Measles encephalitis the unknown known

M

Barts-MS rose-tinted-odometer – zero stars

We ran our third triMS-online this week and apart from a technical problem in the satellite symposium it went reasonably smoothly. The participants were very engaged and asked lots of questions. The topic of vaccination was particularly well received. Which vaccine? Component or live vaccines? When to give the vaccines and whether or not to delay starring a DMT to complete the schedule.? Interestingly and importantly MMR, or mumps, measles and rubella, was not on the radar.

It is my impression that the MS community assume these childhood infections and vaccinations are done and dusted. However, with the rise of the anti-vaccine movement, there is an increasing number of people not being vaccinated in childhood with the MMR. This means that an undefined number of pwMS will be MMR seronegative. Is this a problem? You bet it is! 

To explain the consequences of getting measles infection as an adult on immunosuppression I penned this fictional case scenario. According to the “Donald Rumsfeldometer”, this is an unknown known.

 Rumsfeldometer

  1. Known-knowns – there are things we know that we know
  2. Unknown-knowns – these are the things we know will occur
  3. Known-unknowns – there are things that we now know we don’t know
  4. Unknown-unknowns – there are things we do not know we don’t know

“There are known knowns; there are things we know that we know. There are known unknowns; that is to say, there are things that we now know we don’t know. But there are also unknown unknowns – there are things we do not know we don’t know.” 

Donald Rumsfeld, former United States Secretary of Defense.

Fictional Case

When she finally arrived on the ward she was unable to speak and was clearly confused and disorientated. All four of her limbs were twitching and would jerk when touched; i.e. she had generalised myoclonus. She was drooling from the mouth. Her latest MRI showed hyperintense signal change in the cortical ribbon or the grey matter on the surface of her brain.

Since her last MRI 8 days ago, the involvement of cortex had spread from the left parietal lobe to involve the entire left frontal lobe, the medial surface of the right frontal lobe, the left occipital lobe and the left temporal lobe. There was new signal change in the left thalamus and pulvinar and the white matter of the left hemisphere was diffusely involved. Interestingly, the post-contrast scans showed no obvious gadolinium-enhancement. Her EEG showed diffuse slowing over the left hemisphere with occasional sharp waves. The neurophysiologist did not think the pattern was a burst suppression pattern. 

She was only 24 years of age and had been on natalizumab for 37 months. She was JC virus seronegative and her most recent CSF examination was negative on PCR for JC virus DNA. Apart from a mildly raised protein, the CSF was acellular. Her referring neurologist thought the most likely diagnosis was a secondary CNS lymphoma and had referred to our centre for a brain biopsy. 

What the neurologist had missed was that this patient had recently come into contact with her friend’s 4-year old daughter who had been diagnosed with measles. In fact, there had been a cluster of eight cases of measles in the nursery school her friend’s daughter had attended. The tragedy is that this patient had not received her MMR vaccine as a child because her mother had been concerned about the safety of the MMR vaccine after the now retracted and fraudulent Andrew Wakefield study linking MMR vaccine to autism. 

Once we had this history our working diagnosis was that of a measles inclusion body panencephalitis and our diagnosis was confirmed once we got back the CSF measles PCR result from her repeat lumbar puncture. Sadly the patient passed away 5 days after admission. A post-mortem examination confirmed the diagnosis of measles inclusion-body panencephalitis.

Interestingly, despite being on natalizumab there were was quite a heavy CD8+ T-cell infiltrate, which would indicate that natalizumab does not necessarily block all trafficking of lymphocytes into the brain of someone with viral encephalitis. 

So if you have MS and are about to start an immunosuppressive DMT please review your vaccine history. If you discover you have not had the MMR vaccine or other vaccines you may need, please discuss this with your neurologist or MS nurse. Once you are on specific DMTs live vaccines such as the MMR are contraindicated.

I am sure some of you will be saying that I am scaremongering, but I know that it is only a matter of time before we see MMR-naive patients with MS succumb to wild-type or community-acquired infection with one or more of these viruses (see case study below).

Please note measles and mumps are circulating at present in the community and because of lower rates of MMR vaccine uptake you can’t necessarily rely on herd immunity to shield you from infection. 

Isn’t prevention better than managing the consequences of these infections?

Freeman et al. A new complication of stem cell transplantation: measles inclusion body encephalitis. Pediatrics. 2004 Nov;114(5):e657-60.

Measles inclusion body encephalitis (MIBE) is a disease of the immunocompromised host and typically occurs within 1 year of acute measles infection or vaccination. We report a 13-year-old boy who had chronic granulomatous disease and presented 38 days after stem cell transplantation with afebrile focal seizures that progressed despite multiple anticonvulsants. After an extensive diagnostic evaluation, brain biopsy was performed, revealing numerous intranuclear inclusion bodies consistent with paramyxovirus nucleocapsids. Measles studies including reverse transcriptase-polymerase chain reaction and viral growth confirmed measles virus, genotype D3. Immunohistochemistry was positive for measles nucleoprotein. Despite intravenous ribavirin therapy, the patient died. MIBE has not been described in stem cell recipients but is a disease of immunocompromised hosts and typically occurs within 1 year of measles infection, exposure, or vaccination. Our case is unusual as neither the patient nor the stem cell donor had apparent recent measles exposure or vaccination, and neither had recent travel to measles-endemic regions. The patient had an erythematous rash several weeks before the neurologic symptoms; however, skin biopsy was consistent with graft-versus-host disease, and immunohistochemistry studies for measles nucleoprotein were negative. As measles genotype D3 has not been seen in areas where the child lived since his early childhood, the possibility of an unusually long latency period between initial measles infection and MIBE is raised. In addition, this case demonstrates the utility of brain biopsy in the diagnosis of encephalitis of unknown cause in the immunocompromised host.

CoI: multiple

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.

17 comments

Leave a Reply to Kay Cancel reply

  • Would testing pwMS for antibodies help?
    I didn’t have the MMR vaccination, as it wasn’t available when I was young, but I did have the rubella vaccination.

    • Yes, I testing for antibodies would help. If you are seronegative for mumps and measles it would put you in the at-risk category.

  • I had the MMR vaccine at 11 when it first became available.

    What we didn’t realise until there was a measles outbreak in New Zealand where I grew up, is that I should have had a second vaccination. I was never called for this.

    I didn’t know this until after I started on Tecfidera. My mum called my childhood surgery where she is still a patient. They said not to worry. I had a measles vaccination as a baby and as a child I had mumps (at 3), measles and rubella (at 7/8). They said I should be 99% protected as I should have the antibodies.

    Should I be worried?

    • Sound like you are fine; our advice is that if someone has documented history of being vaccinated we don’t test for immunity. It is only those people who don’t remember or weren’t vaccinated that we test.

  • All patients should have their vaccine history confirmed or I mmunity confirmed before starting any long term immunosuppressive therapies, if at all possible. Especially with the recent global increase in measles. Especially with since most people aged 20-50 likely only had 1 vaccination and it seems that 2 are really needed to ensure immunity (and it seems for mumps as well).

    • If in doubt it is best the be tested for MMR immunity prior to starting longterm immunosuppressive DMTs. The story is different for immune reconstitution therapies or IRTs; once the immune system reconstitutes vaccinations are relatively safe.

  • My only criticism of my MS team is that when offering me a switch from Copaxone to Gilenya I was not made aware that live vaccines would be contra-indicated, with all the implications. Had I known this, I would have had the yellow fever jab at the time, but as it stands I have had my travel plans limited. Not a life-threatening scenario, I know, but annoying – definitely!

    • You can get an exemption from most countries regarding the yellow fever vaccine. If you are exempted then you need to make sure you don’t get bitten by mosquitoes when you travel. The latter is easier said than done.

    • Yes, this applies to fingolimod and the class of S1P modulators (siponimod, ozanimod, ponesimod, etc.). However, the risk is likely to be lower with fingolimod as it does allow immune responses to viruses and does not trap all T-cells within lymph nodes.

    • Yes, immunity to a vaccine strain does not necessarily protect from new wild type strains that have evolved over time. Several of my daughter’s friends at University came down with mumps before the Christmas break despite having had the MMR vaccine. Unfortunately, there is little you can do about this apart from hoping the newer more virulent strain disappears or the vaccine producers upgrade their vaccine to include the new strain. The latter is what happens with the flu vaccine; it needs to be changed on an annual basis to deal with the circulating strains.

  • If you don’t know your childhood vaccination status but a blood test during pregnancy 15 years ago showed immunity to measles does that mean you’re protected?

    • In general showing you have antibodies to the measles virus indicates you have immunological memory and have seen the virus in the past. This means that you should be able to deal with the virus.

    • Yes, Covid-19 is a coronavirus and seems to cause more lower respiratory tract infections or pneumonia that other coronaviruses. People with MS on continuous immunosuppression will almost certainly be at greater risk of this complication that pwMS not on immunosuppressive therapies or the general public.

      • I didn’t let it affect my travel plans. Currently on the last leg of a 30 hour + journey from New Zealand to my home in London, via Singapore (9 hour stop there). I made sure I washed hands well and frequently, and disinfected my tray table!

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