JCV granule cell neuronopathy

Question:
My daughter has had MS for 20 years. She has been on Tysabri for almost 5 years. She was diagnosed with JVC granular cell neuropathy of the cerebellum in September 2014. Her spinal copies were 267. As of feb 2015 they were at 58. Could someone please explain to us in plain English how do we know when this infection is gone? My daughter is tired all the time. How hard should she push herself to do everyday things? Her symptoms are numerous and she doesn't seem to be improving. Does the cerebellum once compromised repair itself? Are their symptoms that indicate we need to be even more worried that something is really wrong or that we could be facing death if not treated? Right now my daughter is on no maintance drugs for her MS. I am really concerned about this but should I be? Lastly is there any layman phamplets or literature you could direct me to. We do have an excellent MS doctor but he is not an expert on this mutant gene of JVC and therefore consults with other doctors. My daughter is on her 7th month of this virus and we are all concerned. Thank you.

Answer:
We are very sorry to hear about your daughter's diagnosis. You seem very knowledgeable about her particular condition but let us provide some general information that may benefit other readers and answer your specific question.

The John Cunningham Virus (JCV) is ubiquitous (meaning it exists everywhere in the world), only infects humans and does not appear to cause any primary illness when a person gets infected. The number of people infected with this virus varies from study to study, but most studies suggest that more than 80 % of all people are infected with this virus. Following infection the JCV remains asymptomatic in the bone marrow and kidneys (whether or not you have MS).  Some people produce detectable antibodies after infection with the JC virus infection, whereas others do not. The present or absence of antibodies to the JC virus using the current assay available for MS patients, does not indicate whether you have a latent or prior infection with the JC virus, but it does indicate your risk of developing a productive JCV infection of the nervous system, if you are receiving treatment with Tysabri.

Due to reasons that are not entirely clear, people who are immunosuppressed and people who are receiving certain treatments, particularly natalizumab, may experience a productive infection of the central nervous system by the JC virus. For this to occur, one or more genes expressed by the virus must become mutated to cause the infection in the brain. What causes the mutations, allows the virus to be transported to the nervous system so that an infection may develop, and allows the virus to enter brain cells not normally infected by the original virus (called the archetypal strain) and reproduce remains unclear at this time.

The most common central nervous system infection by a mutated JC Virus is called Progressive Multifocal Leukoencephalopathy (PML). This is an infection of the oligodendrocytes that make myelin in the brain. It is this same myelin that is the target of inflammation in MS. Therefore, the initial symptoms of PML can be confused with worsening of MS and the diagnosis of PML requires a high degree of vigilance. Less commonly, the mutated virus can infect the granule cell neurons in the cerebellum and cause a condition called JCV granule cell neuronopathy. This condition does not directly affect oligodendrocytes or myelin and  can be very difficult to detect since patients experience a progressive shrinkage of the cerebellar cortex without the white matter changes typically associated with PML on MRI scans. MRI is very good at detecting changes in the white matter of the brain (such as MS and PML) but not as good at detecting changes in the cortex or gray matter (such JCV granule cell neuronopathy). In some cases people present with both typical PML and Granule cell neuropathy of the cerebellum making it easier to establish a diagnosis. The symptoms of JCV granule cell neuronopathy usually include progressive unsteadiness walking (called ataxia or walking like a drunk), slurred slow speech with loss of normal rhythm (called dysarthria) and incoordination of movements. While these same symptoms can be caused by MS, their development or worsening in an otherwise stable MS patient on long term Tysabri therapy is reason to suspect JCV granule cell neuronopathy.

To date, there have been over 130,000 individuals throughout the world that have been exposed to Tysabri. The overwhelming majority of patients with JCV related nervous system infections are reported as PML although it is likely that other JCV related conditions like JCV granule cell neuronopathy may go undetected or misdiagnosed. 

Once a Tysabri treated patient develops PML, there is a 23% mortality rate, and the other 77% of patients survive the infection but are left with varying levels of disability.  In some cases the virus is eliminated and no longer detected after the immune response is restored (read below). In other cases like your daughter, the virus remains detectable in low amounts for variable periods of time because of partial viral clearance by the immune system response.  In this case the condition becomes chronic much like the underlying multiple sclerosis. Physical/Occupational therapy may be indicated to help facilitate some functional recovery.  Your doctors can help direct this when it is most appropriate. We know far less about the outcomes of people with MS who develop JCV granule cell neuritis as there are very few reported cases.

When PML occurs on Tysabri treatment, the generally accepted strategy to manage this situation is to remove the Tysabri from the patient by using plasma exchange (this is a procedure that filters the blood, removing the Tysabri).  This is done in a hospital setting.  The rationale for this is to remove the blockade of white blood cells from the nervous system (so they can get into this space and fight off the infection).  Following plasma exchange the patient often develops a strong inflammatory response against the infected brain that worsens their condition and is usually controlled with steroid treatment. This is call an Immune Response Inflammatory Syndrome or IRIS. Unfortunately, there is no proven additional therapy that can eradicate the virus.  Therefore, we rely on the strength of the immune system to clear the virus.  Periodic testing of the spinal fluid is important to prove that the immune system has successfully cleared the virus. 

To answer your question about a disease modifying therapy to treat your daughter's MS:  we would agree with your daughter's treating physician not to treat at this point in time as she still has copies of the virus in her spinal fluid. From your message, we suspect that the MS doctor appropriately has an infectious disease specialist helping in the medical care of your daughter and her PML. The world’s expert on your daughter’s condition (JCV granule cell neuronopathy) is a former colleague at Beth Israel Deaconess Medical Center in Boston, Dr Igor Koralnik. I would suggest that your daughter's doctor contact Igor for advice on management, if they have not already done so.

Revere Kinkel MD and A. Scott Nielsen MD MMSc