syndrome type 4 and, more rarely, Marfan syndrome. However, ultrastructural abnormalities of the dermal connective tissue components are discernible in two out of three patients with spontaneous dissection. Ehlers–Danlos syndrome type 4, caused by mutations of the COL3A gene, leads to defective production of the collagen, type III, alpha 1 protein and causes skin fragility as well as weakness of the walls of arteries and internal organs. Marfan syndrome results from mutations in the FBN1 gene, defective production of the protein fibrillin-1, and a number of physical abnormalities including aneurysm of the aortic root.There have also been reports in other genetic conditions, such as osteogenesis imperfecta type 1, autosomal dominant polycystic kidney disease and pseudoxanthoma elasticum, α1 antitrypsin deficiency and hereditary hemochromatosis, but evidence for these associations is weaker. Genetic studies in other connective tissue-related genes have mostly yielded negative results. Other abnormalities to the blood vessels, such as fibromuscular dysplasia, have been reported in a proportion of cases. Atherosclerosis does not appear to increase the risk.There have been numerous reports of associated risk factors for vertebral artery dissection; many of these reports suffer from methodological weaknesses, such as selection bias. Elevated homocysteine levels, often due to mutations in the MTHFR gene, appear to increase the risk of vertebral artery dissection. People with an aneurysm of the aortic root and people with a history of migraine may be predisposed to vertebral artery dissection. Vascular tortuosity or redundancy in young patients is associated with an increased risk of spontaneous dissection.
Traumatic
Traumatic vertebral dissection may follow blunt trauma to the neck, such as in a traffic collision, direct blow to the neck, strangulation, or whiplash injury. 1–2% of those with major trauma may have an injury to the carotid or vertebral arteries. In many cases of vertebral dissection, people report recent very mild trauma to the neck or sudden neck movements, e.g. in the context of playing sports. Others report a recent infection, particularly respiratory tract infections associated with coughing. Trauma has been reported to have occurred within a month of dissection in 40% with nearly 90% of the traumas being minor. It has been difficult to prove the association of vertebral artery dissection with mild trauma and infections statistically. It is likely that many "spontaneous" cases may in fact have been caused by such relatively minor insults in someone predisposed by other structural problems to the vessels. A more likely theory, also as yet unproven, is that the low-energy traumatic dissections are actually spontaneous dissections brought to medical attention by the onset of neurological symptoms. These neurological events represent embolic phenomena due to loosening or breakdown of the clot at the site of the dissection, which can be triggered by low energy trauma or even occur spontaneously. The fragments travel within the arterial system downstream to the brain to cause stroke or stroke-like symptoms.
Vertebral artery dissection has also been reported in association with some forms of neck manipulation. There is significant controversy about the level of risk of stroke from neck manipulation. It may be that manipulation can cause dissection, or it may be that the dissection is already present in some people who seek manipulative treatment. At this time, conclusive evidence does not exist to support either a strong association between neck manipulation and stroke, or no association. However, the two most authoritative articles on the subject, recent literature reviews and analyses, conclude that although there exists an association between stroke from vertebral artery dissection and chiropractic adjustment, there is insufficient evidence to indicate that the adjustment caused the dissection. A recent meta-analysis of the published data on the topic also looked to apply Hills criteria for assigning causation in biological systems to the relationship between chiropractic adjustment and cervical artery dissection, finding that the relationship did not fulfill the required criteria for causality.
Mechanism
The vertebral arteries arise from the subclavian artery, and run through the transverse foramen of the upper six vertebrae of the neck. After exiting at the level of the first cervical vertebra, its course changes from vertical to horizontal, and then enters the skull through the foramen magnum. Inside the skull, the arteries merge to form the basilar artery, which joins the circle of Willis. In total, three quarters of the artery are outside the skull; it has a high mobility in this area due to rotational movement in the neck and is therefore vulnerable to trauma. Most dissections happen at the level of the first and second vertebrae. The vertebral artery supplies a number of vital structures in the posterior cranial fossa, such as the brainstem, the cerebellum and the occipital lobes. The brainstem harbors a number of vital functions (such as respiration) and controls the nerves of the face and neck. The cerebellum is part of the diffuse system that coordinates movement. Finally, the occipital lobes participate in the sense of vision.Dissection occurs when blood accumulates in the wall of the blood vessel. This is most likely due to a tear in the tunica intima (the inner layer), allowing blood to enter the tunica media, although other lines of evidence have suggested that the blood may instead arise from the vasa vasorum, the small blood vessels that supply the outer layer of larger blood vessels. Various theories exist as to whether people who sustain carotid and vertebral artery dissection, even if they do not have a connective tissue disorder, have an underlying vulnerability. Biopsy samples of skin and other arteries has indicated that this might be a possibility, but no genetic defect in collagen or elastin genes has been convincingly proven. Other studies have indicated inflammation of the blood vessels, as measured by highly sensitive C-reactive protein (hsCRP, a marker of inflammation) in the blood.Once dissection has occurred, two mechanisms contribute to the development of stroke symptoms. Firstly, the flow through the blood vessel may be disrupted due to the accumulation of blood under the vessel wall, leading to ischemia (insufficient blood supply). Secondly, irregularities in the vessel wall and turbulence increase the risk of thrombosis (the formation of blood clots) and embolism (migration) of these clots of the brain. From various lines of evidence, it appears that thrombosis and embolism is the predominant problem.Subarachnoid hemorrhage due to arterial rupture typically occurs if the dissection extends into the V4 section of the artery. This may be explained by the fact that the arterial wall is thinner and lacks a number of structural supports in this section.
Diagnosis
Various diagnostic modalities exist to demonstrate blood flow or absence thereof in the vertebral arteries. The gold standard is cerebral angiography (with or without digital subtraction angiography). This involves puncture of a large artery (usually the femoral artery) and advancing an intravascular catheter through the aorta towards the vertebral arteries. At that point, radiocontrast is injected and its downstream flow captured on fluoroscopy (continuous X-ray imaging). The vessel may appear stenotic (narrowed, 41–75%), occluded (blocked, 18–49%), or as an aneurysm (area of dilation, 5–13%). The narrowing may be described as "rats tail" or "string sign". Cerebral angiography is an invasive procedure, and it requires large volumes of radiocontrast that can cause complications such as kidney damage. Angiography also does not directly demonstrate the blood in the vessel wall, as opposed to more modern modalities. The only remaining use of angiography is when endovascular treatment is contemplated (see below).More modern methods involve computed tomography (CT angiography) and magnetic resonance imaging (MR angiography). They use smaller amounts of contrast and are not invasive. CT angiography and MR angiography are more or less equivalent when used to diagnose or exclude vertebral artery dissection. CTA has the advantage of showing certain abnormalities earlier, tends to be available outside office hours, and can be performed rapidly. When MR angiography is used, the best results are achieved in the T1 setting using a protocol known as "fat suppression". Doppler ultrasound is less useful as it provides little information about the part of the artery close to the skull base and in the vertebral foramina, and any abnormality detected on ultrasound would still require confirmation with CT or MRI.
Treatment
Treatment is focused on reducing stroke episodes and damage from a distending artery. Four treatment modalities have been reported in the treatment of vertebral artery dissection. The two main treatments involve medication: anticoagulation (using heparin and warfarin) and antiplatelet drugs (usually aspirin). More rarely, thrombolysis (medication that dissolves blood clots) may be administered, and occasionally obstruction may be treated with angioplasty and stenting. No randomized controlled trials have been performed to compare the different treatment modalities. Surgery is only used in exceptional cases.
Anticoagulation and aspirin
From analysis of the existing small treatment trials of cervical artery dissection (carotid and vertebral) it appears that aspirin and anticoagulation (heparin followed by warfarin) are equally effective in reducing the risk of further stroke or death. Anticoagulation is regarded as more powerful than antiplatelet therapy, but anticoagulants may increase the size of the hematoma and worsen obstruction of the affected artery. Anticoagulation may be relatively unsafe if a large stroke has already occurred, as hemorrhagic transformation is relatively common, and if the dissection extends into V4 (carrying a risk of subarachnoid hemorrhage). Anticoagulation may be appropriate if there is rapid blood flow (through a severely narrowed vessel) on transcranial doppler despite the use of aspirin, if there is a completely occluded vessel, if there are recurrent stroke-like episodes, or if free-floating blood clot is visible on scans. Warfarin is typically continued for 3–6 months, as during this time the flow through the artery usually improves, and most strokes happen within the first 6 months after the development of the dissection. Some regard 3 months as sufficient.Professional guidelines in the UK recommend that patients with VA dissection should be enrolled in a clinical trial comparing aspirin and anticoagulation if possible. American guidelines state that the benefit of anticoagulation is not currently established.
Thrombolysis, stenting and surgery
Thrombolysis, stenting and surgery are not used as widely as anticoagulation or antiplatelet drugs. These treatments are invasive, and are typically reserved for situations where symptoms worsen despite medical treatment, or where medical treatment may be unsafe (e.g. an unacceptable bleeding tendency).Thrombolysis is enzymatic destruction of blood clots. This is achieved by the administration of a drug (such as urokinase or alteplase) that activates plasmin, an enzyme that occurs naturally in the body and digests clots when activated. Thrombolysis is an accepted treatment for heart attacks and stroke unrelated to dissection. In cervical artery dissection, only small case series are available. The thrombolytic drug is administered either intravenously or during cerebral angiography through a catheter directly into the affected artery. The data indicates that thrombolysis is safe, but its place in the treatment of VAD is uncertain.Stenting involves the catheterization of the affected artery during angiography, and the insertion of a mesh-like tube; this is known as "endovascular therapy" (inside the blood vessel). This may be performed to allow the blood to flow through a severely narrowed vessel, or to seal off an aneurysm. However, it is unclear whether the technical success of the procedure translates into improved outcomes, as in both cases the problem often resolves spontaneously over time. Stenting, as well as the insertion of coils by means of angiography, may be performed if there is an aneurysm and/or extension of the dissection into the V4 section of the artery.Surgery carries a high risk of complications, and is typically only offered in case of inexorable deterioration or contraindications to any of the other treatments. Various arterial repair procedures have been described.
Prognosis
Prognosis of spontaneous cervical arterial dissection involves neurological and arterial results. The overall functional prognosis of individuals with stroke due to cervical artery dissection does not appear to vary from that of young people with stroke due to other causes. The rate of survival with good outcome (a modified Rankin score of 0–2) is generally about 75%, or possibly slightly better (85.7%) if antiplatelet drugs are used. In studies of anticoagulants and aspirin, the combined mortality with either treatment is 1.8–2.1%.After the initial episode, 2% may experience a further episode within the first month. After this, there is a 1% annual risk of recurrence. Those with high blood pressure and dissections in multiple arteries may have a higher risk of recurrence. Further episodes of cervical artery dissection are more common in those who are younger, have a family history of cervical artery dissection, or have a diagnosis of Ehlers-Danlos syndrome or fibromuscular dysplasia.
Epidemiology
The annual incidence is about 1.1 per 100,000 annually in population studies from the United States and France. From 1994 to 2003, the incidence increased threefold; this has been attributed to the more widespread use of modern imaging modalities rather than a true increase. Similarly, those living in urban areas are more likely to receive appropriate investigations, accounting for increased rates of diagnosis in those dwelling in cities. It is suspected that a proportion of cases in people with mild symptoms remains undiagnosed.There is controversy as to whether VAD is more common in men or in women; an aggregate of all studies shows that it is slightly higher incidence in men (56% versus 44%). Men are on average 37–44 years old at diagnosis, and women 34–44. While dissection of the carotid and vertebral arteries accounts for only 2% of strokes (which are usually caused by high blood pressure and other risk factors, and tend to occur in the elderly), they cause 10–25% of strokes in young and middle-aged people.Dissecting aneurysms of the vertebral artery constitute 4% of all cerebral aneurysms, and are hence a relatively rare but important cause of subarachnoid hemorrhage.
History
Spontaneous vertebral artery dissection was described in the 1970s. Prior to this, there had been isolated case reports about carotid dissection. In 1971, C. Miller Fisher, a Canadian neurologist and stroke physician working at Massachusetts General Hospital, first noted the "string sign" abnormality in carotid arteries on cerebral angiograms of stroke patients, and subsequently discovered that the same abnormality could occur in the vertebral arteries. He reported the discovery in a paper in 1978.
Notable cases
Australian cricketer Phillip Hughes died on 27 November 2014 after developing a vertebral artery dissection as a result of being struck on the side of the neck by a cricket ball during a Sheffield Shield match on 25 November 2014. The ball struck Hughes on the base of the skull just behind his left ear which caused a vertebral artery dissection complicated by subarachnoid hemorrhage.
References
External links
Cervical Artery Dissections and Ischemic Stroke Patients, international research collaboration into cervical artery dissection
See also
Aortic dissection
Carotid artery dissection |
Valvular heart disease | Valvular heart disease is any cardiovascular disease process involving one or more of the four valves of the heart (the aortic and mitral valves on the left side of heart and the pulmonic and tricuspid valves on the right side of heart). These conditions occur largely as a consequence of aging, but may also be the result of congenital (inborn) abnormalities or specific disease or physiologic processes including rheumatic heart disease and pregnancy.Anatomically, the valves are part of the dense connective tissue of the heart known as the cardiac skeleton and are responsible for the regulation of blood flow through the heart and great vessels. Valve failure or dysfunction can result in diminished heart functionality, though the particular consequences are dependent on the type and severity of valvular disease. Treatment of damaged valves may involve medication alone, but often involves surgical valve repair or valve replacement.
Classification
Stenosis and insufficiency/regurgitation represent the dominant functional and anatomic consequences associated with valvular heart disease. Irrespective of disease process, alterations to the valve occur that produce one or a combination of these conditions. Insufficiency and regurgitation are synonymous terms that describe an inability of the valve to prevent backflow of blood as leaflets of the valve fail to join (coapt) correctly. Stenosis is characterized by a narrowing of the valvular orifice that prevents adequate outflow of blood. Stenosis can also result in insufficiency if thickening of the annulus or leaflets results in inappropriate leaf closure.
Aortic and mitral valve disorders
Aortic and mitral valve disorders are left heart diseases that are more prevalent than diseases of the pulmonary or tricuspid valve in the right heart due to the higher pressures in the left heart.Stenosis of the aortic valve is characterized by a thickening of the valvular annulus or leaflets that limits the ability of blood to be ejected from the left ventricle into the aorta. Stenosis is typically the result of valvular calcification but may be the result of a congenitally malformed bicuspid aortic valve. This defect is characterized by the presence of only two valve leaflets. It may occur in isolation or in concert with other cardiac anomalies.Aortic insufficiency, or regurgitation, is characterized by an inability of the valve leaflets to appropriately close at the end systole, thus allowing blood to flow inappropriately backward into the left ventricle. Causes of aortic insufficiency in the majority of cases are unknown, or idiopathic. It may be the result of connective tissue or immune disorders, such as Marfan syndrome or systemic lupus erythematosus, respectively. Processes that lead to aortic insufficiency usually involve dilation of the valve annulus, thus displacing the valve leaflets, which are anchored in the annulus.Mitral stenosis is caused largely by rheumatic heart disease, though is rarely the result of calcification. In some cases, vegetations form on the mitral leaflets as a result of endocarditis, an inflammation of the heart tissue. Mitral stenosis is uncommon and not as age-dependent as other types of valvular disease.Mitral insufficiency can be caused by dilation of the left heart, often a consequence of heart failure. In these cases, the left ventricle of the heart becomes enlarged and causes displacement of the attached papillary muscles, which control the mitral.
Pulmonary and tricuspid valve disorders
Pulmonary and tricuspid valve diseases are right heart diseases. Pulmonary valve diseases are the least common heart valve disease in adults.Pulmonary valve stenosis is often the result of congenital malformations and is observed in isolation or as part of a larger pathologic process, as in Tetralogy of Fallot, Noonan syndrome, and congenital rubella syndrome. Unless the degree of stenosis is severe, individuals with pulmonary stenosis usually have excellent outcomes and better treatment options. Often patients do not require intervention until later in adulthood as a consequence of calcification that occurs with aging.Pulmonary valve insufficiency occurs commonly in healthy individuals to a very mild extent and does not require intervention. More appreciable insufficiency is typically the result of damage to the valve due to cardiac catheterization, intra-aortic balloon pump insertion, or other surgical manipulations. Additionally, insufficiency may be the result of carcinoid syndrome, inflammatory processes such a rheumatoid disease or endocarditis, or congenital malformations. It may also be secondary to severe pulmonary hypertension.Tricuspid valve stenosis without co-occurrent regurgitation is highly uncommon and typically the result of rheumatic disease. It may also be the result of congenital abnormalities, carcinoid syndrome, obstructive right atrial tumors (typically lipomas or myxomas), or hypereosinophilic syndromes.Minor tricuspid insufficiency is common in healthy individuals. In more severe cases it is a consequence of dilation of the right ventricle, leading to displacement of the papillary muscles which control the valves ability to close. Dilation of the right ventricle occurs secondary to ventricular septal defects, right to left shunting of blood, eisenmenger syndrome, hyperthyroidism, and pulmonary stenosis. Tricuspid insufficiency may also be the result of congenital defects of the tricuspid valve, such as Ebsteins anomaly.
Signs and symptoms
Aortic stenosis
Symptoms of aortic stenosis may include heart failure symptoms, such as dyspnea on exertion (most frequent symptom), orthopnea and paroxysmal nocturnal dyspnea, angina pectoris, and syncope, usually exertional.Medical signs of aortic stenosis include pulsus parvus et tardus, that is, diminished and delayed carotid pulse, fourth heart sound, decreased A2 sound, sustained apex beat, precordial thrill. Auscultation may reveal a systolic murmur of a harsh crescendo-decrescendo type, heard in 2nd right intercostal space and radiating to the carotid arteries.
Aortic regurgitation
Patients with aortic regurgitation may experience heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, and angina pectoris. In acute cases patients may experience cyanosis and circulatory shock.Medical signs of aortic regurgitation include increased pulse pressure by increased systolic and decreased diastolic blood pressure, but these findings may not be significant if acute. The patient may have a diastolic decrescendo murmur best heard at left sternal border, water hammer pulse, Austin Flint murmur, and a displaced apex beat down and to the left. A third heart sound may be present
Mitral stenosis
Patients with mitral stenosis may present with heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, chest pain, hemoptysis, thromboembolism, or ascites and edema (if right-sided heart failure develops). Symptoms of mitral stenosis increase with exercise and pregnancyOn auscultation of a patient with mitral stenosis, typically the most prominent sign is a loud S1. Another finding is an opening snap followed by a low-pitched diastolic rumble with presystolic accentuation. The opening snap follows closer to the S2 heart tone with worsening stenosis. The murmur is heard best with the bell of the stethoscope lying on the left side and its duration increases with worsening disease. Advanced disease may present with signs of right-sided heart failure such as parasternal heave, jugular venous distension, hepatomegaly, ascites and/or pulmonary hypertension (presenting with a loud P2). Signs increase with exercise and pregnancy.
Mitral regurgitation
Patients with mitral regurgitation may present with heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, or pulmonary edema.On auscultation of a patient with mitral stenosis, there may be a holosystolic murmur at the apex, radiating to the back or clavicular area, a third heart sound, and a loud, palpable P2, heard best when lying on the left side. Patients also commonly have atrial fibrillation. Patients may have a laterally displaced apex beat, often with heave In acute cases, the murmur and tachycardia may be only distinctive signs.
Tricuspid regurgitation
Patients with tricuspid regurgitation may experience symptoms of right-sided heart failure, such as ascites, hepatomegaly, edema and jugular venous distension.Signs of tricuspid regurgitation include pulsatile liver, prominent V waves and rapid y descents in jugular venous pressure. Auscultatory findings include inspiratory third heart sound at left lower sternal border (LLSB) and a blowing holosystolic murmur at LLSB, intensifying with inspiration, and decreasing with expiration and Valsalva maneuver. Patients may have a parasternal heave along LLSB. Atrial fibrillation is usually present in patients with tricuspid regurgitation
Causes
Calcific disease
Calcification of the leaflets of the aortic valve is a common with increasing age, but the mechanism is likely to be more related to increased lipoprotein deposits and inflammation than the "wear and tear" of advance age. Aortic stenosis due to calcification of tricuspid aortic valve with age comprises >50% of the disease. Aortic stenosis due to calcification of a bicuspid aortic valve comprises about 30-40% of the disease. Hypertension, diabetes mellitus, hyperlipoproteinemia and uremia may speed up the process of valvular calcification.
Dysplasia
Heart valve dysplasia is an error in the development of any of the heart valves, and a common cause of congenital heart defects in humans as well as animals; tetralogy of Fallot is a congenital heart defect with four abnormalities, one of which is stenosis of the pulmonary valve. Ebsteins anomaly is an abnormality of the tricuspid valve, and its presence can lead to tricuspid valve regurgitation. A bicuspid aortic valve is an aortic valve with only 2 cusps as opposed to the normal 3. It is present in about 0.5% to 2% of the general population and causes increased calcification due to higher turbulent flow through the valve.
Connective tissue disorders
Marfans Syndrome is a connective tissue disorder that can lead to chronic aortic or mitral regurgitation. Osteogenesis imperfecta is a disorder in formation of type I collagen and can also lead to chronic aortic regurgitation.
Inflammatory disorders
Inflammation of the heart valves due to any cause is called valvular endocarditis; this is usually due to bacterial infection but may also be due to cancer (marantic endocarditis), certain autoimmune conditions (Libman-Sacks endocarditis, seen in systemic lupus erythematosus) and hypereosinophilic syndrome (Loeffler endocarditis). Endocarditis of the valves can lead to regurgitation through that valve, which is seen in the tricuspid, mitral, and aortic valves. Certain medications have been associated with valvular heart disease, most prominently ergotamine derivatives pergolide and cabergoline.Valvular heart disease resulting from rheumatic fever is referred to as rheumatic heart disease. Acute rheumatic fever, which frequently manifests with carditis and valvulitis, is a late sequela of Group A beta-hemolytic streptococcus infection in the throat, often lagging the initial infection by weeks to months. Cardiac involvement is dependent on the cross-reaction of antibodies directed against M proteins produced by bacteria with human proteins present in the myocardium or endocardium (although acute rheumatic fever may present as pancarditis with additional involvement of the pericardium). This results in generalized inflammation in the heart, producing acute erosions and vegetations with fibrin deposition in the mitral valve that may be followed by chronic changes over years to decades, including shortening of the chordae tendinae and thickening or fusion of the mitral leaflets, leading to a severely compromised "buttonhole" or "fish mouth" valve.In 70% of cases rheumatic heart disease involves only the mitral valve, while 25% of cases involve both the aortic and mitral valves. Involvement of other heart valves without damage to the mitral is exceedingly rare. Mitral stenosis is almost always caused by rheumatic heart disease. Less than 10% of aortic stenosis is caused by rheumatic heart disease. Rheumatic fever can also cause chronic mitral and aortic regurgitation.While developed countries once had a significant burden of rheumatic fever and rheumatic heart disease, medical advances and improved social conditions have dramatically reduced their incidence. Many developing countries, as well as indigenous populations within developed countries, still carry a significant burden of rheumatic fever and rheumatic heart disease and there has been a resurgence in efforts to eradicate the diseases in these populations. Among persons who have experienced rheumatic fever, long-term intramuscular antibiotic therapy is used as secondary prophylaxis against additional streptococcal infections, which can contribute to progression of rheumatic heart disease. In people with severe valvular disease, however, short-term risks of cardiovascular compromise after intramuscular injections may outweigh the benefits, and oral therapy may be considered instead of IM injections in this subset of patients.Diseases of the aortic root can cause chronic aortic regurgitation. These diseases include syphilitic aortitis, Behçets disease, and reactive arthritis.
Heart disease
Tricuspid regurgitation is usually secondary to right ventricular dilation which may be due to left ventricular failure (the most common cause), right ventricular infarction, inferior myocardial infarction, or cor pulmonale Other causes of tricuspid regurgitation include carcinoid syndrome and myxomatous degeneration.
Diagnosis
Aortic stenosis
Patients with aortic stenosis can have chest X-ray findings showing dilation of the ascending aorta, but they may also have a completely normal chest X-ray. Direct visualization of calcifications on chest X-ray is uncommon. Other findings include dilation of the left ventricle. ECG typically shows left ventricular hypertrophy in patients with severe stenosis, but it may also show signs of left heart strain. Echocardiography is the diagnostic gold standard, which shows left ventricular hypertrophy, leaflet calcification, and abnormal leaflet closure.
Aortic regurgitation
Chest X-ray is not as sensitive as other tests, but it may show aortic root dilation (especially in causes involving the aortic root) and apex displacement. An ECG may show left ventricular hypertrophy and signs of left heart strain. Left axis deviation can be a sign of advanced disease. An echocardiogram can be helpful in determining the root cause of the disease, as it will clearly show aortic root dilation or dissection if it exists. Typically the pump function of the heart during systole is normal, but an echocardiogram will show flow reversal during diastole. This disease is classified using regurgitant fraction (RF), or the amount of volume that flows back through the valve divided by the total forward flow through the valve during systole. Severe disease has an RF of >50%, while progressive aortic regurgitation has an RF of 30–49%.
Mitral stenosis
Chest x-ray in mitral stenosis will typically show an enlarged left atrium, and may show dilation of the pulmonary veins. ECG can show left atrial enlargement, due to increased pressures in the left atrium. Echocardiography is helpful in determining the severity of the disease by estimating the pulmonary artery systolic pressure. This test can also show leaflet calcification and the pressure gradient over the mitral valve. Severe mitral stenosis is defined as a mitral valve area <1.5 cm2. Progressive mitral stenosis has a normal valve area but will have increased flow velocity across the mitral valve.
Mitral regurgitation
Chest x-ray in mitral regurgitation can show an enlarged left atrium, as well as pulmonary venous congestion. It may also show valvular calcifications specifically in combined mitral regurgitation and stenosis due to rheumatic heart disease. ECG typically shows left atrial enlargement, but can also show right atrial enlargement if the disease is severe enough to cause pulmonary hypertension. Echocardiography is useful in visualizing the regurgitant flow and calculating the RF. It can also be used to determine the degree of calcification, and the function and closure of the valve leaflets. Severe disease has an RF of >50%, while progressive mitral regurgitation has an RF of <50%.
Treatment
Some of the most common treatments of valvular heart disease are avoiding smoking and excessive alcohol consumption, antibiotics, antithrombotic medications such as aspirin, anticoagulants, balloon dilation, and water pills.
In some cases, surgery may be necessary.
Aortic stenosis
Treatment of aortic stenosis is not necessary in asymptomatic patients, unless the stenosis is classified as severe based on valve hemodynamics. Both asymptomatic severe and symptomatic aortic stenosis are treated with aortic valve replacement (AVR) surgery. Trans-catheter Aortic Valve Replacement (TAVR) is an alternative to AVR and is recommended in high risk patients who may not be suitable for surgical AVR. Any angina is treated with short-acting nitrovasodilators, beta-blockers and/or calcium blockers. Any hypertension is treated aggressively, but caution must be taken in administering beta-blockers. Any heart failure is treated with digoxin, diuretics, nitrovasodilators and, if not contraindicated, cautious inpatient administration of ACE inhibitors. Moderate stenosis is monitored with echocardiography every 1–2 years, possibly with supplementary cardiac stress test. Severe stenosis should be monitored with echocardiography every 3–6 months.
Aortic regurgitation
Aortic regurgitation is treated with aortic valve replacement, which is recommended in patients with symptomatic severe aortic regurgitation. Aortic valve replacement is also recommended in patients that are asymptomatic but have chronic severe aortic regurgitation and left ventricular ejection fraction of less than 50%. Hypertension is treated in patients with chronic aortic regurgitation, with the anti-hypersensives of choice being calcium channel blockers, ACE inhibitors, or ARBs. Also, endocarditis prophylaxis is indicated before dental, gastrointestinal or genitourinary procedures. Mild to moderate aortic regurgitation should be followed with echocardiography and a cardiac stress test once every 1–2 years. In severe moderate/severe cases, patients should be followed with echocardiography and cardiac stress test and/or isotope perfusion imaging every 3–6 months.
Mitral stenosis
For patients with symptomatic severe mitral stenosis, percutaneous balloon mitral valvuloplasty (PBMV) is recommended. If this procedure fails, then it may be necessary to undergo mitral valve surgery, which may involve valve replacement, repair, or commisurotomy. Anticoagulation is recommended for patients that have mitral stenosis in the setting of atrial fibrillation or a previous embolic event. No therapy is required for asymptomatic patients. Diuretics may be used to treat pulmonary congestion or edema.
Mitral regurgitation
Surgery is recommended for chronic severe mitral regurgitation in symptomatic patients with left ventricular ejection fraction (LVEF) of greater than 30%, and asymptomatic patients with LVEF of 30-60% or left ventricular end diastolic volume (LVEDV) > 40%. Surgical repair of the leaflets is preferred to mitral valve replacement as long as the repair is feasible. Mitral regurgitation may be treated medically with vasodilators, diuretics, digoxin, antiarrhythmics, and chronic anticoagulation. Mild to moderate mitral regurgitation should be followed with echocardiography and cardiac stress test every 1–3 years. Severe mitral regurgitation should be followed with echocardiography every 3–6 months.
Epidemiology
In the United States, about 2.5% of the population has moderate to severe valvular heart disease. The prevalence of these diseases increase with age, and 75 year-olds in the United States have a prevalence of about 13%. In industrially underdeveloped regions, rheumatic disease is the most common cause of valve diseases, and it can cause up to 65% of the valve disorders seen in these regions.
Aortic stenosis
Aortic stenosis is typically the result of aging, occurring in 12.4% of the population over 75 years of age, and represents the most common cause of outflow obstruction in the left ventricle. Bicuspid aortic valves are found in up to 1% of the population, making it one of the most common cardiac abnormalities.
Aortic regurgitation
The prevalence of aortic regurgitation also increases with age. Moderate to severe disease has a prevalence of 13% in patients between the ages of 55 and 86. This valve disease is primarily caused by aortic root dilation, but infective endocarditis has been an increased risk factor. It has been found to be the cause of aortic regurgitation in up to 25% of surgical cases.
Mitral stenosis
Mitral stenosis is caused almost exclusively by rheumatic heart disease, and has a prevalence of about 0.1% in the United States. Mitral stenosis is the most common valvular heart disease in pregnancy.
Mitral regurgitation
Mitral regurgitation is significantly associated with normal aging, rising in prevalence with age. It is estimated to be present in over 9% of people over 75.
Special populations
Pregnancy
The evaluation of individuals with valvular heart disease who are or wish to become pregnant is a difficult issue. Issues that have to be addressed include the risks during pregnancy to the mother and the developing fetus by the presence of maternal valvular heart disease as a pre-existing disease in pregnancy.
Normal physiological changes during pregnancy require, on average, a 50% increase in circulating blood volume that is accompanied by an increase in cardiac output that usually peaks between the midportion of the second and third trimesters. The increased cardiac output is due to an increase in the stroke volume, and a small increase in heart rate, averaging 10 to 20 beats per minute. Additionally uterine circulation and endogenous hormones cause systemic vascular resistance to decrease and a disproportionately lowering of diastolic blood pressure causes a wide pulse pressure. Inferior vena caval
obstruction from a gravid uterus in the supine position can result in an abrupt decrease in cardiac preload, which leads to hypotension with weakness and lightheadedness. During labor and delivery cardiac output increases more in part due to the associated anxiety and pain, as well as due to uterine contractions which will cause an increase in systolic and diastolic blood pressure.Valvular heart lesions associated with high maternal and fetal risk during pregnancy include:
Severe aortic stenosis with or without symptoms
Aortic regurgitation with NYHA functional class III-IV symptoms
Mitral stenosis with NYHA functional class II-IV symptoms
Mitral regurgitation with NYHA functional class III-IV symptoms
Aortic and/or mitral valve disease resulting in severe pulmonary hypertension (pulmonary pressure greater than 75% of systemic pressures)
Aortic and/or mitral valve disease with severe LV dysfunction (EF less than 0.40)
Mechanical prosthetic valve requiring anticoagulation
Marfan syndrome with or without aortic regurgitationIn individuals who require an artificial heart valve, consideration must be made for deterioration of the valve over time (for bioprosthetic valves) versus the risks of blood clotting in pregnancy with mechanical valves with the resultant need of drugs in pregnancy in the form of anticoagulation.
== References == |
Edwards syndrome | Edwards syndrome, also known as trisomy 18, is a genetic disorder caused by the presence of a third copy of all or part of chromosome 18. Many parts of the body are affected. Babies are often born small and have heart defects. Other features include a small head, small jaw, clenched fists with overlapping fingers, and severe intellectual disability.Most cases of Edwards syndrome occur due to problems during the formation of the reproductive cells or during early development. The rate of disease increases with the mothers age. Rarely, cases may be inherited from a persons parents. Occasionally, not all cells have the extra chromosome, known as mosaic trisomy, and symptoms in these cases may be less severe. An ultrasound during pregnancy can increase suspicion for the condition, which can be confirmed by amniocentesis.Treatment is supportive. After having one child with the condition, the risk of having a second is typically around one percent. It is the second-most common condition due to a third chromosome at birth, after Down syndrome.Edwards syndrome occurs in around 1 in 5,000 live births. Many of those affected die before birth. Some studies suggest that more babies that survive to birth are female. Survival beyond a year of life is around 5–10%. It is named after English geneticist John Hilton Edwards, who first described the syndrome in 1960.
Signs and symptoms
Children born with Edwards syndrome may have some or all of these characteristics: kidney malformations, structural heart defects at birth (i.e., ventricular septal defect, atrial septal defect, patent ductus arteriosus), intestines protruding outside the body (omphalocele), esophageal atresia, intellectual disability, developmental delays, growth deficiency, feeding difficulties, breathing difficulties, and arthrogryposis (a muscle disorder that causes multiple joint contractures at birth).Some physical malformations associated with Edwards syndrome include small head (microcephaly) accompanied by a prominent back portion of the head (occiput), low-set, malformed ears, abnormally small jaw (micrognathia), cleft lip/cleft palate, upturned nose, narrow eyelid openings (blepharophimosis), widely spaced eyes (ocular hypertelorism), drooping of the upper eyelids (ptosis), a short breast bone, clenched hands, choroid plexus cysts, underdeveloped thumbs and/or nails, absent radius, webbing of the second and third toes, clubfoot or rocker bottom feet, and in males, undescended testicles.In utero, the most common characteristic is cardiac anomalies, followed by central nervous system anomalies such as head shape abnormalities. The most common intracranial anomaly is the presence of choroid plexus cysts, which are pockets of fluid on the brain. These are not problematic in themselves, but their presence may be a marker for trisomy 18. Sometimes, excess amniotic fluid or polyhydramnios is exhibited. Although uncommon in the syndrome, Edwards syndrome causes a large portion of prenatally diagnosed cases of Dandy–Walker malformation.
Genetics
Edwards syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on the 18th chromosome, either in whole (trisomy 18) or in part (such as due to translocations). The additional chromosome usually occurs before conception. The effects of the extra copy vary greatly, depending on the extent of the extra copy, genetic history, and chance. Edwards syndrome occurs in all human populations, but is more prevalent in female offspring.A healthy egg and/or sperm cell contains individual chromosomes, each of which contributes to the 23 pairs of chromosomes needed to form a normal cell with a typical human karyotype of 46 chromosomes. Numerical errors can arise at either of the two meiotic divisions and cause the failure of a chromosome to segregate into the daughter cells (nondisjunction). This results in an extra chromosome, making the haploid number 24 rather than 23. Fertilization of eggs or insemination by sperm that contain an extra chromosome results in trisomy, or three copies of a chromosome rather than two.Trisomy 18 (47,XX,+18) is caused by a meiotic nondisjunction event. With nondisjunction, a gamete (i.e., a sperm or egg cell) is produced with an extra copy of chromosome 18; the gamete thus has 24 chromosomes. When combined with a normal gamete from the other parent, the embryo has 47 chromosomes, with three copies of chromosome 18.A small percentage of cases occur when only some of the bodys cells have an extra copy of chromosome 18, resulting in a mixed population of cells with a differing number of chromosomes. Such cases are sometimes called mosaic Edwards syndrome. Very rarely, a piece of chromosome 18 becomes attached to another chromosome (translocated) before or after conception. Affected individuals have two copies of chromosome 18 plus extra material from chromosome 18 attached to another chromosome. With a translocation, a person has a partial trisomy for chromosome 18, and the abnormalities are often less severe than for the typical Edwards syndrome.
Diagnosis
Ultrasound can increase suspicion for the condition, which can be confirmed by CVS or amniocentesis.Levels of PAPP-A, AFP, uE3, free β-hCG, all of which are generally decreased during pregnancy.
Prognosis
About 95% of pregnancies that are affected do not result in a live birth. Major causes of death include apnea and heart abnormalities. It is impossible to predict an exact prognosis during pregnancy or the neonatal period. Half of the live infants do not survive beyond the first week of life. The median lifespan is five to 15 days. About 8–12% of infants survive longer than 1 year. One percent of children live to age 10. However, these estimates may be pessimistic; a retrospective Canadian study of 254 children with trisomy 18 demonstrated ten-year survival of 9.8%, and another found that 68.6% of children with surgical intervention survived infancy.
Epidemiology
Edwards syndrome occurs in about one in 5,000 live births, but more conceptions are affected by the syndrome because the majority of those diagnosed with the condition prenatally will not survive to birth. Although women in their 20s and early 30s may conceive babies with Edwards syndrome, the risk of conceiving a child with it increases with a womans age. The average maternal age for conceiving a child with this disorder is 32+1⁄2.
History
Edwards syndrome was first identified by John Hilton Edwards in 1960, although he originally believed it to be caused by a trisomy of chromosome 17. Klaus Patau and Eeva Therman reported another two cases shortly thereafter. They identified the extra chromosome as being part of what Pataus lab called "group E", containing chromosomes 16, 17, and 18, but were unable to determine which chromosome was responsible at the time. Analyzing 5 more cases, they were able to determine that the extra chromosome was in fact chromosome 18.
See also
18q deletion syndrome
References
External links
Edwards syndrome at Curlie
Perinatal Hospice Care - Preparing for birth and death"
Humpath #5389 |
Intraoperative floppy iris syndrome | Intraoperative floppy iris syndrome (IFIS) is a complication that may occur during cataract extraction in certain patients. This syndrome is characterized by a flaccid iris which billows in response to ordinary intraocular fluid currents, a propensity for this floppy iris to prolapse towards the area of cataract extraction during surgery, and progressive intraoperative pupil constriction despite standard procedures to prevent this.IFIS has been associated with tamsulosin (e.g., Flomax), a medication widely prescribed for urinary symptoms associated with benign prostatic hyperplasia (BPH). Tamsulosin is a selective alpha blocker that works by relaxing the bladder and prostatic smooth muscle. As such, it also relaxes the iris dilator muscle by binding to its postsynaptic nerve endings. Various alpha-blockers are associated with IFIS, but tamsulosin has a stronger association than the others.A joint statement of two ophthalmologic societies states that "the other major class of drugs to treat BPH — 5-alpha reductase inhibitors — do not appear to cause IFIS to any significant degree." 5-ARIs include finasteride, a medication typically used as first line therapy for BPH and androgenic alopecia. The medication is also associated with cataract formation.IFIS may also be associated with other causes of small pupil like synechiae, pseudoexfoliation and other medications (used for conditions such as glaucoma, diabetes and high blood pressure). IFIS does not usually cause significant changes in postoperative outcomes. Patients may experience more pain, a longer recovery period, and less improvement in visual acuity than a patient with an uncomplicated cataract removal.
The severity of the condition is not linked to the duration of tamsulosin intake.
References
== External links == |
Mother | A mother is the female parent of a child. A woman may be considered a mother by virtue of having given birth, by raising a child who may or may not be her biological offspring, or by supplying her ovum for fertilisation in the case of gestational surrogacy.
An adoptive mother is a female who has become the childs parent through the legal process of adoption. A biological mother is the female genetic contributor to the creation of the infant, through sexual intercourse or egg donation. A biological mother may have legal obligations to a child not raised by her, such as an obligation of monetary support. A putative mother is a female whose biological relationship to a child is alleged but has not been established. A stepmother is a woman who is married to a childs father and they may form a family unit, but who generally does not have the legal rights and responsibilities of a parent in relation to the child.
A father is the male counterpart of a mother. Women who are pregnant may be referred to as expectant mothers or mothers-to-be, though such appellations are less readily applied to (biological) fathers or adoptive parents. The process of becoming a mother has been referred to as "matrescence".The adjective "maternal" refers to a mother and comparatively to "paternal" for a father. The verb "to mother" means to procreate or to sire a child, or to provide care for a child, from which also derives the noun "mothering". Related terms of endearment are mom (mama, mommy), mum (mummy), mumsy, mamacita (ma, mam) and mammy. A female role model that children can look up to is sometimes referred to as a mother-figure.
Types of motherhood
Biological mother
Biological motherhood for humans, as in other mammals, occurs when a pregnant female gestates a fertilized ovum (the "egg"). A female can become pregnant through sexual intercourse after she has begun to ovulate. In well-nourished girls, menarche (the first menstrual period) usually takes place around the age of 12 or 13.Typically, a fetus develops from the viable zygote, resulting in an embryo. Gestation occurs in the womans uterus until the fetus (assuming it is carried to term) is sufficiently developed to be born. In humans, gestation is often around 9 months in duration, after which the woman experiences labor and gives birth. This is not always the case, however, as some babies are born prematurely, late, or in the case of stillbirth, do not survive gestation. Usually, once the baby is born, the mother produces milk via the lactation process. The mothers breast milk is the source of antibodies for the infants immune system, and commonly the sole source of nutrition for newborns before they are able to eat and digest other foods; older infants and toddlers may continue to be breastfed, in combination with other foods, which should be introduced from approximately six months of age.Childlessness is the state of not having children. Childlessness may have personal, social or political significance. Childlessness may be voluntary childlessness, which occurs by choice, or may be involuntary due to health problems or social circumstances. Motherhood is usually voluntary, but may also be the result of forced pregnancy, such as pregnancy from rape. Unwanted motherhood occurs especially in cultures which practice forced marriage and child marriage.
Non-biological mother
Mother can often apply to a woman other than the biological parent, especially if she fulfills the main social role in raising the child. This is commonly either an adoptive mother or a stepmother (the biologically unrelated partner of a childs father). The term "othermother" or "other mother" is also used in some contexts for women who provide care for a child not biologically their own in addition to the childs primary mother.
Adoption, in various forms, has been practiced throughout history, even predating human civilization. Modern systems of adoption, arising in the 20th century, tend to be governed by comprehensive statutes and regulations. In recent decades, international adoptions have become more and more common.
Adoption in the United States is common and relatively easy from a legal point of view (compared to other Western countries). In 2001, with over 127,000 adoptions, the US accounted for nearly half of the total number of adoptions worldwide.
Surrogate mother
A surrogate mother is a woman who bears a child that came from another womans fertilized ovum on behalf of a couple unable to give birth to children. Thus the surrogate mother carries and gives birth to a child that she is not the biological mother of. Surrogate motherhood became possible with advances in reproductive technologies, such as in vitro fertilization.
Not all women who become pregnant via in vitro fertilization are surrogate mothers. Surrogacy involves both a genetic mother, who provides the ovum, and a gestational (or surrogate) mother, who carries the child to term.
Lesbian and bisexual motherhood
The possibility for lesbian and bisexual women in same-sex relationships to become mothers has increased over the past few decades due to technological developments. Modern lesbian parenting originated with women who were in heterosexual relationships who later identified as lesbian or bisexual, as changing attitudes provided more acceptance for non-heterosexual relationships. Other ways for such women to become mothers is through adopting, foster parenting or in vitro fertilization.
Transgender motherhood
Transgender women may have biological children with a partner by utilizing their sperm to fertilize an egg and form an embryo. For transgender women, there is currently no accessible way to carry a child. However, research is being done on uterus transplants, which could potentially allow transgender women to carry and give birth to children through Caesarean section. Other types of motherhood include adoption or foster parenting. However, adoption agencies often refuse to work with transgender parents or are reluctant to do so.
Social role
The social roles associated with motherhood are variable across time, culture, and social class.
Historically, the role of women was confined to some extent to being a mother and wife, with women being expected to dedicate most of their energy to these roles, and to spend most of their time taking care of the home. In many cultures, women received significant help in performing these tasks from older female relatives, such as mothers in law or their own mothers.
Regarding women in the workforce, mothers are said to often follow a "mommy track" rather than being entirely "career women". Mothers may be stay at home mothers or working mothers. In recent decades there has been an increase in stay at home fathers too. Social views on these arrangements vary significantly by culture: in Europe for instance, in German-speaking countries there is a strong tradition of mothers exiting the workforce and being homemakers. Mothers have historically fulfilled the primary role in raising children, but since the late 20th century, the role of the father in child care has been given greater prominence and social acceptance in some Western countries. The 20th century also saw more and more women entering paid work. Mothers rights within the workforce include maternity leave and parental leave.
The social role and experience of motherhood varies greatly depending upon location. Mothers are more likely than fathers to encourage assimilative and communion-enhancing patterns in their children. Mothers are more likely than fathers to acknowledge their childrens contributions in conversation. The way mothers speak to their children ("motherese") is better suited to support very young children in their efforts to understand speech (in context of the reference English) than fathers.Since the 1970s, in vitro fertilization has made pregnancy possible at ages well beyond "natural" limits, generating ethical controversy and forcing significant changes in the social meaning of motherhood. This is, however, a position highly biased by Western world locality: outside the Western world, in-vitro fertilization has far less prominence, importance or currency compared to primary, basic healthcare, womens basic health, reducing infant mortality and the prevention of life-threatening diseases such as polio, typhus and malaria.
Traditionally, and still in most parts of the world today, a mother was expected to be a married woman, with birth outside of marriage carrying a strong social stigma. Historically, this stigma not only applied to the mother, but also to her child. This continues to be the case in many parts of the developing world today, but in many Western countries the situation has changed radically, with single motherhood being much more socially acceptable now. For more details on these subjects, see Legitimacy (family law) and single parent.
The total fertility rate (TFR), that is, the number of children born per woman, differs greatly from country to country. The TFR in 2013 was estimated to be highest in Niger (7.03 children born per woman) and lowest in Singapore (0.79 children/woman).In the United States, the TFR was estimated for 2013 at 2.06 births per woman. In 2011, the average age at first birth was 25.6 and 40.7% of births were to unmarried women.
Health
A maternal death is defined by WHO as "the death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the duration and site of the pregnancy, from any cause related to or aggravated by the pregnancy or its management but not from accidental or incidental causes".About 56% of maternal deaths occur in Sub-Saharan Africa and another 29% in South Asia.In 2006, the organization Save the Children has ranked the countries of the world, and found that Scandinavian countries are the safest places to give birth, whereas countries in sub-Saharan Africa are the least safe to give birth. This study argues a mother in the bottom ten ranked countries is over 750 times more likely to die in pregnancy or childbirth, compared to a mother in the top ten ranked countries, and a mother in the bottom ten ranked countries is 28 times more likely to see her child die before reaching their first birthday.
The most recent data suggests that Italy, Sweden and Luxembourg are the safest countries in terms of maternal death and Afghanistan, Central African Republic and Malawi are the most dangerous.Childbirth is an inherently dangerous and risky process, subject to many complications. The "natural" mortality rate of childbirth—where nothing is done to avert maternal death—has been estimated as being 1500 deaths per 100,000 births. Modern medicine has greatly alleviated the risk of childbirth. In modern Western countries the current maternal mortality rate is around 10 deaths per 100,000 births.
Religious
Nearly all world religions define tasks or roles for mothers through either religious law or through the glorification of mothers who served in substantial religious events. There are many examples of religious law relating to mothers and women.
Major world religions which have specific religious law or scriptural canon regarding mothers include: Christianity, Judaism, and Islam. Some examples of honoring motherhood include the Madonna or Blessed Virgin Mother Mary for Catholics, and the multiple positive references to active womanhood as a mother in the Book of Proverbs.
Hindus Mother Goddess and Demeter of ancient Greek pre-Christian belief are also mothers.
Mother-offspring violence
History records many conflicts between mothers and their children. Some even resulted in murder, such as the conflict between Cleopatra III of Egypt and her son Ptolemy X.
In modern cultures, matricide (the killing of ones mother) and filicide (the killing of ones son or daughter) have been studied but remain poorly understood. Psychosis and schizophrenia are common causes of both, and young, indigent mothers with a history of domestic abuse are slightly more likely to commit filicide. Mothers are more likely to commit filicide than fathers when the child is 8 years old or younger. Matricide is most frequently committed by adult sons.In the United States in 2012, there were 130 matricides (0.4 per million people) and 383 filicides (1.2 per million), or 1.4 incidents per day.
In art
Throughout history, mothers have been depicted in a variety of art works, including paintings, sculptures and written texts, that have helped define the cultural meaning of ‘mother’, as well as ideals and taboos of motherhood.
Fourth century grave reliefs on the island of Rhodes depicted mothers with children.Paintings of mothers with their children have a long tradition in France. In the 18th century, these works embodied the Enlightenments preoccupation with strong family bonds and the relation between mothers and children.At the end of the nineteenth century, Mary Cassatt was a painter well known for her portraits of mothers.
American poet, essayist and feminist Adrienne Rich has noted “the disjuncture between motherhood as patriarchal institution and motherhood as complexly and variously lived experience”. The vast majority of works depicting motherhood in western art history have been created by artists who are men, with very few having been created by women or mothers themselves, and these often focus on the “institution of motherhood” rather than diverse lived experiences. At the same time, art concerning motherhood has been historically marginalized within the feminist art movement, though this is changing with an increasing number of feminist publications addressing this topic.The institution of motherhood in western art is often depicted through “the myth of the all-loving, all-forgiving and all-sacrificing mother” and related ideals. Examples include works featuring the Virgin Mary, an archetypal mother and a key historical basis for depictions of mothers in western art from the European Renaissance onwards. Mothers depicted in dominant art works are also primarily white, heterosexual, middle class and young or attractive.These ideals of motherhood have been challenged by artists with lived experience as mothers. An example in western contemporary art is Mary Kelly’s Post-Partum Document. Bypassing typical themes of tenderness or nostalgia, this work documents in extensive detail the challenges, complexities and day-to-day realities of the mother-child relationship. Other artists have addressed similar aspects of motherhood that fall outside dominant ideals, including maternal ambivalence, desire, and the pursuit of self-fulfillment. While the ideal of maternal self-sacrifice and the ‘good mother’ forms an important part of many works of art relating to the Holocaust, other women’s Holocaust and post-Holocaust art has engaged more deeply with mothers’ trauma, taboos, and the experiences of second and third-generation Holocaust survivors. For example, works by first-generation survivors of the Holocaust such as Ella Liebermann-Shiber and Shoshana Neuman have depicted mothers abandoning and suffocating their children in an effort to stay alive themselves.
Increasingly diverse representations of motherhood can be found in contemporary works of art. Catherine Opie’s self-portrait photographs, including of herself nursing, reference the existing Virgin Mary archetype while subverting its norms around sexuality by centering her identity as a lesbian. Rather than attempting to make her experience of motherhood fit into existing norms, Opie’s photographs are “non-traditional and non-apologetic representations”.In her 2020 photography collection, Solana Cain explored the meaning of joy for Black mothers to challenge the lack of images in mainstream media that represent Black motherhood. Renee Cox’s Yo Mama series of nude self-portraits challenge historical representations of both the black female body and of maternity and slavery in the US, the latter of which is often characterized by the “extreme passivity and devalued love” typically associated with motherhood.
Synonyms and translations
The proverbial "first word" of an infant often sounds like "ma" or "mama". This strong association of that sound with "mother" has persisted in nearly every language on earth, countering the natural localization of language.
Familiar or colloquial terms for mother in English are:
Ma(মা), Mata (মাতা), Amma (আম্মা), Ammu (আম্মু) used in Bangladesh, India.
Aama, Mata used in Nepal
Mom and mommy are used in the United States, Canada, South Africa, and parts of the West Midlands including Birmingham in the United Kingdom.
Inay, Nanay, Mama, Ma, Mom, Mommy are used in the Philippines
Mum and mummy and mama are used in the United Kingdom, Canada, Singapore, Australia, New Zealand, India, Pakistan, Hong Kong and Ireland.
Ma, mam, and mammy are used in Netherlands, Ireland, the Northern areas of the United Kingdom, and Wales; it is also used in some areas of the United States.
Mama was imported into Japan from American influence post-World War II, and is a less formal term for motherIn many other languages, similar pronunciations apply:
Amma (அம்மா) or Thai (தாய்) in Tamil.
Bi-ma (बिमा) in Bodo.
Maa, aai, amma, and mata are used in languages of India like Assamese, Bengali, Hindi, Marathi, Tamil, Telugu etc.
Mamá, mama, ma, and mami in Spanish
Mama in Polish, German, Dutch, Russian and Slovak
Māma (妈妈/媽媽) in Chinese
Máma in Czech and in Ukrainian
Maman in French and Persian
Ma, mama in Indonesian
Mamaí, mam in Irish
Mamma in Italian, Icelandic, Latvian and Swedish
Māman or mādar in Persian
Mamãe or mãe in Portuguese
Mā̃ (ਮਾਂ) in Punjabi
Mõujì in Kashmiri
Maa(ମା), Bou/Bau(ବୋଉ/ବଉ) in Odia
Mama in Swahili
Em (אם) in Hebrew
Ama (ܐܡܐ) in Aramaic
Má or mẹ in Vietnamese
Mam in Welsh
Eomma (엄마, pronounced [ʌmma]) in Korean
Mma in Tyap
In many south Asian cultures and the Middle East, the mother is known as amma, oma, ammi or "ummi", or variations thereof. Many times, these terms denote affection or a maternal role in a childs life.
Etymology
The modern English word is from Middle English moder, from Old English mōdor, from Proto-Germanic *mōdēr (cf. East Frisian muur, Dutch moeder, German Mutter), from Proto-Indo-European *méh₂tēr (cf. Irish máthair, Tocharian A mācar, B mācer, Lithuanian mótė). Other cognates include Latin māter, Greek μήτηρ, Common Slavic *mati (thence Russian мать (mat’)), Persian مادر (madar), and Sanskrit मातृ (mātṛ).
Notable mothers
Zoology
In zoology, particularly in mammals, a mother fills many similar biological functions as a human mother.
Mammals
Many other mammal mothers also have numerous commonalities with humans.
Primates
The behavior and role of mothers in non-human species is most similar in species most closely related to humans. This means great apes are most similar, then the broader superfamily of all apes, then all primates.
See also
References
Further reading
External links
Quotations related to Mother at Wikiquote
Media related to Mothers at Wikimedia Commons
The dictionary definition of mother at Wiktionary |
Level | Level or levels may refer to:
Engineering
Level (instrument), a device used to measure true horizontal or relative heights
Spirit level, an instrument designed to indicate whether a surface is horizontal or vertical
Canal pound or level
Regrading or levelling, the process of raising and/or lowering the levels of land
Storey or level, a vertical unit of a building or a mine
Level (coordinate), vertical position
Gaming
Level (video games), a stage of the game
Level (role-playing games), a measurement of character development
Music
Level (music), similar to but more general and basic than a chord
Levels (album), an album by AKA
"Levels" (Avicii song)
"Levels" (Bilal song)
"Levels" (Nick Jonas song)
"Levels" (Meek Mill song)
"Level" (The Raconteurs song)
"Levels" (NorthSideBenji song), featuring Houdini
Places
Level Mountain, a volcano in northern British Columbia, Canada
Levél, Győr-Moson-Sopron, Hungary
Levels, New Zealand
Level, Ohio, United States
Level Valley
Levels, West Virginia
Science and mathematics
A quantity, generally
Level (algebra), the lowest number of squares that sum to
−
1
{\displaystyle -1}
in a field
Level (logarithmic quantity), a logarithmic measure defined as the logarithm of a ratio of two like quantities
Level, the different values that a categorical variable can have
Level, the different values that a factor can have in factor analysis
Level, the different treatments that are applied within a factor in the design of experiments
Other uses
Level (airline), a pan-European airline brand
LeveL, a games magazine in the Czech Republic, Romania, and Turkey
The Level, Brighton, a park in Brighton, UK
Level Vodka, a brand of vodka
Level, a collection of objects with the same rank in an overlapping hierarchy
Level, a layer of defense in two-level defense in American football
Level, an indication of the number of previous posts to a forum thread
LEVEL, a website for men of color published by Medium
The Level (TV series)
People with the surname
Annick Level (born 1942), French fencer
Calvin Levels (born 1954), American film actor
Dwayne Levels (born 1979), American football player
Janou Levels (born 2000), Dutch footballer
Léon Level (1910–1949), French professional road bicycle racer
Maurice Level (1875–1926), French writer
Tobias Levels (born 1986), German-Dutch footballer
See also
A-Scale Sound Level
Biological organisation
Derived no-effect level
Energy levels, discrete amounts of energy that can be held by a quantum mechanical system or confined particle
Flesch-Kincaid Grade Level
GCE Ordinary Level
Gal Level, an R&B girl duo from Windhoek, Namibia
ILR scale, descriptions of abilities to communicate in a language
Level crossing, a place where track and road meet at the same level
Level 3 (disambiguation)
Level 42, an English pop rock and jazz-funk band
Level measurement, instrumentation techniques to measure height within a vessel
Level of measurement, a theory of the kinds of scales or levels used for measuring
Level playing field, a concept about fairness where all play by the same set of rules
Level set, a set where a function takes on a given constant value
Leveling (disambiguation)
Leveling seat
Levellers
Pevensey Levels
Sea level, the average height of the oceans surface, reference of height systems
Somerset Levels
Terror Alert Level
Water level, the average height of a water |
Electrode | An electrode is an electrical conductor used to make contact with a nonmetallic part of a circuit (e.g. a semiconductor, an electrolyte, a vacuum or air). Electrodes are essential parts of batteries that can consist of a variety of materials depending on the type of battery.
The electrophore, invented by Johan Wilcke, was an early version of an electrode used to study static electricity.
Anode and cathode in electrochemical cells
Electrodes are an essential part of any battery. The first electrochemical battery made was devised by Alessandro Volta and was aptly named the Voltaic cell. This battery consisted of a stack of copper and zinc electrodes separated by brine-soaked paper disks. Due to fluctuation in the voltage provided by the voltaic cell it wasnt very practical. The first practical battery was invented in 1839 and named the Daniell cell after John Frederic Daniell. Still making use of the zinc–copper electrode combination. Since then many more batteries have been developed using various materials (see List of batteries). The basis of all these is still making use of two electrodes which can be divided in two categories: Anodes and Cathodes.
Anode
A term coined by William Whewell at Faradays request, derived from the Greek words ἄνο (ano), upwards and ὁδός (hodós), a way. The Anode is the electrode through which the conventional current enters from the electrical circuit of an electrochemical cell (battery) into the non-metallic cell. The electrons then flow to the other side of the battery. Note the difference in the flow of current and the flow of electrons, this is due to the discovery of the flow of current prior to the discovery of the electron. Benjamin Franklin surmised that the electrical flow moved from positive to negative. The electrons flow away from the anode and the conventional current towards it. From both can be concluded that the charge of the anode is negative. The electron entering the anode comes from the oxidation reaction that takes place next to it.
Cathode
The cathode is in many ways the opposite of the anode. The name (also coined by William Whewell) comes from the Greek words κάτω (kato), downwards and ὁδός (hodós), a way. It is the positive electrode, meaning the electrons flow from the electrical circuit through the cathode into the non-metallic part of the electrochemical cell. At the cathode, the reduction reaction takes place with the electrons arriving from the wire connected to the cathode and are absorbed by the oxidizing agent.
Primary cell
A primary cell is a battery designed to be used once and then discarded. This is due to the electrochemical reactions taking place at the electrodes in the cell not being reversible. An example of a primary cell is the discardable alkaline battery used in for example flashlights. Consisting of a zinc anode and a manganese oxide cathode in which ZnO is formed.
The half-reactions are:
Zn(s) + 2OH−(aq) → ZnO(s) + H2O(l) + 2e−
{\displaystyle \qquad \qquad }
[E0oxidation = -1.28 V]
2MnO2(s) + H2O(l) + 2e− → Mn2O3(s) + 2OH−(aq)
{\displaystyle \qquad }
[E0reduction = +0.15 V]Overall reaction:
Zn(s) + 2MnO2(s) ⇌ ZnO(s) + Mn2O3(s)
{\displaystyle \qquad \qquad }
[E0total = +1.43 V]The ZnO is prone to clumping and will give less efficient discharge if recharged again. It is possible to recharge these batteries but is due to safety concerns advised against by the manufacturer. Other primary cells include zinc-carbon, zinc-chloride, and lithium iron disulfide batteries.
Secondary cell
Contrary to the primary cell a secondary cell can be recharged. The first of which was the lead-acid battery invented in 1859 by French Gaston Planté. This type of battery is still the most widely used in among others automobiles. The cathode consists of lead dioxide (PbO2) and the anode of solid lead. Other commonly used rechargeable batteries are nickel-cadmium, nickel-metal hydride battery, and Lithium-ion batteries. The last of which will be more explained more thoroughly in this article due to its importance.
Marcus theory of electron transfer
Marcus theory is a theory originally developed by Nobel laureate Rudolph A. Marcus and explains the rate at which an electron can move from one chemical species to another, for this article this can be seen as jumping from the electrode to a species in the solvent or vice versa.
We can represent the problem as calculating the transfer rate for the transfer of an electron from donor to an acceptor
D + A → D+ + A−
The potential energy of the system is a function of the translational, rotational, and vibrational coordinates of the reacting species and the molecules of the surrounding medium, collectively called the reaction coordinates. The abscissa the figure to the right represents these. From the classical electron transfer theory, the expression of the reaction rate constant (probability of reaction) can be calculated, if a non-adiabatic process and parabolic potential energy are assumed, by finding the point of intersection (Qx). One important thing to note, and was noted by Marcus when he came up with the theory, the electron transfer must abide by the law of conservation of energy and the Frank-Condon principle.
Doing this and then rearranging this leads to the expression of the free energy activation (
Δ
G
†
{\displaystyle \Delta G^{\dagger }}
) in terms of the overall free energy of the reaction (
Δ
G
0
{\displaystyle \Delta G^{0}}
).
In which the
λ
{\displaystyle \lambda }
is the reorganisation energy.
Filling this result in the classically derived Arrhenius equation
leads to
With A being the pre-exponential factor which is usually experimentally determined, although a semi classical derivation provides more information as will be explained below.
This classically derived result qualitatively reproduced observations of a maximum electron transfer rate under the conditions
Δ
G
†
=
λ
{\displaystyle \Delta G^{\dagger }=\lambda }
. For a more extensive mathematical treatment one could read the paper by Newton. An interpretation of this result and what a closer look at the physical meaning of the
λ
{\displaystyle \lambda }
one can read the paper by Marcus.the situation at hand can be more accurately described by using the displaced harmonic oscillator model, in this model quantum tunneling is allowed. This is needed in order to explain why even at near-zero Kelvin there still are electron transfers, in contradiction to the classical theory.
Without going into too much detail on how the derivation is done, it rests on using Fermis golden rule from time-dependent perturbation theory with the full Hamiltonian of the system. It is possible to look at the overlap in the wavefunctions of both the reactants and the products (the right and the left side of the chemical reaction) and therefore when their energies are the same and allow for electron transfer. As touched on before this must happen because only then conservation of energy is abided by. Skipping over a few mathematical steps the probability of electron transfer can be calculated (albeit quite difficult) using the following formula
With
J
{\displaystyle J}
being the electronic coupling constant describing the interaction between the two states (reactants and products) and
g
(
t
)
{\displaystyle g(t)}
being the line shape function. Taking the classical limit of this expression, meaning
ℏ
ω
≪
k
T
{\displaystyle \hbar \omega \ll kT}
, and making some substitution an expression is obtained very similar to the classically derived formula, as expected.
The main difference is now the pre-exponential factor has now been described by more physical parameters instead of the experimental factor
A
{\displaystyle A}
. One is once again revered to the sources as listed below for a more in-depth and rigorous mathematical derivation and interpretation.
Efficiency
The physical properties of electrodes are mainly determined by the material of the electrode and the topology of the electrode. The properties required depend on the application and therefore there are many kinds of electrodes in circulation. The defining property for a material to be used as an electrode is that it be conductive. Any conducting material such as metals, semiconductors, graphite or conductive polymers can therefore be used as an electrode. Often electrodes consist of a combination of materials, each with a specific task. Typical constituents are the active materials which serve as the particles which oxidate or reduct, conductive agents which improve the conductivity of the electrode and binders which are used to contain the active particles within the electrode. The efficiency of electrochemical cells is judged by a number of properties, important quantities are the self-discharge time, the discharge voltage and the cycle performance. The physical properties of the electrodes play an important role in determining these quantities. Important properties of the electrodes are: the electrical resistivity, the specific heat capacity (c_p), the electrode potential and the hardness. Of course, for technological applications, the cost of the material is also an important factor. The values of these properties at room temperature (T = 293 K) for some commonly used materials are listed in the table below.
Surface effects
The surface topology of the electrode plays an important factor in determining the efficiency of an electrode. The efficiency of the electrode can be reduced due to contact resistance. To create an efficient electrode it is therefore important to design it such that it minimizes the contact resistance.
Manufacturing
The production of electrodes for Li-Ion batteries is done in various steps as follows:
The various constituents of the electrode are mixed into a solvent. This mixture is designed such that it improves the performance of the electrodes. Common components of this mixture are:
The active electrode particles.
A binder used to contain the active electrode particles.
A conductive agent used to improve the conductivity of the electrode.The mixture created is known as an ‘electrode slurry’.
The electrode slurry above is coated onto a conductor which acts as the current collector in the electrochemical cell. Typical current collectors are copper for the cathode and aluminum for the anode.
After the slurry has been applied to the conductor it is dried and then pressed to the required thickness.
Structure of the electrode
For a given selection of constituents of the electrode, the final efficiency is determined by the internal structure of the electrode. The important factors in the internal structure in determining the performance of the electrode are:
Clustering of the active material and the conductive agent. In order for all the components of the slurry to perform their task, they should all be spread out evenly within the electrode.
An even distribution of the conductive agent over the active material. This makes sure that the conductivity of the electrode is optimal.
The adherence of the electrode to the current collectors. The adherence makes sure that the electrode does not dissolve into the electrolyte.
The density of the active material. A balance should be found between the amount of active material, the conductive agent and the binder. Since the active material is the important factor in the electrode, the slurry should be designed such that the density of the active material is as high as possible, without the conductive agent and the binder not functioning properly.These properties can be influenced in the production of the electrodes in a number of manners. The most important step in the manufacturing of the electrodes is creating the electrode slurry. As can be seen above, the important properties of the electrode all have to do with the even distribution of the components of the electrode. Therefore, it is very important that the electrode slurry be as homogeneous as possible. Multiple procedures have been developed to improve this mixing stage and current research is still being done.
Electrodes in lithium ion batteries
A modern application of electrodes is in Lithium-ion batteries (li-ion batteries). A Li-ion battery is a kind of flow battery which can be seen in the image on the right.
Furthermore, a Li-ion battery is an example of a secondary cell since it is rechargeable. It can both act as a galvanic or electrolytic cell. Li-ion batteries use lithium ions as the solute in the electrolyte which are dissolved in an organic solvent. Lithium electrodes were first studied by G.N. Lewis and F.G. Keyes in 1913. In the following century these electrodes were used to create and study the first Li-ion batteries. Li-ion batteries are very popular due to their great performance. Applications include mobile phones and electric cars. Due to their popularity, much research is being done to reduce the cost and increase the safety of Li-ion batteries. An integral part of the Li-ion batteries are their anodes and cathodes, therefore much research is being done into increasing the efficiency, safety and reducing the costs of these electrodes specifically.
Cathodes
In Li-ion batteries the cathode consists of a intercalated lithium compound (a layered material consisting of layers of molecules composed of lithium and other elements). A common element which makes up part of the molecules in the compound is cobalt. Another frequently used element is manganese. The best choice of compound usually depends on the application of the battery. Advantages for cobalt-based compounds over manganese-based compounds are their high specific heat capacity, high volumetric heat capacity, low self-discharge rate, high discharge voltage and high cycle durability. There are however also drawbacks in using cobalt-based compounds such as their high cost and their low thermostability. Manganese has similar advantages and a lower cost, however there are some problems associated with using manganese. The main problem is that manganese tends to dissolve into the electrolyte over time. For this reason cobalt is still the most common element which is used in the lithium compounds. There is much research being done into finding new materials which can be used to create cheaper and longer lasting Li-ion batteries
Anodes
The anodes used in mass-produced Li-ion batteries are either carbon based (usually graphite) or made out of spinel lithium titanate (Li4Ti5O12). Graphite anodes have been successfully implemented in many modern commercially available batteries due to its cheap price, longevity and high energy density. However, it presents issues of dendrite growth, with risks of shorting the battery and posing a safety issue. Li4Ti5O12 has the second largest market share of anodes, due to its stability and good rate capability, but with challenges such as low capacity. During the early 2000, Silicon anode research began picking up pace, becoming one of the 2020s most promising candidates for future Lithium ion battery anodes. Silicon has one of the highest gravimetric capacities when compared to graphite and Li4Ti5O12 as well as a high volumetric one . Furthermore, Silicon has the advantage of operating under a reasonable open circuit voltage without parasitic lithium reactions. However, Silicon anodes have a major issue of volumetric expansion during lithiation of around 360%. This expansion may pulverize the anode, resulting in poor performance. To fix this problem scientists looked into varying the dimensionality of the Si. Many studies have been developed in Si nanowires, Si tubes as well as Si sheets. As a result, composite hierarchical Si anodes have become the major technology for future applications in Lithium Ion Batteries. In the early 2020s technology is reaching commercial levels with factories being built for mass production of anodes in the United States. Furthermore, metallic Lithium is another possible candidate for the anode. It boasts a higher specific capacity than Silicon, however, does come with the drawback of working with the highly unstable metallic lithium. Similarly to graphite anodes, dendrite formation is another major limitation of metallic lithium, with the solid electrolyte interphase being a major design challenge. In the end, if stabilized, metallic lithium would be able to produce batteries that hold the most charge, while being the lightest.
Mechanical Properties
A common failure mechanism of batteries is mechanical shock, which breaks either the electrode or the system’s container, leading to poor conductivity and electrolyte leakage. However, the relevance of mechanical properties of electrodes goes beyond the resistance to collisions due to its environment. During standard operation, the incorporation of ions into electrodes leads to a change in volume. This is well exemplified by Si electrodes in Lithium-ion batteries expanding around 300% during lithiation. Such change may lead to the deformations in the lattice and, therefore stresses in the material. The origin of stresses may be due to geometric constraints in the electrode or inhomogeneous plating of the ion. This phenomenon is very concerning as it may lead to electrode fracture and performance loss. Thus, mechanical properties are crucial to enable the development of new electrodes for long lasting batteries. A possible strategy for measuring the mechanical behavior of electrodes during operation is by using nanoindentation. The method is able to analyze how the stresses evolve during the electrochemical reactions, being a valuable tool in evaluating possible pathways for coupling mechanical behavior and electrochemistry.
More than just affecting the electrode’s morphology, stresses are also able to impact electrochemical reactions. While the chemical driving forces are usually higher in magnitude than the mechanical energies, this is not true for Li-Ion Batteries. A study by Dr. Larché established a direct relation between the applied stress and the chemical potential of the electrode. Though it neglects multiple variables such as the variation of elastic constraints, it subtracts from the total chemical potential the elastic energy induced by the stress.
μ
=
μ
o
+
k
⋅
T
⋅
log
(
γ
⋅
x
)
+
Ω
⋅
σ
{\displaystyle \mu =\mu ^{o}+k\cdot T\cdot \log(\gamma \cdot x)+\Omega \cdot \sigma }
In this equation μ represents the chemical potential, with μ° being its reference value. T stands for the temperature and k the Boltzmann constant. The term γ inside the logarithm is the activity and x is the ratio of the ion to the total composition of the electrode. The novel term Ω is the partial molar volume of the ion in the host and σ corresponds to the mean stress felt by the system. The result of this equation is that diffusion, which is dependent on chemical potential, gets impacted by the added stress and, therefore changes the battery’s performance. Furthermore, mechanical stresses may also impact the electrode’s solid-electrolyte-interphase layer. The interface which regulates the ion and charge transfer and can be degraded by stress. Thus, more ions in the solution will be consumed to reform it, diminishing the overall efficiency of the system.
Other anodes and cathodes
In a vacuum tube or a semiconductor having polarity (diodes, electrolytic capacitors) the anode is the positive (+) electrode and the cathode the negative (−). The electrons enter the device through the cathode and exit the device through the anode. Many devices have other electrodes to control operation, e.g., base, gate, control grid.
In a three-electrode cell, a counter electrode, also called an auxiliary electrode, is used only to make a connection to the electrolyte so that a current can be applied to the working electrode. The counter electrode is usually made of an inert material, such as a noble metal or graphite, to keep it from dissolving.
Welding electrodes
In arc welding, an electrode is used to conduct current through a workpiece to fuse two pieces together. Depending upon the process, the electrode is either consumable, in the case of gas metal arc welding or shielded metal arc welding, or non-consumable, such as in gas tungsten arc welding. For a direct current system, the weld rod or stick may be a cathode for a filling type weld or an anode for other welding processes. For an alternating current arc welder, the welding electrode would not be considered an anode or cathode.
Alternating current electrodes
For electrical systems which use alternating current, the electrodes are the connections from the circuitry to the object to be acted upon by the electric current but are not designated anode or cathode because the direction of flow of the electrons changes periodically, usually many times per second.
Chemically modified electrodes
Chemically modified electrodes are electrodes that have their surfaces chemically modified to change the electrodes physical, chemical, electrochemical, optical, electrical, and transportive properties. These electrodes are used for advanced purposes in research and investigation.
Uses
Electrodes are used to provide current through nonmetal objects to alter them in numerous ways and to measure conductivity for numerous purposes. Examples include:
Electrodes for fuel cells
Electrodes for medical purposes, such as EEG (for recording brain activity), ECG (recording heart beats), ECT (electrical brain stimulation), defibrillator (recording and delivering cardiac stimulation)
Electrodes for electrophysiology techniques in biomedical research
Electrodes for execution by the electric chair
Electrodes for electroplating
Electrodes for arc welding
Electrodes for cathodic protection
Electrodes for grounding
Electrodes for chemical analysis using electrochemical methods
Nanoelectrodes for high-precision measurements in nanoelectrochemistry
Inert electrodes for electrolysis (made of platinum)
Membrane electrode assembly
Electrodes for Taser electroshock weapon
See also
References
Further reading
Kebede, Mesfin A.; Ezema, Fabian I., eds. (2022). Electrode materials for energy storage and conversion (First ed.). Boca Raton: CRC Press/Taylor & Francis. doi:10.1201/9781003145585. ISBN 978-0-367-70304-2. S2CID 240536462.
Doeff, MM; Chen, G; Cabana, J; Richardson, TJ; Mehta, A; Shirpour, M; Duncan, H; Kim, C; Kam, KC; Conry, T (11 November 2013). "Characterization of electrode materials for lithium ion and sodium ion batteries using synchrotron radiation techniques". Journal of Visualized Experiments (81): e50594. doi:10.3791/50594. PMC 3989498. PMID 24300777. |
Chronic fatigue | Chronic fatigue may refer to:
Fatigue (medical)#Chronic, a long-term state of physical or mental exhaustion, a symptom of many chronic illnesses
Chronic fatigue syndrome, a medical condition characterized by long-term fatigue and other long term symptoms that limit a persons ability to carry out ordinary daily activities. |
Hallucination | A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combination of 2 conscious states of brain wakefulness and REM sleep. They are distinguishable from several related phenomena, such as dreaming (REM sleep), which does not involve wakefulness; pseudohallucination, which does not mimic real perception, and is accurately perceived as unreal; illusion, which involves distorted or misinterpreted real perception; and mental imagery, which does not mimic real perception, and is under voluntary control. Hallucinations also differ from "delusional perceptions", in which a correctly sensed and interpreted stimulus (i.e., a real perception) is given some additional significance. Many hallucinations happen also during sleep paralyses.Hallucinations can occur in any sensory modality—visual, auditory, olfactory, gustatory, tactile, proprioceptive, equilibrioceptive, nociceptive, thermoceptive and chronoceptive. Hallucinations are referred to as multimodal if multiple sensory modalities occur.A mild form of hallucination is known as a disturbance, and can occur in most of the senses above. These may be things like seeing movement in peripheral vision, or hearing faint noises or voices. Auditory hallucinations are very common in schizophrenia. They may be benevolent (telling the subject good things about themselves) or malicious, cursing the subject. 55% of auditory hallucinations are malicious in content, for example, people talking about the subject, not speaking to them directly. Like auditory hallucinations, the source of the visual counterpart can also be behind the subject. This can produce a feeling of being looked or stared at, usually with malicious intent. Frequently, auditory hallucinations and their visual counterpart are experienced by the subject together.Hypnagogic hallucinations and hypnopompic hallucinations are considered normal phenomena. Hypnagogic hallucinations can occur as one is falling asleep and hypnopompic hallucinations occur when one is waking up. Hallucinations can be associated with drug use (particularly deliriants), sleep deprivation, psychosis, neurological disorders, and delirium tremens.
The word "hallucination" itself was introduced into the English language by the 17th-century physician Sir Thomas Browne in 1646 from the derivation of the Latin word alucinari meaning to wander in the mind. For Browne, hallucination means a sort of vision that is "depraved and receive[s] its objects erroneously".
Classification
Hallucinations may be manifested in a variety of forms. Various forms of hallucinations affect different senses, sometimes occurring simultaneously, creating multiple sensory hallucinations for those experiencing them.
Auditory
Auditory hallucinations (also known as paracusia) are the perception of sound without outside stimulus. Auditory hallucinations can be divided into elementary and complex, along with verbal and nonverbal. These hallucinations are the most common type of hallucination, with auditory verbal hallucinations being more common than nonverbal. Elementary hallucinations are the perception of sounds such as hissing, whistling, an extended tone, and more. In many cases, tinnitus is an elementary auditory hallucination. However, some people who experience certain types of tinnitus, especially pulsatile tinnitus, are actually hearing the blood rushing through vessels near the ear. Because the auditory stimulus is present in this situation, it does not qualify it as a hallucination.
Complex hallucinations are those of voices, music, or other sounds that may or may not be clear, may or may not be familiar, and may be friendly, aggressive, or among other possibilities. A hallucination of a single individual person of one or more talking voices is particularly associated with psychotic disorders such as schizophrenia, and hold special significance in diagnosing these conditions.
In schizophrenia voices are normally perceived coming from outside the person but in dissociative disorders they are perceived as originating from within the person, commenting in their head instead of behind their back. Differential diagnosis between schizophrenia and dissociative disorders is challenging due to many overlapping symptoms, especially Schneiderian first rank symptoms such as hallucinations. However, many people who do not have a diagnosable mental illness may sometimes hear voices as well. One important example to consider when forming a differential diagnosis for a patient with paracusia is lateral temporal lobe epilepsy. Despite the tendency to associate hearing voices, or otherwise hallucinating, and psychosis with schizophrenia or other psychiatric illnesses, it is crucial to take into consideration that, even if a person does exhibit psychotic features, they do not necessarily have a psychiatric disorder on its own. Disorders such as Wilsons disease, various endocrine diseases, numerous metabolic disturbances, multiple sclerosis, systemic lupus erythematosus, porphyria, sarcoidosis, and many others can present with psychosis.
Musical hallucinations are also relatively common in terms of complex auditory hallucinations and may be the result of a wide range of causes ranging from hearing-loss (such as in musical ear syndrome, the auditory version of Charles Bonnet syndrome), lateral temporal lobe epilepsy, arteriovenous malformation, stroke, lesion, abscess, or tumor.The Hearing Voices Movement is a support and advocacy group for people who hallucinate voices, but do not otherwise show signs of mental illness or impairment.
High caffeine consumption has been linked to an increase in likelihood of one experiencing auditory hallucinations. A study conducted by the La Trobe University School of Psychological Sciences revealed that as few as five cups of coffee a day (approximately 500 mg of caffeine) could trigger the phenomenon.
Visual
A visual hallucination is "the perception of an external visual stimulus where none exists". A separate but related phenomenon is a visual illusion, which is a distortion of a real external stimulus. Visual hallucinations are classified as simple or complex:
Simple visual hallucinations (SVH) are also referred to as non-formed visual hallucinations and elementary visual hallucinations. These terms refer to lights, colors, geometric shapes, and indiscrete objects. These can be further subdivided into phosphenes which are SVH without structure, and photopsias which are SVH with geometric structures.
Complex visual hallucinations (CVH) are also referred to as formed visual hallucinations. CVHs are clear, lifelike images or scenes such as people, animals, objects, places, etc.For example, one may report hallucinating a giraffe. A simple visual hallucination is an amorphous figure that may have a similar shape or color to a giraffe (looks like a giraffe), while a complex visual hallucination is a discrete, lifelike image that is, unmistakably, a giraffe.
Command
Command hallucinations are hallucinations in the form of commands; they appear to be from an external source, or can appear coming from the subjects head. The contents of the hallucinations can range from the innocuous to commands to cause harm to the self or others. Command hallucinations are often associated with schizophrenia. People experiencing command hallucinations may or may not comply with the hallucinated commands, depending on the circumstances. Compliance is more common for non-violent commands.Command hallucinations are sometimes used to defend a crime that has been committed, often homicides. In essence, it is a voice that one hears and it tells the listener what to do. Sometimes the commands are quite benign directives such as "Stand up" or "Shut the door." Whether it is a command for something simple or something that is a threat, it is still considered a "command hallucination." Some helpful questions that can assist one in determining if they may have this includes: "What are the voices telling you to do?", "When did your voices first start telling you to do things?", "Do you recognize the person who is telling you to harm yourself (or others)?", "Do you think you can resist doing what the voices are telling you to do?"
Olfactory
Phantosmia (olfactory hallucinations), smelling an odor that is not actually there, and parosmia (olfactory illusions), inhaling a real odor but perceiving it as different scent than remembered, are distortions to the sense of smell (olfactory system), and in most cases, are not caused by anything serious and will usually go away on their own in time. It can result from a range of conditions such as nasal infections, nasal polyps, dental problems, migraines, head injuries, seizures, strokes, or brain tumors. Environmental exposures can sometimes cause it as well, such as smoking, exposure to certain types of chemicals (e.g., insecticides or solvents), or radiation treatment for head or neck cancer. It can also be a symptom of certain mental disorders such as depression, bipolar disorder, intoxication, substance withdrawal, or psychotic disorders (e.g., schizophrenia). The perceived odors are usually unpleasant and commonly described as smelling burned, foul, spoiled, or rotten.
Tactile
Tactile hallucinations are the illusion of tactile sensory input, simulating various types of pressure to the skin or other organs. One subtype of tactile hallucination, formication, is the sensation of insects crawling underneath the skin and is frequently associated with prolonged cocaine use. However, formication may also be the result of normal hormonal changes such as menopause, or disorders such as peripheral neuropathy, high fevers, Lyme disease, skin cancer, and more.
Gustatory
This type of hallucination is the perception of taste without a stimulus. These hallucinations, which are typically strange or unpleasant, are relatively common among individuals who have certain types of focal epilepsy, especially temporal lobe epilepsy. The regions of the brain responsible for gustatory hallucination in this case are the insula and the superior bank of the sylvian fissure.
General somatic sensations
General somatic sensations of a hallucinatory nature are experienced when an individual feels that their body is being mutilated, i.e. twisted, torn, or disemboweled. Other reported cases are invasion by animals in the persons internal organs, such as snakes in the stomach or frogs in the rectum. The general feeling that ones flesh is decomposing is also classified under this type of this hallucination.
Multimodal
A hallucination involving sensory modalities is called multimodal, analogous to unimodal hallucinations which have only one sensory modality. The multiple sensory modalities can occur at the same time (simultaneously) or with a delay (serial), be related or unrelated to each other, and be consistent with reality (congruent) or not (incongruent). For example, a person talking in a hallucination would be congruent with reality, but a cat talking would not be.
Multimodal hallucinations are correlated to poorer mental health outcomes, and are often experienced as feeling more real.
Cause
Hallucinations can be caused by a number of factors.
Hypnagogic hallucination
These hallucinations occur just before falling asleep and affect a high proportion of the population: in one survey 37% of the respondents experienced them twice a week. The hallucinations can last from seconds to minutes; all the while, the subject usually remains aware of the true nature of the images. These may be associated with narcolepsy. Hypnagogic hallucinations are sometimes associated with brainstem abnormalities, but this is rare.
Peduncular hallucinosis
Peduncular means pertaining to the peduncle, which is a neural tract running to and from the pons on the brain stem. These hallucinations usually occur in the evenings, but not during drowsiness, as in the case of hypnagogic hallucination. The subject is usually fully conscious and then can interact with the hallucinatory characters for extended periods of time. As in the case of hypnagogic hallucinations, insight into the nature of the images remains intact. The false images can occur in any part of the visual field, and are rarely polymodal.
Delirium tremens
One of the more enigmatic forms of visual hallucination is the highly variable, possibly polymodal delirium tremens. Individuals with delirium tremens may be agitated and confused, especially in the later stages of this disease. Insight is gradually reduced with the progression of this disorder. Sleep is disturbed and occurs for a shorter period of time, with rapid eye movement sleep.
Parkinsons disease and Lewy body dementia
Parkinsons disease is linked with Lewy body dementia for their similar hallucinatory symptoms. The symptoms strike during the evening in any part of the visual field, and are rarely polymodal. The segue into hallucination may begin with illusions where sensory perception is greatly distorted, but no novel sensory information is present. These typically last for several minutes, during which time the subject may be either conscious and normal or drowsy/inaccessible. Insight into these hallucinations is usually preserved and REM sleep is usually reduced. Parkinsons disease is usually associated with a degraded substantia nigra pars compacta, but recent evidence suggests that PD affects a number of sites in the brain. Some places of noted degradation include the median raphe nuclei, the noradrenergic parts of the locus coeruleus, and the cholinergic neurons in the parabrachial area and pedunculopontine nuclei of the tegmentum.
Migraine coma
This type of hallucination is usually experienced during the recovery from a comatose state. The migraine coma can last for up to two days, and a state of depression is sometimes comorbid. The hallucinations occur during states of full consciousness, and insight into the hallucinatory nature of the images is preserved. It has been noted that ataxic lesions accompany the migraine coma.
Charles Bonnet syndrome
Charles Bonnet syndrome is the name given to visual hallucinations experienced by a partially or severely sight impaired person. The hallucinations can occur at any time and can distress people of any age, as they may not initially be aware that they are hallucinating. They may fear for their own mental health initially, which may delay them sharing with carers until they start to understand it themselves. The hallucinations can frighten and disconcert as to what is real and what is not. The hallucinations can sometimes be dispersed by eye movements, or by reasoned logic such as, "I can see fire but there is no smoke and there is no heat from it" or perhaps, "We have an infestation of rats but they have pink ribbons with a bell tied on their necks." Over elapsed months and years, the hallucinations may become more or less frequent with changes in ability to see. The length of time that the sight impaired person can have these hallucinations varies according to the underlying speed of eye deterioration. A differential diagnosis are ophthalmopathic hallucinations.
Focal epilepsy
Visual hallucinations due to focal seizures differ depending on the region of the brain where the seizure occurs. For example, visual hallucinations during occipital lobe seizures are typically visions of brightly colored, geometric shapes that may move across the visual field, multiply, or form concentric rings and generally persist from a few seconds to a few minutes. They are usually unilateral and localized to one part of the visual field on the contralateral side of the seizure focus, typically the temporal field. However, unilateral visions moving horizontally across the visual field begin on the contralateral side and move toward the ipsilateral side.Temporal lobe seizures, on the other hand, can produce complex visual hallucinations of people, scenes, animals, and more as well as distortions of visual perception. Complex hallucinations may appear to be real or unreal, may or may not be distorted with respect to size, and may seem disturbing or affable, among other variables. One rare but notable type of hallucination is heautoscopy, a hallucination of a mirror image of ones self. These "other selves" may be perfectly still or performing complex tasks, may be an image of a younger self or the present self, and tend to be briefly present. Complex hallucinations are a relatively uncommon finding in temporal lobe epilepsy patients. Rarely, they may occur during occipital focal seizures or in parietal lobe seizures.Distortions in visual perception during a temporal lobe seizure may include size distortion (micropsia or macropsia), distorted perception of movement (where moving objects may appear to be moving very slowly or to be perfectly still), a sense that surfaces such as ceilings and even entire horizons are moving farther away in a fashion similar to the dolly zoom effect, and other illusions. Even when consciousness is impaired, insight into the hallucination or illusion is typically preserved.
Drug-induced hallucination
Drug-induced hallucinations are caused by hallucinogens, dissociatives, and deliriants, including many drugs with anticholinergic actions and certain stimulants, which are known to cause visual and auditory hallucinations. Some psychedelics such as lysergic acid diethylamide (LSD) and psilocybin can cause hallucinations that range in the spectrum of mild to intense.
Hallucinations, pseudohallucinations, or intensification of pareidolia, particularly auditory, are known side effects of opioids to different degrees—it may be associated with the absolute degree of agonism or antagonism of especially the kappa opioid receptor, sigma receptors, delta opioid receptor and the NMDA receptors or the overall receptor activation profile as synthetic opioids like those of the pentazocine, levorphanol, fentanyl, pethidine, methadone and some other families are more associated with this side effect than natural opioids like morphine and codeine and semi-synthetics like hydromorphone, amongst which there also appears to be a stronger correlation with the relative analgesic strength. Three opioids, Cyclazocine (a benzormorphan opioid/pentazocine relative) and two levorphanol-related morphinan opioids, Cyclorphan and Dextrorphan are classified as hallucinogens, and Dextromethorphan as a dissociative. These drugs also can induce sleep (relating to hypnagogic hallucinations) and especially the pethidines have atropine-like anticholinergic activity, which was possibly also a limiting factor in the use, the psychotomimetic side effects of potentiating morphine, oxycodone, and other opioids with scopolamine (respectively in the Twilight Sleep technique and the combination drug Skophedal, which was eukodal (oxycodone), scopolamine and ephedrine, called the "wonder drug of the 1930s" after its invention in Germany in 1928, but only rarely specially compounded today) (q.q.v.).
Sensory deprivation hallucination
Hallucinations can be caused by sensory deprivation when it occurs for prolonged periods of time, and almost always occurs in the modality being deprived (visual for blindfolded/darkness, auditory for muffled conditions, etc.)
Experimentally-induced hallucinations
Anomalous experiences, such as so-called benign hallucinations, may occur in a person in a state of good mental and physical health, even in the apparent absence of a transient trigger factor such as fatigue, intoxication or sensory deprivation.
The evidence for this statement has been accumulating for more than a century. Studies of benign hallucinatory experiences go back to 1886 and the early work of the Society for Psychical Research, which suggested approximately 10% of the population had experienced at least one hallucinatory episode in the course of their life. More recent studies have validated these findings; the precise incidence found varies with the nature of the episode and the criteria of "hallucination" adopted, but the basic finding is now well-supported.
Non-celiac gluten sensitivity
There is tentative evidence of a relationship with non-celiac gluten sensitivity, the so-called "gluten psychosis".
Pathophysiology
Dopaminergic and serotonergic hallucinations
It has been reported that in serotonergic hallucinations, the person maintains an awareness that they are hallucinating, unlike dopaminergic hallucinations.
Neuroanatomy
Hallucinations are associated with structural and functional abnormalities in primary and secondary sensory cortices. Reduced grey matter in regions of the superior temporal gyrus/middle temporal gyrus, including Brocas area, is associated with auditory hallucinations as a trait, while acute hallucinations are associated with increased activity in the same regions along with the hippocampus, parahippocampus, and the right hemispheric homologue of Brocas area in the inferior frontal gyrus. Grey and white matter abnormalities in visual regions are associated with visual hallucinations in diseases such as Alzheimers disease, further supporting the notion of dysfunction in sensory regions underlying hallucinations.
One proposed model of hallucinations posits that over-activity in sensory regions, which is normally attributed to internal sources via feedforward networks to the inferior frontal gyrus, is interpreted as originating externally due to abnormal connectivity or functionality of the feedforward network. This is supported by cognitive studies of those with hallucinations, who have demonstrated abnormal attribution of self generated stimuli.Disruptions in thalamocortical circuitry may underlie the observed top down and bottom up dysfunction. Thalamocortical circuits, composed of projections between thalamic and cortical neurons and adjacent interneurons, underlie certain electrophysical characteristics (gamma oscillations) that are underlie sensory processing. Cortical inputs to thalamic neurons enable attentional modulation of sensory neurons. Dysfunction in sensory afferents, and abnormal cortical input may result in pre-existing expectations modulating sensory experience, potentially resulting in the generation of hallucinations. Hallucinations are associated with less accurate sensory processing, and more intense stimuli with less interference are necessary for accurate processing and the appearance of gamma oscillations (called "gamma synchrony"). Hallucinations are also associated with the absence of reduction in P50 amplitude in response to the presentation of a second stimuli after an initial stimulus; this is thought to represent failure to gate sensory stimuli, and can be exacerbated by dopamine release agents.Abnormal assignment of salience to stimuli may be one mechanism of hallucinations. Dysfunctional dopamine signaling may lead to abnormal top down regulation of sensory processing, allowing expectations to distort sensory input.
Treatments
There are few treatments for many types of hallucinations. However, for those hallucinations caused by mental disease, a psychologist or psychiatrist should be consulted, and treatment will be based on the observations of those doctors. Antipsychotic and atypical antipsychotic medication may also be utilized to treat the illness if the symptoms are severe and cause significant distress. For other causes of hallucinations there is no factual evidence to support any one treatment is scientifically tested and proven. However, abstaining from hallucinogenic drugs, stimulant drugs, managing stress levels, living healthily, and getting plenty of sleep can help reduce the prevalence of hallucinations. In all cases of hallucinations, medical attention should be sought out and informed of ones specific symptoms. Meta-analyses show that cognitive behavioral therapy and metacognitive training can also reduce the severity of hallucinations.
Epidemiology
Prevalence of hallucinations varies depending on underlying medical conditions, which sensory modalities are affected, age and culture. As of 2022, auditory hallucinations are the most well studied and most common sensory modality of hallucinations, with an estimated lifetime prevalence of 9.6%. Children and adolescents have been found to experience similar rates (12.7% and 12.4% respectively) which occur mostly during late childhood and adolescence. This is compared with adults and those over 60 (with rates of 5.8% and 4.8% respectively). For those with schizophrenia, the lifetime prevalence of hallucinations is 80% and the estimated prevalence of visual hallucinations is 27%, compared to 79% for auditory hallucinations. A 2019 study suggested 16.2% of adults with hearing impairment experience hallucinations, with prevalence rising to 24% in the most hearing impaired group.A risk factor for multimodal hallucinations is prior experience of unimodal hallucinations. In 90% cases of psychosis, a visual hallucination occurs in combination with another sensory modality, most often being auditory or somatic. In schizophrenia, multimodal hallucinations are twice as common as unimodal ones.A 2015 review of 55 publications from 1962 to 2014 found 16–28.6% of those experiencing hallucinations report at least some religious content in them,: 415 along with 20-60% reporting some religious content in delusions.: 415 There is some evidence for delusions being a risk factor for religious hallucinations, with and 61.7% of people having experienced any delusion and 75.9% of those having experienced a religious delusion found to also experience hallucinations.: 421
See also
References
Further reading
Johnson FH (1978). The Anatomy of Hallucinations. Chicago: Nelson-Hall Co. ISBN 0-88229-155-6.
Bentall RP, Slade PD (1988). Sensory Deception: A Scientific Analysis of Hallucination. London: Croom Helm. ISBN 0-7099-3961-2.
Aleman A, Larøi F (2008). Hallucinations: The Science of Idiosyncratic Perception. American Psychological Association (APA). ISBN 1-4338-0311-9.
Sacks O (2012). Hallucinations. New York: Alfred A. Knopf. ISBN 978-0307957245
External links
Hearing Voices Network
"Anthropology and Hallucinations; chapter from The Making of Religion". psychanalyse-paris.com. November 4, 2006. Archived from the original on May 29, 2016. Retrieved October 4, 2016.
"The voice inside: A practical guide to coping with hearing voices"
Psychology Terms
Hallucination: A Normal Phenomenon?
Fasting-induced hallucination
Geometric visual hallucinations, Euclidean symmetry and the functional architecture of striate cortex |
Oculomotor nerve palsy | Oculomotor nerve palsy or oculomotor neuropathy is an eye condition resulting from damage to the third cranial nerve or a branch thereof. As the name suggests, the oculomotor nerve supplies the majority of the muscles controlling eye movements (four of the six extraocular muscles, excluding only the lateral rectus and superior oblique). Damage to this nerve will result in an inability to move the eye normally. The nerve also supplies the upper eyelid muscle (levator palpebrae superioris) and is accompanied by parasympathetic fibers innervating the muscles responsible for pupil constriction (sphincter pupillae). The limitations of eye movement resulting from the condition are generally so severe that patients are often unable to maintain normal eye alignment when gazing straight ahead, leading to strabismus and, as a consequence, double vision (diplopia).
Presentation
A complete oculomotor nerve palsy will result in a characteristic displacement outward (exotropia) and downward (hypotropia). The outward displacement occurs because the lateral rectus muscle (innervated by the sixth cranial nerve) maintains muscle tone in comparison to the paralyzed medial rectus. The downward displacement occurs because the superior oblique muscle (innervated by the fourth cranial or trochlear nerve) is unantagonized by the paralyzed superior rectus, inferior rectus and inferior oblique. The affected individual will also have a ptosis, or drooping of the eyelid, and mydriasis (pupil dilation).
Causes
Oculomotor palsy can arise as a result of a number of different conditions. Non traumatic pupil-sparing oculomotor nerve palsies are often referred to as a "medical third," with those affecting the pupil being known as a "surgical third."
Congenital oculomotor palsy
The origins of the vast majority of congenital oculomotor palsies are idiopathic. There is some evidence of a familial tendency to the condition, particularly to a partial palsy involving the superior division of the nerve with an autosomal recessive inheritance. The condition can also result from aplasia or hypoplasia of one or more of the muscles supplied by the oculomotor nerve. It can also occur as a consequence of severe birth trauma.
Acquired oculomotor palsy
Vascular disorders such as diabetes, heart disease, atherosclerosis and aneurysm, particularly of the posterior communicating artery
Space occupying lesions or tumours, both malignant and non-malignant
Inflammation and infection
Trauma
Demyelinating disease (multiple sclerosis)
Autoimmune disorders such as myasthenia gravis
Post-operatively as a complication of neurosurgery
Cavernous sinus thrombosis
Mechanism
As the pair of oculomotor nerves arises from different subnuclei in the midbrain, courses through different structures in the brain and branches into superior and inferior divisions after exiting the cavernous sinuses, any lesions along its path will produce different pathological features of the third nerve palsy. The parasympathetic aspect of the nerve (which constricts pupils and thicken the lens) is located on the nerve surface, supplied by pial blood vessels. The nerves core contains the main trunk of the oculomotor nerve, supplied by vasa vasorum. Thus pathologies affecting the nerves core without affecting the superficial part of the nerve (thus sparing the pupillary reflex) are known as "medical" oculomotor nerve palsy. The "surgical" type of oculomotor nerve palsy is caused by external structures compressing on the nerve or trauma, which affects the entire nerve, thus affecting pupillary reflex.Ischemic stroke selectively affects somatic fibers over parasympathetic fibers, while traumatic stroke affects both types more equally. Ischemic stroke affects the vasoneurium, which starts to supply the nerve from outside to inside. As the somatic fibers are located in the inner part of the nerve, these fibres are affected more in the setting of ischemia. A similar mechanism is also accurate for diabetes. Therefore, while almost all forms cause ptosis and impaired movement of the eye, pupillary abnormalities are more commonly associated with trauma and the "surgical third" rather than with ischemia (the "medical third"). A posterior communicating artery aneurysm will generally cause compression of the entire third nerve and will this prevent any nerve signal conduction, affecting the somatic system as well as the autonomic. The compression of the external autonomic fibres renders the pupil nonreactive and leads to the "surgical third" nerve palsy.
Oculomotor palsy can be of acute onset over hours with symptoms of headache when associated with diabetes mellitus. Diabetic neuropathy of the oculomotor nerve in a majority of cases does not affect the pupil. The sparing of the pupil is thought to be associated with the microfasciculation of the fibers that control the pupillomotor function located on the outmost aspect of the occulomotor nerve fibres; these fibres are spared because they are outermost and therefore less prone to ischemic damage than are the innermost fibres.
References
== External links == |
Respiratory disease | Respiratory diseases, or lung diseases, are pathological conditions affecting the organs and tissues that make gas exchange difficult in air-breathing animals. They include conditions of the respiratory tract including the trachea, bronchi, bronchioles, alveoli, pleurae, pleural cavity, the nerves and muscles of respiration. Respiratory diseases range from mild and self-limiting, such as the common cold, influenza, and pharyngitis to life-threatening diseases such as bacterial pneumonia, pulmonary embolism, tuberculosis, acute asthma, lung cancer, and severe acute respiratory syndromes, such as COVID-19. Respiratory diseases can be classified in many different ways, including by the organ or tissue involved, by the type and pattern of associated signs and symptoms, or by the cause of the disease.
The study of respiratory disease is known as pulmonology. A physician who specializes in respiratory disease is known as a pulmonologist, a chest medicine specialist, a respiratory medicine specialist, a respirologist or a thoracic medicine specialist.
Obstructive lung disease
Asthma, chronic bronchitis, bronchiectasis and chronic obstructive pulmonary disease (COPD) are all obstructive lung diseases characterised by airway obstruction. This limits the amount of air that is able to enter alveoli because of constriction of the bronchial tree, due to inflammation. Obstructive lung diseases are often identified because of symptoms and diagnosed with pulmonary function tests such as spirometry. Many obstructive lung diseases are managed by avoiding triggers (such as dust mites or smoking), with symptom control such as bronchodilators, and with suppression of inflammation (such as through corticosteroids) in severe cases. One common cause of COPD including emphysema, and chronic bronchitis, is tobacco smoking, and common causes of bronchiectasis include severe infections and cystic fibrosis. The definitive cause of asthma is not yet known.
Restrictive lung diseases
Restrictive lung diseases are a category of respiratory disease characterized by a loss of lung compliance, causing incomplete lung expansion and increased lung stiffness, such as in infants with respiratory distress syndrome. Restrictive lung diseases can be divided into two categories: those caused by intrinsic factors and those caused by extrinsic factors. Restrictive lung diseases yielding from intrinsic factors occur within the lungs themselves, such as tissue death due to inflammation or toxins. Conversely, restrictive lung diseases caused by extrinsic factors result from conditions originating from outside the lungs such as neuromuscular dysfunction and irregular chest wall movements.
Chronic respiratory disease
Chronic respiratory diseases (CRDs) are long-term diseases of the airways and other structures of the lung. They are characterized by a high inflammatory cell recruitment (neutrophil) and/or destructive cycle of infection, (e.g. mediated by Pseudomonas aeruginosa). Some of the most common are asthma, chronic obstructive pulmonary disease, and acute respiratory distress syndrome. CRDs are not curable; however, various forms of treatment that help dilate major air passages and improve shortness of breath can help control symptoms and increase the quality of life.Telerehabilitation for chronic respiratory disease
The latest evidence suggests that primary pulmonary rehabilitation and maintenance rehabilitation delivered through telerehabilitation for people with chronic respiratory disease reaches outcomes similar to centre-based rehabilitation. While there are no safety issues identified, the findings are based on evidence limited by a small number of studies.
Respiratory tract infections
Infections can affect any part of the respiratory system. They are traditionally divided into upper respiratory tract infections and lower respiratory tract infections.
Upper respiratory tract infection
The upper airway is defined as all the structures connecting the glottis to the mouth and nose. The most common upper respiratory tract infection is the common cold. However, infections of specific organs of the upper respiratory tract such as sinusitis, tonsillitis, otitis media, pharyngitis and laryngitis are also considered upper respiratory tract infections.
Epiglottitis is a bacterial infection of the larynx which causes life-threatening swelling of the epiglottis with a mortality rate of 7% in adults and 1% in children. Haemophilus influenzae is still the primary cause even with vaccinations. Symptoms include drooling, stridor, difficulty breathing and swallowing, and a hoarse voice.Croup (Laryngotracheobronchitis) is a viral infection of the vocal cords typically lasting five to six days. The main symptom is a barking cough and low-grade fever. On an X-ray, croup can be recognized by the "steeple sign", which is a narrowing of the trachea. It most commonly occurs in winter months in children between the ages of 3 months and 5 years. A severe form caused by bacteria is called bacterial tracheitis.Tonsillitis is swelling of the tonsils by a bacterial or viral infection. This inflammation can lead to airway obstruction. From tonsillitis can come a peritonsillar abscess which is the most common upper airway infection and occurs primarily in young adults. It causes one swelling of one of tonsils pushing the uvula to the unaffected side. Diagnosis is usually made based on the presentation and examination. Symptoms generally include fever, sore throat, trouble swallowing, and sounding like they have a “hot potato” in their mouth.
Lower respiratory tract infection
The most common lower respiratory tract infection is pneumonia, an infection of the lungs which is usually caused by bacteria, particularly Streptococcus pneumoniae in Western countries. Worldwide, tuberculosis is an important cause of pneumonia. Other pathogens such as viruses and fungi can cause pneumonia, for example severe acute respiratory syndrome, COVID-19 and pneumocystis pneumonia. Pneumonia may develop complications such as a lung abscess, a round cavity in the lung caused by the infection, or may spread to the pleural cavity.Poor oral care may be a contributing factor to lower respiratory disease, as bacteria from gum disease may travel through airways and into the lungs.
Upper and lower respiratory tract infection
Primary ciliary dyskinesia is a genetic disorder causing the cilia to not move in a coordinated manner. This causes chronic respiratory infections, cough, and nasal congestion. This can lead to bronchiectasis, which can cause life-threatening breathing issues.
Tumors
Malignant tumors
Malignant tumors of the respiratory system, particularly primary carcinomas of the lung, are a major health problem responsible for 15% of all cancer diagnoses and 30% of all cancer deaths. The majority of respiratory system cancers are attributable to smoking tobacco.The major histological types of respiratory system cancer are:
Small cell lung cancer
Non-small cell lung cancer
Adenocarcinoma of the lung
Squamous cell carcinoma of the lung
Large cell lung carcinoma
Other lung cancers (carcinoid, Kaposi’s sarcoma, melanoma)
Lymphoma
Head and neck cancer
Pleural mesothelioma, almost always caused by exposure to asbestos dust.In addition, since many cancers spread via the bloodstream and the entire cardiac output passes through the lungs, it is common for cancer metastases to occur within the lung. Breast cancer may invade directly through local spread, and through lymph node metastases. After metastasis to the liver, colon cancer frequently metastasizes to the lung. Prostate cancer, germ cell cancer and renal cell carcinoma may also metastasize to the lung.
Treatment of respiratory system cancer depends on the type of cancer. Surgical removal of part of a lung (lobectomy, segmentectomy, or wedge resection) or of an entire lung pneumonectomy), along with chemotherapy and radiotherapy, are all used. The chance of surviving lung cancer depends on the cancer stage at the time the cancer is diagnosed, and to some extent on the histology, and is only about 14–17% overall. In the case of metastases to the lung, treatment can occasionally be curative but only in certain, rare circumstances.
Benign tumors
Benign tumors are relatively rare causes of respiratory disease. Examples of benign tumors are:
Pulmonary hamartoma
Congenital malformations such as pulmonary sequestration and congenital cystic adenomatoid malformation (CCAM).
Pleural cavity diseases
Pleural cavity diseases include pleural mesothelioma which are mentioned above.
A collection of fluid in the pleural cavity is known as a pleural effusion. This may be due to fluid shifting from the bloodstream into the pleural cavity due to conditions such as congestive heart failure and cirrhosis. It may also be due to inflammation of the pleura itself as can occur with infection, pulmonary embolus, tuberculosis, mesothelioma and other conditions.A pneumothorax is a hole in the pleura covering the lung allowing air in the lung to escape into the pleural cavity. The affected lung "collapses" like a deflated balloon. A tension pneumothorax is a particularly severe form of this condition where the air in the pleural cavity cannot escape, so the pneumothorax keeps getting bigger until it compresses the heart and blood vessels, leading to a life-threatening situation.
Pulmonary vascular disease
Pulmonary vascular diseases are conditions that affect the pulmonary circulation. Examples are:
Pulmonary embolism, a blood clot that forms in a vein, breaks free, travels through the heart and lodges in the lungs (thromboembolism). Large pulmonary emboli are fatal, causing sudden death. A number of other substances can also embolise (travel through the blood stream) to the lungs but they are much more rare: fat embolism (particularly after bony injury), amniotic fluid embolism (with complications of labour and delivery), air embolism (iatrogenic – caused by invasive medical procedures).
Pulmonary arterial hypertension, elevated pressure in the pulmonary arteries. Most commonly it is idiopathic (i.e. of unknown cause) but it can be due to the effects of another disease, particularly COPD. This can lead to strain on the right side of the heart, a condition known as cor pulmonale.
Pulmonary edema, leakage of fluid from capillaries of the lung into the alveoli (or air spaces). It is usually due to congestive heart failure.
Pulmonary hemorrhage, inflammation and damage to capillaries in the lung resulting in blood leaking into the alveoli. This may cause blood to be coughed up. Pulmonary hemorrhage can be due to auto-immune disorders such as granulomatosis with polyangiitis and Goodpastures syndrome.
Neonatal diseases
Pulmonary diseases also impact newborns and the disorders are often unique from those that affect adults.
Infant respiratory distress syndrome most commonly occurs in less than six hours after birth in about 1% of all births in the United States. The main risk factor is prematurity with the likelihood of it occurring going up to 71% in infants under 750g. Other risk factors include infant of a diabetic mother (IDM), method of delivery, fetal asphyxia, genetics, prolonged rupture of membranes (PROM), maternal toxemia, chorioamnionitis, and male sex. The widely accepted pathophysiology of respiratory distress syndrome is it caused by insufficient surfactant production and immature lung and vascular development. The lack of surfactant makes the lungs atelectatic causing a ventilation to perfusion mismatch, lowered compliance, and increased air resistance. This causes hypoxia and respiratory acidosis which can lead to pulmonary hypertension. It has a ground glass appearance on an x-ray. Symptoms can include tachypnea, nasal flaring, paradoxical chest movement, grunting, and subcostal retractions.Bronchopulmonary Dysplasia is a condition that occurs after birth usually from mechanical ventilation and oxygen use. It happens almost exclusively in pre-mature infants and is characterized by the alveoli, and lung vasculature becoming inflamed and damaged. Complications from BPD can follow a patient into adulthood. As a child they may experience learning disabilities, pulmonary hypertension, and hearing problems. As an adult, there is an increased likelihood for asthma and exercise intolerance.Meconium Aspiration Syndrome occurs in full term or post-term infants who aspirate meconium. Risk factors include a diabetic mother, fetal hypoxia, precipitous delivery, and maternal high blood pressure. Its diagnosis is based on meconium stained amniotic fluid at delivery and staining on the skin, nails, and umbilical cord. Aspiration can cause airway obstruction, air-trapping, pneumonia, lung inflammation, and inactivated surfactant. It presents as patchy atelectasis and hyperinflation on an x-ray with a pneumothorax of pneumomediastinum also possible.Persistent Pulmonary Hypertension of the Newborn (PPHN) is a syndrome that occurs from an abnormal transition to extra-uterine life. It is marked by an elevated pulmonary vascular resistance and vasoconstriction causing a right-to-left shunt of the blood through the foramen ovale or ductus arteriosus. There are three main causes of PPHN are parenchymal diseases such as meconium aspiration syndrome, idiopathic, and hypoplastic vasculature like in a diaphragmatic hernia. It will eventually resolve in most infants. This is the only syndrome that inhaled nitric oxide is approved for by the FDA.
Transient Tachypnea of the Newborn is caused by the retention of alveolar fluid in the lungs. It commonly occurs in infants who are delivered via caesarean section without the onset of labor because absorption of amniotic fluid in the lungs has not yet commenced. Other risk factors are male sex, macrosomia, multiple gestations, and maternal asthma. It usually presents with tachypnea and increased work of breathing. On an x-ray diffuse infiltrates, interlobar fissures, and sometimes pleural effusions can be seen. It is a diagnosis of exclusion because of its similarity to other diseases and frequently CPAP is used to help push the lung fluid into the pulmonary vasculature.Pulmonary interstitial emphysema is the condition of air escaping overdistended alveoli into the pulmonary interstitium. It is a rare disease that occurs most often in premature infants, even though it is possible to appear in adults. It often presents as a slow deterioration with the need for increased ventilatory support. Chest x-ray is the standard for diagnosis where it is seen as linear or cystic translucencies extending to the edges of the lungs.Bronchiolitis is the swelling and buildup of mucus in the bronchioles. It is usually caused by respiratory syncytial virus (RSV), which is spread when an infant touches the nose or throat fluids of someone infected. The virus infects the cells causing ciliary dysfunction and death. The debris, edema, and inflammation eventually leads to the symptoms. It is the most common reason for admission of children under the age of one year. It can present widely from a mild respiratory infection to respiratory failure. Since there is no medication to treat the disease, it is only managed supportively with fluids and oxygen.
Diagnosis
Respiratory diseases may be investigated by performing one or more of the following tests:
Biopsy of the lung or pleura
Blood test
Bronchoscopy
Chest X-ray
CT scan, including high-resolution computed tomography
Culture of microorganisms from secretions such as sputum
Ultrasound scanning can be useful to detect fluid such as pleural effusion
Pulmonary function test
Ventilation–perfusion scan
Epidemiology
Respiratory disease is a common and significant cause of illness and death around the world. In the US, approximately one billion common colds occur each year. A study found that in 2010, there were approximately 6.8 million emergency department visits for respiratory disorders in the U.S. for patients under the age of 18. In 2012, respiratory conditions were the most frequent reasons for hospital stays among children.In the UK, approximately 1 in 7 individuals are affected by some form of chronic lung disease, most commonly chronic obstructive pulmonary disease, which includes asthma, chronic bronchitis and emphysema.
Respiratory diseases (including lung cancer) are responsible for over 10% of hospitalizations and over 16% of deaths in Canada.In 2011, respiratory disease with ventilator support accounted for 93.3% of ICU utilization in the United States.
References
== External links == |
Functional gastrointestinal disorder | Functional gastrointestinal disorders (FGID), also known as disorders of gut–brain interaction, include a number of separate idiopathic disorders which affect different parts of the gastrointestinal tract and involve visceral hypersensitivity and motility disturbances.
Classification
Terms such as functional colonic disease (or functional bowel disorder) refer in medicine to a group of bowel disorders which are characterised by chronic abdominal complaints without a structural or biochemical cause that could explain symptoms. Other functional disorders relate to other aspects of the process of digestion.The consensus review process of meetings and publications organised by the Rome Foundation, known as the Rome process, has helped to define the functional gastrointestinal disorders. Successively, the Rome I, Rome II, Rome III and Rome IV proposed consensual classification system and terminology, as recommended by the Rome Coordinating Committee. These now include classifications appropriate for adults, children and neonates/toddlers.The current Rome IV classification, published in 2016, is as follows:A. Esophageal disorders
A1. Functional chest pain
A2. Functional heartburn
A3. Reflux hypersensitivity
A4. Globus
A5. Functional dysphagiaB. Gastroduodenal disorders
B1. Functional dyspepsia
B1a. Postprandial distress syndrome (PDS)
B1b. Epigastric pain syndrome (EPS)
B2. Belching disorders
B2a. Excessive supragastric belching
B2b. Excessive gastric belching
B3. Nausea and vomiting disorders
B3a. Chronic nausea vomiting syndrome (CNVS)
B3b. Cyclic vomiting syndrome (CVS)
B3c. Cannabinoid hyperemesis syndrome (CHS)
B4. Rumination syndromeC. Bowel disorders
C1. Irritable bowel syndrome (IBS)
IBS with predominant constipation (IBS-C)
IBS with predominant diarrhea (IBS-D)
IBS with mixed bowel habits (IBS-M)
IBS unclassified (IBS-U)
C2. Functional constipation
C3. Functional diarrhea
C4. Functional abdominal bloating/distension
C5. Unspecified functional bowel disorder
C6. Opioid-induced constipationD. Centrally mediated disorders of gastrointestinal pain
D1. Centrally mediated abdominal pain syndrome (CAPS)
D2. Narcotic bowel syndrome (NBS)/ Opioid-induced GI hyperalgesiaE. Gallbladder and sphincter of Oddi disorders
E1. Biliary pain
E1a. Functional gallbladder disorder
E1b. Functional biliary sphincter of Oddi disorder
E2. Functional pancreatic sphincter of Oddi disorderF. Anorectal disorders
F1. Fecal incontinence
F2. Functional anorectal pain
F2a. Levator ani syndrome
F2b. Unspecified functional anorectal pain
F2c. Proctalgia fugax
F3. Functional defecation disorders
F3a. Inadequate defecatory propulsion
F3b. Dyssynergic defecationG. Childhood functional GI disorders: Neonate/Toddler
G1. Infant regurgitation
G2. Rumination syndrome
G3. Cyclic vomiting syndrome (CVS)
G4. Infant colic
G5. Functional diarrhea
G6. Infant dyschezia
G7. Functional constipationH. Childhood functional GI disorders: Child/Adolescent
H1. Functional nausea and vomiting disorders
H1a. Cyclic vomiting syndrome (CVS)
H1b. Functional nausea and functional vomiting
H1b1. Functional nausea
H1b2. Functional vomiting
H1c. Rumination syndrome
H1d. Aerophagia
H2. Functional abdominal pain disorders
H2a. Functional dyspepsia
H2a1. Postprandial distress syndrome
H2a2. Epigastric pain syndrome
H2b. Irritable bowel syndrome (IBS)
H2c. Abdominal migraine
H2d. Functional abdominal pain ‒ NOS
H3. Functional defecation disorders
H3a. Functional constipation
H3b. Nonretentive fecal incontinence
Epidemiology
Functional gastrointestinal disorders are very common. Globally, irritable bowel syndrome and functional dyspepsia alone may affect 16–26% of the population.
Research
There is considerable research into the causes, diagnosis and treatments for FGIDs. Diet, microbiome, genetics, neuromuscular function and immunological response all interact. A role for mast cell activation has been proposed as one of the factors.
See also
Allergy
Food intolerance
Functional indigestion
Histamine intolerance
References
== External links == |
Sepsis | Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the bodys response to infection causes injury to its own tissues and organs. This initial stage is followed by suppression of the immune system. Common signs and symptoms include fever, increased heart rate, increased breathing rate, and confusion. There may also be symptoms related to a specific infection, such as a cough with pneumonia, or painful urination with a kidney infection. The very young, old, and people with a weakened immune system may have no symptoms of a specific infection, and the body temperature may be low or normal instead of having a fever. Severe sepsis causes poor organ function or blood flow. The presence of low blood pressure, high blood lactate, or low urine output may suggest poor blood flow. Septic shock is low blood pressure due to sepsis that does not improve after fluid replacement.Sepsis is caused by many organisms including bacteria, viruses and fungi. Common locations for the primary infection include the lungs, brain, urinary tract, skin, and abdominal organs. Risk factors include being very young or old, a weakened immune system from conditions such as cancer or diabetes, major trauma, and burns. Previously, a sepsis diagnosis required the presence of at least two systemic inflammatory response syndrome (SIRS) criteria in the setting of presumed infection. In 2016, a shortened sequential organ failure assessment score (SOFA score), known as the quick SOFA score (qSOFA), replaced the SIRS system of diagnosis. qSOFA criteria for sepsis include at least two of the following three: increased breathing rate, change in the level of consciousness, and low blood pressure. Sepsis guidelines recommend obtaining blood cultures before starting antibiotics; however, the diagnosis does not require the blood to be infected. Medical imaging is helpful when looking for the possible location of the infection. Other potential causes of similar signs and symptoms include anaphylaxis, adrenal insufficiency, low blood volume, heart failure, and pulmonary embolism.Sepsis requires immediate treatment with intravenous fluids and antimicrobials. Ongoing care often continues in an intensive care unit. If an adequate trial of fluid replacement is not enough to maintain blood pressure, then the use of medications that raise blood pressure becomes necessary. Mechanical ventilation and dialysis may be needed to support the function of the lungs and kidneys, respectively. A central venous catheter and an arterial catheter may be placed for access to the bloodstream and to guide treatment. Other helpful measurements include cardiac output and superior vena cava oxygen saturation. People with sepsis need preventive measures for deep vein thrombosis, stress ulcers, and pressure ulcers unless other conditions prevent such interventions. Some people might benefit from tight control of blood sugar levels with insulin. The use of corticosteroids is controversial, with some reviews finding benefit, and others not.Disease severity partly determines the outcome. The risk of death from sepsis is as high as 30%, while for severe sepsis it is as high as 50%, and septic shock 80%. Sepsis affected about 49 million people in 2017, with 11 million deaths (1 in 5 deaths worldwide). In the developed world, approximately 0.2 to 3 people per 1000 are affected by sepsis yearly, resulting in about a million cases per year in the United States. Rates of disease have been increasing. Some data indicate that sepsis is more common among males than females, however, other data show a greater prevalence of the disease among women. Descriptions of sepsis date back to the time of Hippocrates.
Signs and symptoms
In addition to symptoms related to the actual cause, people with sepsis may have a fever, low body temperature, rapid breathing, a fast heart rate, confusion, and edema. Early signs include a rapid heart rate, decreased urination, and high blood sugar. Signs of established sepsis include confusion, metabolic acidosis (which may be accompanied by a faster breathing rate that leads to respiratory alkalosis), low blood pressure due to decreased systemic vascular resistance, higher cardiac output, and disorders in blood-clotting that may lead to organ failure. Fever is the most common presenting symptom in sepsis, but fever may be absent in some people such as the elderly or those who are immunocompromised.The drop in blood pressure seen in sepsis can cause lightheadedness and is part of the criteria for septic shock.Oxidative stress is observed in septic shock, with circulating levels of copper and vitamin C being decreased.
Cause
Infections leading to sepsis are usually bacterial but may be fungal, parasitic or viral. Gram-positive bacteria were the primary cause of sepsis before the introduction of antibiotics in the 1950s. After the introduction of antibiotics, gram-negative bacteria became the predominant cause of sepsis from the 1960s to the 1980s. After the 1980s, gram-positive bacteria, most commonly staphylococci, are thought to cause more than 50% of cases of sepsis. Other commonly implicated bacteria include Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella species. Fungal sepsis accounts for approximately 5% of severe sepsis and septic shock cases; the most common cause of fungal sepsis is an infection by Candida species of yeast, a frequent hospital-acquired infection. The most common causes for parasitic sepsis are Plasmodium (which leads to malaria), Schistosoma and Echinococcus.
The most common sites of infection resulting in severe sepsis are the lungs, the abdomen, and the urinary tract. Typically, 50% of all sepsis cases start as an infection in the lungs. In one-third to one-half of cases, the source of infection is unclear.
Pathophysiology
Sepsis is caused by a combination of factors related to the particular invading pathogen(s) and to the status of the immune system of the host. The early phase of sepsis characterized by excessive inflammation (sometimes resulting in a cytokine storm) may be followed by a prolonged period of decreased functioning of the immune system. Either of these phases may prove fatal. On the other hand, systemic inflammatory response syndrome (SIRS) occurs in people without the presence of infection, for example, in those with burns, polytrauma, or the initial state in pancreatitis and chemical pneumonitis. However, sepsis also causes similar response to SIRS.
Microbial factors
Bacterial virulence factors, such as glycocalyx and various adhesins, allow colonization, immune evasion, and establishment of disease in the host. Sepsis caused by gram-negative bacteria is thought to be largely due to a response by the host to the lipid A component of lipopolysaccharide, also called endotoxin. Sepsis caused by gram-positive bacteria may result from an immunological response to cell wall lipoteichoic acid. Bacterial exotoxins that act as superantigens also may cause sepsis. Superantigens simultaneously bind major histocompatibility complex and T-cell receptors in the absence of antigen presentation. This forced receptor interaction induces the production of pro-inflammatory chemical signals (cytokines) by T-cells.There are a number of microbial factors that may cause the typical septic inflammatory cascade. An invading pathogen is recognized by its pathogen-associated molecular patterns (PAMPs). Examples of PAMPs include lipopolysaccharides and flagellin in gram-negative bacteria, muramyl dipeptide in the peptidoglycan of the gram-positive bacterial cell wall, and CpG bacterial DNA. These PAMPs are recognized by the pattern recognition receptors (PRRs) of the innate immune system, which may be membrane-bound or cytosolic. There are four families of PRRs: the toll-like receptors, the C-type lectin receptors, the NOD-like receptors, and the RIG-I-like receptors. Invariably, the association of a PAMP and a PRR will cause a series of intracellular signalling cascades. Consequentially, transcription factors such as nuclear factor-kappa B and activator protein-1, will up-regulate the expression of pro-inflammatory and anti-inflammatory cytokines.
Host factors
Upon detection of microbial antigens, the host systemic immune system is activated. Immune cells not only recognise pathogen-associated molecular patterns but also damage-associated molecular patterns from damaged tissues. An uncontrolled immune response is then activated because leukocytes are not recruited to the specific site of infection, but instead they are recruited all over the body. Then, an immunosuppression state ensues when the proinflammatory T helper cell 1 (TH1) is shifted to TH2, mediated by interleukin 10, which is known as "compensatory anti-inflammatory response syndrome". The apoptosis (cell death) of lymphocytes further worsens the immunosuppression. Neutrophils, monocytes, macrophages, dendritic cells, CD4+ T cells, and B cells all undergo apoptosis, whereas regulatory T cells are more apoptosis resistant. Subsequently, multiple organ failure ensues because tissues are unable to use oxygen efficiently due to inhibition of cytochrome c oxidase.Inflammatory responses cause multiple organ dysfunction syndrome through various mechanisms as described below. Increased permeability of the lung vessels causes leaking of fluids into alveoli, which results in pulmonary edema and acute respiratory distress syndrome (ARDS). Impaired utilization of oxygen in the liver impairs bile salt transport, causing jaundice (yellowish discoloration of the skin). In kidneys, inadequate oxygenation results in tubular epithelial cell injury (of the cells lining the kidney tubules), and thus causes acute kidney injury (AKI). Meanwhile, in the heart, impaired calcium transport, and low production of adenosine triphosphate (ATP), can cause myocardial depression, reducing cardiac contractility and causing heart failure. In the gastrointestinal tract, increased permeability of the mucosa alters the microflora, causing mucosal bleeding and paralytic ileus. In the central nervous system, direct damage of the brain cells and disturbances of neurotransmissions causes altered mental status. Cytokines such as tumor necrosis factor, interleukin 1, and interleukin 6 may activate procoagulation factors in the cells lining blood vessels, leading to endothelial damage. The damaged endothelial surface inhibits anticoagulant properties as well as increases antifibrinolysis, which may lead to intravascular clotting, the formation of blood clots in small blood vessels, and multiple organ failure.The low blood pressure seen in those with sepsis is the result of various processes, including excessive production of chemicals that dilate blood vessels such as nitric oxide, a deficiency of chemicals that constrict blood vessels such as vasopressin, and activation of ATP-sensitive potassium channels. In those with severe sepsis and septic shock, this sequence of events leads to a type of circulatory shock known as distributive shock.
Diagnosis
Early diagnosis is necessary to properly manage sepsis, as the initiation of rapid therapy is key to reducing deaths from severe sepsis. Some hospitals use alerts generated from electronic health records to bring attention to potential cases as early as possible.
Within the first three hours of suspected sepsis, diagnostic studies should include white blood cell counts, measuring serum lactate, and obtaining appropriate cultures before starting antibiotics, so long as this does not delay their use by more than 45 minutes. To identify the causative organism(s), at least two sets of blood cultures using bottles with media for aerobic and anaerobic organisms are necessary. At least one should be drawn through the skin and one through each vascular access device (such as an IV catheter) that has been in place more than 48 hours. Bacteria are present in the blood in only about 30% of cases. Another possible method of detection is by polymerase chain reaction. If other sources of infection are suspected, cultures of these sources, such as urine, cerebrospinal fluid, wounds, or respiratory secretions, also should be obtained, as long as this does not delay the use of antibiotics.Within six hours, if blood pressure remains low despite initial fluid resuscitation of 30 mL/kg, or if initial lactate is ≥ four mmol/L (36 mg/dL), central venous pressure and central venous oxygen saturation should be measured. Lactate should be re-measured if the initial lactate was elevated. Evidence for point of care lactate measurement over usual methods of measurement, however, is poor.Within twelve hours, it is essential to diagnose or exclude any source of infection that would require emergent source control, such as a necrotizing soft tissue infection, an infection causing inflammation of the abdominal cavity lining, an infection of the bile duct, or an intestinal infarction. A pierced internal organ (free air on an abdominal X-ray or CT scan), an abnormal chest X-ray consistent with pneumonia (with focal opacification), or petechiae, purpura, or purpura fulminans may indicate the presence of an infection.
Definitions
Previously, SIRS criteria had been used to define sepsis. If the SIRS criteria are negative, it is very unlikely the person has sepsis; if it is positive, there is just a moderate probability that the person has sepsis. According to SIRS, there were different levels of sepsis: sepsis, severe sepsis, and septic shock. The definition of SIRS is shown below:
SIRS is the presence of two or more of the following: abnormal body temperature, heart rate, respiratory rate, or blood gas, and white blood cell count.
Sepsis is defined as SIRS in response to an infectious process.
Severe sepsis is defined as sepsis with sepsis-induced organ dysfunction or tissue hypoperfusion (manifesting as hypotension, elevated lactate, or decreased urine output). Severe sepsis is an infectious disease state associated with multiple organ dysfunction syndrome (MODS)
Septic shock is severe sepsis plus persistently low blood pressure, despite the administration of intravenous fluids.In 2016 a new consensus was reached to replace screening by systemic inflammatory response syndrome (SIRS) with the sequential organ failure assessment (SOFA score) and the abbreviated version (qSOFA). The three criteria for the qSOFA score include a respiratory rate greater than or equal to 22 breaths per minute, systolic blood pressure 100 mmHg or less and altered mental status. Sepsis is suspected when 2 of the qSOFA criteria are met. The SOFA score was intended to be used in the intensive care unit (ICU) where it is administered upon admission to the ICU and then repeated every 48 hours, whereas the qSOFA could be used outside the ICU. Some advantages of the qSOFA score are that it can be administered quickly and does not require labs. However, the American College of Chest Physicians (CHEST) raised concerns that qSOFA and SOFA criteria may lead to delayed diagnosis of serious infection, leading to delayed treatment. Although SIRS criteria can be too sensitive and not specific enough in identifying sepsis, SOFA also has its limitations and is not intended to replace the SIRS definition. qSOFA has also been found to be poorly sensitive though decently specific for the risk of death with SIRS possibly better for screening. NOTE - Surviving Sepsis Campaign 2021 Guidelines recommends "against using qSOFA compared with SIRS, NEWS, or MEWS as a single screening tool for sepsis or septic shock".
End-organ dysfunction
Examples of end-organ dysfunction include the following:
Lungs: acute respiratory distress syndrome (ARDS) (PaO2/FiO2 ratio < 300), different ratio in pediatric acute respiratory distress syndrome
Brain: encephalopathy symptoms including agitation, confusion, coma; causes may include ischemia, bleeding, formation of blood clots in small blood vessels, microabscesses, multifocal necrotizing leukoencephalopathy
Liver: disruption of protein synthetic function manifests acutely as progressive disruption of blood clotting due to an inability to synthesize clotting factors and disruption of metabolic functions leads to impaired bilirubin metabolism, resulting in elevated unconjugated serum bilirubin levels
Kidney: low urine output or no urine output, electrolyte abnormalities, or volume overload
Heart: systolic and diastolic heart failure, likely due to chemical signals that depress myocyte function, cellular damage, manifest as a troponin leak (although not necessarily ischemic in nature)More specific definitions of end-organ dysfunction exist for SIRS in pediatrics.
Cardiovascular dysfunction (after fluid resuscitation with at least 40 mL/kg of crystalloid)
hypotension with blood pressure < 5th percentile for age or systolic blood pressure < 2 standard deviations below normal for age, or
vasopressor requirement, or
two of the following criteria:
unexplained metabolic acidosis with base deficit > 5 mEq/L
lactic acidosis: serum lactate 2 times the upper limit of normal
oliguria (urine output < 0.5 mL/kg/h)
prolonged capillary refill > 5 seconds
core to peripheral temperature difference > 3 °C
Respiratory dysfunction (in the absence of a cyanotic heart defect or a known chronic respiratory disease)
the ratio of the arterial partial-pressure of oxygen to the fraction of oxygen in the gases inspired (PaO2/FiO2) < 300 (the definition of acute lung injury), or
arterial partial-pressure of carbon dioxide (PaCO2) > 65 torr (20 mmHg) over baseline PaCO2 (evidence of hypercapnic respiratory failure), or
supplemental oxygen requirement of greater than FiO2 0.5 to maintain oxygen saturation ≥ 92%
Neurologic dysfunction
Glasgow Coma Score (GCS) ≤ 11, or
altered mental status with drop in GCS of 3 or more points in a person with developmental delay/intellectual disability
Hematologic dysfunction
platelet count < 80,000/mm3 or 50% drop from maximum in chronically thrombocytopenic, or
international normalized ratio (INR) > 2
Disseminated intravascular coagulation
Kidney dysfunction
serum creatinine ≥ 2 times the upper limit of normal for age or 2-fold increase in baseline creatinine in people with chronic kidney disease
Liver dysfunction (only applicable to infants > 1 month)
total serum bilirubin ≥ 4 mg/dL, or
alanine aminotransferase (ALT) ≥ 2 times the upper limit of normalConsensus definitions, however, continue to evolve, with the latest expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience.
Biomarkers
Biomarkers can help diagnosis because they can point to the presence or severity of sepsis, although their exact role in the management of sepsis remains undefined. A 2013 review concluded moderate-quality evidence exists to support the use of the procalcitonin level as a method to distinguish sepsis from non-infectious causes of SIRS. The same review found the sensitivity of the test to be 77% and the specificity to be 79%. The authors suggested that procalcitonin may serve as a helpful diagnostic marker for sepsis, but cautioned that its level alone does not definitively make the diagnosis. A 2012 systematic review found that soluble urokinase-type plasminogen activator receptor (SuPAR) is a nonspecific marker of inflammation and does not accurately diagnose sepsis. This same review concluded, however, that SuPAR has prognostic value, as higher SuPAR levels are associated with an increased rate of death in those with sepsis. Serial measurement of lactate levels (approximately every 4 to 6 hours) may guide treatment and is associated with lower mortality in sepsis.
Differential diagnosis
The differential diagnosis for sepsis is broad and has to examine (to exclude) the non-infectious conditions that may cause the systemic signs of SIRS: alcohol withdrawal, acute pancreatitis, burns, pulmonary embolism, thyrotoxicosis, anaphylaxis, adrenal insufficiency, and neurogenic shock. Hyperinflammatory syndromes such as hemophagocytic lymphohistiocytosis (HLH) may have similar symptoms and are on the differential diagnosis.
Neonatal sepsis
In common clinical usage, neonatal sepsis refers to a bacterial blood stream infection in the first month of life, such as meningitis, pneumonia, pyelonephritis, or gastroenteritis, but neonatal sepsis also may be due to infection with fungi, viruses, or parasites. Criteria with regard to hemodynamic compromise or respiratory failure are not useful because they present too late for intervention.
Management
Early recognition and focused management may improve the outcomes in sepsis. Current professional recommendations include a number of actions ("bundles") to be followed as soon as possible after diagnosis. Within the first three hours, someone with sepsis should have received antibiotics and, intravenous fluids if there is evidence of either low blood pressure or other evidence for inadequate blood supply to organs (as evidenced by a raised level of lactate); blood cultures also should be obtained within this time period. After six hours the blood pressure should be adequate, close monitoring of blood pressure and blood supply to organs should be in place, and the lactate should be measured again if initially it was raised. A related bundle, the "Sepsis Six", is in widespread use in the United Kingdom; this requires the administration of antibiotics within an hour of recognition, blood cultures, lactate, and hemoglobin determination, urine output monitoring, high-flow oxygen, and intravenous fluids.Apart from the timely administration of fluids and antibiotics, the management of sepsis also involves surgical drainage of infected fluid collections and appropriate support for organ dysfunction. This may include hemodialysis in kidney failure, mechanical ventilation in lung dysfunction, transfusion of blood products, and drug and fluid therapy for circulatory failure. Ensuring adequate nutrition—preferably by enteral feeding, but if necessary, by parenteral nutrition—is important during prolonged illness. Medication to prevent deep vein thrombosis and gastric ulcers also may be used.
Antibiotics
Two sets of blood cultures (aerobic and anaerobic) are recommended without delaying the initiation of antibiotics. Cultures from other sites such as respiratory secretions, urine, wounds, cerebrospinal fluid, and catheter insertion sites (in-situ more than 48 hours) are recommended if infections from these sites are suspected. In severe sepsis and septic shock, broad-spectrum antibiotics (usually two, a β-lactam antibiotic with broad coverage, or broad-spectrum carbapenem combined with fluoroquinolones, macrolides, or aminoglycosides) are recommended. The choice of antibiotics is important in determining the survival of the person. Some recommend they be given within one hour of making the diagnosis, stating that for every hour of delay in the administration of antibiotics, there is an associated 6% rise in mortality. Others did not find a benefit with early administration.Several factors determine the most appropriate choice for the initial antibiotic regimen. These factors include local patterns of bacterial sensitivity to antibiotics, whether the infection is thought to be a hospital or community-acquired infection, and which organ systems are thought to be infected. Antibiotic regimens should be reassessed daily and narrowed if appropriate. Treatment duration is typically 7–10 days with the type of antibiotic used directed by the results of cultures. If the culture result is negative, antibiotics should be de-escalated according to the persons clinical response or stopped altogether if an infection is not present to decrease the chances that the person is infected with multiple drug resistance organisms. In case of people having a high risk of being infected with multiple drug resistant organisms such as Pseudomonas aeruginosa, Acinetobacter baumannii, the addition of an antibiotic specific to the gram-negative organism is recommended. For methicillin-resistant Staphylococcus aureus (MRSA), vancomycin or teicoplanin is recommended. For Legionella infection, addition of macrolide or fluoroquinolone is chosen. If fungal infection is suspected, an echinocandin, such as caspofungin or micafungin, is chosen for people with severe sepsis, followed by triazole (fluconazole and itraconazole) for less ill people. Prolonged antibiotic prophylaxis is not recommended in people who has SIRS without any infectious origin such as acute pancreatitis and burns unless sepsis is suspected.Once-daily dosing of aminoglycoside is sufficient to achieve peak plasma concentration for a clinical response without kidney toxicity. Meanwhile, for antibiotics with low volume distribution (vancomycin, teicoplanin, colistin), a loading dose is required to achieve an adequate therapeutic level to fight infections. Frequent infusions of beta-lactam antibiotics without exceeding total daily dose would help to keep the antibiotics level above minimum inhibitory concentration (MIC), thus providing a better clinical response. Giving beta-lactam antibiotics continuously may be better than giving them intermittently. Access to therapeutic drug monitoring is important to ensure adequate drug therapeutic level while at the same time preventing the drug from reaching toxic level.
Intravenous fluids
The Surviving Sepsis Campaign has recommended 30 mL/kg of fluid to be given in adults in the first three hours followed by fluid titration according to blood pressure, urine output, respiratory rate, and oxygen saturation with a target mean arterial pressure (MAP) of 65 mmHg. In children an initial amount of 20 mL/kg is reasonable in shock. In cases of severe sepsis and septic shock where a central venous catheter is used to measure blood pressures dynamically, fluids should be administered until the central venous pressure reaches 8–12 mmHg. Once these goals are met, the central venous oxygen saturation (ScvO2), i.e., the oxygen saturation of venous blood as it returns to the heart as measured at the vena cava, is optimized. If the ScvO2 is less than 70%, blood may be given to reach a hemoglobin of 10 g/dL and then inotropes are added until the ScvO2 is optimized. In those with acute respiratory distress syndrome (ARDS) and sufficient tissue blood fluid, more fluids should be given carefully.Crystalloid solution is recommended as the fluid of choice for resuscitation. Albumin can be used if a large amount of crystalloid is required for resuscitation. Crystalloid solutions shows little difference with hydroxyethyl starch in terms of risk of death. Starches also carry an increased risk of acute kidney injury, and need for blood transfusion. Various colloid solutions (such as modified gelatin) carry no advantage over crystalloid. Albumin also appears to be of no benefit over crystalloids.
Blood products
The Surviving Sepsis Campaign recommended packed red blood cells transfusion for hemoglobin levels below 70 g/L if there is no myocardial ischemia, hypoxemia, or acute bleeding. In a 2014 trial, blood transfusions to keep target hemoglobin above 70 or 90 g/L did not make any difference to survival rates; meanwhile, those with a lower threshold of transfusion received fewer transfusions in total. Erythropoietin is not recommended in the treatment of anemia with septic shock because it may precipitate blood clotting events. Fresh frozen plasma transfusion usually does not correct the underlying clotting abnormalities before a planned surgical procedure. However, platelet transfusion is suggested for platelet counts below (10 × 109/L) without any risk of bleeding, or (20 × 109/L) with high risk of bleeding, or (50 × 109/L) with active bleeding, before a planned surgery or an invasive procedure. IV immunoglobulin is not recommended because its beneficial effects are uncertain. Monoclonal and polyclonal preparations of intravenous immunoglobulin (IVIG) do not lower the rate of death in newborns and adults with sepsis. Evidence for the use of IgM-enriched polyclonal preparations of IVIG is inconsistent. On the other hand |
Sepsis | , the use of antithrombin to treat disseminated intravascular coagulation is also not useful. Meanwhile, the blood purification technique (such as hemoperfusion, plasma filtration, and coupled plasma filtration adsorption) to remove inflammatory mediators and bacterial toxins from the blood also does not demonstrate any survival benefit for septic shock.
Vasopressors
If the person has been sufficiently fluid resuscitated but the mean arterial pressure is not greater than 65 mmHg, vasopressors are recommended. Norepinephrine (noradrenaline) is recommended as the initial choice. Delaying initiation of vasopressor therapy during septic shock is associated with increased mortality.Norepinephrine is often used as a first-line treatment for hypotensive septic shock because evidence shows that there is a relative deficiency of vasopressin when shock continues for 24 to 48 hours. Norepinephrine raises blood pressure through a vasoconstriction effect, with little effect on stroke volume and heart rate. In some people, the required dose of vasopressor needed to increase the mean arterial pressure can become exceedingly high that it becomes toxic. In order to reduce the required dose of vasopressor, epinephrine may be added. Epinephrine is not often used as a first-line treatment for hypotensive shock because it reduces blood flow to the abdominal organs and increases lactate levels. Vasopressin can be used in septic shock because studies have shown that there is a relative deficiency of vasopressin when shock continues for 24 to 48 hours. However, vasopressin reduces blood flow to the heart, finger/toes, and abdominal organs, resulting in a lack of oxygen supply to these tissues. Dopamine is typically not recommended. Although dopamine is useful to increase the stroke volume of the heart, it causes more abnormal heart rhythms than norepinephrine and also has an immunosuppressive effect. Dopamine is not proven to have protective properties on the kidneys. Dobutamine can also be used in hypotensive septic shock to increase cardiac output and correct blood flow to the tissues. Dobutamine is not used as often as epinephrine due to its associated side effects, which include reducing blood flow to the gut. Additionally, dobutamine increases the cardiac output by abnormally increasing the heart rate.
Steroids
The use of steroids in sepsis is controversial. Studies do not give a clear picture as to whether and when glucocorticoids should be used. The 2016 Surviving Sepsis Campaign recommends low dose hydrocortisone only if both intravenous fluids and vasopressors are not able to adequately treat septic shock. The 2021 Surviving Sepsis Campaign recommends IV corticosteroids for adults with septic shock who have an ongoing requirement for vasopressor therapy. A 2019 Cochrane review found low-quality evidence of benefit, as did two 2019 reviews.During critical illness, a state of adrenal insufficiency and tissue resistance to corticosteroids may occur. This has been termed critical illness–related corticosteroid insufficiency. Treatment with corticosteroids might be most beneficial in those with septic shock and early severe ARDS, whereas its role in others such as those with pancreatitis or severe pneumonia is unclear. However, the exact way of determining corticosteroid insufficiency remains problematic. It should be suspected in those poorly responding to resuscitation with fluids and vasopressors. Neither ACTH stimulation testing nor random cortisol levels are recommended to confirm the diagnosis. The method of stopping glucocorticoid drugs is variable, and it is unclear whether they should be slowly decreased or simply abruptly stopped. However, the 2016 Surviving Sepsis Campaign recommended to taper steroids when vasopressors are no longer needed.
Anesthesia
A target tidal volume of 6 mL/kg of predicted body weight (PBW) and a plateau pressure less than 30 cm H2O is recommended for those who require ventilation due to sepsis-induced severe ARDS. High positive end expiratory pressure (PEEP) is recommended for moderate to severe ARDS in sepsis as it opens more lung units for oxygen exchange. Predicted body weight is calculated based on sex and height, and tools for this are available. Recruitment maneuvers may be necessary for severe ARDS by briefly raising the transpulmonary pressure. It is recommended that the head of the bed be raised if possible to improve ventilation. However, β2 adrenergic receptor agonists are not recommended to treat ARDS because it may reduce survival rates and precipitate abnormal heart rhythms. A spontaneous breathing trial using continuous positive airway pressure (CPAP), T piece, or inspiratory pressure augmentation can be helpful in reducing the duration of ventilation. Minimizing intermittent or continuous sedation is helpful in reducing the duration of mechanical ventilation.General anesthesia is recommended for people with sepsis who require surgical procedures to remove the infective source. Usually, inhalational and intravenous anesthetics are used. Requirements for anesthetics may be reduced in sepsis. Inhalational anesthetics can reduce the level of proinflammatory cytokines, altering leukocyte adhesion and proliferation, inducing apoptosis (cell death) of the lymphocytes, possibly with a toxic effect on mitochondrial function. Although etomidate has a minimal effect on the cardiovascular system, it is often not recommended as a medication to help with intubation in this situation due to concerns it may lead to poor adrenal function and an increased risk of death. The small amount of evidence there is, however, has not found a change in the risk of death with etomidate.Paralytic agents are not suggested for use in sepsis cases in the absence of ARDS, as a growing body of evidence points to reduced durations of mechanical ventilation, ICU and hospital stays. However, paralytic use in ARDS cases remains controversial. When appropriately used, paralytics may aid successful mechanical ventilation, however, evidence has also suggested that mechanical ventilation in severe sepsis does not improve oxygen consumption and delivery.
Source control
Source control refers to physical interventions to control a focus of infection and reduce conditions favorable to microorganism growth or host defense impairment, such as drainage of pus from an abscess. It is one of the oldest procedures for control of infections, giving rise to the Latin phrase Ubi pus, ibi evacua, and remains important despite the emergence of more modern treatments.
Early goal directed therapy
Early goal directed therapy (EGDT) is an approach to the management of severe sepsis during the initial 6 hours after diagnosis. It is a step-wise approach, with the physiologic goal of optimizing cardiac preload, afterload, and contractility. It includes giving early antibiotics. EGDT also involves monitoring of hemodynamic parameters and specific interventions to achieve key resuscitation targets which include maintaining a central venous pressure between 8–12 mmHg, a mean arterial pressure of between 65 and 90 mmHg, a central venous oxygen saturation (ScvO2) greater than 70% and a urine output of greater than 0.5 mL/kg/hour. The goal is to optimize oxygen delivery to tissues and achieve a balance between systemic oxygen delivery and demand. An appropriate decrease in serum lactate may be equivalent to ScvO2 and easier to obtain.In the original trial, early goal-directed therapy was found to reduce mortality from 46.5% to 30.5% in those with sepsis, and the Surviving Sepsis Campaign has been recommending its use. However, three more recent large randomized control trials (ProCESS, ARISE, and ProMISe), did not demonstrate a 90-day mortality benefit of early goal-directed therapy when compared to standard therapy in severe sepsis. It is likely that some parts of EGDT are more important than others. Following these trials the use of EGDT is still considered reasonable.
Newborns
Neonatal sepsis can be difficult to diagnose as newborns may be asymptomatic. If a newborn shows signs and symptoms suggestive of sepsis, antibiotics are immediately started and are either changed to target a specific organism identified by diagnostic testing or discontinued after an infectious cause for the symptoms has been ruled out. Despite early intervention, death occurs in 13% of children who develop septic shock, with the risk partly based on other health problems. Those without multiple organ system failures or who require only one inotropic agent mortality is low.
Other
Treating fever in sepsis, including people in septic shock, has not been associated with any improvement in mortality over a period of 28 days. Treatment of fever still occurs for other reasons.A 2012 Cochrane review concluded that N-acetylcysteine does not reduce mortality in those with SIRS or sepsis and may even be harmful.Recombinant activated protein C (drotrecogin alpha) was originally introduced for severe sepsis (as identified by a high APACHE II score), where it was thought to confer a survival benefit. However, subsequent studies showed that it increased adverse events—bleeding risk in particular—and did not decrease mortality. It was removed from sale in 2011. Another medication known as eritoran also has not shown benefit.In those with high blood sugar levels, insulin to bring it down to 7.8–10 mmol/L (140–180 mg/dL) is recommended with lower levels potentially worsening outcomes. Glucose levels taken from capillary blood should be interpreted with care because such measurements may not be accurate. If a person has an arterial catheter, arterial blood is recommended for blood glucose testing.Intermittent or continuous renal replacement therapy may be used if indicated. However, sodium bicarbonate is not recommended for a person with lactic acidosis secondary to hypoperfusion. Low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), and mechanical prophylaxis with intermittent pneumatic compression devices are recommended for any person with sepsis at moderate to high risk of venous thromboembolism. Stress ulcer prevention with proton-pump inhibitor (PPI) and H2 antagonist are useful in a person with risk factors of developing upper gastrointestinal bleeding (UGIB) such as on mechanical ventilation for more than 48 hours, coagulation disorders, liver disease, and renal replacement therapy. Achieving partial or full enteral feeding (delivery of nutrients through a feeding tube) is chosen as the best approach to provide nutrition for a person who is contraindicated for oral intake or unable to tolerate orally in the first seven days of sepsis when compared to intravenous nutrition. However, omega-3 fatty acids are not recommended as immune supplements for a person with sepsis or septic shock. The usage of prokinetic agents such as metoclopramide, domperidone, and erythromycin are recommended for those who are septic and unable to tolerate enteral feeding. However, these agents may precipitate prolongation of the QT interval and consequently provoke a ventricular arrhythmia such as torsades de pointes. The usage of prokinetic agents should be reassessed daily and stopped if no longer indicated.
Prognosis
Sepsis will prove fatal in approximately 24.4% of people, and septic shock will prove fatal in 34.7% of people within 30 days (32.2% and 38.5% after 90 days).
Lactate is a useful method of determining prognosis, with those who have a level greater than 4 mmol/L having a mortality of 40% and those with a level of less than 2 mmol/L having a mortality of less than 15%.There are a number of prognostic stratification systems, such as APACHE II and Mortality in Emergency Department Sepsis. APACHE II factors in the persons age, underlying condition, and various physiologic variables to yield estimates of the risk of dying of severe sepsis. Of the individual covariates, the severity of the underlying disease most strongly influences the risk of death. Septic shock is also a strong predictor of short- and long-term mortality. Case-fatality rates are similar for culture-positive and culture-negative severe sepsis. The Mortality in Emergency Department Sepsis (MEDS) score is simpler and useful in the emergency department environment.Some people may experience severe long-term cognitive decline following an episode of severe sepsis, but the absence of baseline neuropsychological data in most people with sepsis makes the incidence of this difficult to quantify or to study.
Epidemiology
Sepsis causes millions of deaths globally each year and is the most common cause of death in people who have been hospitalized. The number of new cases worldwide of sepsis is estimated to be 18 million cases per year. In the United States sepsis affects approximately 3 in 1,000 people, and severe sepsis contributes to more than 200,000 deaths per year.Sepsis occurs in 1–2% of all hospitalizations and accounts for as much as 25% of ICU bed utilization. Due to it rarely being reported as a primary diagnosis (often being a complication of cancer or other illness), the incidence, mortality, and morbidity rates of sepsis are likely underestimated. A study of U.S. states found approximately 651 hospital stays per 100,000 population with a sepsis diagnosis in 2010. It is the second-leading cause of death in non-coronary intensive care unit (ICU) and the tenth-most-common cause of death overall (the first being heart disease). Children under 12 months of age and elderly people have the highest incidence of severe sepsis. Among people from the U.S. who had multiple sepsis hospital admissions in 2010, those who were discharged to a skilled nursing facility or long-term care following the initial hospitalization were more likely to be readmitted than those discharged to another form of care. A study of 18 U.S. states found that, amongst people with Medicare in 2011, sepsis was the second most common principal reason for readmission within 30 days.Several medical conditions increase a persons susceptibility to infection and developing sepsis. Common sepsis risk factors include age (especially the very young and old); conditions that weaken the immune system such as cancer, diabetes, or the absence of a spleen; and major trauma and burns.From 1979 to 2000, data from the United States National Hospital Discharge Survey showed that the incidence of sepsis increased fourfold, to 240 cases per 100,000 population, with a higher incidence in men when compared to women. However, the global prevalence of sepsis has been estimated to be higher in women. During the same time frame, the in-hospital case fatality rate was reduced from 28% to 18%. However, according to the nationwide inpatient sample from the United States, the incidence of severe sepsis increased from 200 per 10,000 population in 2003 to 300 cases in 2007 for population aged more than 18 years. The incidence rate is particularly high among infants, with an incidence of 500 cases per 100,000 population. Mortality related to sepsis increases with age, from less than 10% in the age group of 3 to 5 years to 60% by sixth decade of life. The increase in the average age of the population, alongside the presence of more people with chronic diseases or on immunosuppressive medications, and also the increase in the number of invasive procedures being performed, has led to an increased rate of sepsis.
History
The term "σήψις" (sepsis) was introduced by Hippocrates in the fourth century BC, and it meant the process of decay or decomposition of organic matter. In the eleventh century, Avicenna used the term "blood rot" for diseases linked to severe purulent process. Though severe systemic toxicity had already been observed, it was only in the 19th century that the specific term – sepsis – was used for this condition.
The terms "septicemia", also spelled "septicaemia", and "blood poisoning" referred to the microorganisms or their toxins in the blood. The International Statistical Classification of Diseases and Related Health Problems (ICD) version 9, which was in use in the US until 2013, used the term septicemia with numerous modifiers for different diagnoses, such as "Streptococcal septicemia". All those diagnoses have been converted to sepsis, again with modifiers, in ICD-10, such as "Sepsis due to streptococcus".The current terms are dependent on the microorganism that is present: bacteremia if bacteria are present in the blood at abnormal levels and are the causative issue, viremia for viruses, and fungemia for a fungus.By the end of the 19th century, it was widely believed that microbes produced substances that could injure the mammalian host and that soluble toxins released during infection caused the fever and shock that were commonplace during severe infections. Pfeiffer coined the term endotoxin at the beginning of the 20th century to denote the pyrogenic principle associated with Vibrio cholerae. It was soon realized that endotoxins were expressed by most and perhaps all gram-negative bacteria. The lipopolysaccharide character of enteric endotoxins was elucidated in 1944 by Shear. The molecular character of this material was determined by Luderitz et al. in 1973.It was discovered in 1965 that a strain of C3H/HeJ mouse was immune to the endotoxin-induced shock. The genetic locus for this effect was dubbed Lps. These mice were also found to be hyper susceptible to infection by gram-negative bacteria. These observations were finally linked in 1998 by the discovery of the toll-like receptor gene 4 (TLR 4). Genetic mapping work, performed over a period of five years, showed that TLR4 was the sole candidate locus within the Lps critical region; this strongly implied that a mutation within TLR4 must account for the lipopolysaccharide resistance phenotype. The defect in the TLR4 gene that led to the endotoxin resistant phenotype was discovered to be due to a mutation in the cytoplasm.Controversy occurred in the scientific community over the use of mouse models in research into sepsis in 2013 when scientists published a review of the mouse immune system compared to the human immune system and showed that on a systems level, the two worked very differently; the authors noted that as of the date of their article over 150 clinical trials of sepsis had been conducted in humans, almost all of them supported by promising data in mice and that all of them had failed. The authors called for abandoning the use of mouse models in sepsis research; others rejected that but called for more caution in interpreting the results of mouse studies, and more careful design of preclinical studies. One approach is to rely more on studying biopsies and clinical data from people who have had sepsis, to try to identify biomarkers and drug targets for intervention.
Society and culture
Economics
Sepsis was the most expensive condition treated in United States hospital stays in 2013, at an aggregate cost of $23.6 billion for nearly 1.3 million hospitalizations. Costs for sepsis hospital stays more than quadrupled since 1997 with an 11.5 percent annual increase. By payer, it was the most costly condition billed to Medicare and the uninsured, the second-most costly billed to Medicaid, and the fourth-most costly billed to private insurance.
Education
A large international collaboration entitled the "Surviving Sepsis Campaign" was established in 2002 to educate people about sepsis and to improve outcomes with sepsis. The Campaign has published an evidence-based review of management strategies for severe sepsis, with the aim to publish a complete set of guidelines in subsequent years. The guidelines were updated in 2016 and again in 2021.Sepsis Alliance is a charitable organization that was created to raise sepsis awareness among both the general public and healthcare professionals.
Research
Some authors suggest that initiating sepsis by the normally mutualistic (or neutral) members of the microbiome may not always be an accidental side effect of the deteriorating host immune system. Rather it is often an adaptive microbial response to a sudden decline of host survival chances. Under this scenario, the microbe species provoking sepsis benefit from monopolizing the future cadaver, utilizing its biomass as decomposers, and then transmitted through soil or water to establish mutualistic relations with new individuals. The bacteria Streptococcus pneumoniae, Escherichia coli, Proteus spp., Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella spp., Clostridium spp., Lactobacillus spp., Bacteroides spp. and the fungi Candida spp. are all capable of such a high level of phenotypic plasticity. Evidently, not all cases of sepsis arise through such adaptive microbial strategy switches.Paul E. Mariks "Marik protocol", also known as the "HAT" protocol, proposed a combination of hydrocortisone, vitamin C, and thiamine as a treatment for preventing sepsis for people in intensive care. Mariks own initial research, published in 2017, showed a dramatic evidence of benefit, leading to the protocol becoming popular among intensive care physicians, especially after the protocol received attention on social media and National Public Radio, leading to criticism of science by press conference from the wider medical community. Subsequent independent research failed to replicate Mariks positive results, indicating the possibility that they had been compromised by bias. A systematic review of trials in 2021 found that the claimed benefits of the protocol could not be confirmed. Another more recent review found that "HAT therapy significantly reduced the duration of vasopressor use and improved the SOFA score but appeared not to have significant benefits in other outcomes for patients with sepsis."Overall, the evidence for any role for vitamin C in the treatment of sepsis remains unclear as of 2021.
References
External links
Sepsis at Curlie
SIRS, Sepsis, and Septic Shock Criteria Archived 17 February 2015 at the Wayback Machine
"Sepsis". MedlinePlus. U.S. National Library of Medicine. |
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