Progressive multifocal leucoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal viral disease characterized by progressive damage (-pathy) or inflammation of the white matter (leuko-) of the brain (-encephalo-) at multiple locations (multifocal). It is caused by the JC virus, which is normally present and kept under control by the immune system. The JC virus is harmless except in cases of weakened immune systems. In general, PML has a mortality rate of 30–50% in the first few months, and those who survive can be left with varying degrees of neurological disabilities. Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal viral disease characterized by progressive damage (-pathy) or inflammation of the white matter (leuko-) of the brain (-encephalo-) at multiple locations (multifocal). It is caused by the JC virus, which is normally present and kept under control by the immune system. The JC virus is harmless except in cases of weakened immune systems. In general, PML has a mortality rate of 30–50% in the first few months, and those who survive can be left with varying degrees of neurological disabilities. PML occurs almost exclusively in patients with severe immune deficiency, most commonly among patients with acquired immune deficiency syndrome (AIDS), but people on chronic immunosuppressive medications including chemotherapy are also at increased risk of PML, such as patients with transplants, Hodgkin's lymphoma, multiple sclerosis, psoriasis, and other autoimmune diseases. Symptoms can develop over several weeks to months, and they depend on location of damage in the brain and the degree of damage. The most prominent symptoms are 'clumsiness, progressive weakness, and visual, speech, and sometimes personality changes'.The lesions affecting the parietal and occipital lobes of the brain can lead to a phenomenon known as alien hand syndrome. The cause of PML is a type of polyomavirus called the JC virus (JCV), after the initials of the person from whose tissue the virus was first successfully cultured. Recent publications indicate 39 to 58% of the general population are seropositive for antibodies to JCV, indicating current or previous infection with the virus. Other publications put the percentage at 70 to 90% of the general population. JCV causes persistent asymptomatic infection in about one-third of the adult population, based on viral shedding into the urine from the site of asymptomatic infection in the kidney. The virus causes disease only when the immune system has been severely weakened. PML is most common in people with HIV1 infection; prior to the advent of effective antiretroviral therapy, as many as 5% of people with AIDS eventually developed PML. It is unclear why PML occurs more frequently in people with AIDS than in other immunosuppressive conditions; some research suggests the effects of HIV on brain tissue, or on JCV itself, make JCV more likely to become active in the brain and increase its damaging inflammatory effects. PML can still occur in people on immunosuppressive therapy, such as efalizumab, belatacept, and various transplant drugs, which are meant to weaken the immune system. Natalizumab (Tysabri) was approved in 2004 by the FDA for MS. It was subsequently withdrawn from the market by its manufacturer after it was linked with three cases of PML. All three initial cases were taking natalizumab in combination with interferon beta-1a. After a safety review, the drug was returned to the market in 2006 as a monotherapy for MS under a special prescription program. As of May 2011, over 130 cases of PML had been reported in MS patients, all in patients who had taken natalizumab for more than a year. While none of them had taken the drug in combination with other disease-modifying treatments, previous use of MS treatments increases the risk of PML between three and four-fold. The estimated prevalence of PML in MS is 1.5 cases per thousand natalizumab users. Around 20% of MS patients with PML die, and most of the rest are very disabled.A person with MS developed PML and died during a 4-year course of dimethyl fumarate. Fingolimod (Gilenya) was approved in 2010 by the FDA for MS. In 2015, the first case of PML, as well as a case of 'probable PML' was reported by two Gilenya users that could not be tied to previous immunosuppressant therapies. These new cases are now being added to the drug information sheet included with every prescription (i.e. the 'drug label'). PML is a demyelinating disease, in which the myelin sheath covering the axons of nerve cells is gradually destroyed, impairing the transmission of nerve impulses. It affects the subcortical white matter, particularly that of the parietal and occipital lobes. PML destroys oligodendrocytes and produces intranuclear inclusions. It is similar to another demyelinating disease, MS, but progresses much more quickly. The breakdown of myelin is commensurate with the degree of immunocompromise.