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Wednesday, December 3, 2014

Progressive Multifocal Leukoencephalopathy - PML Symptoms

What Is PML (Progressive multifocal leukoencephalopathy)?

The progressive multifocal leukoencephalopathy (PML) is a disorder of the central nervous system (CNS), which is caused by the belonging to the genus of the polyomavirus JC virus. The name of the virus is derived from the initials of the patient in whom it was first isolated. The disease occurs almost exclusively in severely immunocompromised persons. It is an acute, progressive disease in which numerous functional changes in the nervous system, such as motor and cognitive disorders may occur.


The PML occurs rarely and almost exclusively in immunocompromised individuals who have a significant defect in T-cell immunity. Immunocompetent persons or in which only deficits in humoral defense system consist (antibody and complement), ill not to PML usually. People with relevant T-cell immunodeficiency either suffer from diseases of the immune treated immunosuppressive due to another disease. Immunosuppression may as a side effect - such as in the chemotherapy of tumors - or as desired effect of drugs - after organ transplantation or for treating autoimmune diseases - occur. Heaped PML occurs after bone marrow transplantation.

The majority of cases of PML occurs in the context of the acquired immune deficiency syndrome (AIDS) in stage C3 - about 80-90% of PML patients also suffer from AIDS. In 1980, the prevalence of PML was among AIDS patients but not more than 5% seems to decline continuously since then, which is mainly attributed to the fact that the highly active antiretroviral therapy (HAART) has become widespread. According to the classification of the Centers for Disease Control and Prevention, the PML is one of the "AIDS-defining illnesses".

Rarely, the disease occurs in the context of tumors of the lymphoreticular system - especially in Hodgkin's disease - as well as in chronic inflammatory diseases, organ transplantation and increasingly frequent as adverse effects of immunosuppressive drugs on (such as infliximab, natalizumab, rituximab, efalizumab or fingolimod) , which are increasingly being used. The intake of fumaric acid esters can potentially contribute to the development of PML as four case reports in the New England Journal of Medicine (2013; 368: 1657-1661) show. In an opinion by two dermatologists in Dt. Aerzteblatt but this is questioned.

Pathogenesis and Pathology

It is the disease is reinfection by reactivation of JC virus. The initial or primary infection with the virus are asymptomatic. The prevalence begins in childhood and reaches an adult infection rate of 40-60%. The pathogen persists lifelong.

JC virus probably reached in T-cell Immunocompromised of his place of persistence (possibly kidney tissue and / or bone marrow) on leukocytes into the central nervous system and replicates in the white matter of the cerebrum, brainstem, cerebellum (cerebellum) and spinal cord , It is a demyelinating disease (demyelinating disease), that is, the nerve sheath (myelin sheath) of the oligodendrocytes, which insulation of nerve fibers (axons) of the neurons are affected and degenerate. Since the gray matter consists mainly of neurons, and only a small proportion of axons, it is almost not affected by the infection. Histologically, an inflammatory demyelination with perivascular leukocyte infiltration. In particular, the pronounced polymorphism of the infected glial cells is typical. The neuropathological diagnosis is confirmed by the detection of the JC virus protein in immunohistochemistry, or detection of JC virus genome in the in-situ hybridization.

PML Symptoms

The symptoms of PML depend on the localization of demyelination in the central nervous system. If this example are in the language center, there is language disorders (aphasia) when the sensory nerves are affected, to numbness, the motor nerves are affected it comes to motor deficits in the form of fine motor disorders or paralysis. In an infestation of the visual pathway leads to visual field defects (for example hemianopia). In the further course of the disease can cause cognitive impairment, impaired concentration, confusion and dementia. Also epileptic seizures may occur in the course of the disease.


A relatively reliable diagnosis is possible only by demonstrating the JC virus DNA in the cerebrospinal fluid medium polymerase chain reaction (PCR). The detection of the virus in the urine can be a correlation with the disease, since about 20% of the population excrete the virus permanently. The relatively nonspecific Demyelinisierungsherde, which can be detected with magnetic resonance imaging (MRI, magnetic resonance imaging) may contribute to the diagnosis. The herd arise with T1 weighting hypointense, T2 and flair in the sequence hyperintense and take no contrast agent. Typical are confluent flat and symmetrical signal changes with sparing of the cerebral cortex. These are often parietal. A differentiation to other changes same appearance (for example, in multiple sclerosis (MS) or the posterior reversible encephalopathy syndrome (PRES)) is not only possible, without medical history due to the MRI findings. The virus may also be detected by electron microscopy in brain tissue.

Differential Diagnosis

From the suspicion of progressive multifocal leukoencephalopathy (PML) in the context of AIDS must first be ruled by a toxoplasmosis or cryptococcosis, a CNS lymphoma, HIV encephalopathy, but also leukodystrophies in children and the Subacute sclerosing panencephalitis (SSPE) the frequent encephalitis. In case of suspected PML during treatment of multiple sclerosis with natalizumab is a MS attack is the main differential diagnosis.

PML Treatment

The currently most effective treatment of PML are measures to restore immunocompetence:

-In AIDS patients, the mortality and the severity of the disease by Highly Active Anti-Retroviral Therapy (HAART) could be reduced because the number of T-cells rises again in the course of such treatment.
-In patients who are receiving immunosuppressive therapy, this treatment should be suspended. For medicinal products containing long biological effect measures for the removal of the drug is recommended.
-In patients who are being treated for organ transplantation with immunosuppressive drugs, may the transplanted organ must be removed.

A causal treatment of PML does not exist. For the effect of some drugs were case reports or small case series published (for example, foscarnet, cytosine arabinoside, cidofovir, interferon, cortisone), their verification in larger patient cohorts but disappointing.

A Case Report 2010 describes a successful treatment with mefloquine, an antimalarial, which seems to have an impact inhibit the JC virus. An elimination of the virus particles from the patient's body, as well as prevented progression of a progressive multifocal leukoencephalopathy (PML) have been reported.

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