Progressive multifocal leukoencephalopathy (PML) is a disease of the white matter of the brain, caused by lytic infection of oligodendrocytes by the JC polyomavirus (JCV) that targets cells that make myelin – the material that insulates nerve cells (neurons).
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 a normal healthy individual but begin showing symptoms of Progressive Multifocal Leukoencephalopathy if the individual has an extremely weak immune system.
Pathophysiology of Progressive Multifocal Leukoencephalopathy
The pathogenesis of PML is not well understood. It is known that the development of PML, while dependent on the presence of the JC virus, is the result of a confluence of specific viral and host risk factors.
JCV infection is chronic; kidney appears to be the primary site of infection and it shed in the urine with the prevalence of shedding dependent on gender and age. JCV is rarely found in blood, and while there have been reports of JCV in the brain, bone marrow, tonsil, and peripheral blood lymphocytes, viral tropism, and lifecycle beyond kidney is not understood. It is therefore unclear how JCV accesses the central nervous system (CNS) and ultimately infects oligodendrocytes in the brain.
There are few research findings suggest that viral mutations in the VP1 capsid protein and/or the noncoding control regions (NCCRs) might result in a change in tropism or replication capacity that is permissive for the pathogenic demyelinating brain infection.
The conversion of JCV from a common benign peripheral infection to a rare pathogenic brain infection is dependent on the convergence of host and viral factors. In addition to viral mutations, significant changes to host immune function are also required. HIV-AIDS is the most common context where PML is observed, but it is also associated with pathological conditions and certain therapeutics that result in significant immune suppression or immune modulation.
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 the weak immune system include:
- Immunosuppressive medications like Cyclophosphamide, Cyclosporine, Methotrexate, Prednisone, etc. in treating autoimmune ailments, such as Rheumatoid Arthritis, Multiple Sclerosis and many more.
- A blood-related cancerous disease like lymphoma or leukemia.
- If any patients have 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.
Risk factors of Progressive Multifocal Leukoencephalopathy
- PML is very rare and is likely caused by a combination of factors. Infection with the JC virus (JCV) is required for PML to develop. Other patient-specific factors, including a weakened immune system and possibly genetic factors, may increase the risk of PML.
- People who have multiple sclerosis, which attacks the central nervous system, or other immune system problems, like rheumatoid arthritis or lupus, may be at risk as well.
- People who have some types of cancer or take drugs that keep their body from rejecting a transplanted organ also have a higher risk.
Since the brain is the primary organ affected, the symptoms are reflective of brain dysfunction or even damage. Symptoms of progressive multifocal leukoencephalopathy include the following:
- Visual impairment or loss
- Tingling sensation or loss of sensation from the limbs
- Changes in hearing, smell, and taste
- Non-reaction to a strong or painful sensory stimuli
- Speech Impairment or even aphasia (loss of speech)
- Inability to understand speech
- Unilateral or bilateral weakness
- Face drooping
- Loss of balance or clumsiness
- Disorientation to time, place and people
- Progressive loss of memory
- Inability to focus or solve problems
- Inability to execute activities of daily living
- Progressive loss of consciousness
Symptoms of the disease occur in a quick and progressive manner.
Complications of Progressive Multifocal Leukoencephalopathy
The possible complications associated with Progressive Multifocal Leukoencephalopathy include:
- Progressive weakness of the body with complete paralysis
- Speech defects with eventual aphasia (complete loss of speech)
- Memory-related signs and symptoms
- Balance and coordination difficulties
Diagnosis and Test
The diagnosis of Progressive Multifocal Leukoencephalopathy may include a detailed evaluation of medical history and a thorough physical exam. Other diagnostic tests performed to confirm PML may include:
- MRI scan of the brain, which uses magnetic waves to take pictures of the brain structure and evaluate the extent of damage caused by the JC virus
- Spinal tap: A small amount of cerebrospinal fluid (CSF) is removed and examined for the presence of JC virus in the brain
- Brain biopsy: This procedure is very rarely used
Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.
Treatment and Medications
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 progression 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:
Potent Anti-HIV Therapy
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.
Cytosine Arabinoside (Ara-C)
Cytosine arabinoside (ara-C, cytarabine, Cytosar-Ur) is currently used as chemotherapy for leukemia and cancer. For treating PML it was commonly given through a shunt into the brain and/or directly into a vein (intravenously). Experienced neurologists may dose ara-C through a shunt (called intrathecally) into the brain at doses of 10mg/m2 for three days, followed by 10mg/m2 twice a week for two weeks, then 20-30mg/m2 each week thereafter. The common dose of ara-C when given into a vein is 2mg/kg in 5-day cycles, every 15 or 30 days.
Side effects include nausea, consistent fevers, and bone marrow toxicity. These effects are dependent on its dose and schedule and vary in severity. Ara-C can harm an unborn child in pregnant women
Treatments under research experiments
Cidofovir: Several studies of the anti-CMV drug, cidofovir, first looked encouraging for treating PML. However, over time these studies failed to show any benefit and so it is no longer recommended for treating PML.
Corticosteroids: There is some debate about adding corticosteroids to potent anti-HIV therapy for treating PML. Those opposed to using them say they may further weaken the immune system, which is critical in successfully treating PML. There are also a few cases where the development of PML has been associated with their use. Those in favor of using corticosteroids note that increased inflammation associated with using anti-HIV therapy may be quieted by using these steroids and thus aid PML recovery. Currently, experts are interested in studying corticosteroids as an added therapy to potent anti-HIV therapy for PML.
Interferon Therapy: Researchers have been interested in using both Interferon-alpha and Interferon-beta to treat PML. In test tube studies, both are active against the JC virus. However, studies in people with PML have been terribly underwhelming. Researchers feel that if there were better ways to target the therapy to the brain lesions and the virus, it may be worth revisiting the research on these therapies.
5HT2a Antagonists: This includes drugs like Remeron (mirtazapine) – a drug usually used to treat depression – and other similar drugs. Some speculate that this class of drugs might be useful in treating PML. Experts have gathered anecdotal information as they ponder further research. Their first reaction to the anecdotes is that they are not terribly impressive. Even still, when added to anti-HIV therapy, this class may provide a new therapy.
Other Possible Interventions: for study include interleukin-2 (IL-2), topoisomerase inhibitors (topotecan, camptothecin, etc.), adoptive cell therapy (enhancing JC virus-specific cellular immunity) and RNAs.
Prevention of Progressive Multifocal Leukoencephalopathy
- The JC polyomavirus is latently found in most humans; the virus affects a large percentage of the population
- The viral infection can be prevented by averting immunodeficiency situations, by providing suitable treatment and medical care after major surgeries (organ transplant), or when a body immunity system is weakened by other illnesses
- The key preventive strategy against Progressive Multifocal Leukoencephalopathy is to keep the immune system healthy