​Here is My Question:
Should I start Tysabri with JCV index of 2.21?

I am 30 yr old caucasian male, I was diagnosed sept 2016 with MS. I had JC index of 1.82 and declined to start Tysabri or any meds. Jan 2017 2 new T2 lesions on brain, 4 total T2, now a JC index of 2.21.

I am willing to start meds now, Tysabri for 12 months is what's being recommended by my nuero. Her argument against other meds are that they are not as effective and we need to stop new lesions.

Are there any other meds you could recommend that are effective but not as risky for PML??

Thank you!!

Answer:
I agree with the decision to treat your MS (there are multiple blog posts on this site that detail the benefits of treating and treating early for MS).

The choice of disease modifying therapy (DMT) can be a little complicated and comes down to how aggressive your MS really is (which you allude to in your question).  Other considerations depend on certain prognostic factors of your MS.  Male gender tends to have a more difficult disease course than women (on average).  Other considerations include a history of motor attacks (ie, weakness or clumsiness), frequent and recurrent attacks early on, presence of spinal cord or brainstem lesions, etc.  These are poorer prognostic factors which can argue for use of a highly effective therapy such as tysabri.  However, your risk for PML is higher than an individual with negative JC virus antibody titers.

Because I do not know you and haven't had the opportunity to examine your or review your imaging, I cannot realistically suggest a different course for your MS than what has been suggested by your neurologist.  If you are a candidate for a highly effective therapy, the off label use of rituximab 500mg would be an option for you.  This is very similar to the soon to be approved medication called ocrelizumab.  The estimated risk of PML is ~1:25,000 (based on treatment of rheumatoid arthritis patients on rituximab).  Your risk with Tysabri for PML is much higher than this.  I'd suggest reviewing options with your neurologist as there are 15+ FDA approved therapies now.

A. Scott Nielsen MD MMSc
Neurologist and MS Specialist at Kaiser Permanente
KP Fontana and Riverside Medical Centers

Here is My Question:
Is it dangerous to drink alcohol when an MS patient has the JC virus?

Answer:
This wins the funniest question of the year. Drink away and enjoy :)

Revere (Rip) Kinkel MD
Director of the Multiple Sclerosis Program
Professor of Clinical Neurosciences
University of California San Diego

Here is My Question:
I have 3 lesions on my spinal cord. What could cause this? Does this mean I have JC virus or PML?

Answer:
I have always hated the term, “lesions”, because it so non-specific. The literal translation is something structurally abnormal. In the context of Multiple sclerosis, a lesion usually refers to a white spot (T2 hyper intense) on MRI. These T2 hyper intensities or white spots are common in both the spinal cord and brain. In fact it is extremely rare for a person to have MS without these white spots on MRI. The good news is that PML does not typically involve the spinal cord so you do not have to be concerned about that diagnosis. If you have MS, then that is the most likely cause of the white spots on your MRI can.

Revere (Rip) Kinkel MD
Director of the Multiple Sclerosis Program
Professor of Clinical Neurosciences
University of California San Diego

Here is My Question:
I was on Tysabri for two years and then switched to Tecfidera. After 7 months on Tecfidera my WBC count dropped to lymphocyte 3500; absolute 795; cd3 562; cd4 508; cd8 55. All LOW as in half of the lowest number on the scale. My doctor said to stop Tecfidera and that I NEED to be back on Tysabri. If the cd8 number is the wbc that holds off the JC virus, then wouldn't it mean that the barn door is now wide open? Why would he put me back on a drug know to have a greater risk of PML with prior immunosuppressant especially when my blood test reflect a major suppression? Plus being on Tysabri for 2 years and feeling like I dodged the PML and rebound by exiting the drug at the appropriate time. He retested my JC virus. Waiting for results. He feels that being off Tecfidera for 30 days will give my immune system time to get normal and I can restart Tysabri with no risk of PML pending a negative or low number on JC virus test. I don't want to start Tysabri again, but I'm not seeing any other options?? Forget CRABS. Made me very ill. Hoping for a long term solution without PML risk. 

Answer:
This is a common concern facing patients and physicians, so let me take some time to address it today. As I have stated in previous responses, there is really no way to totally eliminate the risk of PML. 

There are or I suspect there will be reports of PML with all highly active therapies for MS, although the risk varies dramatically between different treatments. The highest risk occurs in JC virus antibody positive people with MS receiving Tysabri for over 2 years. Within this group, the risk appears to be higher in those with JCV antibody index values greater than 1.5. 

Unfortunately, the risk factors for the development of PML in patients on therapies other than Tysabri remain unclear. For instance, we do not yet know if JCV antibody results are a risk factor for PML in patients on therapies other than Tysabri. It is clear that prolonged lymphocyte depletion is a risk factor for PML in multiple clinical situations, but guidelines for the use of this information to monitor different treatments is not available, and will likely differ between treatments depending on their mechanism of action. 

For instance, Tecfidera actually depletes lymphocytes, particularly CD8 positive lymphocytes, and there is a general recommendation to stop treatment in individuals with prolonged depletion of absolute lymphocytes counts below 500 to 600. Yet, there is already a report of a patient on Tecfidera developing PML with a less severe reduction in lymphocyte count, prompting concerns related to the degree of lymphocyte reduction that should prompt patients to discontinue therapy. 

Lastly, lymphocyte depletion tends to persist for longer periods after discontinuation of Tecfidera compared to other agents. 

So how can you use this information to make your treatment decision?

1. Given your reduction in absolute lymphocyte count (795) and CD8 count (55) and your elevation in CD4/CD8 ratio (> 5.0) you should consider stopping Tecfidera if the reductions worsen over the next few months. It is probably too early to determine if it is necessary to stop Tecfidera now. It is the persistence of lymphocyte reduction over time that should be a concern.

2. Restarting Tysabri treatment depends on a number of factors but should probably be avoided if you are JCV antibody positive (esp with an index > 1.5) and if your absolute lymphocyte count and subsets have not returned to normal after stopping Tecfidera.

3. Gilenya may be a reasonable treatment option for you. The risk of PML is exceedingly low and the drug itself only sequesters lymphocytes without actually depleting them. For instance, it is very common for the measured lymphocyte count to drop below 500 in patients on Gilenya, but this drop is not associated with a significant increase in the risk of any infection. I would certainly consider a trial of Gilenya before returning to Tysabri, if you are JCV antibody positive. Again, I would not start Gilenya until your absolute lymphocyte count returns towards normal (over 1000).

4. Depending on your prognostic features, Aubagio may be an alternative.  This is generally well tolerated and to my knowledge there has not been a report of PML developing in a patient on this treatment.

I am not recommending any particular treatment, but aim to inform you of your options so that you can discuss what is best for you with your physician.

Revere (Rip) Kinkel MD
Director of the Multiple Sclerosis Program
Professor of Clinical Neurosciences
University of California San Diego


PLEASE NOTE:  The information/opinions on this site should be used as an information resource only.  This information does not create any patient-HCP relationship, and should not be used as a substitute for professional diagnosis and treatment.  Please consult your health care provider before making any healthcare decisions or for guidance about a specific medical condition.

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

Here is My Question:
This September will be my 46th infusion of Tysabri. In October 2013 I continued to test negative for JCV. In March 2014 I tested positive, with a titer of .33. With every subsequent infusion we have tested for JCV. The titers have ranged from .27 to .43.

Now for my question...for my latest infusion (August 20th) my test came back negative. How can that be? Lab error? All tests have been done through Quest with a 92675 code.

I am seriously considering coming off Tysabri and starting Rituxan in October. I have done incredibly well on Tysabri and really hate to come off it, though I do have concerns. What are your thoughts? Can you offer an explanation? Thank you so much for your time. This is a wonderful service you provide.

Answer:
Your experience is very common and illustrates some important points. The bottom line is that I see little reason to stop Tysabri if you have done well. Here is why I say this:

1. The JC virus antibody index does not tell us if you’ve been exposed to the JC virus, nor does it tell us if the virus exists in a latent form in your body. In fact we and other groups have shown that the JC virus (in it’s harmless form, not the form that causes PML) can be found in people who are JC virus antibody negative.
2. The JC virus antibody index is, at present, only useful as a risk factor for the development of PML while taking Tysabri.  Why this test result is associated with the risk of PML is still a matter of speculation.
3. The JC virus antibody index results often fluctuate but tend to stay in either the negative/low, intermediate or high range. Generally those patients with index values less than 0.9 have a relative low long term risk of PML (less than 1 in 2500 treated patients)
4. To my knowledge no one with an antibody index less than 0.4 has developed PML and your highest test result has only been 0.43; This information could change with more testing and follow-up of Tysabri treated patients but is reassuring in your case. The fact that your most recent result is negative is even more reassuring.
   

Remember, all test results exhibit normal biologic variation (that due to natural changes in your body of no significance) and normal testing variation (that due to the normal variability of the actual test even if run on the same blood sample). You need to keep this in mind when interpreting results.

Rip Kinkel, MD

PLEASE NOTE:  The information/opinions on this site should be used as an information resource only.  This information does not create any patient-HCP relationship, and should not be used as a substitute for professional diagnosis and treatment.  Please consult your health care provider before making any healthcare decisions or for guidance about a specific medical condition.