Progressive Multifocal Leukoencephalopathy: Causes, Symptoms, Treatment, Prognosis, Pathophysiology

Progressive Multifocal Leukoencephalopathy or commonly referred to as PML is a kind of rare, life-threatening viral, infectious health condition resulting in advance inflammation or damaging of white matter in multiple areas of the brain. Progressive Multifocal Leukoencephalopathy is mainly caused by a virus named as JC or John Cunningham virus previously called as Papovavirus. This virus attacks only when the immune system is very much weak or if the patient is suffering from severe immunodeficiency ailments like AIDS, Hodgkin’s Lymphoma, psoriasis, multiple sclerosis or any other autoimmune diseases. Progressive Multifocal Leukoencephalopathy also occurs if the patient is under immunosuppressants like cyclophosphamide, cyclosporine, methotrexate, prednisone, etc. or have undergone any sorts of transplantation or immune therapy. Generally, the mortality rate for Progressive Multifocal Leukoencephalopathy varies from 30% to 50% in the first few days of the infection and by chance if the patients survive he may go through other neurological dysfunctions.

Progressive Multifocal Leukoencephalopathy is actually a neurological disorder characterized by the demyelination of the central nervous system due to the infection of a human polyomavirus named as JC virus which is a minute double stranded DNA virus without any envelop surrounding it. This etiological virus was isolated and identified during the brain postmortem of a patient named John Cunningham post his death and thus named as JC virus in his honor. This virus is quite widespread and has been seen to be present in almost 80-85% of normal adult populations. Although these viruses remain inactive in normal healthy individual but begins showing symptoms of Progressive Multifocal Leukoencephalopathy if the individual has extremely weak immune system. Progressive Multifocal Leukoencephalopathy occurs in 1 in 200,000 populations, approximately and thus is very rare.

The word ‘progressive’ in Progressive Multifocal Leukoencephalopathy means that the diseases keep on getting worse and thus leads to death by severe brain damage. ‘Multifocal’ in Progressive Multifocal Leukoencephalopathy refers to that JC virus causes infections in various parts of the brain. Finally the term ‘leukoencephalopathy’ signifies that the infection spreads mainly in the myelin sheath or white matter of the brain and very rarely to the grey matter of the neurons.

Although the occurrence of JCV infections is asymptomatic as well as chronic in human populations, but the incidence of this infection is hardly found in general healthy populations. Wild type JCV infection is usually benign, whereas Progressive Multifocal Leukoencephalopathy is resulted due to viral infection along with rare genetic modifications. The appearance of Progressive Multifocal Leukoencephalopathy also depends on loss of host-immune abilities and therefore susceptibility of the disease is caused by the combination of host factors and erratic viral infection.

Signs and symptoms of Progressive Multifocal Leukoencephalopathy start developing over few weeks or months, depending on the degree and location of the damage in the brain. Progressive Multifocal Leukoencephalopathy symptoms usually vary from one patient to another and likewise the lesions of infection also vary from one site to the other mainly in the occipital or parietal lobes of the brain. Progressive Multifocal Leukoencephalopathy patients normally show signs of neurological impairment. Some of these common and frequently appeared signs and symptoms of the disease include:

• Subacute neural destruction with some grade of mental disorder
• Coordination dysfunction
• Clumsiness
• Speech disability or aphasia
• Loss of memory
• Loss of senses
• Vision difficulties including hemianopia or diplopia
• Drooping of face
• Progressive weakness or ataxia in arms and legs
• Alteration in personality or gait
• Motor and cerebellar deficits
• Multifocal cortical mutilation resulting in cognitive impairment
• Coma or paralysis
• Convulsive seizure or frequent headaches (in later stage when PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY progresses in the grey matter of neuron).

Progressive Multifocal Leukoencephalopathy is seen to be linked with immunosuppressed conditions, but also seen to happen in leukemia or organ transplanted patients. Nowadays non-HIV people are also getting the disease. In the primary stage, it is found that progressive multifocal leukoencephalopathy seldom occurs in immunocompetent patients. The frequency of progressive multifocal leukoencephalopathy is quite low in Africa and India because of probable diagnostic difference or barriers in isolation of JCV.

In case of an AIDS patient, if CD4 counts as 50 to 100 cells per uL, then usually these patients get progressive multifocal leukoencephalopathy symptoms and researches have shown that progressive multifocal leukoencephalopathy tends to occur in 5% (approx.) of the autopsies of fatal AIDS patients. Recently, progressive multifocal leukoencephalopathy has seen to be related with Natalizumab, i.e., an IgG monoclonal antibody used for treating relapsing remitting multiple sclerosis. Additionally, Progressive Multifocal Leukoencephalopathy is also seen to be triggered in immunocompromised patients, that is, whose immune system is just on the edge of recovery. Progressive Multifocal Leukoencephalopathy is also classically involved with IRIS (immune reconstitution inflammatory syndrome).

Prognosis of Progressive Multifocal Leukoencephalopathy varies with different comorbidities. Within the first 3-9 months of the disease occurrence, mortality rate is quite high i.e., about 30-50% and without any treatment progressive multifocal leukoencephalopathy can be fatal just in about a year. Presence of JC virus-specific cytotoxic T-cells generally tend to increase the survival of individuals affected with progressive multifocal leukoencephalopathy. Therefore prognosis of the disease is very much poor and with the intervention of medical assistance survival chance increase a bit along with unavoidable long-term neurological dysfunctions. However, recent researches have proved that Progressive Multifocal Leukoencephalopathy can be resolved with viral clearance along with providing support and restoring host immune function. Nevertheless, this may lead to IRIS with symptoms like massive inflammation in the brain and drastically degraded clinical and pathological conditions. Therefore, only way to encounter progressive multifocal leukoencephalopathy is early diagnosis, controlling inflammation and managing immune functions in order to provide the patient maximum relief from the disease symptoms till some effective medical therapy is discovered.

The foremost causative agent of Progressive Multifocal Leukoencephalopathy is a human polyomavirus named as JC virus. People with feeble immune system usually get the infection of JCV that ultimately lead to progressive multifocal leukoencephalopathy. Other reasons to develop progressive multifocal leukoencephalopathy with weak immune system include:

• AIDS
• Immunosuppressive medications like Cyclophosphamide, Cyclosporine, Methotrexate, Prednisone, etc. in treating autoimmune ailments, such as Rheumatoid Arthritis, Multiple Sclerosis and many more.
• Blood related cancerous disease like lymphoma or leukemia.
• If any patients has undergone immune therapy or any type of transplant procedures.

This JC virus is usually present in the brain or bone marrow of healthy people in an inactive state. Many people get infected by the virus but very few actually show symptoms.

The pathophysiology of Progressive Multifocal Leukoencephalopathy is still under research. JCV infection is usually chronic and the kidney is the primary site from where the infection starts spreading and thus the virus is commonly shredded through urine. JCV enters into the body following the oral or respiratory path and remain latent in the brain, kidney or lymph reticular tissues. JCV is carried to the CNS by B lymphocytes and due to immunosuppression the virus gets active and causes systemic dissemination in the brain.

Tat, an HIV gene product, has the ability to trans-activate the JCV promoter directly. In oligodendrocytes, the viral infection is lytic. It goes through DNA replication and viral capsid protein synthesis inside the cell. After this, JCV infects other cells from the circumference mainly near the central nidus and thus leads to the spreading of the demyelinating lesion. Astrocytes enlarge and mostly get infected by JCV and therefore lead to bizarre appearances which resemble the giant tumor cells known as astrocytomas.

According to some recent study, the transformation of benign JCV peripheral infection to a rare pathogenic CNS infection mainly depends on the combination of viral and host immune factors and the replicating capacity of JCV which varies with the mutation in the NCCRs or VP1 viral capsid protein and this also alters the pathogenic demyelination infection in the brain.

Patients get infected with JCV and develop progressive multifocal leukoencephalopathy mainly because of weak immune system. Probable risk factors which may alter or weaken immune system include:

• AIDS
• Cancer or Lupus together with their ongoing treatment.
• Certain autoimmune conditions like multiple sclerosis, rheumatoid arthritis, psoriasis or Crohn’s disease.
• Organ transplantation along with certain immunosuppressant medications.
• Tysabri treatment for more than two years.
• Ongoing treatments with immunomodulatory therapy or immunosuppressant like Cyclophosphamide, Azathioprine, Mycophenolate mofetil, Methotrexate, Mitoxantrone, etc.
• Genetic factors. Some typical genetic factors are involved in developing progressive multifocal leukoencephalopathy but yet not properly identified.

Progressive Multifocal Leukoencephalopathy can be investigated through histopathological or by virological, clinical or radiological confirmation. Tests may include:

• Cerebro-spinal Fluid test to confirm JCV infection.
• EEG of brain also helps in detecting the condition.
• Brain Tissue Biopsy: This shows presence of enlarged oligodendroglial nuclei; bizarre astrocytes; and histopathology of demyelination.
• CT scan of the Brain: Images consists of non-contrasting asymmetric multifocal hypodense lesions without any mass effect mainly in the subcortical or periventricular white matter.
• MRI of Brain: MRI shows presence of subcortical U-fibers in the parieto-occipital lobe and lessions are seen normally in exterior capsula, posterior cranial fossa or basal ganglia of cerebellum or throughout brain stem. JCV DNA is found in spinal fluid along with white matter lesions.
• MR Spectroscopy: Progressive Multifocal Leukoencephalopathy lesions are usually seen to get reduced in presence of lactate or NAA, and Choline and lipids are seen to have increased value.

Till now there are no specific drugs to cure or inhibit viral causing JCV without any toxic effect. Thus, treatment only involves in stopping or slowing of the disease progress or just reversing back the patient’s immune system. AIDS patient with Progressive Multifocal Leukoencephalopathy and undergoing HAART have shown little chance of long-term survival. Therefore, treatment strategies for Progressive Multifocal Leukoencephalopathy include:

• To start antiretroviral therapy as soon as the patients are diagnosed with progressive multifocal leukoencephalopathy and are not undergoing therapy
• To optimize antiretroviral treatment for viral suppression among patients getting antiretroviral therapy, but are actually HIV-viremic due to antiretroviral resistance. Serious treatment with certain antiretroviral medicines, including Enfuvirtide has been seen to provide probable survival assistance in progressive multifocal leukoencephalopathy patients with unnoticeable plasma HIV.

Hexadecyloxypropyl-Cidofovir is currently studied as a probable treatment for JVC because the drug is able to suppress JVC by obstructing viral DNA replication.

Chemotherapeutic drug Cytarabine or ARA-C has been advised experimentally for non-AIDS Progressive Multifocal Leukoencephalopathy patients and is seen to calm down minor neurological complaints. It is found that some of the patients recovered cognitive functioning. It is also seen that Mefloquine, antimalarial drug has effectively been used against JCV activity. According to the patients report, there was complete viral clearance and also no signs of deterioration of neurological condition further.

A number of other drugs work effectively against JCV in culture media, but there is no particular drug or therapy still now discovered to provide successful cure against progressive multifocal leukoencephalopathy in humans.

Due to the fact that no proper treatment is yet identified for Progressive Multifocal Leukoencephalopathy, a person with compromised immune system must be very cautious. Although, the prognosis is very low, a proper diagnosis and timely treatment can increase the survival days.

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