Progressive multifocal leukoencephalopathy (PML) is a rare and usually fatal
viral disease that is characterized by progressive damage or inflammation of the
white matter of the brain at multiple locations. It's an opportunistic viral
infection of the central nervous system (CNS) that typically occurs in people
with an immune deficiency due to immunosuppressive medications. It's normally kept
under control by the immune system, causing no problems. If the immune system is
weakened and the body is less able to fight an infection, the virus can reactivate
and cause serious and potentially fatal inflammation and damage to the brain known
The cause of PML is a type of polyomavirus called the John Cunningham or JC virus, a common
infection completely unrelated to MS. The virus is widespread, with some estimates
showing 86% of the general population presenting antibodies, but it usually remains
latent, causing PML to arise or activate only when the immune system has been severely
weakened. More recent estimates are showing the general population up to 50% having
the JC virus. PML is a demyelinating disease, just as in multiple sclerosis (MS).
It affects the white matter, which is mostly composed of axons from the outermost
parts of the brain or cortex.
The risk of developing the infection has been identified as a potential side effect
of treatment with some of the disease modifying drugs for MS, in particular Tysabri
When you are infected with the JC virus you develop antibodies to the virus. A blood
test can detect the presence and level of these antibodies and help give an estimate
of your risk of developing PML. The test indicates your relative level of risk which
can help you and your doctor make decisions about treatment options.
To understand what PML is, let's break its name up into what it means:
- Progressive because the damage it causes becomes more severe over time.
- Multifocal means multiple locations within the brain.
- Leuko means white.
- Encephalo means brain.
- Pathy means disease.
Typical symptoms associated with PML are diverse, since they are related to the
location and amount of damage in the brain, and evolve over the course of
several days to several weeks. The most prominent symptoms include paralysis,
clumsiness, progressive weakness, vision loss, impaired speech, and cognitive
deterioration including personality changes.
PML destroys oligodendrocytes and produces intranuclear inclusions. Since it
destroys the cells that produce myelin (unlike MS, in which myelin itself is
attacked but can be replaced), it progresses much more quickly.
The JC Virus
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The JC Virus was first discovered in 1971. It's a common virus that is unrelated to
MS that many people have been exposed to, typically in childhood.
The virus is dormant in most people who are exposed don't know it or have any symptoms.
But for people with weakened immune systems, such as people taking Tysabri, the virus
is able to mutate, spread to the brain, and multiply. This infection causes damage
that can lead to symptoms that may be similar to MS symptoms, so it's important to
recognize the common signs and symptoms of PML.
The JC Virus more specifically is a polyomavirus and is the sole genus of viruses
within the family polyomaviridae. Polyomaviruses are DNA-based (double-stranded
DNA,~5000 base pairs, circular genome), small (40 to 50 nanometers in diameter), and
icosahedral in shape, and don't have a lipoprotein envelope. They are potentially
oncogenic (tumor-causing); they often persist as latent infections in a host without
causing disease, but may produce tumors in a host of a different species, or a
host with an ineffective immune system.
Five polyomaviruses have been found in humans:
||JC virus can infect the
respiratory system, kidneys, or brain (sometimes causing PML in
the latter case).
||BK virus produces a mild
respiratory infection and can affect the kidneys of immunosuppressed
transplant patients. Both of these viruses are very widespread:
Approximately 80% of the adult population in the United States have
antibodies to BK and JC.
||Two recently discovered polyomaviruses,
KI virus (Karolinska Institute) and
WU virus (Washington University), both
viruses are closely related to each other and have been isolated
from respiratory secretions.
||In January 2008, a new species,
Merkel cell polyomavirus, was described as the likely causative
agent of Merkel skin cancer.
JC Virus and PML
Having the JC Virus doesn't necessarily mean you'll get PML, but it does put you at a
higher risk. To determine if you have been exposed to the JC Virus, your doctor may recommend
taking the JC Virus Test. Remember, this test does not diagnose PML, but it is an important
step in assessing your level of risk for PML. An MRI is one of the tools that can be helpful
in the early identification of PML.
JC Virus Antibodies & Testing
Recent studies have looked into JC virus antibodies and assay testing for
patients. Those patients were either positive or negative for the antibody. It's
felt that those who test negative for the JC virus antibody are not at risk of
PML at the time of the test or in the immediate future. Those who test positive
will need to be monitored more closely for signs of PML.
Those studies found that the number of patients tested for the antibody, there
were 50% that tested positive and 50% that tested negative. These figures,
at this early stage, are showing that if a patient tested positive, then their
risk of PML increased to 1 in 500. For those that tested negative, their
risk of PML is close to zero. Put together, this matches the current figures of
a 1 in 1000 chance of developing PML for all patients together.
As of mid-2013, the figures are showing that those using Tysabri and having a
negative JC virus result will have about a 1 in 2000 chance of contracting PML.
For those with the JC virus, their chance of contracting PML increases with the
number of antibodies does. A titer test can determine where each person stands
and their associated risk.
The titer test looks for the number of antibodies. When a result is under 1,
there has been the feeling that it is safe. A result that is above 1 has those
more concerned and a change of treatment may be suggested.
Many of those who have tested positive for the antivirus have chosen to
remain on Tysabri even knowing the additional risk involved. Again the benefits
seems to outweigh the risk since the alternatives are few. With more
alternatives arriving, this will probably change.
JC Virus in Natalizumab Users: Test for
Virus Exposure Approved
Commercial availability of a JC virus antibody assay will change practice in caring
for patients with MS.
Patients with MS or Crohn disease who are taking natalizumab
face an increased risk for PML if they
have been exposed to JC virus, the FDA warned in January. The agency also announced
approval of a new blood test to detect JC virus antibodies.
JC virus is common and usually harmless, the agency said, but its presence can be
dangerous in patients taking immunomodulating drugs like natalizumab. Other risk
factors associated with developing PML while on natalizumab are treatment with
natalizumab for longer than 2 years and previous treatment with immunosuppressant
drugs such as methotrexate or cyclophosphamide (but not prior use of first-line
injectable immunomodulatory agents, interferon-beta, or glatiramer acetate).
The FDA estimates that patients with all three risk factors face about a 1% risk
for PML with natalizumab therapy (11 cases per 1000 patients treated).
Natalizumab's label will be changed to reflect the new information.
Commercial availability of a JC virus antibody assay will change practice
in caring for patients with MS. The risk for PML with natalizumab was previously
said to be about 1 in 1000, but recent safety data provided by the manufacturer
indicate that the overall incidence of PML is more than double that (2.11 per
1000 as of February 2012). The major advance for patient safety is recognition
that the PML risk can be stratified by three risk factors (treatment duration >2
years, prior immunosuppressant use, and JC virus antibody seropositivity). As
highlighted by the FDA, in patients with all three risk factors, the risk for PML
is very high (>1 in 100). On the other end of the spectrum, the PML risk with
natalizumab appears to be quite low in patients who are JC virus–seronegative.
For these patients, the manufacturer estimates the PML risk to be about 1 in 10,000,
with a 95% confidence interval potentially as high as 1 in 2000 and as low as zero,
based on the lack of observed PML cases in JC virus–seronegative patients to date
and the false-negative rate of the assay (3%). The seroconversion rate for JC virus
in MS patients is about 2% per year; the optimal frequency of testing for the virus
in patients taking natalizumab remains to be defined. This is a fast-moving field,
so further refinement of these numbers is likely as more safety data become available.
This report published in
Journal Watch Neurology
by Jeffrey M. Gelfand, MD on February 28, 2012
Signs of PML
Typical symptoms associated with PML progress quickly over days to weeks, and
||personality or behavioral changes
||disturbances of vision
||change in thinking, memory, & orientation leading to
||onset of seizures, clumsiness
or progressive weakness on one side of the body, or
clumsiness of limbs
The progression of deficits can lead to death or severe disability over weeks
or months. If individuals experience new, unusual symptoms, they should contact
their physician immediately.
The PML Consortium is a joint effort between several companies to identify more
effective methods of predicting and preventing, and potentially, in the future,
treating, PML. The mission of the Consortium is to perform research to reduce
occurrence, morbidity and mortality of PML through a multi-company, not-for-profit,
collaborative approach with shared strategy, investment, data acquisition and
analysis and communication.
The PML Consortium website pmlconsortium.org
provides an accessible, centralized source of information about PML for patients,
caregivers and health care professionals.