Partial recovery after PML

Staying alive: surviving PML IRIS or not? #MSBlog #MSResearch

“In keeping with the theme of natalizumab-associated PML this case study demonstrates a complication of washing-out natalizumab and letting a competent immune system access to the brain in someone with PML. The anti-viral lymphocytes that were being kept out of the brain by natalizumab flood back in and set-up a severe viral encephalitis. The resulting inflammation and swelling can be fatal, particularly if the PML load is large or is an area that can compromise vital brain functions, i.e. the brain stem. This is why this case needed to be treated with steroids. A confounding factor in PML IRIS could be MS rebound. The latter is the recurrence of MS disease activity that occurs 3-4 months after stopping natalizumab. In someone with PML we assume all the inflammation is due to PML-IRIS, but a substantial amount of it could be MS-related.”

“I have been promoting MS-rebound post-natalizumab as the best model to study MS relapses. Understanding, why it occurs and in response to what may help us pin down the cause of MS. I think the rebound is in response to the virus that is causing MS; in other words MS-rebound is IRIS to another virus.”

“IRIS TO ANOTHER VIRUS; rolls off the tongue like a line in a limerick.”

“I proposed at meeting 18 months ago that we take volunteer MSers on natalizumab and  treat them with different lymphocyte depleting antibodies to see which cell is important in the evolution of relapses; i.e. anti-CD4, anti-CD8 and anti-CD20. I suspect the anti-CD8 and the anti-CD20 will prevent the rebound, but not the anti-CD4 therapy. If this was the case it would be a strong argument against MS being a CD4 T cell mediated autoimmune disease. Unfortunately, I would be surprised any ethics committee would allow you to perform this experiment.”


Calvi et al. Partial recovery after severe immune reconstitution inflammatory syndrome in a multiple sclerosispatient with progressive multifocal leukoencephalopathy. Immunotherapy. 20146(1):23-8. doi: 10.2217/imt.13.155.

Progressive multifocal leukoencephalopathy (PML) is a rare and severe complication of natalizumab therapy in MSers and it may be accompanied by immune reconstitution inflammatory syndrome (IRIS). Here, we describe a case of abnormally severe IRIS, which occurred 2 months after natalizumab-associated PML in a 38-year-old woman affected by multiple sclerosis. The patient was John Cunningham virus-positive and was treated for 21 months when she developed PML. The subsequent IRIS diffusely afflicted the brain, producing edema and signs of intracranial hypertension (increased pressure within the skull), with a clinically severe form compromising the state of consciousness, requiring intensive care and high-dosage steroid treatment. Nevertheless, she survived and partially recovered. There is still difficulty in differentiating PML progression from IRIS onset and there is not a clear description in the literature about different clinical forms of IRIS, prognostic factors and guidelines to properly treat this complication in order to reduce the residual disability of the patient surviving this treatment complication.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • Prof G,

    I know you are testing the viral theory through the Charcot Project. I thank you for putting your head above the parapet. However, I would be rather naffed off with the wider MS research world if MS does turn out to be EBV infected cells in the CNS which the immune seeks to destroy with consequent collateral damage. After 50 years experimenting on mice and coming up with more theories than I've had hot dinners, who will be accountable? MS research has been a gravy train for thousands of researchers – I think you can count the number of EAE research papers in the tens of thousands. To think that a common viral infection is the cause (EBV was suggested as a possible cause over 30 years ago). I think PML can teach us a lot about MS. Your observation about the rebound effect are very telling i.e. once the immune system is let free again it does what was designed to do – irradicate viruses. Pity your work didn't start 50 years ago – we would have buried MS in the 1980s. Best of luck your work. I admire your tenacity.

    • EAE about 10,000 papers, MS about 60,000…so not exactly 10s of thousands.

      So who will be accountable for theories …..surely not the EAEologists, who if not clinically qualified have little power to do anything in MS, Maybe the MSologists who do the studies in MS :-).

  • "In someone with PML we assume all the inflammation is due to PML-IRIS, but a substantial amount of it could be MS-related." Substitute HIV for MS. Recently in the HIV realm there was an interesting study that showed a majority of CD4 cells were dying from pyroptosis even when uninfected with HIV causing immune suppression. All the more reason to control inflammation to prevent collateral damage.

  • So, you are gradually adopting the idea that the immune response in MS may be nothing but a biologically sound reaction to "something" happening in the CNS.

    Of course you rush to dress that "something" in a viral costume to keep your research agenda occupied for the next 20 years.

    But who knows, maybe in 20 years you may see that the ever delicate CNS might get damaged by forces that seem negligible today. This future understanding would hardly change your life then, but could mean the end of torture for many MSers now.

  • "I think the rebound is in response to the virus that is causing MS; in other words MS-rebound is IRIS to another virus."

    If MS is caused by a virus such as EBV, I take this as meaning the virus is directly responsible for causing damage, rather than a defect in the immune system that mistakes parts of the CNS as a virus.

    The later explanation I very much believe in, but the former is hard to swallow. First off if EBV was the primary cause of MS, then Tysabri should have no effect because the virus would be able to do its worst in the CNS without the immune system trying to fight it.

    As we know, Tysabri is very effective in halting disease activity.

    Secondly, almost all humans have the EBV, so why don't almost all humans have MS? Clearly there are some basic issues with logic in the notion that MS is caused by a viral infection (as you have proclaimed EBV).

    How do you rectify this?

    • It is not the virus doing the damage but the immune response to the virus doing the damage (IRIS). However it can be immune response to something made in response to a virus, e.g. Alpha B crystallin tht is the problem. The the virus has evolved mechanisms to not have itself destroyed so why don't we all have MS, some will argue Treg function and viral defense mechanisms.

      We all have cells capable of recognising MBP and yet we do not all get encephalititis. This is because the immune response is held in check. If it is a virus that is the target then it should be found in all of the lesions and if the virus is not seeming present then lesions would not form.Remember some viruses like EBV and the virus causing cold sores can become dormant

  • Ultamately, EBV virus is not causing direct damage in the CNS (unlike what can happen with the JC virus and PML). So EBV is not the cause of MS. A better explanation is that it is an antagonist in suseptible people. But I do agree that if EBV could be eliminated, it might prevent MS from occuring.

By Prof G



Recent Posts

Recent Comments