Clinic Speak: Asymptomatic PML

Asymptomatic PML: do you want to learn about it? #ClinicSpeak #MSblog #MSResearch

“Progressive multifocal leukoencephalopathy or PML is an infection of the so called glial cells of the brain due to the JC virus. The glial cells the virus infects are the oligodendrocyte (myelin producing cell) and astrocyte (the cell that supports the neurones). JC doesn’t refer to Jesus Christ but to John Cunningham the first patient that was described with this infection; yes, it is surprising but in the past virologists used to name viruses after the people they isolated them from. Outside of the setting of natalizumab PML is relatively rare and occurs almost exclusively in patients with compromised immune systems or in those with cancers, in particular cancers of the white blood cells. Examples, of people who get PML are those with AIDS and organ transplants. Only rarely do we see PML in people without a risk factor; all the cases I have seen without risk factors have been elderly people and I have assumed their risk factor is immune senescence. The latter is when the immune system becomes less responsive with age.

To get PML you need to be infected with the JC virus. Only about half the population are infected with this virus. When you are infected with the virus you won’t know you have been infected as JCV infection does not cause any known symptoms, i.e. it causes an asymptomatic infection. Once infected the virus continues to live and replicate in the body. We have evidence that this occurs in the kidney as we can intermittently detect the virus in the urine. The virus may also reside in the tonsils in your throat and in your bone marrow. We suspect that the virus is transmitted between people via urine and/or saliva. About 0.5% of JCV negative adults become positive per year. In other words you remain at risk of being infected with this virus as an adult. This is not surprising considering so many people in the herd, or general population, are intermittently shedding the virus.

The so called wildtype JC virus that lives in your body is unable to infect glial cells and cause PML. A strain of the virus has to mutate and develop the ability to infect glial cells. PML strains of the JC virus harbor at least 4 or 5 mutations in the receptor on their surface that allows it change its binding properties and infect glial cells. In addition, the PML strain of the virus has mutations in their gene that controls how they function, this is in the so called regulatory region of its genome. 

You can see that the development of a mutant strain that can cause PML is not a simple process; in fact it is very complex. At present we don’t know where these mutations are occurring in the body and why. We assume there must be some kind of evolutionary selection process that that is selecting these mutant strains; in other words these mutants must have some survival advantage over the wild type JC virus to survive. We think that the immune system must be important in preventing these mutants from developing, which is why being immune compromised is a risk factor for PML.

Natalizumab is not really a immunosuppressant therefore how does it increase your risk of PML? What natalizumab does is that it blocks trafficking of immune cells into the central nervous system (CNS) and gut. Therefore if the JCV mutants are evolving in these sites then the immune cells won’t see the mutants and won’t clear them. This is why I believe that mutant PML strains must be developing within the brain, in the environment with the necessary receptors on glial cells to provide a selective survival advantage. Please note this is a hypothesis and there is no evidence to support it at present.

So once you have the mutant virus in the brain it can start infecting and killing glial cells and spreading. Initially this infection will be asymptomatic. Once the infection spreads to enough cells it will start to cause symptoms. The ability to cause symptoms depends on where the PML lesions are and their size. Lesions in so called eloquent sites are more likely to cause symptoms when they are small. Lesions in ineloquent, or silent sites, will need to get large and spread into eloquent sites of the brain to cause symptoms. The good news is that we can detect PML lesions early using MRI in the so called asymptomatic phase of PML. If we do detect these lesions early we can stop natalizumab, wash it out of your body with plasma exchange, or PLEX, and allow the immune cells of your body to traffic back into the brain to find the mutant virus and destroy it. The latter process is called immune reconstitution inflammatory syndrome or IRIS. IRIS is a form of encephalitis and is in itself damaging to the brain, which is why it often need to be dampened down the immune response with steroids in MSers who develop PML.

Neuroradiologists have noticed that early PML lesions look different to MS lesions. They tend to occur in the white matter beneath the cortex and have a so called ground glass or microcystic (multiple cysts) appearance to them. By doing 3 monthly MRI scans using a very short imaging protocol, that is most sensitive to detecting these lesions, we hope to pick-up PML at a very early stage in MSers on natalizumab with high-risk of getting PML.

MSers on natalizumab detected with asymptomatic PML do better than those with overt or symptomatic PML. In the following tables and graphs from a poster at ECTRIMS last year you can see in the 17 cases of asymptomatic PML their EDSS and Karnofsky Performance Scores (KPS) scores deteriorated a lot less than in the group with symptomatic PML. In addition, only 1 of 30 (3%) cases of asymptomatic PML died, compared to 84 out of 258 (25%) cases of symptomatic PML. This is why we have implemented our 3 monthly MRI scanning protocols. We are not doing this so we can keep people on natalizumab, but to try and give them best chance of doing well if they develop PML. My preference would be for these MSers to switch to another drug. 

I am aware that you are concerned with rebound post-natalizumab, but since we have stopped doing a wash-out and starting fingolimod within weeks of the last natalizumab infusion we have stopped seeing rebound. It is however important to make sure before you switch to fingolimod you don’t have asymptomatic PML; we therefore do a MRI and a lumbar puncture on all our MSers before switching to exclude asymptomatic PML. The lumbar puncture is simply an extra precaution.”

“I hope this post has answered your questions. If not I would gladly respond to questions via comments.”

The following is the December 2013 Biogen-Idec PML risk update. As of the 3rd December 2013 there have been 423 confirmed cases of PML in MSers treated with natalizumab.

CoI: multiple

7 thoughts on “Clinic Speak: Asymptomatic PML”

  1. Sounds similar to MS – viral infection, virus lives in cells, a trigger leads to damage to brain cells (oligos etc), immune system wades in, lesions in the brain, disability for patient… Could charcot project also be used against JC virus? Perhaps using a different combo of antivirals?My main questions – why aren't virologist and immunologists taking the lead on MS? I recognise that the brain is the organ affected, but the disease process would appear to fall under different specialisms.

    1. Re: "Are you saying that everyone on tysabri will henceforth undergo an mri every three months?"No only those MSers at high risk!

  2. I think any immunosuppressive therapy runs the risk of PML. You may not define Tysabri as an immunospressant, but ths is exactly what it does by preventing immunosurveilance in th CNS.Likewise, Gilenia restricts immune cells to the lympnodes. I would also be concerned if I were on this, and it looks like the FDA is as well: there will be more robust monitoring protocols for all of these new immunosuppressive drugs now before deaths start occuring such as what happened with the initial Tsyabri launch.

  3. Thank you Prof G, really interesting post.As a 'high risk' MSer on 24+ Tysabri infusions, I have some questions about the MRI scans please.Outside of Barts and The London (I am based in the north of England), would you expect all radiologists who are examining a Tysabri MSers scans…a) to be looking for PML lesions?b) know how to spot PML lesions?Assuming the answer is no, how would I go about having an MRI scan that is examined by a radiologist who has the necessary experience? Is it important to use the same scanner as used with my previous scans to compare, or can a new scanner (with a very short imaging protocol) be used to assess for PML lesions? I haven't had a scan since June!ThanksGeorge

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