Acquired immune deficiency syndrome or acquired immunodeficiency syndrome (AIDS) is a disease of the human immune system caused by the human immunodeficiency virus (HIV).[1][2][3] This condition progressively reduces the effectiveness of the immune system and leaves individuals susceptible to opportunistic infections and tumors. HIV is transmitted through direct contact of a mucous membrane or the bloodstream with a bodily fluid containing HIV, such as blood, semen, vaginal fluid, preseminal fluid, and breast milk.[4][5] This transmission can involve anal, vaginal or oral sex, blood transfusion, contaminated hypodermic needles, exchange between mother and baby during pregnancy, childbirth, breastfeeding or other exposure to one of the above bodily fluids.
AIDS is now a pandemic.[6] As of 2009, AVERT estimated that there are 33.3 million people worldwide living with HIV/AIDS, with 2.6 million new HIV infections per year and 1.8 million annual deaths due to AIDS.[7] In 2007, UNAIDS estimated: 33.2 million people worldwide had AIDS that year; AIDS killed 2.1 million people in the course of that year, including 330,000 children, and 76% of those deaths occurred in sub-Saharan Africa.[8] According to UNAIDS 2009 report, worldwide some 60 million people have been infected, with some 25 million deaths, and 14 million orphaned children in southern Africa alone since the epidemic began.[9]
Genetic research indicates that HIV originated in west-central Africa during the late nineteenth or early twentieth century.[10][11] AIDS was first recognized by the U.S. Centers for Disease Control and Prevention in 1981 and its cause, HIV, identified in the early 1980s.[12]
Although treatments for AIDS and HIV can slow the course of the disease, there is no known cure or vaccine. Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection, but these drugs are expensive and routine access to antiretroviral medication is not available in all countries.[13] Due to the difficulty in treating HIV infection, preventing infection is a key aim in controlling the AIDS pandemic, with health organizations promoting safe sex and needle-exchange programmes in attempts to slow the spread of the virus.
Contents
[hide]
* 1 Signs and symptoms
o 1.1 Pulmonary
o 1.2 Gastrointestinal
o 1.3 Neurological and psychiatric
o 1.4 Tumors
o 1.5 Other infections
* 2 Cause
o 2.1 Sexual transmission
o 2.2 Blood products
o 2.3 Perinatal transmission
* 3 Pathophysiology
o 3.1 Cells affected
+ 3.1.1 The effect
+ 3.1.2 Molecular basis
* 4 Diagnosis
o 4.1 WHO disease staging system
o 4.2 CDC classification system
o 4.3 HIV test
* 5 Prevention
o 5.1 Sexual contact
o 5.2 Body fluid exposure
o 5.3 Mother-to-child
o 5.4 Education
* 6 Management
o 6.1 Antiviral therapy
o 6.2 Complementary and alternative medicine
* 7 Prognosis
* 8 Epidemiology
* 9 History and origin
* 10 Society and culture
o 10.1 Stigma
o 10.2 Economic impact
o 10.3 Religion and AIDS
o 10.4 AIDS denialism
o 10.5 KGB disinformation
o 10.6 Government reaction
* 11 Research directions
* 12 See also
* 13 Notes and references
* 14 Further reading
* 15 External links
Signs and symptoms
Main symptoms of AIDS.
X-ray of Pneumocystis pneumonia (PCP). There is increased white (opacity) in the lower lungs on both sides, characteristic of PCP
The symptoms of AIDS are primarily the result of conditions that do not normally develop in individuals with healthy immune systems. Most of these conditions are infections caused by bacteria, viruses, fungi and parasites that are normally controlled by the elements of the immune system that HIV damages.
Opportunistic infections are common in people with AIDS.[14] These infections affect nearly every organ system.
People with AIDS also have an increased risk of developing various cancers such as Kaposi's sarcoma, cervical cancer and cancers of the immune system known as lymphomas. Additionally, people with AIDS often have systemic symptoms of infection like fevers, sweats (particularly at night), swollen glands, chills, weakness, and weight loss.[15][16] The specific opportunistic infections that AIDS patients develop depend in part on the prevalence of these infections in the geographic area in which the patient lives.
Pulmonary
Pneumocystis pneumonia (originally known as Pneumocystis carinii pneumonia, and still abbreviated as PCP, which now stands for Pneumocystis pneumonia) is relatively rare in healthy, immunocompetent people, but common among HIV-infected individuals. It is caused by Pneumocystis jirovecii.
Before the advent of effective diagnosis, treatment and routine prophylaxis in Western countries, it was a common immediate cause of death. In developing countries, it is still one of the first indications of AIDS in untested individuals, although it does not generally occur unless the CD4 count is less than 200 cells per µL of blood.[17]
Tuberculosis (TB) is unique among infections associated with HIV because it is transmissible to immunocompetent people via the respiratory route, and is not easily treatable once identified,[18] Multidrug resistance is a serious problem. Tuberculosis with HIV co-infection (TB/HIV) is a major world health problem according to the World Health Organization: in 2007, 456,000 deaths among incident TB cases were HIV-positive, a third of all TB deaths and nearly a quarter of the estimated 2 million HIV deaths in that year.[19]
Even though its incidence has declined because of the use of directly observed therapy and other improved practices in Western countries, this is not the case in developing countries where HIV is most prevalent. In early-stage HIV infection (CD4 count >300 cells per µL), TB typically presents as a pulmonary disease. In advanced HIV infection, TB often presents atypically with extrapulmonary (systemic) disease a common feature. Symptoms are usually constitutional and are not localized to one particular site, often affecting bone marrow, bone, urinary and gastrointestinal tracts, liver, regional lymph nodes, and the central nervous system.[20]
Gastrointestinal
Esophagitis is an inflammation of the lining of the lower end of the esophagus (gullet or swallowing tube leading to the stomach). In HIV infected individuals, this is normally due to fungal (candidiasis) or viral (herpes simplex-1 or cytomegalovirus) infections. In rare cases, it could be due to mycobacteria.[21]
Unexplained chronic diarrhea in HIV infection is due to many possible causes, including common bacterial (Salmonella, Shigella, Listeria or Campylobacter) and parasitic infections; and uncommon opportunistic infections such as cryptosporidiosis, microsporidiosis, Mycobacterium avium complex (MAC) and viruses,[22] astrovirus, adenovirus, rotavirus and cytomegalovirus, (the latter as a course of colitis).
In some cases, diarrhea may be a side effect of several drugs used to treat HIV, or it may simply accompany HIV infection, particularly during primary HIV infection. It may also be a side effect of antibiotics used to treat bacterial causes of diarrhea (common for Clostridium difficile). In the later stages of HIV infection, diarrhea is thought to be a reflection of changes in the way the intestinal tract absorbs nutrients, and may be an important component of HIV-related wasting.[23]
Neurological and psychiatric
HIV infection may lead to a variety of neuropsychiatric sequelae, either by infection of the now susceptible nervous system by organisms, or as a direct consequence of the illness itself.[24]
Toxoplasmosis is a disease caused by the single-celled parasite called Toxoplasma gondii; it usually infects the brain, causing toxoplasma encephalitis, but it can also infect and cause disease in the eyes and lungs.[25] Cryptococcal meningitis is an infection of the meninx (the membrane covering the brain and spinal cord) by the fungus Cryptococcus neoformans. It can cause fevers, headache, fatigue, nausea, and vomiting. Patients may also develop seizures and confusion; left untreated, it can be lethal.
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease, in which the gradual destruction of the myelin sheath covering the axons of nerve cells impairs the transmission of nerve impulses. It is caused by a virus called JC virus which occurs in 70% of the population in latent form, causing disease only when the immune system has been severely weakened, as is the case for AIDS patients. It progresses rapidly, usually causing death within months of diagnosis.[26]
AIDS dementia complex (ADC) is a metabolic encephalopathy induced by HIV infection and fueled by immune activation of HIV infected brain macrophages and microglia. These cells are productively infected by HIV and secrete neurotoxins of both host and viral origin.[27] Specific neurological impairments are manifested by cognitive, behavioral, and motor abnormalities that occur after years of HIV infection and are associated with low CD4+ T cell levels and high plasma viral loads.
Prevalence is 10–20% in Western countries[28] but only 1–2% of HIV infections in India.[29][30] This difference is possibly due to the HIV subtype in India. AIDS related mania is sometimes seen in patients with advanced HIV illness; it presents with more irritability and cognitive impairment and less euphoria than a manic episode associated with true bipolar disorder. Unlike the latter condition, it may have a more chronic course. This syndrome is less often seen with the advent of multi-drug therapy.
Tumors
Kaposi's sarcoma
Patients with HIV infection have substantially increased incidence of several cancers. This is primarily due to co-infection with an oncogenic DNA virus, especially Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV) (also known as human herpesvirus-8 [HHV-8]), and human papillomavirus (HPV).[31][32]
Kaposi's sarcoma (KS) is the most common tumor in HIV-infected patients. The appearance of this tumor in young homosexual men in 1981 was one of the first signals of the AIDS epidemic. Caused by a gammaherpes virus called Kaposi's sarcoma-associated herpes virus (KSHV), it often appears as purplish nodules on the skin, but can affect other organs, especially the mouth, gastrointestinal tract, and lungs. High-grade B cell lymphomas such as Burkitt's lymphoma, Burkitt's-like lymphoma, diffuse large B-cell lymphoma (DLBCL), and primary central nervous system lymphoma present more often in HIV-infected patients. These particular cancers often foreshadow a poor prognosis. Epstein-Barr virus (EBV) or KSHV cause many of these lymphomas. In HIV-infected patients, lymphoma often arises in extranodal sites such as the gastrointestinal tract.[33] When they occur in an HIV-infected patient, KS and aggressive B cell lymphomas confer a diagnosis of AIDS.
Invasive cervical cancer in HIV-infected women is also considered AIDS-defining, it is caused by human papillomavirus (HPV).[34]
In addition to the AIDS-defining tumors listed above, HIV-infected patients are at increased risk of certain other tumors, notably Hodgkin's disease, anal and rectal carcinomas, hepatocellular carcinomas, head and neck cancers, and lung cancer. Some of these are causes by viruses, such as Hodgkin's disease (EBV), anal/rectal cancers (HPV), head and neck cancers (HPV), and hepatocellular carcinoma (hepatitis B or C). Other contributing factors include exposure to carcinogens (cigarette smoke for lung cancer), or living for years with subtle immune defects.
Interestingly, the incidence of many common tumors, such as breast cancer or colon cancer, does not increase in HIV-infected patients. In areas where HAART is extensively used to treat AIDS, the incidence of many AIDS-related malignancies has decreased, but at the same time malignant cancers overall have become the most common cause of death of HIV-infected patients.[35] In recent years, an increasing proportion of these deaths have been from non-AIDS-defining cancers.
Other infections
AIDS patients often develop opportunistic infections that present with non-specific symptoms, especially low-grade fevers and weight loss. These include opportunistic infection with Mycobacterium avium-intracellulare and cytomegalovirus (CMV). CMV can cause colitis, as described above, and CMV retinitis can cause blindness.
Penicilliosis due to Penicillium marneffei is now the third most common opportunistic infection (after extrapulmonary tuberculosis and cryptococcosis) in HIV-positive individuals within the endemic area of Southeast Asia.[36]
An infection that often goes unrecognized in AIDS patients is Parvovirus B19. Its main consequence is anemia, which is difficult to distinguish from the effects of antiretroviral drugs used to treat AIDS itself.[37]
Cause
For more details on this topic, see HIV.
Scanning electron micrograph of HIV-1, colored green, budding from a cultured lymphocyte.
A generalized graph of the relationship between HIV copies (viral load) and CD4 counts over the average course of untreated HIV infection; any particular individual's disease course may vary considerably. CD4+ T Lymphocyte count (cells/mm³) HIV RNA copies per mL of plasma
AIDS is the ultimate clinical consequence of infection with HIV. HIV is a retrovirus that primarily infects vital organs of the human immune system such as CD4+ T cells (a subset of T cells), macrophages and dendritic cells. It directly and indirectly destroys CD4+ T cells.[38]
Once HIV has killed so many CD4+ T cells that there are fewer than 200 of these cells per microliter (µL) of blood, cellular immunity is lost. Acute HIV infection usually progresses over time to clinical latent HIV infection and then to early symptomatic HIV infection and later to AIDS, which is identified either on the basis of the amount of CD4+ T cells remaining in the blood, and/or the presence of certain infections, as noted above.[39]
In the absence of antiretroviral therapy, the median time of progression from HIV infection to AIDS is nine to ten years, and the median survival time after developing AIDS is only 9.2 months.[40] However, the rate of clinical disease progression varies widely between individuals, from two weeks up to 20 years.
Many factors affect the rate of progression. These include factors that influence the body's ability to defend against HIV such as the infected person's general immune function.[41][42] Older people have weaker immune systems, and therefore have a greater risk of rapid disease progression than younger people.
Poor access to health care and the existence of coexisting infections such as tuberculosis also may predispose people to faster disease progression.[40][43][44] The infected person's genetic inheritance plays an important role and some people are resistant to certain strains of HIV. An example of this is people with the homozygous CCR5-Δ32 variation are resistant to infection with certain strains of HIV.[45] HIV is genetically variable and exists as different strains, which cause different rates of clinical disease progression.[46][47][48]
There are a number HIV and AIDS misconceptions. Three of the most common are that AIDS can spread through casual contact, that sexual intercourse with a virgin will cure AIDS, and that HIV can infect only homosexual men and drug users. Other misconceptions are that any act of anal intercourse between gay men can lead to AIDS infection, and that open discussion of homosexuality and HIV in schools will lead to increased rates of homosexuality and AIDS.[49][50]
Sexual transmission
Main article: sexually transmitted disease
Sexual transmission occurs with the contact between sexual secretions of one person with the rectal, genital or oral mucous membranes of another. Unprotected sexual acts are riskier for the receptive partner than for the insertive partner, and the risk for transmitting HIV through unprotected anal intercourse is greater than the risk from vaginal intercourse or oral sex.
However, oral sex is not entirely safe, as HIV can be transmitted through both insertive and receptive oral sex.[51][52] Sexual assault greatly increases the risk of HIV transmission as condoms are rarely employed and physical trauma to the vagina or rectum occurs frequently, facilitating the transmission of HIV.[53] Drug use has been studied as a possible predictor of HIV transmission. Perry N. Halkitis [54] found that methamphetamine usage does significantly relate to unprotected sexual behavior. As a result of these findings, methamphetamine users are at a higher risk for contracting HIV.[55]
Other sexually transmitted infections (STI) increase the risk of HIV transmission and infection, because they cause the disruption of the normal epithelial barrier by genital ulceration and/or microulceration; and by accumulation of pools of HIV-susceptible or HIV-infected cells (lymphocytes and macrophages) in semen and vaginal secretions. Epidemiological studies from sub-Saharan Africa, Europe and North America suggest that genital ulcers, such as those caused by syphilis and/or chancroid, increase the risk of becoming infected with HIV by about fourfold. There is also a significant although lesser increase in risk from STIs such as gonorrhea, chlamydia and trichomoniasis, which all cause local accumulations of lymphocytes and macrophages.[56]
Transmission of HIV depends on the infectiousness of the index case and the susceptibility of the uninfected partner. Infectivity seems to vary during the course of illness and is not constant between individuals. An undetectable plasma viral load does not necessarily indicate a low viral load in the seminal liquid or genital secretions.
However, each 10-fold increase in the level of HIV in the blood is associated with an 81% increased rate of HIV transmission.[56][57] Women are more susceptible to HIV-1 infection due to hormonal changes, vaginal microbial ecology and physiology, and a higher prevalence of sexually transmitted diseases.[58][59]
People who have been infected with one strain of HIV can still be infected later on in their lives by other, more virulent strains.
Infection is unlikely in a single encounter. High rates of infection have been linked to a pattern of overlapping long-term sexual relationships. This allows the virus to quickly spread to multiple partners who in turn infect their partners. A pattern of serial monogamy or occasional casual encounters is associated with lower rates of infection.[60]
HIV spreads readily through heterosexual sex in Africa, but less so elsewhere. One possibility being researched is that schistosomiasis, which affects up to 50% of women in parts of Africa, damages the lining of the vagina.[61][62]
Blood products
CDC poster from 1989 highlighting the threat of AIDS associated with drug use
This transmission route is particularly relevant to intravenous drug users, hemophiliacs and recipients of blood transfusions and blood products. Sharing and reusing syringes contaminated with HIV-infected blood represents a major risk for infection with HIV.
Needle sharing is the cause of one third of all new HIV-infections in North America, China, and Eastern Europe. The risk of being infected with HIV from a single prick with a needle that has been used on an HIV-infected person is thought to be about 1 in 150 (see table above). Post-exposure prophylaxis with anti-HIV drugs can further reduce this risk.[63]
This route can also affect people who give and receive tattoos and piercings. Universal precautions are frequently not followed in both sub-Saharan Africa and much of Asia because of both a shortage of supplies and inadequate training.
The WHO estimates that approximately 2.5% of all HIV infections in sub-Saharan Africa are transmitted through unsafe healthcare injections.[64] Because of this, the United Nations General Assembly has urged the nations of the world to implement precautions to prevent HIV transmission by health workers.[65]
The risk of transmitting HIV to blood transfusion recipients is extremely low in developed countries where improved donor selection and HIV screening is performed. However, according to the WHO, the overwhelming majority of the world's population does not have access to safe blood and between 5% and 10% of the world's HIV infections come from transfusion of infected blood and blood products.[66]
Perinatal transmission
The transmission of the virus from the mother to the child can occur in utero during the last weeks of pregnancy and at childbirth. In the absence of treatment, the transmission rate between a mother and her child during pregnancy, labor and delivery is 25%.
However, when the mother takes antiretroviral therapy and gives birth by caesarean section, the rate of transmission is just 1%.[67] The risk of infection is influenced by the viral load of the mother at birth, with the higher the viral load, the higher the risk. Breastfeeding also increases the risk of transmission by about 4 %.
Sunday, January 30, 2011
Haemophilia
Haemophilia (also spelled hemophilia in North America, from the Greek haima αἷμα 'blood' and philia φιλος 'love'[1]) is a group of hereditary genetic disorders that impair the body's ability to control blood clotting or coagulation, which is used to stop bleeding when a blood vessel is broken. Haemophilia A (clotting factor VIII deficiency) is the most common form of the disorder, occurring at about 1 in 5,000–10,000 male births.[2] Haemophilia B (factor IX deficiency) occurs at about 1 in about 20,000–34,000 male births.
Like most recessive sex-linked, X chromosome disorders, haemophilia is more likely to occur in males than females. This is because females have two X chromosomes while males have only one, so the defective gene is guaranteed to manifest in any male who carries it. Because females have two X chromosomes and haemophilia is rare, the chance of a female having two defective copies of the gene is very low, so females are almost exclusively asymptomatic carriers of the disorder. Female carriers can inherit the defective gene from either their mother or father, or it may be a new mutation. Only under rare circumstances do females actually have haemophilia.
Haemophilia lowers blood plasma clotting factor levels of the coagulation factors needed for a normal clotting process. Thus when a blood vessel is injured, a temporary scab does form, but the missing coagulation factors prevent fibrin formation, which is necessary to maintain the blood clot. A haemophiliac does not bleed more intensely than a normal person, but can bleed for a much longer time. In severe haemophiliacs even a minor injury can result in blood loss lasting days or weeks, or even never healing completely. In areas such as the brain or inside joints, this can be fatal or permanently debilitating.
Contents
[hide]
* 1 Signs and symptoms
o 1.1 Complications
o 1.2 Life expectancy
* 2 Causes
o 2.1 Genetics
o 2.2 Severity
* 3 Diagnosis
* 4 Management
o 4.1 Preventive exercises
o 4.2 Alternative medicine
o 4.3 Contraindications
* 5 Epidemiology
* 6 History
o 6.1 Scientific discovery
o 6.2 European royalty
o 6.3 Blood contamination issues
* 7 See also
* 8 References
* 9 External links
[edit] Signs and symptoms
Characteristic symptoms vary with severity. In general symptoms are internal or external bleeding episodes, which are called "bleeds".[3][4] Patients with more severe haemophilia suffer more severe and more frequent bleeds, while patients with mild haemophilia typically suffer more minor symptoms except after surgery or serious trauma. Moderate haemophiliacs have variable symptoms which manifest along a spectrum between severe and mild forms.
Prolonged bleeding and re-bleeding are the diagnostic symptoms of haemophilia. 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.[5] 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.[5] 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.
[edit] Complications
Severe complications are much more common in severe and moderate haemophiliacs. Complications may be both directly from the disease or from its treatment:[6]
* Deep internal bleeding, e.g. deep-muscle bleeding, leading to swelling, numbness or pain of a limb.
* Joint damage from haemarthrosis, 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.
[edit] Life expectancy
Like most aspects of the disorder, life expectancy varies with severity and adequate treatment. People with severe haemophilia who don't 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.[5] By the 1980s the life span of the average haemophiliac receiving appropriate treatment was 50–60 years.[5] 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.[7]
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.[5] The second leading cause of death related to severe haemophilia complications is intracranial haemorrhage which today accounts for one third of all deaths of patients 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.[5]
[edit] Causes
* Haemophilia A is a recessive X-linked genetic disorder involving a lack of functional clotting Factor VIII and represents 80% of haemophilia cases.
* Haemophilia B is a recessive X-linked genetic disorder involving a lack of functional clotting Factor IX. It comprises approximately 20% of haemophilia cases.[8]
* Haemophilia C is an autosomal genetic disorder (i.e. not X-linked) involving a lack of functional clotting Factor XI. Haemophilia C is not completely recessive: heterozygous individuals also show increased bleeding.[9]
[edit] Genetics
X-linked recessive inheritance
Females possess two X-chromosomes, males have one X and one Y chromosome. Since the mutations causing the disease are X-linked, a woman carrying the defect on one of her X-chromosomes may not be affected by it, as the equivalent allele on her other chromosome should express itself to produce the necessary clotting factors, due to X inactivation. However, the Y-chromosome in men has no gene for factors VIII or IX. If the genes responsible for production of factor VIII or factor IX present on a male's X-chromosome are deficient there is no equivalent on the Y-chromosome to cancel it out, so the deficient gene is not masked and he will develop the illness.
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 far more common among males than females. 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 of course 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 child, either the female is a carrier for the disease 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. Generally, the more healthy sons she bore, the higher the probability that she was not a carrier.
If a male is afflicted with the disease and has children with a female who is not even 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).
[edit] Severity
There are numerous different mutations which cause each type of haemophilia. Due to differences in changes to the genes involved, patients 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 5-40% of normal levels of active clotting factor.[5]
[edit] Diagnosis
Haemophilia A can be mimicked by von Willebrand disease.
* von Willebrand Disease could significantly affect as many as 1 in 10,000 people.[10]
* von Willebrand Disease type 2A, where decreased levels of von Willebrand Factor can lead to premature proteolysis of Factor VIII. In contrast to haemophilia, vWD type 2A is inherited in an autosomal dominant fashion.
* von Willebrand Disease type 2N, where von Willebrand Factor cannot bind Factor VIII, autosomal recessive inheritance. (i.e.; both parents need to give the child a copy of the gene).
* von Willebrand Disease type 3, where lack of von Willebrand Factor causes premature proteolysis of Factor VIII. In contrast to haemophilia, vWD type 3 is inherited in an autosomal recessive fashion.
Additionally, severe cases of vitamin K deficiency can present similar symptoms to haemophilia. This is due to the fact that vitamin K is necessary for the human body to produce several protein clotting factors. This vitamin deficiency is rare in adults and older children but is common in newborns. Infants are born with naturally low levels of vitamin K and do not yet have the symbiotic gut flora to properly synthesise their own vitamin K. Bleeding issues due to vitamin K deficiency in infants is known as "haemorrhagic disease of the newborn", to avoid this complication newborns are routinely injected with vitamin K supplements.
Condition↓ Prothrombin time↓ Partial thromboplastin time↓ Bleeding time↓ Platelet count↓
Vitamin K deficiency or warfarin prolonged prolonged unaffected unaffected
Disseminated intravascular coagulation prolonged prolonged prolonged decreased
Von Willebrand disease unaffected prolonged prolonged unaffected
Haemophilia unaffected prolonged unaffected unaffected
Aspirin unaffected unaffected prolonged unaffected
Thrombocytopenia unaffected unaffected prolonged decreased
Early Liver failure prolonged unaffected unaffected unaffected
End-stage Liver failure prolonged prolonged prolonged decreased
Uremia unaffected unaffected prolonged unaffected
Congenital afibrinogenemia prolonged prolonged prolonged unaffected
Factor V deficiency prolonged prolonged unaffected unaffected
Factor X deficiency as seen in amyloid purpura prolonged prolonged unaffected unaffected
Glanzmann's thrombasthenia unaffected unaffected prolonged unaffected
Bernard-Soulier syndrome unaffected unaffected prolonged decreased
[edit] Management
Commercially produced factor concentrates such as "Advate", a recombinant Factor VIII produced by Baxter International, come as a white powder in a vial which must be mixed with sterile water prior to intravenous injection.
Though there is no cure for haemophilia, it can be controlled with regular infusions of the deficient clotting factor, i.e. factor VIII in haemophilia A or factor IX in haemophilia B. Factor replacement can be either isolated from human blood serum, recombinant, or a combination of the two. Some haemophiliacs 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 patient becomes refractory to replacement coagulation factor as a result of circulating inhibitors, this may be partially overcome with recombinant human factor VII (NovoSeven), which is registered for this indication in many countries.
In early 2008, the US Food and Drug Administration (FDA) approved Xyntha (Wyeth) anti-haemophilic factor, genetically engineered from the genes of Chinese hamster ovary cells. Since 1993 (Dr. Mary Nugent) 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.
In Western countries, common standards of care fall into one of two categories: prophylaxis or on-demand. Prophylaxis 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 treatment involves treating bleeding episodes once they arise. In 2007, a clinical trial was published in the New England Journal of Medicine 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.[11] Prophylactic 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.[12] This study resulted in the first (October 2008) FDA approval to label any Factor VIII product to be used prophylactically.[13] As a result, the factor product used in the study (Bayer's Kognate) is now labelled for use to prevent bleeds, making it more likely that insurance carries in the US will reimburse consumers who are prescribed and use this product prophylactically. Despite Kognate only recently being "approved" for this use in the US, it and other factor products have been well studied and are often prescribed to treat Haemophilia prophylactically to prevent bleeds, especially joint bleeds.[14]
[edit] Preventive exercises
It is recommended that people affected with haemophilia do specific exercises to strengthen the joints, particularly the elbows, knees, and ankles.[15] Exercises include elements which increase flexibility, tone, and strength of muscles, increasing their ability to protect joints from damaging bleeds. These exercises are recommended after an internal bleed occurs and on a daily basis to strengthen the muscles and joints to prevent new bleeding problems. Many recommended exercises include standard sports warm-up and training exercises such as stretching of the calves, ankle circles, elbow flexions, and quadriceps sets.
[edit] Alternative medicine
While not a replacement for traditional treatments, preliminary scientific studies indicate that hypnosis and self-hypnosis can be effective at reducing bleeds and the severity of bleeds and thus the frequency of factor treatment.[16][17][18][19] Herbs which strengthen blood vessels and act as astringents may benefit patients with haemophilia, however there are no peer reviewed scientific studies to support these claims. Suggested herbs include: Bilberry (Vaccinium myrtillus), Grape seed extract (Vitis vinifera), Scotch broom (Cytisus scoparius), Stinging nettle (Urtica dioica), Witch hazel (Hamamelis virginiana), and yarrow (Achillea millefolium).[16]
[edit] 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, medications which contain aspirin, ibuprofen, or naproxen sodium should not be taken because they are well known to have the side effect of prolonged bleeding.[20]
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.[20][21] 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.[20]
[edit] Epidemiology
Haemophilia is rare, with only 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.[22] 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.[23] It is estimated that about 2500 Canadians have haemophilia A, and about 500 Canadians have haemophilia B.[24]
Like most recessive sex-linked, X chromosome disorders, haemophilia is more likely to occur in males than females. This is because females have two X chromosomes while males have only one, so the defective gene is guaranteed to manifest in any male who carries it. Because females have two X chromosomes and haemophilia is rare, the chance of a female having two defective copies of the gene is very low, so females are almost exclusively asymptomatic carriers of the disorder. Female carriers can inherit the defective gene from either their mother or father, or it may be a new mutation. Only under rare circumstances do females actually have haemophilia.
Haemophilia lowers blood plasma clotting factor levels of the coagulation factors needed for a normal clotting process. Thus when a blood vessel is injured, a temporary scab does form, but the missing coagulation factors prevent fibrin formation, which is necessary to maintain the blood clot. A haemophiliac does not bleed more intensely than a normal person, but can bleed for a much longer time. In severe haemophiliacs even a minor injury can result in blood loss lasting days or weeks, or even never healing completely. In areas such as the brain or inside joints, this can be fatal or permanently debilitating.
Contents
[hide]
* 1 Signs and symptoms
o 1.1 Complications
o 1.2 Life expectancy
* 2 Causes
o 2.1 Genetics
o 2.2 Severity
* 3 Diagnosis
* 4 Management
o 4.1 Preventive exercises
o 4.2 Alternative medicine
o 4.3 Contraindications
* 5 Epidemiology
* 6 History
o 6.1 Scientific discovery
o 6.2 European royalty
o 6.3 Blood contamination issues
* 7 See also
* 8 References
* 9 External links
[edit] Signs and symptoms
Characteristic symptoms vary with severity. In general symptoms are internal or external bleeding episodes, which are called "bleeds".[3][4] Patients with more severe haemophilia suffer more severe and more frequent bleeds, while patients with mild haemophilia typically suffer more minor symptoms except after surgery or serious trauma. Moderate haemophiliacs have variable symptoms which manifest along a spectrum between severe and mild forms.
Prolonged bleeding and re-bleeding are the diagnostic symptoms of haemophilia. 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.[5] 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.[5] 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.
[edit] Complications
Severe complications are much more common in severe and moderate haemophiliacs. Complications may be both directly from the disease or from its treatment:[6]
* Deep internal bleeding, e.g. deep-muscle bleeding, leading to swelling, numbness or pain of a limb.
* Joint damage from haemarthrosis, 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.
[edit] Life expectancy
Like most aspects of the disorder, life expectancy varies with severity and adequate treatment. People with severe haemophilia who don't 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.[5] By the 1980s the life span of the average haemophiliac receiving appropriate treatment was 50–60 years.[5] 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.[7]
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.[5] The second leading cause of death related to severe haemophilia complications is intracranial haemorrhage which today accounts for one third of all deaths of patients 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.[5]
[edit] Causes
* Haemophilia A is a recessive X-linked genetic disorder involving a lack of functional clotting Factor VIII and represents 80% of haemophilia cases.
* Haemophilia B is a recessive X-linked genetic disorder involving a lack of functional clotting Factor IX. It comprises approximately 20% of haemophilia cases.[8]
* Haemophilia C is an autosomal genetic disorder (i.e. not X-linked) involving a lack of functional clotting Factor XI. Haemophilia C is not completely recessive: heterozygous individuals also show increased bleeding.[9]
[edit] Genetics
X-linked recessive inheritance
Females possess two X-chromosomes, males have one X and one Y chromosome. Since the mutations causing the disease are X-linked, a woman carrying the defect on one of her X-chromosomes may not be affected by it, as the equivalent allele on her other chromosome should express itself to produce the necessary clotting factors, due to X inactivation. However, the Y-chromosome in men has no gene for factors VIII or IX. If the genes responsible for production of factor VIII or factor IX present on a male's X-chromosome are deficient there is no equivalent on the Y-chromosome to cancel it out, so the deficient gene is not masked and he will develop the illness.
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 far more common among males than females. 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 of course 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 child, either the female is a carrier for the disease 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. Generally, the more healthy sons she bore, the higher the probability that she was not a carrier.
If a male is afflicted with the disease and has children with a female who is not even 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).
[edit] Severity
There are numerous different mutations which cause each type of haemophilia. Due to differences in changes to the genes involved, patients 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 5-40% of normal levels of active clotting factor.[5]
[edit] Diagnosis
Haemophilia A can be mimicked by von Willebrand disease.
* von Willebrand Disease could significantly affect as many as 1 in 10,000 people.[10]
* von Willebrand Disease type 2A, where decreased levels of von Willebrand Factor can lead to premature proteolysis of Factor VIII. In contrast to haemophilia, vWD type 2A is inherited in an autosomal dominant fashion.
* von Willebrand Disease type 2N, where von Willebrand Factor cannot bind Factor VIII, autosomal recessive inheritance. (i.e.; both parents need to give the child a copy of the gene).
* von Willebrand Disease type 3, where lack of von Willebrand Factor causes premature proteolysis of Factor VIII. In contrast to haemophilia, vWD type 3 is inherited in an autosomal recessive fashion.
Additionally, severe cases of vitamin K deficiency can present similar symptoms to haemophilia. This is due to the fact that vitamin K is necessary for the human body to produce several protein clotting factors. This vitamin deficiency is rare in adults and older children but is common in newborns. Infants are born with naturally low levels of vitamin K and do not yet have the symbiotic gut flora to properly synthesise their own vitamin K. Bleeding issues due to vitamin K deficiency in infants is known as "haemorrhagic disease of the newborn", to avoid this complication newborns are routinely injected with vitamin K supplements.
Condition↓ Prothrombin time↓ Partial thromboplastin time↓ Bleeding time↓ Platelet count↓
Vitamin K deficiency or warfarin prolonged prolonged unaffected unaffected
Disseminated intravascular coagulation prolonged prolonged prolonged decreased
Von Willebrand disease unaffected prolonged prolonged unaffected
Haemophilia unaffected prolonged unaffected unaffected
Aspirin unaffected unaffected prolonged unaffected
Thrombocytopenia unaffected unaffected prolonged decreased
Early Liver failure prolonged unaffected unaffected unaffected
End-stage Liver failure prolonged prolonged prolonged decreased
Uremia unaffected unaffected prolonged unaffected
Congenital afibrinogenemia prolonged prolonged prolonged unaffected
Factor V deficiency prolonged prolonged unaffected unaffected
Factor X deficiency as seen in amyloid purpura prolonged prolonged unaffected unaffected
Glanzmann's thrombasthenia unaffected unaffected prolonged unaffected
Bernard-Soulier syndrome unaffected unaffected prolonged decreased
[edit] Management
Commercially produced factor concentrates such as "Advate", a recombinant Factor VIII produced by Baxter International, come as a white powder in a vial which must be mixed with sterile water prior to intravenous injection.
Though there is no cure for haemophilia, it can be controlled with regular infusions of the deficient clotting factor, i.e. factor VIII in haemophilia A or factor IX in haemophilia B. Factor replacement can be either isolated from human blood serum, recombinant, or a combination of the two. Some haemophiliacs 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 patient becomes refractory to replacement coagulation factor as a result of circulating inhibitors, this may be partially overcome with recombinant human factor VII (NovoSeven), which is registered for this indication in many countries.
In early 2008, the US Food and Drug Administration (FDA) approved Xyntha (Wyeth) anti-haemophilic factor, genetically engineered from the genes of Chinese hamster ovary cells. Since 1993 (Dr. Mary Nugent) 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.
In Western countries, common standards of care fall into one of two categories: prophylaxis or on-demand. Prophylaxis 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 treatment involves treating bleeding episodes once they arise. In 2007, a clinical trial was published in the New England Journal of Medicine 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.[11] Prophylactic 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.[12] This study resulted in the first (October 2008) FDA approval to label any Factor VIII product to be used prophylactically.[13] As a result, the factor product used in the study (Bayer's Kognate) is now labelled for use to prevent bleeds, making it more likely that insurance carries in the US will reimburse consumers who are prescribed and use this product prophylactically. Despite Kognate only recently being "approved" for this use in the US, it and other factor products have been well studied and are often prescribed to treat Haemophilia prophylactically to prevent bleeds, especially joint bleeds.[14]
[edit] Preventive exercises
It is recommended that people affected with haemophilia do specific exercises to strengthen the joints, particularly the elbows, knees, and ankles.[15] Exercises include elements which increase flexibility, tone, and strength of muscles, increasing their ability to protect joints from damaging bleeds. These exercises are recommended after an internal bleed occurs and on a daily basis to strengthen the muscles and joints to prevent new bleeding problems. Many recommended exercises include standard sports warm-up and training exercises such as stretching of the calves, ankle circles, elbow flexions, and quadriceps sets.
[edit] Alternative medicine
While not a replacement for traditional treatments, preliminary scientific studies indicate that hypnosis and self-hypnosis can be effective at reducing bleeds and the severity of bleeds and thus the frequency of factor treatment.[16][17][18][19] Herbs which strengthen blood vessels and act as astringents may benefit patients with haemophilia, however there are no peer reviewed scientific studies to support these claims. Suggested herbs include: Bilberry (Vaccinium myrtillus), Grape seed extract (Vitis vinifera), Scotch broom (Cytisus scoparius), Stinging nettle (Urtica dioica), Witch hazel (Hamamelis virginiana), and yarrow (Achillea millefolium).[16]
[edit] 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, medications which contain aspirin, ibuprofen, or naproxen sodium should not be taken because they are well known to have the side effect of prolonged bleeding.[20]
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.[20][21] 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.[20]
[edit] Epidemiology
Haemophilia is rare, with only 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.[22] 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.[23] It is estimated that about 2500 Canadians have haemophilia A, and about 500 Canadians have haemophilia B.[24]
Poliomyelities
Poliomyelitis, often called polio or infantile paralysis, is an acute viral infectious disease spread from person to person, primarily via the fecal-oral route.[1] The term derives from the Greek poliós (πολιός), meaning "grey", myelós (µυελός), referring to the "spinal cord", and the suffix -itis, which denotes inflammation.[2]
Although around 90% of polio infections cause no symptoms at all, affected individuals can exhibit a range of symptoms if the virus enters the blood stream.[3] In about 1% of cases the virus enters the central nervous system, preferentially infecting and destroying motor neurons, leading to muscle weakness and acute flaccid paralysis. Different types of paralysis may occur, depending on the nerves involved. Spinal polio is the most common form, characterized by asymmetric paralysis that most often involves the legs. Bulbar polio leads to weakness of muscles innervated by cranial nerves. Bulbospinal polio is a combination of bulbar and spinal paralysis.[4]
Poliomyelitis was first recognized as a distinct condition by Jakob Heine in 1840.[5] Its causative agent, poliovirus, was identified in 1908 by Karl Landsteiner.[5] Although major polio epidemics were unknown before the late 19th century, polio was one of the most dreaded childhood diseases of the 20th century. Polio epidemics have crippled thousands of people, mostly young children; the disease has caused paralysis and death for much of human history. Polio had existed for thousands of years quietly as an endemic pathogen until the 1880s, when major epidemics began to occur in Europe; soon after, widespread epidemics appeared in the United States.[6]
By 1910, much of the world experienced a dramatic increase in polio cases and frequent epidemics became regular events, primarily in cities during the summer months. These epidemics—which left thousands of children and adults paralyzed—provided the impetus for a "Great Race" towards the development of a vaccine. Developed in the 1950s, polio vaccines are credited with reducing the global number of polio cases per year from many hundreds of thousands to around a thousand.[7] Enhanced vaccination efforts led by the World Health Organization, UNICEF, and Rotary International could result in global eradication of the disease.[8]
Contents
[hide]
* 1 Classification
* 2 Cause
* 3 Transmission
* 4 Pathophysiology
o 4.1 Paralytic polio
+ 4.1.1 Spinal polio
+ 4.1.2 Bulbar polio
+ 4.1.3 Bulbospinal polio
* 5 Diagnosis
* 6 Prevention
o 6.1 Passive immunization
o 6.2 Vaccine
* 7 Treatment
* 8 Prognosis
o 8.1 Recovery
o 8.2 Complications
o 8.3 Post-polio syndrome
* 9 Eradication
* 10 History
* 11 See also
* 12 Notes and references
* 13 Further reading
* 14 External links
[edit] Classification
Outcomes of poliovirus infectionOutcome Proportion of cases[4]
Asymptomatic 90–95%
Minor illness 4–8%
Non-paralytic aseptic
meningitis 1–2%
Paralytic poliomyelitis 0.1–0.5%
— Spinal polio 79% of paralytic cases
— Bulbospinal polio 19% of paralytic cases
— Bulbar polio 2% of paralytic cases
The term poliomyelitis is used to identify the disease caused by any of the three serotypes of poliovirus. Two basic patterns of polio infection are described: a minor illness which does not involve the central nervous system (CNS), sometimes called abortive poliomyelitis, and a major illness involving the CNS, which may be paralytic or non-paralytic.[9] In most people with a normal immune system, a poliovirus infection is asymptomatic. Rarely the infection produces minor symptoms; these may include upper respiratory tract infection (sore throat and fever), gastrointestinal disturbances (nausea, vomiting, abdominal pain, constipation or, rarely, diarrhea), and influenza-like illness.[4]
The virus enters the central nervous system in about 3% of infections. Most patients with CNS involvement develop non-paralytic aseptic meningitis, with symptoms of headache, neck, back, abdominal and extremity pain, fever, vomiting, lethargy and irritability.[2][10] Approximately 1 in 200 to 1 in 1000 cases progress to paralytic disease, in which the muscles become weak, floppy and poorly controlled, and finally completely paralyzed; this condition is known as acute flaccid paralysis.[11] Depending on the site of paralysis, paralytic poliomyelitis is classified as spinal, bulbar, or bulbospinal. Encephalitis, an infection of the brain tissue itself, can occur in rare cases and is usually restricted to infants. It is characterized by confusion, changes in mental status, headaches, fever, and less commonly seizures and spastic paralysis.[12]
[edit] Cause
Main article: Poliovirus
A TEM micrograph of poliovirus
Poliomyelitis is caused by infection with a member of the genus Enterovirus known as poliovirus (PV). This group of RNA viruses colonize the gastrointestinal tract[1] — specifically the oropharynx and the intestine. The incubation time (to the first signs and symptoms) ranges from 3 to 35 days with a more common span of 6 to 20 days[4]. PV infects and causes disease in humans alone.[3] Its structure is very simple, composed of a single (+) sense RNA genome enclosed in a protein shell called a capsid.[3] In addition to protecting the virus’s genetic material, the capsid proteins enable poliovirus to infect certain types of cells. Three serotypes of poliovirus have been identified—poliovirus type 1 (PV1), type 2 (PV2), and type 3 (PV3)—each with a slightly different capsid protein.[13] All three are extremely virulent and produce the same disease symptoms.[3] PV1 is the most commonly encountered form, and the one most closely associated with paralysis.[14]
Individuals who are exposed to the virus, either through infection or by immunization with polio vaccine, develop immunity. In immune individuals, IgA antibodies against poliovirus are present in the tonsils and gastrointestinal tract and are able to block virus replication; IgG and IgM antibodies against PV can prevent the spread of the virus to motor neurons of the central nervous system.[15] Infection or vaccination with one serotype of poliovirus does not provide immunity against the other serotypes, and full immunity requires exposure to each serotype.[15]
A rare condition with a similar presentation, non-poliovirus poliomyelitis, may result from infections with non-poliovirus enteroviruses.[16]
[edit] Transmission
Poliomyelitis is highly contagious via the oral-oral (oropharyngeal source) and fecal-oral (intestinal source) routes.[15] In endemic areas, wild polioviruses can infect virtually the entire human population.[17] It is seasonal in temperate climates, with peak transmission occurring in summer and autumn.[15] These seasonal differences are far less pronounced in tropical areas.[17] The time between first exposure and first symptoms, known as the incubation period, is usually 6 to 20 days, with a maximum range of 3 to 35 days.[18] Virus particles are excreted in the feces for several weeks following initial infection.[18] The disease is transmitted primarily via the fecal-oral route, by ingesting contaminated food or water. It is occasionally transmitted via the oral-oral route,[14] a mode especially visible in areas with good sanitation and hygiene.[15] Polio is most infectious between 7–10 days before and 7–10 days after the appearance of symptoms, but transmission is possible as long as the virus remains in the saliva or feces.[14]
Factors that increase the risk of polio infection or affect the severity of the disease include immune deficiency,[19] malnutrition,[20] tonsillectomy,[21] physical activity immediately following the onset of paralysis,[22] skeletal muscle injury due to injection of vaccines or therapeutic agents,[23] and pregnancy.[24] Although the virus can cross the placenta during pregnancy, the fetus does not appear to be affected by either maternal infection or polio vaccination.[25] Maternal antibodies also cross the placenta, providing passive immunity that protects the infant from polio infection during the first few months of life.[26]
[edit] Pathophysiology
A blockage of the lumbar anterior spinal cord artery due to polio (PV3)
Poliovirus enters the body through the mouth, infecting the first cells it comes in contact with—the pharynx (throat) and intestinal mucosa. It gains entry by binding to an immunoglobulin-like receptor, known as the poliovirus receptor or CD155, on the cell membrane.[27] The virus then hijacks the host cell's own machinery, and begins to replicate. Poliovirus divides within gastrointestinal cells for about a week, from where it spreads to the tonsils (specifically the follicular dendritic cells residing within the tonsilar germinal centers), the intestinal lymphoid tissue including the M cells of Peyer's patches, and the deep cervical and mesenteric lymph nodes, where it multiplies abundantly. The virus is subsequently absorbed into the bloodstream.[28]
Known as viremia, the presence of virus in the bloodstream enables it to be widely distributed throughout the body. Poliovirus can survive and multiply within the blood and lymphatics for long periods of time, sometimes as long as 17 weeks.[29] In a small percentage of cases, it can spread and replicate in other sites such as brown fat, the reticuloendothelial tissues, and muscle.[30] This sustained replication causes a major viremia, and leads to the development of minor influenza-like symptoms. Rarely, this may progress and the virus may invade the central nervous system, provoking a local inflammatory response. In most cases this causes a self-limiting inflammation of the meninges, the layers of tissue surrounding the brain, which is known as non-paralytic aseptic meningitis.[2] Penetration of the CNS provides no known benefit to the virus, and is quite possibly an incidental deviation of a normal gastrointestinal infection.[31] The mechanisms by which poliovirus spreads to the CNS are poorly understood, but it appears to be primarily a chance event—largely independent of the age, gender, or socioeconomic position of the individual.[31]
[edit] Paralytic polio
Denervation of skeletal muscle tissue secondary to poliovirus infection can lead to paralysis.
In around 1% of infections, poliovirus spreads along certain nerve fiber pathways, preferentially replicating in and destroying motor neurons within the spinal cord, brain stem, or motor cortex. This leads to the development of paralytic poliomyelitis, the various forms of which (spinal, bulbar, and bulbospinal) vary only with the amount of neuronal damage and inflammation that occurs, and the region of the CNS that is affected.
The destruction of neuronal cells produces lesions within the spinal ganglia; these may also occur in the reticular formation, vestibular nuclei, cerebellar vermis, and deep cerebellar nuclei.[31] Inflammation associated with nerve cell destruction often alters the color and appearance of the gray matter in the spinal column, causing it to appear reddish and swollen.[2] Other destructive changes associated with paralytic disease occur in the forebrain region, specifically the hypothalamus and thalamus.[31] The molecular mechanisms by which poliovirus causes paralytic disease are poorly understood.
Early symptoms of paralytic polio include high fever, headache, stiffness in the back and neck, asymmetrical weakness of various muscles, sensitivity to touch, difficulty swallowing, muscle pain, loss of superficial and deep reflexes, paresthesia (pins and needles), irritability, constipation, or difficulty urinating. Paralysis generally develops one to ten days after early symptoms begin, progresses for two to three days, and is usually complete by the time the fever breaks.[32]
The likelihood of developing paralytic polio increases with age, as does the extent of paralysis. In children, non-paralytic meningitis is the most likely consequence of CNS involvement, and paralysis occurs in only 1 in 1000 cases. In adults, paralysis occurs in 1 in 75 cases.[33] In children under five years of age, paralysis of one leg is most common; in adults, extensive paralysis of the chest and abdomen also affecting all four limbs—quadriplegia—is more likely.[34] Paralysis rates also vary depending on the serotype of the infecting poliovirus; the highest rates of paralysis (1 in 200) are associated with poliovirus type 1, the lowest rates (1 in 2,000) are associated with type 2.[35]
[edit] Spinal polio
The location of motor neurons in the anterior horn cells of the spinal column.
Spinal polio is the most common form of paralytic poliomyelitis; it results from viral invasion of the motor neurons of the anterior horn cells, or the ventral (front) gray matter section in the spinal column, which are responsible for movement of the muscles, including those of the trunk, limbs and the intercostal muscles.[11] Virus invasion causes inflammation of the nerve cells, leading to damage or destruction of motor neuron ganglia. When spinal neurons die, Wallerian degeneration takes place, leading to weakness of those muscles formerly innervated by the now dead neurons.[36] With the destruction of nerve cells, the muscles no longer receive signals from the brain or spinal cord; without nerve stimulation, the muscles atrophy, becoming weak, floppy and poorly controlled, and finally completely paralyzed.[11] Progression to maximum paralysis is rapid (two to four days), and is usually associated with fever and muscle pain.[36] Deep tendon reflexes are also affected, and are usually absent or diminished; sensation (the ability to feel) in the paralyzed limbs, however, is not affected.[36]
The extent of spinal paralysis depends on the region of the cord affected, which may be cervical, thoracic, or lumbar.[37] The virus may affect muscles on both sides of the body, but more often the paralysis is asymmetrical.[28] Any limb or combination of limbs may be affected—one leg, one arm, or both legs and both arms. Paralysis is often more severe proximally (where the limb joins the body) than distally (the fingertips and toes).[28]
[edit] Bulbar polio
The location and anatomy of the bulbar region (in orange)
Making up about 2% of cases of paralytic polio, bulbar polio occurs when poliovirus invades and destroys nerves within the bulbar region of the brain stem.[4] The bulbar region is a white matter pathway that connects the cerebral cortex to the brain stem. The destruction of these nerves weakens the muscles supplied by the cranial nerves, producing symptoms of encephalitis, and causes difficulty breathing, speaking and swallowing.[10] Critical nerves affected are the glossopharyngeal nerve, which partially controls swallowing and functions in the throat, tongue movement and taste; the vagus nerve, which sends signals to the heart, intestines, and lungs; and the accessory nerve, which controls upper neck movement. Due to the effect on swallowing, secretions of mucus may build up in the airway causing suffocation.[32] Other signs and symptoms include facial weakness, caused by destruction of the trigeminal nerve and facial nerve, which innervate the cheeks, tear ducts, gums, and muscles of the face, among other structures; double vision; difficulty in chewing; and abnormal respiratory rate, depth, and rhythm, which may lead to respiratory arrest. Pulmonary edema and shock are also possible, and may be fatal.[37]
[edit] Bulbospinal polio
Approximately 19% of all paralytic polio cases have both bulbar and spinal symptoms; this subtype is called respiratory polio or bulbospinal polio.[4] Here, the virus affects the upper part of the cervical spinal cord (C3 through C5), and paralysis of the diaphragm occurs. The critical nerves affected are the phrenic nerve, which drives the diaphragm to inflate the lungs, and those that drive the muscles needed for swallowing. By destroying these nerves this form of polio affects breathing, making it difficult or impossible for the patient to breathe without the support of a ventilator. It can lead to paralysis of the arms and legs and may also affect swallowing and heart functions.[38]
[edit] Diagnosis
Paralytic poliomyelitis may be clinically suspected in individuals experiencing acute onset of flaccid paralysis in one or more limbs with decreased or absent tendon reflexes in the affected limbs that cannot be attributed to another apparent cause, and without sensory or cognitive loss.[39]
A laboratory diagnosis is usually made based on recovery of poliovirus from a stool sample or a swab of the pharynx. Antibodies to poliovirus can be diagnostic, and are generally detected in the blood of infected patients early in the course of infection.[4] Analysis of the patient's cerebrospinal fluid (CSF), which is collected by a lumbar puncture ("spinal tap"), reveals an increased number of white blood cells (primarily lymphocytes) and a mildly elevated protein level. Detection of virus in the CSF is diagnostic of paralytic polio, but rarely occurs.[4]
If poliovirus is isolated from a patient experiencing acute flaccid paralysis, it is further tested through oligonucleotide mapping (genetic fingerprinting), or more recently by PCR amplification, to determine whether it is "wild type" (that is, the virus encountered in nature) or "vaccine type" (derived from a strain of poliovirus used to produce polio vaccine).[40] It is important to determine the source of the virus because for each reported case of paralytic polio caused by wild poliovirus, it is estimated that another 200 to 3,000 contagious asymptomatic carriers exist.[41]
[edit] Prevention
[edit] Passive immunization
In 1950, William Hammon at the University of Pittsburgh purified the gamma globulin component of the blood plasma of polio survivors.[42] Hammon proposed that the gamma globulin, which contained antibodies to poliovirus, could be used to halt poliovirus infection, prevent disease, and reduce the severity of disease in other patients who had contracted polio. The results of a large clinical trial were promising; the gamma globulin was shown to be about 80% effective in preventing the development of paralytic poliomyelitis.[43] It was also shown to reduce the severity of the disease in patients that developed polio.[42] The gamma globulin approach was later deemed impractical for widespread use, however, due in large part to the limited supply of blood plasma, and the medical community turned its focus to the development of a polio vaccine.[44]
[edit] Vaccine
Main article: Polio vaccine
A child receives oral polio vaccine.
Two types of vaccine are used throughout the world to combat polio. Both types induce immunity to polio, efficiently blocking person-to-person transmission of wild poliovirus, thereby protecting both individual vaccine recipients and the wider community (so-called herd immunity).[45]
The first candidate polio vaccine, based on one serotype of a live but attenuated (weakened) virus, was developed by the virologist Hilary Koprowski. Koprowski's prototype vaccine was given to an eight-year-old boy on February 27, 1950.[46] Koprowski continued to work on the vaccine throughout the 1950s, leading to large-scale trials in the then Belgian Congo and the vaccination of seven million children in Poland against serotypes PV1 and PV3 between 1958 and 1960.[47]
The second inactivated virus vaccine was developed in 1952 by Jonas Salk, and announced to the world on April 12, 1955.[48] The Salk vaccine, or inactivated poliovirus vaccine (IPV), is based on poliovirus grown in a type of monkey kidney tissue culture (Vero cell line), which is chemically inactivated with formalin.[15] After two doses of IPV (given by injection), 90% or more of individuals develop protective antibody to all three serotypes of poliovirus, and at least 99% are immune to poliovirus following three doses.[4]
Subsequently, Albert Sabin developed another live, oral polio vaccine (OPV). It was produced by the repeated passage of the virus through non-human cells at sub-physiological temperatures.[49] The attenuated poliovirus in the Sabin vaccine replicates very efficiently in the gut, the primary site of wild poliovirus infection and replication, but the vaccine strain is unable to replicate efficiently within nervous system tissue.[50] A single dose of Sabin's oral polio vaccine produces immunity to all three poliovirus serotypes in approximately 50% of recipients. Three doses of live-attenuated OPV produce protective antibody to all three poliovirus types in more than 95% of recipients.[4] Human trials of Sabin's vaccine began in 1957,[51] and in 1958 it was selected, in competition with the live vaccines of Koprowski and other researchers, by the US National Institutes of Health.[47] It was licensed in 1962[51] and rapidly became the only polio vaccine used worldwide.[47]
Because OPV is inexpensive, easy to administer, and produces excellent immunity in the intestine (which helps prevent infection with wild virus in areas where it is endemic), it has been the vaccine of choice for controlling poliomyelitis in many countries.[52] On very rare occasions (about 1 case per 750,000 vaccine recipients) the attenuated virus in OPV reverts into a form that can paralyze.[18] Most industrialized countries have switched to IPV, which cannot revert, either as the sole vaccine against poliomyelitis or in combination with oral polio vaccine.[53]
[edit] Treatment
A modern negative pressure ventilator (iron lung)
There is no cure for polio. The focus of modern treatment has been on providing relief of symptoms, speeding recovery and preventing complications. Supportive measures include antibiotics to prevent infections in weakened muscles, analgesics for pain, moderate exercise and a nutritious diet.[54] Treatment of polio often requires long-term rehabilitation, including physical therapy, braces, corrective shoes and, in some cases, orthopedic surgery.[37]
Portable ventilators may be required to support breathing. Historically, a noninvasive negative-pressure ventilator, more commonly called an iron lung, was used to artificially maintain respiration during an acute polio infection until a person could breathe independently (generally about one to two weeks). Today many polio survivors with permanent respiratory paralysis use modern jacket-type negative-pressure ventilators that are worn over the chest and abdomen.[55]
Other historical treatments for polio include hydrotherapy, electrotherapy, massage and passive motion exercises, and surgical treatments such as tendon lengthening and nerve grafting.[11] Devices such as rigid braces and body casts—which tended to cause muscle atrophy due to the limited movement of the user—were also touted as effective treatments.[56]
[edit] Prognosis
Patients with abortive polio infections recover completely. In those that develop only aseptic meningitis, the symptoms can be expected to persist for two to ten days, followed by complete recovery.[57] In cases of spinal polio, if the affected nerve cells are completely destroyed, paralysis will be permanent; cells that are not destroyed but lose function temporarily may recover within four to six weeks after onset.[57] Half the patients with spinal polio recover fully; one quarter recover with mild disability and the remaining quarter are left with severe disability.[58] The degree of both acute paralysis and residual paralysis is likely to be proportional to the degree of viremia, and inversely proportional to the degree of immunity.[31] Spinal polio is rarely fatal.[32]
A child with a deformity of her right leg due to polio
Without respiratory support, consequences of poliomyelitis with respiratory involvement include suffocation or pneumonia from aspiration of secretions.[55] Overall, 5–10% of patients with paralytic polio die due to the paralysis of muscles used for breathing. The mortality rate varies by age: 2–5% of children and up to 15–30% of adults die.[4] Bulbar polio often causes death if respiratory support is not provided;[38] with support, its mortality rate ranges from 25 to 75%, depending on the age of the patient.[4][59] When positive pressure ventilators are available, the mortality can be reduced to 15%.[60]
[edit] Recovery
Many cases of poliomyelitis result in only temporary paralysis.[11] Nerve impulses return to the formerly paralyzed muscle within a month, and recovery is usually complete in six to eight months.[57] The neurophysiological processes involved in recovery following acute paralytic poliomyelitis are quite effective; muscles are able to retain normal strength even if half the original motor neurons have been lost.[61] Paralysis remaining after one year is likely to be permanent, although modest recoveries of muscle strength are possible 12 to 18 months after infection.[57]
One mechanism involved in recovery is nerve terminal sprouting, in which remaining brainstem and spinal cord motor neurons develop new branches, or axonal sprouts.[62] These sprouts can reinnervate orphaned muscle fibers that have been denervated by acute polio infection,[63] restoring the fibers' capacity to contract and improving strength.[64] Terminal sprouting may generate a few significantly enlarged motor neurons doing work previously performed by as many as four or five units:[33] a single motor neuron that once controlled 200 muscle cells might control 800 to 1000 cells. Other mechanisms that occur during the rehabilitation phase, and contribute to muscle strength restoration, include myofiber hypertrophy—enlargement of muscle fibers through exercise and activity—and transformation of type II muscle fibers to type I muscle fibers.[63][65]
In addition to these physiological processes, the body possesses a number of compensatory mechanisms to maintain function in the presence of residual paralysis. These include the use of weaker muscles at a higher than usual intensity relative to the muscle's maximal capacity, enhancing athletic development of previously little-used muscles, and using ligaments for stability, which enables greater mobility.[65]
Although around 90% of polio infections cause no symptoms at all, affected individuals can exhibit a range of symptoms if the virus enters the blood stream.[3] In about 1% of cases the virus enters the central nervous system, preferentially infecting and destroying motor neurons, leading to muscle weakness and acute flaccid paralysis. Different types of paralysis may occur, depending on the nerves involved. Spinal polio is the most common form, characterized by asymmetric paralysis that most often involves the legs. Bulbar polio leads to weakness of muscles innervated by cranial nerves. Bulbospinal polio is a combination of bulbar and spinal paralysis.[4]
Poliomyelitis was first recognized as a distinct condition by Jakob Heine in 1840.[5] Its causative agent, poliovirus, was identified in 1908 by Karl Landsteiner.[5] Although major polio epidemics were unknown before the late 19th century, polio was one of the most dreaded childhood diseases of the 20th century. Polio epidemics have crippled thousands of people, mostly young children; the disease has caused paralysis and death for much of human history. Polio had existed for thousands of years quietly as an endemic pathogen until the 1880s, when major epidemics began to occur in Europe; soon after, widespread epidemics appeared in the United States.[6]
By 1910, much of the world experienced a dramatic increase in polio cases and frequent epidemics became regular events, primarily in cities during the summer months. These epidemics—which left thousands of children and adults paralyzed—provided the impetus for a "Great Race" towards the development of a vaccine. Developed in the 1950s, polio vaccines are credited with reducing the global number of polio cases per year from many hundreds of thousands to around a thousand.[7] Enhanced vaccination efforts led by the World Health Organization, UNICEF, and Rotary International could result in global eradication of the disease.[8]
Contents
[hide]
* 1 Classification
* 2 Cause
* 3 Transmission
* 4 Pathophysiology
o 4.1 Paralytic polio
+ 4.1.1 Spinal polio
+ 4.1.2 Bulbar polio
+ 4.1.3 Bulbospinal polio
* 5 Diagnosis
* 6 Prevention
o 6.1 Passive immunization
o 6.2 Vaccine
* 7 Treatment
* 8 Prognosis
o 8.1 Recovery
o 8.2 Complications
o 8.3 Post-polio syndrome
* 9 Eradication
* 10 History
* 11 See also
* 12 Notes and references
* 13 Further reading
* 14 External links
[edit] Classification
Outcomes of poliovirus infectionOutcome Proportion of cases[4]
Asymptomatic 90–95%
Minor illness 4–8%
Non-paralytic aseptic
meningitis 1–2%
Paralytic poliomyelitis 0.1–0.5%
— Spinal polio 79% of paralytic cases
— Bulbospinal polio 19% of paralytic cases
— Bulbar polio 2% of paralytic cases
The term poliomyelitis is used to identify the disease caused by any of the three serotypes of poliovirus. Two basic patterns of polio infection are described: a minor illness which does not involve the central nervous system (CNS), sometimes called abortive poliomyelitis, and a major illness involving the CNS, which may be paralytic or non-paralytic.[9] In most people with a normal immune system, a poliovirus infection is asymptomatic. Rarely the infection produces minor symptoms; these may include upper respiratory tract infection (sore throat and fever), gastrointestinal disturbances (nausea, vomiting, abdominal pain, constipation or, rarely, diarrhea), and influenza-like illness.[4]
The virus enters the central nervous system in about 3% of infections. Most patients with CNS involvement develop non-paralytic aseptic meningitis, with symptoms of headache, neck, back, abdominal and extremity pain, fever, vomiting, lethargy and irritability.[2][10] Approximately 1 in 200 to 1 in 1000 cases progress to paralytic disease, in which the muscles become weak, floppy and poorly controlled, and finally completely paralyzed; this condition is known as acute flaccid paralysis.[11] Depending on the site of paralysis, paralytic poliomyelitis is classified as spinal, bulbar, or bulbospinal. Encephalitis, an infection of the brain tissue itself, can occur in rare cases and is usually restricted to infants. It is characterized by confusion, changes in mental status, headaches, fever, and less commonly seizures and spastic paralysis.[12]
[edit] Cause
Main article: Poliovirus
A TEM micrograph of poliovirus
Poliomyelitis is caused by infection with a member of the genus Enterovirus known as poliovirus (PV). This group of RNA viruses colonize the gastrointestinal tract[1] — specifically the oropharynx and the intestine. The incubation time (to the first signs and symptoms) ranges from 3 to 35 days with a more common span of 6 to 20 days[4]. PV infects and causes disease in humans alone.[3] Its structure is very simple, composed of a single (+) sense RNA genome enclosed in a protein shell called a capsid.[3] In addition to protecting the virus’s genetic material, the capsid proteins enable poliovirus to infect certain types of cells. Three serotypes of poliovirus have been identified—poliovirus type 1 (PV1), type 2 (PV2), and type 3 (PV3)—each with a slightly different capsid protein.[13] All three are extremely virulent and produce the same disease symptoms.[3] PV1 is the most commonly encountered form, and the one most closely associated with paralysis.[14]
Individuals who are exposed to the virus, either through infection or by immunization with polio vaccine, develop immunity. In immune individuals, IgA antibodies against poliovirus are present in the tonsils and gastrointestinal tract and are able to block virus replication; IgG and IgM antibodies against PV can prevent the spread of the virus to motor neurons of the central nervous system.[15] Infection or vaccination with one serotype of poliovirus does not provide immunity against the other serotypes, and full immunity requires exposure to each serotype.[15]
A rare condition with a similar presentation, non-poliovirus poliomyelitis, may result from infections with non-poliovirus enteroviruses.[16]
[edit] Transmission
Poliomyelitis is highly contagious via the oral-oral (oropharyngeal source) and fecal-oral (intestinal source) routes.[15] In endemic areas, wild polioviruses can infect virtually the entire human population.[17] It is seasonal in temperate climates, with peak transmission occurring in summer and autumn.[15] These seasonal differences are far less pronounced in tropical areas.[17] The time between first exposure and first symptoms, known as the incubation period, is usually 6 to 20 days, with a maximum range of 3 to 35 days.[18] Virus particles are excreted in the feces for several weeks following initial infection.[18] The disease is transmitted primarily via the fecal-oral route, by ingesting contaminated food or water. It is occasionally transmitted via the oral-oral route,[14] a mode especially visible in areas with good sanitation and hygiene.[15] Polio is most infectious between 7–10 days before and 7–10 days after the appearance of symptoms, but transmission is possible as long as the virus remains in the saliva or feces.[14]
Factors that increase the risk of polio infection or affect the severity of the disease include immune deficiency,[19] malnutrition,[20] tonsillectomy,[21] physical activity immediately following the onset of paralysis,[22] skeletal muscle injury due to injection of vaccines or therapeutic agents,[23] and pregnancy.[24] Although the virus can cross the placenta during pregnancy, the fetus does not appear to be affected by either maternal infection or polio vaccination.[25] Maternal antibodies also cross the placenta, providing passive immunity that protects the infant from polio infection during the first few months of life.[26]
[edit] Pathophysiology
A blockage of the lumbar anterior spinal cord artery due to polio (PV3)
Poliovirus enters the body through the mouth, infecting the first cells it comes in contact with—the pharynx (throat) and intestinal mucosa. It gains entry by binding to an immunoglobulin-like receptor, known as the poliovirus receptor or CD155, on the cell membrane.[27] The virus then hijacks the host cell's own machinery, and begins to replicate. Poliovirus divides within gastrointestinal cells for about a week, from where it spreads to the tonsils (specifically the follicular dendritic cells residing within the tonsilar germinal centers), the intestinal lymphoid tissue including the M cells of Peyer's patches, and the deep cervical and mesenteric lymph nodes, where it multiplies abundantly. The virus is subsequently absorbed into the bloodstream.[28]
Known as viremia, the presence of virus in the bloodstream enables it to be widely distributed throughout the body. Poliovirus can survive and multiply within the blood and lymphatics for long periods of time, sometimes as long as 17 weeks.[29] In a small percentage of cases, it can spread and replicate in other sites such as brown fat, the reticuloendothelial tissues, and muscle.[30] This sustained replication causes a major viremia, and leads to the development of minor influenza-like symptoms. Rarely, this may progress and the virus may invade the central nervous system, provoking a local inflammatory response. In most cases this causes a self-limiting inflammation of the meninges, the layers of tissue surrounding the brain, which is known as non-paralytic aseptic meningitis.[2] Penetration of the CNS provides no known benefit to the virus, and is quite possibly an incidental deviation of a normal gastrointestinal infection.[31] The mechanisms by which poliovirus spreads to the CNS are poorly understood, but it appears to be primarily a chance event—largely independent of the age, gender, or socioeconomic position of the individual.[31]
[edit] Paralytic polio
Denervation of skeletal muscle tissue secondary to poliovirus infection can lead to paralysis.
In around 1% of infections, poliovirus spreads along certain nerve fiber pathways, preferentially replicating in and destroying motor neurons within the spinal cord, brain stem, or motor cortex. This leads to the development of paralytic poliomyelitis, the various forms of which (spinal, bulbar, and bulbospinal) vary only with the amount of neuronal damage and inflammation that occurs, and the region of the CNS that is affected.
The destruction of neuronal cells produces lesions within the spinal ganglia; these may also occur in the reticular formation, vestibular nuclei, cerebellar vermis, and deep cerebellar nuclei.[31] Inflammation associated with nerve cell destruction often alters the color and appearance of the gray matter in the spinal column, causing it to appear reddish and swollen.[2] Other destructive changes associated with paralytic disease occur in the forebrain region, specifically the hypothalamus and thalamus.[31] The molecular mechanisms by which poliovirus causes paralytic disease are poorly understood.
Early symptoms of paralytic polio include high fever, headache, stiffness in the back and neck, asymmetrical weakness of various muscles, sensitivity to touch, difficulty swallowing, muscle pain, loss of superficial and deep reflexes, paresthesia (pins and needles), irritability, constipation, or difficulty urinating. Paralysis generally develops one to ten days after early symptoms begin, progresses for two to three days, and is usually complete by the time the fever breaks.[32]
The likelihood of developing paralytic polio increases with age, as does the extent of paralysis. In children, non-paralytic meningitis is the most likely consequence of CNS involvement, and paralysis occurs in only 1 in 1000 cases. In adults, paralysis occurs in 1 in 75 cases.[33] In children under five years of age, paralysis of one leg is most common; in adults, extensive paralysis of the chest and abdomen also affecting all four limbs—quadriplegia—is more likely.[34] Paralysis rates also vary depending on the serotype of the infecting poliovirus; the highest rates of paralysis (1 in 200) are associated with poliovirus type 1, the lowest rates (1 in 2,000) are associated with type 2.[35]
[edit] Spinal polio
The location of motor neurons in the anterior horn cells of the spinal column.
Spinal polio is the most common form of paralytic poliomyelitis; it results from viral invasion of the motor neurons of the anterior horn cells, or the ventral (front) gray matter section in the spinal column, which are responsible for movement of the muscles, including those of the trunk, limbs and the intercostal muscles.[11] Virus invasion causes inflammation of the nerve cells, leading to damage or destruction of motor neuron ganglia. When spinal neurons die, Wallerian degeneration takes place, leading to weakness of those muscles formerly innervated by the now dead neurons.[36] With the destruction of nerve cells, the muscles no longer receive signals from the brain or spinal cord; without nerve stimulation, the muscles atrophy, becoming weak, floppy and poorly controlled, and finally completely paralyzed.[11] Progression to maximum paralysis is rapid (two to four days), and is usually associated with fever and muscle pain.[36] Deep tendon reflexes are also affected, and are usually absent or diminished; sensation (the ability to feel) in the paralyzed limbs, however, is not affected.[36]
The extent of spinal paralysis depends on the region of the cord affected, which may be cervical, thoracic, or lumbar.[37] The virus may affect muscles on both sides of the body, but more often the paralysis is asymmetrical.[28] Any limb or combination of limbs may be affected—one leg, one arm, or both legs and both arms. Paralysis is often more severe proximally (where the limb joins the body) than distally (the fingertips and toes).[28]
[edit] Bulbar polio
The location and anatomy of the bulbar region (in orange)
Making up about 2% of cases of paralytic polio, bulbar polio occurs when poliovirus invades and destroys nerves within the bulbar region of the brain stem.[4] The bulbar region is a white matter pathway that connects the cerebral cortex to the brain stem. The destruction of these nerves weakens the muscles supplied by the cranial nerves, producing symptoms of encephalitis, and causes difficulty breathing, speaking and swallowing.[10] Critical nerves affected are the glossopharyngeal nerve, which partially controls swallowing and functions in the throat, tongue movement and taste; the vagus nerve, which sends signals to the heart, intestines, and lungs; and the accessory nerve, which controls upper neck movement. Due to the effect on swallowing, secretions of mucus may build up in the airway causing suffocation.[32] Other signs and symptoms include facial weakness, caused by destruction of the trigeminal nerve and facial nerve, which innervate the cheeks, tear ducts, gums, and muscles of the face, among other structures; double vision; difficulty in chewing; and abnormal respiratory rate, depth, and rhythm, which may lead to respiratory arrest. Pulmonary edema and shock are also possible, and may be fatal.[37]
[edit] Bulbospinal polio
Approximately 19% of all paralytic polio cases have both bulbar and spinal symptoms; this subtype is called respiratory polio or bulbospinal polio.[4] Here, the virus affects the upper part of the cervical spinal cord (C3 through C5), and paralysis of the diaphragm occurs. The critical nerves affected are the phrenic nerve, which drives the diaphragm to inflate the lungs, and those that drive the muscles needed for swallowing. By destroying these nerves this form of polio affects breathing, making it difficult or impossible for the patient to breathe without the support of a ventilator. It can lead to paralysis of the arms and legs and may also affect swallowing and heart functions.[38]
[edit] Diagnosis
Paralytic poliomyelitis may be clinically suspected in individuals experiencing acute onset of flaccid paralysis in one or more limbs with decreased or absent tendon reflexes in the affected limbs that cannot be attributed to another apparent cause, and without sensory or cognitive loss.[39]
A laboratory diagnosis is usually made based on recovery of poliovirus from a stool sample or a swab of the pharynx. Antibodies to poliovirus can be diagnostic, and are generally detected in the blood of infected patients early in the course of infection.[4] Analysis of the patient's cerebrospinal fluid (CSF), which is collected by a lumbar puncture ("spinal tap"), reveals an increased number of white blood cells (primarily lymphocytes) and a mildly elevated protein level. Detection of virus in the CSF is diagnostic of paralytic polio, but rarely occurs.[4]
If poliovirus is isolated from a patient experiencing acute flaccid paralysis, it is further tested through oligonucleotide mapping (genetic fingerprinting), or more recently by PCR amplification, to determine whether it is "wild type" (that is, the virus encountered in nature) or "vaccine type" (derived from a strain of poliovirus used to produce polio vaccine).[40] It is important to determine the source of the virus because for each reported case of paralytic polio caused by wild poliovirus, it is estimated that another 200 to 3,000 contagious asymptomatic carriers exist.[41]
[edit] Prevention
[edit] Passive immunization
In 1950, William Hammon at the University of Pittsburgh purified the gamma globulin component of the blood plasma of polio survivors.[42] Hammon proposed that the gamma globulin, which contained antibodies to poliovirus, could be used to halt poliovirus infection, prevent disease, and reduce the severity of disease in other patients who had contracted polio. The results of a large clinical trial were promising; the gamma globulin was shown to be about 80% effective in preventing the development of paralytic poliomyelitis.[43] It was also shown to reduce the severity of the disease in patients that developed polio.[42] The gamma globulin approach was later deemed impractical for widespread use, however, due in large part to the limited supply of blood plasma, and the medical community turned its focus to the development of a polio vaccine.[44]
[edit] Vaccine
Main article: Polio vaccine
A child receives oral polio vaccine.
Two types of vaccine are used throughout the world to combat polio. Both types induce immunity to polio, efficiently blocking person-to-person transmission of wild poliovirus, thereby protecting both individual vaccine recipients and the wider community (so-called herd immunity).[45]
The first candidate polio vaccine, based on one serotype of a live but attenuated (weakened) virus, was developed by the virologist Hilary Koprowski. Koprowski's prototype vaccine was given to an eight-year-old boy on February 27, 1950.[46] Koprowski continued to work on the vaccine throughout the 1950s, leading to large-scale trials in the then Belgian Congo and the vaccination of seven million children in Poland against serotypes PV1 and PV3 between 1958 and 1960.[47]
The second inactivated virus vaccine was developed in 1952 by Jonas Salk, and announced to the world on April 12, 1955.[48] The Salk vaccine, or inactivated poliovirus vaccine (IPV), is based on poliovirus grown in a type of monkey kidney tissue culture (Vero cell line), which is chemically inactivated with formalin.[15] After two doses of IPV (given by injection), 90% or more of individuals develop protective antibody to all three serotypes of poliovirus, and at least 99% are immune to poliovirus following three doses.[4]
Subsequently, Albert Sabin developed another live, oral polio vaccine (OPV). It was produced by the repeated passage of the virus through non-human cells at sub-physiological temperatures.[49] The attenuated poliovirus in the Sabin vaccine replicates very efficiently in the gut, the primary site of wild poliovirus infection and replication, but the vaccine strain is unable to replicate efficiently within nervous system tissue.[50] A single dose of Sabin's oral polio vaccine produces immunity to all three poliovirus serotypes in approximately 50% of recipients. Three doses of live-attenuated OPV produce protective antibody to all three poliovirus types in more than 95% of recipients.[4] Human trials of Sabin's vaccine began in 1957,[51] and in 1958 it was selected, in competition with the live vaccines of Koprowski and other researchers, by the US National Institutes of Health.[47] It was licensed in 1962[51] and rapidly became the only polio vaccine used worldwide.[47]
Because OPV is inexpensive, easy to administer, and produces excellent immunity in the intestine (which helps prevent infection with wild virus in areas where it is endemic), it has been the vaccine of choice for controlling poliomyelitis in many countries.[52] On very rare occasions (about 1 case per 750,000 vaccine recipients) the attenuated virus in OPV reverts into a form that can paralyze.[18] Most industrialized countries have switched to IPV, which cannot revert, either as the sole vaccine against poliomyelitis or in combination with oral polio vaccine.[53]
[edit] Treatment
A modern negative pressure ventilator (iron lung)
There is no cure for polio. The focus of modern treatment has been on providing relief of symptoms, speeding recovery and preventing complications. Supportive measures include antibiotics to prevent infections in weakened muscles, analgesics for pain, moderate exercise and a nutritious diet.[54] Treatment of polio often requires long-term rehabilitation, including physical therapy, braces, corrective shoes and, in some cases, orthopedic surgery.[37]
Portable ventilators may be required to support breathing. Historically, a noninvasive negative-pressure ventilator, more commonly called an iron lung, was used to artificially maintain respiration during an acute polio infection until a person could breathe independently (generally about one to two weeks). Today many polio survivors with permanent respiratory paralysis use modern jacket-type negative-pressure ventilators that are worn over the chest and abdomen.[55]
Other historical treatments for polio include hydrotherapy, electrotherapy, massage and passive motion exercises, and surgical treatments such as tendon lengthening and nerve grafting.[11] Devices such as rigid braces and body casts—which tended to cause muscle atrophy due to the limited movement of the user—were also touted as effective treatments.[56]
[edit] Prognosis
Patients with abortive polio infections recover completely. In those that develop only aseptic meningitis, the symptoms can be expected to persist for two to ten days, followed by complete recovery.[57] In cases of spinal polio, if the affected nerve cells are completely destroyed, paralysis will be permanent; cells that are not destroyed but lose function temporarily may recover within four to six weeks after onset.[57] Half the patients with spinal polio recover fully; one quarter recover with mild disability and the remaining quarter are left with severe disability.[58] The degree of both acute paralysis and residual paralysis is likely to be proportional to the degree of viremia, and inversely proportional to the degree of immunity.[31] Spinal polio is rarely fatal.[32]
A child with a deformity of her right leg due to polio
Without respiratory support, consequences of poliomyelitis with respiratory involvement include suffocation or pneumonia from aspiration of secretions.[55] Overall, 5–10% of patients with paralytic polio die due to the paralysis of muscles used for breathing. The mortality rate varies by age: 2–5% of children and up to 15–30% of adults die.[4] Bulbar polio often causes death if respiratory support is not provided;[38] with support, its mortality rate ranges from 25 to 75%, depending on the age of the patient.[4][59] When positive pressure ventilators are available, the mortality can be reduced to 15%.[60]
[edit] Recovery
Many cases of poliomyelitis result in only temporary paralysis.[11] Nerve impulses return to the formerly paralyzed muscle within a month, and recovery is usually complete in six to eight months.[57] The neurophysiological processes involved in recovery following acute paralytic poliomyelitis are quite effective; muscles are able to retain normal strength even if half the original motor neurons have been lost.[61] Paralysis remaining after one year is likely to be permanent, although modest recoveries of muscle strength are possible 12 to 18 months after infection.[57]
One mechanism involved in recovery is nerve terminal sprouting, in which remaining brainstem and spinal cord motor neurons develop new branches, or axonal sprouts.[62] These sprouts can reinnervate orphaned muscle fibers that have been denervated by acute polio infection,[63] restoring the fibers' capacity to contract and improving strength.[64] Terminal sprouting may generate a few significantly enlarged motor neurons doing work previously performed by as many as four or five units:[33] a single motor neuron that once controlled 200 muscle cells might control 800 to 1000 cells. Other mechanisms that occur during the rehabilitation phase, and contribute to muscle strength restoration, include myofiber hypertrophy—enlargement of muscle fibers through exercise and activity—and transformation of type II muscle fibers to type I muscle fibers.[63][65]
In addition to these physiological processes, the body possesses a number of compensatory mechanisms to maintain function in the presence of residual paralysis. These include the use of weaker muscles at a higher than usual intensity relative to the muscle's maximal capacity, enhancing athletic development of previously little-used muscles, and using ligaments for stability, which enables greater mobility.[65]
Meningities
The most common symptoms of meningitis are headache and neck stiffness associated with fever, confusion or altered consciousness, vomiting, and an inability to tolerate light (photophobia) or loud noises (phonophobia). Sometimes, especially in small children, only nonspecific symptoms may be present, such as irritability and drowsiness. If a rash is present, it may indicate a particular cause of meningitis; for instance, meningitis caused by meningococcal bacteria may be accompanied by a characteristic rash.[1][4]
A lumbar puncture may be used to diagnose or exclude meningitis. This involves inserting a needle into the spinal canal to extract a sample of cerebrospinal fluid (CSF), the fluid that envelops the brain and spinal cord. The CSF is then examined in a medical laboratory.[3] The usual treatment for meningitis is the prompt application of antibiotics and sometimes antiviral drugs. In some situations, corticosteroid drugs can also be used to prevent complications from overactive inflammation.[3][4] Meningitis can lead to serious long-term consequences such as deafness, epilepsy, hydrocephalus and cognitive deficits, especially if not treated quickly.[1][4] Some forms of meningitis (such as those associated with meningococci, Haemophilus influenzae type B, pneumococci or mumps virus infections) may be prevented by immunization.[1]
Contents
[hide]
* 1 Signs and symptoms
o 1.1 Clinical features
o 1.2 Early complications
* 2 Causes
o 2.1 Bacterial
o 2.2 Aseptic
o 2.3 Viral
o 2.4 Parasitic
o 2.5 Non-infectious
* 3 Mechanism
* 4 Diagnosis
o 4.1 Blood tests and imaging
o 4.2 Lumbar puncture
o 4.3 Postmortem
* 5 Prevention
* 6 Treatment
o 6.1 Initial treatment
o 6.2 Bacterial meningitis
+ 6.2.1 Antibiotics
+ 6.2.2 Steroids
o 6.3 Viral meningitis
o 6.4 Fungal meningitis
* 7 Prognosis
* 8 Epidemiology
* 9 History
* 10 See also
* 11 References
* 12 External links
[edit] Signs and symptoms
[edit] Clinical features
In adults, a severe headache is the most common symptom of meningitis – occurring in almost 90% of cases of bacterial meningitis, followed by nuchal rigidity (inability to flex the neck forward passively due to increased neck muscle tone and stiffness).[5] The classic triad of diagnostic signs consists of nuchal rigidity, sudden high fever, and altered mental status; however, all three features are present in only 44–46% of all cases of bacterial meningitis.[5][6] If none of the three signs is present, meningitis is extremely unlikely.[6] Other signs commonly associated with meningitis include photophobia (intolerance to bright light) and phonophobia (intolerance to loud noises). Small children often do not exhibit the aforementioned symptoms, and may only be irritable and looking unwell.[1] In infants up to 6 months of age, bulging of the fontanelle (the soft spot on top of a baby's head) may be present. Other features that might distinguish meningitis from less severe illnesses in young children are leg pain, cold extremities, and an abnormal skin color.[7]
Nuchal rigidity occurs in 70% of adult cases of bacterial meningitis.[6] Other signs of meningism include the presence of positive Kernig's sign or Brudzinski's sign. Kernig's sign is assessed with the patient lying supine, with the hip and knee flexed to 90 degrees. In a patient with a positive Kernig's sign, pain limits passive extension of the knee. A positive Brudzinski's sign occurs when flexion of the neck causes involuntary flexion of the knee and hip. Although Kernig's and Brudzinski's signs are both commonly used to screen for meningitis, the sensitivity of these tests is limited.[6][8] They do, however, have very good specificity for meningitis: the signs rarely occur in other diseases.[6] Another test, known as the "jolt accentuation maneuver" helps determine whether meningitis is present in patients reporting fever and headache. The patient is told to rapidly rotate his or her head horizontally; if this does not make the headache worse, meningitis is unlikely.[6]
Meningitis caused by the bacterium Neisseria meningitidis (known as "meningococcal meningitis") can be differentiated from meningitis with other causes by a rapidly spreading petechial rash which may precede other symptoms.[7] The rash consists of numerous small, irregular purple or red spots ("petechiae") on the trunk, lower extremities, mucous membranes, conjuctiva, and (occasionally) the palms of the hands or soles of the feet. The rash is typically non-blanching: the redness does not disappear when pressed with a finger or a glass tumbler. Although this rash is not necessarily present in meningococcal meningitis, it is relatively specific for the disease; it does, however, occasionally occur in meningitis due to other bacteria.[1] Other clues as to the nature of the cause of meningitis may be the skin signs of hand, foot and mouth disease and genital herpes, both of which are associated with various forms of viral meningitis.[9]
[edit] Early complications
A severe case of meningococcal meningitis in which the petechial rash progressed to gangrene and required amputation of all limbs. The patient, Charlotte Cleverley-Bisman, survived the disease and became a poster child for a meningitis vaccination campaign in New Zealand.
People with meningitis may develop additional problems in the early stages of their illness. These may require specific treatment, and sometimes indicate severe illness or worse prognosis. The infection may trigger sepsis, a systemic inflammatory response syndrome of falling blood pressure, fast heart rate, high or abnormally low temperature and rapid breathing. Very low blood pressure may occur early, especially but not exclusively in meningococcal illness; this may lead to insufficient blood supply to other organs.[1] Disseminated intravascular coagulation, the excessive activation of blood clotting, may cause both the obstruction of blood flow to organs and a paradoxical increase of bleeding risk. In meningococcal disease, gangrene of limbs can occur.[1] Severe meningococcal and pneumococcal infections may result in hemorrhaging of the adrenal glands, leading to Waterhouse-Friderichsen syndrome, which is often lethal.[10]
The brain tissue may swell, with increasing pressure inside the skull and a risk of swollen brain tissue causing herniation. This may be noticed by a decreasing level of consciousness, loss of the pupillary light reflex, and abnormal posturing.[4] Inflammation of the brain tissue may also obstruct the normal flow of CSF around the brain (hydrocephalus).[4] Seizures may occur for various reasons; in children, seizures are common in the early stages of meningitis (30% of cases) and do not necessarily indicate an underlying cause.[3] Seizures may result from increased pressure and from areas of inflammation in the brain tissue.[4] Focal seizures (seizures that involve one limb or part of the body), persistent seizures, late-onset seizures and those that are difficult to control with medication are indicators of a poorer long-term outcome.[1]
The inflammation of the meninges may lead to abnormalities of the cranial nerves, a group of nerves arising from the brain stem that supply the head and neck area and control eye movement, facial muscles and hearing, among other functions.[1][6] Visual symptoms and hearing loss may persist after an episode of meningitis (see below).[1] Inflammation of the brain (encephalitis) or its blood vessels (cerebral vasculitis), as well as the formation of blood clots in the veins (cerebral venous thrombosis), may all lead to weakness, loss of sensation, or abnormal movement or function of the part of the body supplied by the affected area in the brain.[1][4]
[edit] Causes
Meningitis is usually caused by infection from viruses or micro-organisms. Most cases are due to infection with viruses,[6] with bacteria, fungi, and parasites being the next most common causes.[2] It may also result from various non-infectious causes.[2]
[edit] Bacterial
The types of bacteria that cause bacterial meningitis vary by age group. In premature babies and newborns up to three months old, common causes are group B streptococci (subtypes III which normally inhabit the vagina and are mainly a cause during the first week of life) and those that normally inhabit the digestive tract such as Escherichia coli (carrying K1 antigen). Listeria monocytogenes (serotype IVb) may affect the newborn and occurs in epidemics. Older children are more commonly affected by Neisseria meningitidis (meningococcus), Streptococcus pneumoniae (serotypes 6, 9, 14, 18 and 23) and those under five by Haemophilus influenzae type B (in countries that do not offer vaccination, see below).[1][3] In adults, N. meningitidis and S. pneumoniae together cause 80% of all cases of bacterial meningitis, with increased risk of L. monocytogenes in those over 50 years old.[3][4] Since the pneumococcal vaccine was introduced, however, rates of pneumococcal meningitis have declined in children and adults.[11]
Recent trauma to the skull gives bacteria in the nasal cavity the potential to enter the meningeal space. Similarly, individuals with a cerebral shunt or related device (such as an extraventricular drain or Ommaya reservoir) are at increased risk of infection through those devices. In these cases, infections with staphylococci are more likely, as well as infections by pseudomonas and other Gram-negative bacilli.[3] The same pathogens are also more common in those with an impaired immune system.[1] In a small proportion of people, an infection in the head and neck area, such as otitis media or mastoiditis, can lead to meningitis.[3] Recipients of cochlear implants for hearing loss are at an increased risk of pneumococcal meningitis.[12]
Tuberculous meningitis, meningitis due to infection with Mycobacterium tuberculosis, is more common in those from countries where tuberculosis is common, but is also encountered in those with immune problems, such as AIDS.[13]
Recurrent bacterial meningitis may be caused by persisting anatomical defects, either congenital or acquired, or by disorders of the immune system.[14] Anatomical defects allow continuity between the external environment and the nervous system. The most common cause of recurrent meningitis is skull fracture,[14] particularly fractures that affect the base of the skull or extend towards the sinuses and petrous pyramids.[14] A literature review of 363 reported cases of recurrent meningitis showed that 59% of cases are due to such anatomical abnormalities, 36% due to immune deficiencies (such as complement deficiency, which predisposes especially to recurrent meningococcal meningitis), and 5% due to ongoing infections in areas adjacent to the meninges.[14]
[edit] Aseptic
The term aseptic meningitis refers loosely to all cases of meningitis in which no bacterial infection can be demonstrated. This is usually due to viruses, but it may be due to bacterial infection that has already been partially treated, with disappearance of the bacteria from the meninges, or by infection in a space adjacent to the meninges (e.g. sinusitis). Endocarditis (infection of the heart valves with spread of small clusters of bacteria through the bloodstream) may cause aseptic meningitis. Aseptic meningitis may also result from infection with spirochetes, a type of bacteria that includes Treponema pallidum (the cause of syphilis) and Borrelia burgdorferi (known for causing Lyme disease). Meningitis may be encountered in cerebral malaria (malaria infecting the brain). Fungal meningitis, e.g. due to Cryptococcus neoformans, is typically seen in people with immune deficiency such as AIDS. Amoebic meningitis, meningitis due to infection with amoebae such as Naegleria fowleri, is contracted from freshwater sources.[2]
[edit] Viral
Viruses that can cause meningitis include enteroviruses, herpes simplex virus type 2 (and less commonly type 1), varicella zoster virus (known for causing chickenpox and shingles), mumps virus, HIV, and LCMV.[9]
[edit] Parasitic
A parasitic cause is often assumed when there is a predominance of eosinophils in the CSF. The most common parasites implicated are Angiostrongylus cantonensis and Gnathostoma spinigerum. Tuberculosis, syphilis, cryptococcosis, and coccidiodomycosis are rare causes of eosinophilic meningitis that may need to be considered.[15][16][17]
[edit] Non-infectious
Meningitis may occur as the result of several non-infectious causes: spread of cancer to the meninges (malignant meningitis)[18] and certain drugs (mainly non-steroidal anti-inflammatory drugs, antibiotics and intravenous immunoglobulins).[19] It may also be caused by several inflammatory conditions such as sarcoidosis (which is then called neurosarcoidosis), connective tissue disorders such as systemic lupus erythematosus, and certain forms of vasculitis (inflammatory conditions of the blood vessel wall) such as Behçet's disease.[2] Epidermoid cysts and dermoid cysts may cause meningitis by releasing irritant matter into the subarachnoid space.[2][14] Mollaret's meningitis is a syndrome of recurring episodes of aseptic meningitis; it is now thought to be caused by herpes simplex virus type 2. Rarely, migraine may cause meningitis, but this diagnosis is usually only made when other causes have been eliminated.[2]
[edit] Mechanism
The meninges comprise three membranes that, together with the cerebrospinal fluid, enclose and protect the brain and spinal cord (the central nervous system). The pia mater is a very delicate impermeable membrane that firmly adheres to the surface of the brain, following all the minor contours. The arachnoid mater (so named because of its spider-web-like appearance) is a loosely fitting sac on top of the pia mater. The subarachnoid space separates the arachnoid and pia mater membranes, and is filled with cerebrospinal fluid. The outermost membrane, the dura mater, is a thick durable membrane, which is attached to both the arachnoid membrane and the skull.
In bacterial meningitis, bacteria reach the meninges by one of two main routes: through the bloodstream or through direct contact between the meninges and either the nasal cavity or the skin. In most cases, meningitis follows invasion of the bloodstream by organisms that live upon mucous surfaces such as the nasal cavity. This is often in turn preceded by viral infections, which break down the normal barrier provided by the mucous surfaces. Once bacteria have entered the bloodstream, they enter the subarachnoid space in places where the blood-brain barrier is vulnerable—such as the choroid plexus. Meningitis occurs in 25% of newborns with bloodstream infections due to group B streptococci; this phenomenon is less common in adults.[1] Direct contamination of the cerebrospinal fluid may arise from indwelling devices, skull fractures, or infections of the nasopharynx or the nasal sinuses that have formed a tract with the subarachnoid space (see above); occasionally, congenital defects of the dura mater can be identified.[1]
The large-scale inflammation that occurs in the subarachnoid space during meningitis is not a direct result of bacterial infection but can rather largely be attributed to the response of the immune system to the entrance of bacteria into the central nervous system. When components of the bacterial cell membrane are identified by the immune cells of the brain (astrocytes and microglia), they respond by releasing large amounts of cytokines, hormone-like mediators that recruit other immune cells and stimulate other tissues to participate in an immune response. The blood-brain barrier becomes more permeable, leading to "vasogenic" cerebral edema (swelling of the brain due to fluid leakage from blood vessels). Large numbers of white blood cells enter the CSF, causing inflammation of the meninges, and leading to "interstitial" edema (swelling due to fluid between the cells). In addition, the walls of the blood vessels themselves become inflamed (cerebral vasculitis), which leads to a decreased blood flow and a third type of edema, "cytotoxic" edema. The three forms of cerebral edema all lead to an increased intracranial pressure; together with the lowered blood pressure often encountered in acute infection, this means that it is harder for blood to enter the brain, and brain cells are deprived of oxygen and undergo apoptosis (automated cell death).[1]
It is recognized that administration of antibiotics may initially worsen the process outlined above, by increasing the amount of bacterial cell membrane products released through the destruction of bacteria. Particular treatments, such as the use of corticosteroids, are aimed at dampening the immune system's response to this phenomenon.[1][4]
[edit] Diagnosis
CSF findings in different forms of meningitis[20]Type of meningitis Glucose Protein Cells
Acute bacterial low high PMNs,
often > 300/mm³
Acute viral normal normal or high mononuclear,
< 300/mm³
Tuberculous low high mononuclear and
PMNs, < 300/mm³
Fungal low high < 300/mm³
Malignant low high usually
mononuclear
[edit] Blood tests and imaging
In someone suspected of having meningitis, blood tests are performed for markers of inflammation (e.g. C-reactive protein, complete blood count), as well as blood cultures.[3][21]
The most important test in identifying or ruling out meningitis is analysis of the cerebrospinal fluid through lumbar puncture (LP, spinal tap).[22] However, lumbar puncture is contraindicated if there is a mass in the brain (tumor or abscess) or the intracranial pressure (ICP) is elevated, as it may lead to brain herniation. If someone is at risk for either a mass or raised ICP (recent head injury, a known immune system problem, localizing neurological signs, or evidence on examination of a raised ICP), a CT or MRI scan is recommended prior to the lumbar puncture.[3][21][23] This applies in 45% of all adult cases.[4] If a CT or MRI is required before LP, or if LP proves difficult, professional guidelines suggest that antibiotics should be administered first to prevent delay in treatment,[3] especially if this may be longer than 30 minutes.[21][23] Often, CT or MRI scans are performed at a later stage to assess for complications of meningitis.[1]
In severe forms of meningitis, monitoring of blood electrolytes may be important; for example, hyponatremia is common in bacterial meningitis, due to a combination of factors including dehydration, the inappropriate excretion of the antidiuretic hormone (SIADH), or overly aggressive intravenous fluid administration.[4][24]
[edit] Lumbar puncture
A lumbar puncture is done by positioning the patient, usually lying on the side, applying local anesthetic, and inserting a needle into the dural sac (a sac around the spinal cord) to collect cerebrospinal fluid (CSF). When this has been achieved, the "opening pressure" of the CSF is measured using a manometer. The pressure is normally between 6 and 18 cm water (cmH2O);[22] in bacterial meningitis the pressure is typically elevated.[3][21] The initial appearance of the fluid may prove an indication of the nature of the infection: cloudy CSF indicates higher levels of protein, white and red blood cells and/or bacteria, and therefore may suggest bacterial meningitis.[3]
Gram stain of meningococci from a culture showing Gram negative (pink) bacteria, often in pairs
The CSF sample is examined for presence and types of white blood cells, red blood cells, protein content and glucose level.[3] Gram staining of the sample may demonstrate bacteria in bacterial meningitis, but absence of bacteria does not exclude bacterial meningitis as they are only seen in 60% of cases; this figure is reduced by a further 20% if antibiotics were administered before the sample was taken, and Gram staining is also less reliable in particular infections such as listeriosis. Microbiological culture of the sample is more sensitive (it identifies the organism in 70–85% of cases) but results can take up to 48 hours to become available.[3] The type of white blood cell predominantly present (see table) indicates whether meningitis is bacterial (usually neutrophil-predominant) or viral (usually lymphocyte-predominant),[3] although in the beginning of the disease this is not always a reliable indicator. Less commonly, eosinophils predominate, suggesting parasitic or fungal etiology, among others.[16]
The concentration of glucose in CSF is normally above 40% that in blood. In bacterial meningitis it is typically lower; the CSF glucose level is therefore divided by the blood glucose (CSF glucose to serum glucose ratio). A ratio ≤0.4 is indicative of bacterial meningitis;[22] in the newborn, glucose levels in CSF are normally higher, and a ratio below 0.6 (60%) is therefore considered abnormal.[3] High levels of lactate in CSF indicate a higher likelihood of bacterial meningitis, as does a higher white blood cell count.[22]
Various more specialized tests may be used to distinguish between various types of meningitis. A latex agglutination test may be positive in meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Escherichia coli and group B streptococci; its routine use is not encouraged as it rarely leads to changes in treatment, but it may be used if other tests are not diagnostic. Similarly, the limulus lysate test may be positive in meningitis caused by Gram-negative bacteria, but it is of limited use unless other tests have been unhelpful.[3] Polymerase chain reaction (PCR) is a technique used to amplify small traces of bacterial DNA in order to detect the presence of bacterial or viral DNA in cerebrospinal fluid; it is a highly sensitive and specific test since only trace amounts of the infecting agent's DNA is required. It may identify bacteria in bacterial meningitis and may assist in distinguishing the various causes of viral meningitis (enterovirus, herpes simplex virus 2 and mumps in those not vaccinated for this).[9] Serology (identification of antibodies to viruses) may be useful in viral meningitis.[9] If tuberculous meningitis is suspected, the sample is processed for Ziehl-Neelsen stain, which has a low sensitivity, and tuberculosis culture, which takes a long time to process; PCR is being used increasingly.[13] Diagnosis of cryptococcal meningitis can be made at low cost using an India ink stain of the CSF; however, testing for cryptococcal antigen in blood or CSF is more sensitive, particularly in persons with AIDS.[25][26][27]
A diagnostic and therapeutic conundrum is the "partially treated meningitis", where there are meningitis symptoms after receiving antibiotics (such as for presumptive sinusitis). When this happens, CSF findings may resemble those of viral meningitis, but antibiotic treatment may need to be continued until there is definitive positive evidence of a viral cause (e.g. a positive enterovirus PCR).[9]
[edit] Postmortem
Histopathology of bacterial meningitis: autopsy case of a patient with pneumococcal meningitis showing inflammatory infiltrates of the pia mater consisting of neutrophil granulocytes (inset, higher magnification).
Meningitis can be diagnosed after death has occurred. The findings from a post mortem are usually a widespread inflammation of the pia mater and arachnoid layers of the meninges covering the brain and spinal cord. Neutrophil granulocytes tend to have migrated to the cerebrospinal fluid and the base of the brain, along with cranial nerves and the spinal cord, may be surrounded with pus—as may the meningeal vessels.[28]
[edit] Prevention
For some causes of meningitis, prophylaxis can be provided in the long term with vaccine, or in the short term with antibiotics.
Since the 1980s, many countries have included immunization against Haemophilus influenzae type B in their routine childhood vaccination schemes. This has practically eliminated this pathogen as a cause of meningitis in young children in those countries. In the countries where the disease burden is highest, however, the vaccine is still too expensive.[29][30] Similarly, immunization against mumps has led to a sharp fall in the number of cases of mumps meningitis, which prior to vaccination occurred in 15% of all cases of mumps.[9]
Meningococcus vaccines exist against groups A, C, W135 and Y.[31] In countries where the vaccine for meningococcus group C was introduced, cases caused by this pathogen have decreased substantially.[29] A quadrivalent vaccine now exists, which combines all four vaccines. Immunization with the ACW135Y vaccine against four strains is now a visa requirement for taking part in the Hajj.[32] Development of a vaccine against group B meningococci has proved much more difficult, as its surface proteins (which would normally be used to make a vaccine) only elicit a weak response from the immune system, or cross-react with normal human proteins.[29][31] Still, some countries (New Zealand, Cuba, Norway and Chile) have developed vaccines against local strains of group B meningococci; some have shown good results and are used in local immunization schedules.[31] In Africa, the current approach for prevention and control of meningococcal epidemics is based on early detection of the disease and emergency reactive mass vaccination of the at-risk population with bivalent A/C or trivalent A/C/W135 polysaccharide vaccines.[33]
Routine vaccination against Streptococcus pneumoniae with the pneumococcal conjugate vaccine (PCV), which is active against seven common serotypes of this pathogen, significantly reduces the incidence of pneumococcal meningitis.[29][34] The pneumococcal polysaccharide vaccine, which covers 23 strains, is only administered in certain groups (e.g. those who have had a splenectomy, the surgical removal of the spleen); it does not elicit a significant immune response in all recipients, e.g. small children.[34]
Childhood vaccination with Bacillus Calmette-Guérin has been reported to significantly reduce the rate of tuberculous meningitis, but its waning effectiveness in adulthood has prompted a search for a better vaccine.[29]
Short-term antibiotic prophylaxis is also a method of prevention, particularly of meningococcal meningitis. In cases of meningococcal meningitis, prophylactic treatment of close contacts with antibiotics (e.g. rifampicin, ciprofloxacin or ceftriaxone) can reduce their risk of contracting the condition, but does not protect against future infections.[21][35]
[edit] Treatment
[edit] Initial treatment
Meningitis is potentially life-threatening and has a high mortality rate if untreated;[3] delay in treatment has been associated with a poorer outcome.[4] Thus treatment with wide-spectrum antibiotics should not be delayed while confirmatory tests are being conducted.[23] If meningococcal disease is suspected in primary care, guidelines recommend that benzylpenicillin be administered before transfer to hospital.[7] Intravenous fluids should be administered if hypotension (low blood pressure) or shock are present.[23] Given that meningitis can cause a number of early severe complications, regular medical review is recommended to identify these complications early,[23] as well as admission to an intensive care unit if deemed necessary.[4]
Mechanical ventilation may be needed if the level of consciousness is very low, or if there is evidence of respiratory failure. If there are signs of raised intracranial pressure, measures to monitor the pressure may be taken; this would allow the optimization of the cerebral perfusion pressure and various treatments to decrease the intracranial pressure with medication (e.g. mannitol).[4] Seizures are treated with anticonvulsants.[4] Hydrocephalus (obstructed flow of CSF) may require insertion of a temporary or long-term drainage device, such as a cerebral shunt.[4]
[edit] Bacterial meningitis
[edit] Antibiotics
Structural formula of ceftriaxone, one of the third-generation cefalosporin antibiotics recommended for the initial treatment of bacterial meningitis.
Empiric antibiotics (treatment without exact diagnosis) must be started immediately, even before the results of the lumbar puncture and CSF analysis are known. The choice of initial treatment depends largely on the kind of bacteria that cause meningitis in a particular place. For instance, in the United Kingdom empirical treatment consists of a third-generation cefalosporin such as cefotaxime or ceftriaxone.[21][23] In the USA, where resistance to cefalosporins is increasingly found in streptococci, addition of vancomycin to the initial treatment is recommended.[3][4][21] Empirical therapy may be chosen on the basis of the age of the patient, whether the infection was preceded by head injury, whether the patient has undergone neurosurgery and whether or not a cerebral shunt is present.[3] For instance, in young children and those over 50 years of age, as well as those who are immunocompromised, addition of ampicillin is recommended to cover Listeria monocytogenes.[3][21] Once the Gram stain results become available, and the broad type of bacterial cause is known, it may be possible to change the antibiotics to those likely to deal with the presumed group of pathogens.[3]
The results of the CSF culture generally take longer to become available (24–48 hours). Once they do, empiric therapy may be switched to specific antibiotic therapy targeted to the specific causative organism and its sensitivities to antibiotics.[3] For an antibiotic to be effective in meningitis, it must not only be active against the pathogenic bacterium, but also reach the meninges in adequate quantities; some antibiotics have inadequate penetrance and therefore have little use in meningitis. Most of the antibiotics used in meningitis have not been tested directly on meningitis patients in clinical trials. Rather, the relevant knowledge has mostly derived from laboratory studies in rabbits.[3]
Tuberculous meningitis requires prolonged treatment with antibiotics. While tuberculosis of the lungs is typically treated for six months, those with tuberculous meningitis are typically treated for a year or longer.[13] In tuberculous meningitis there is a strong evidence base for treatment with corticosteroids, although this evidence is restricted to those without AIDS.[36]
[edit] Steroids
Adjuvant treatment with corticosteroids (usually dexamethasone) has been shown in some studies to reduce rates of mortality, severe hearing loss and neurological damage in adolescents and adults from high income countries which have low rates of HIV.[37] The likely mechanism is suppression of overactive inflammation.[38] Professional guidelines therefore recommend the commencement of dexamethasone or a similar corticosteroid just before the first dose of antibiotics is given, and continued for four days.[21][23] Given that most of the benefit of the treatment is confined to those with pneumococcal meningitis, some guidelines suggest that dexamethasone be discontinued if another cause for meningitis is identified.[3][21]
Adjuvant corticosteroids have a different role in children than in adults. Though the benefit of corticosteroids has been demonstrated in adults as well as in children from high-income countries, their use in children from low-income countries is not supported by evidence; the reason for this discrepancy is not clear.[39] Even in high-income countries, the benefit of corticosteroids is only seen when they are given prior to the first dose of antibiotics, and is greatest in cases of H. influenzae meningitis,[3][40] the incidence of which has decreased dramatically since the introduction of the Hib vaccine. Thus, corticosteroids are recommended in the treatment of pediatric meningitis if the cause is H. influenzae and only if given prior to the first dose of antibiotics, whereas other uses are controversial.[3]
A 2010 analysis of previous studies has shown that the benefit from steroids may not be as significant as previously found. The one possible significant benefit is reduction of hearing loss in survivors,[41] and adverse neurological outcomes.[42]
[edit] Viral meningitis
Viral meningitis typically requires supportive therapy only; most viruses responsible for causing meningitis are not amenable to specific treatment. Viral meningitis tends to run a more benign course than bacterial meningitis. Herpes simplex virus and varicella zoster virus may respond to treatment with antiviral drugs such as aciclovir, but there are no clinical trials that have specifically addressed whether this treatment is effective.[9] Mild cases of viral meningitis can be treated at home with conservative measures such as fluid, bedrest, and analgesics.[43]
[edit] Fungal meningitis
Fungal meningitis, such as cryptococcal meningitis, is treated with long courses of highly dosed antifungals, such as amphotericin B and flucytosine.[25][44] Raised intracranial pressure is common in fungal meningitis, and frequent (ideally daily) lumbar punctures to relieve the pressure are recommended,[25] or alternatively a lu
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