As neurologists, we are well familiar with the term “PML”. In fact, I almost have to be grateful that a patient recently asked me quite sincerely what it actually is. Risking to bore experienced MS sufferers who read my blog, I thought I should write a few lines about it. Because this side effect/disease seems to be not as well understood by MS patients as one/neurologist might think.
PML stands for “progressive multifocal leukoencephalopathy” – translated, this means it is a progressive degeneration of the myelin sheaths in the brain, which can be traced back to a viral infection of the oligodendrocytes (these are the cells that form myelin in the brain) with the JC virus. JC stands for John Cunningham – that was the name of the patient in whom this pathogen was first isolated (in 1971).
The rate of infection with the JC virus is relatively high in the German population. It averages between 40 – 60% and correlates with age (the older you get, the more likely you are to have been infected with the virus at some point in your life). However, the virus is a rather quiet fellow – after infection it remains in our body but is effectively kept in check by the immune system for life.
If the immune system breaks down for whatever reason, then the virus can cause PML in the brain. In the past, this was almost exclusively observed in end-stage AIDS patients and severe blood cancer diseases. PML was an extremely rare disease that only interested a few AIDS researchers and was only marginally interesting to neurologists.
This changed abruptly when it became clear that patients treated with the MS drug natalizumab (Tysabri) were often observed to develop PML. Even though the probability of PML with natalizumab therapy was estimated on average at 1:1,000 – which is still very rare – it was quite alarming compared to the previously reported probability of 1:1,000,000.
To this day, we do not know exactly why natalizumab causes the JC virus to escape the immune system in a few patients and who is particularly at risk for such side effects (apart from the very rough division of patients who carry the virus or do not yet have it – also referred to as antibody-positive and negative). Finding this out is currently the subject of intensive research efforts – and would also be a rather important insight.
But we have learned from the experience with natalizumab that every drug with which we influence the immune system carries a potential risk that, for example, PML is triggered. This is extremely rare, but there are case reports of PML cases associated with almost all effective immune drugs including cortisone. Therefore, for none of the currently available MS drugs, perhaps apart from the interferons and Copaxone, can it be ruled out that PML occurs as a rare side effect. Therefore, vigilance is the highest priority with all immunotherapies. However, it should also be emphasized again that this is a rare and sporadic possibility. Except for natalizumab, there is no MS drug for which a regular occurrence of PML cases is described.
Therefore, PML is a very rare, but certainly existing companion when we therapeutically approach the immune system. On the other hand, we cannot achieve our therapeutic goals in many autoimmune diseases including MS without influencing the immune system. As long as the benefit-risk balance is right, we and especially patients will have to accept this side effect – and hope that we will eventually have a reliable risk assessment available.
