#COVIDMS COVID-19 and Ondine’s curse

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As a non-virologist, I have been relying on basic principles to make recommendations, and predictions, about what may happen to someone with MS who is infected with COVID-19. However, over time an observational evidence-base will emerge that will either confirm or refute some of these predictions. 

One thing I would not have predicted is Twitter being the platform for some of the early reports. Four patients with MS two on ocrelizumab, one on oral cladribine and other post alemtuzumab have acquired the infection and are apparently doing well. This is good news and congruent with expectations based on the mode of action of these DMTs. Both ocrelizumab and oral cladribine are predominantly anti-B cell therapies and only have a small impact on the T-cell compartment, which is the immunological compartment that is critical for fighting viruses. Anti-viral immunity post-alemtuzumab appears to be normal post immune reconstitution.

It will be interesting to know what the antibody responses to COVID-19 will be in these patients. A serological or antibody test is urgently needed; this will allow us to test whether or not people have been exposed to the virus. I predict that despite these patients being in anti-B cell therapies they will have detectable anti-COVID-19 antibodies. The reason I say this is that both these agents are unlikely to block antibody responses completely; we already know this for ocrelizumab and as cladribine only depletes B-cells by about 90% it is likely to be similar. The immune system is remarkably resilient and there are deep tissue compartments that are relatively protected from ocrelizumab and cladribine. The latter is supported by data from phase 3 and extension trials and now real-life data, which show that severe viral infections are not a major problem in patients ocrelizumab or cladribine.  

An anti-COVID-19 serology test will allow seroepidemiology studies to be performed, which will allow us to determine how many people have had asymptomatic or undiagnosed mild COVID-19 disease. Variants of this assay will also be fundamental to testing a vaccine.  We will need to know which anti-COVID-19 antibodies are neutralizing, i.e. capable of preventing infection, and which are not. The effective vaccine will probably only have two or three COVID-19 components (antigens or antigen-epitopes) and hence the presence of these epitope-specific antibodies and the absence of antibodies against other COVID-19 antigens will be able to differentiate between vaccine immunity and wild-type infection. 

The following is a list of hypotheses or questions that will need to be answered once we have the tools at hand. 

  1. What is the asymptomatic infection rate in people with multiple sclerosis?
  2. Which DMTs prevent COVID-19 seroconversion after vaccination? I suspect none of the DMTs will suppress seroconversion completely, but based on other vaccine studies ocrelizumab and fingolimod and other S1P modulators will blunt the response. 
  3. Do people with MS on DMTs who are infected become superspreaders, i.e. continue to shed the virus in large amounts for longer periods of time? I predict that natalizumab will be the most likely DMT to do this. This is because it reduces lymphocyte trafficking into mucosal sites that may blunt antiviral responses, which will allow the virus to continue reproducing and being shed in oral and respiratory tract secretions and faeces. 
  4. When an effective antiviral emerges will it reduce or prevent prolonged viral shedding? The corollary to this is the question of whether pwMS on interferon-beta or teriflunomide shed less virus because these classes of DMT are antiviral?  
  5. Are people with MS on DMTs more likely to get severe COVID-19 infection? At the moment we are assuming that immunosuppressed patients will do worse. But this assumption may not necessarily be correct. It appears that severe infection may in fact be due to the immunological response to the virus and that by suppressing the immune response you dampen-down the damage in the lungs. This is why several anti-inflammatory therapies, for example, anti-IL6 and fingolimod, are currently being tested in acute COVID-19 infection. 
  6. How neurotropic is COVID-19 and will MS DMTs, in particular natalizumab, increase the neurotropism of the virus (ability to infect the CNS)? Natalizumab, by partially blocking immune surveillance of the CNS, may create a viral niche that will allow the virus to escape immune detection and cause encephalitis. This is analogous to what happens with PML. This remains my major concern for pwMS on natalizumab. 

In relation to neurotropism, the review paper below is quite sobering; it is extrapolating data on the SARS coronavirus epidemic to COVID-19 and suggests that a lot of the respiratory distress we see from COVID-19 is due to brainstem encephalitis. The hypothesis is that COVID-19 infects small nerves in the lung and other mucosal surfaces. The nerves then transport the virus up their fibres and across synapses into the neurons within the brains of people infected with COVID-19. This so-called retrograde and trans-synaptic transmission of viruses is well described, for example with rabies and other coronaviruses. Once the COVID-19 gets to the brain it destroys nerves cells. In relation to their hypothesis, they suggest the virus damages the respiratory centre in the brainstem that is responsible for the automatic reflex that drives involuntary breathing. If the respiratory centre is damaged you then develop central sleep apnoea; in other words, if you go to sleep you stop breathing and die. This is also referred to as Ondine’s curse or central hypoventilation syndrome

In their paper, Li and colleagues describe a survivor: “According to the complaints of a survivor, the medical graduate student (24 years old) from Wuhan University, she must stay awake and breathe consciously and actively during the intensive care. She said that if she fell asleep, she might die because she had lost her natural breath. This description is typical of central sleep apnoea or Ondine’s curse. 

I think it is too early to accept the central apnoea hypothesis to explain at least part of the COVID-19 respiratory distress syndrome. This will require specific clinical studies on patients in intensive care units to see if they have central sleep apnoea and imaging and post-mortem studies to see if COVID-19 causes brainstem encephalitis. Based on the importance of this hypothesis I suspect intensive care clinicians, neurologists, neuroradiologists, virologists and pathologists are on the case and testing the hypothesis below using several different paradigms. 

If any pwMS have read this paper and are alarmed please don’t be. Like everything in medicine and science, their observations have to be confirmed. At the moment it doesn’t change much except the urgency of the need for an effective anti-COVID-19 antiviral. Ideally, any antiviral will also need to penetrate the CNS, in the event that COVID-19 causes encephalitis. I am also reassured that the one case report of COVID-19 encephalitis reported from China appears to have done well and recovered spontaneously. 

Importantly, this article does not change any of the general advice we are giving to pwMS. Please be vigilant about hand hygiene and avoid high-risk travel and contacts. This epidemic will eventually pass. It is important that we learn as much as possible from the pandemic for the future. 

Li et al. The neuroinvasive potential of SARS‐CoV2 may be at least partially responsible for the respiratory failure of COVID‐19 patients. Journal of Medical Virology Received: 14 February 2020, accepted: 24 February 2020 DOI: 10.1002/jmv.25728 

Following the severe acute respiratory syndrome coronavirus (SARS‐CoV) and Middle East respiratory syndrome coronavirus (MERS‐CoV), another highly pathogenic coronavirus named SARS‐CoV‐2 (previously known as 2019‐nCoV) emerged in December 2019 in Wuhan, China, and rapidly spreads around the world. This virus shares highly homological sequence with SARS‐CoV and causes acute, highly lethal pneumonia coronavirus disease 2019 (COVID‐19) with clinical symptoms similar to those reported for SARS‐CoV and MERS‐CoV. The most characteristic symptom of patients with COVID‐19 is respiratory distress, and most of the patients admitted to the intensive care could not breathe spontaneously. Additionally, some patients with COVID‐19 also showed neurologic signs, such as headache, nausea, and vomiting. Increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases. The infection of SARS‐CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Furthermore, some coronaviruses have been demonstrated able to spread via a synapse‐connected route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lung and lower respiratory airways. In light of the high similarity between SARS‐CoV and SARS‐CoV2, it is quite likely that the potential invasion of SARS‐CoV2 is partially responsible for the acute respiratory failure of patients with COVID‐19. Awareness of this will have important guiding significance for the prevention and treatment of the SARS‐CoV‐2‐induced respiratory failure.

Acknowledgements: I would like to thank one of our blog readers for bringing this paper to my attention.

Disclaimer: Please note this post, as with all of my blog posts, represents my personal opinions and not the views of my colleagues at Barts-MS.

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.

10 comments

  • Hi Prof G, I’m just asking about myself. I have MS and am on Tysabri but I feel fine and I’m not ill. I’m just asking about the risk for Covid-19?

    Thank u Janet Brockbank

  • In yesterday’s press briefing the Chief Medical Officer was asked about the underlying conditions for those who had died in the UK and in his reply he mentioned neurological conditions. Do we know which conditions and whether we can extrapolate anything from those cases in regards to MS and potential impact of DMTs?
    Realise it’s way too early to know, but can’t help but to ask.

  • The nerves then transport the virus up their fibres and across synapses into the neurons within the brains of people infected with COVID-19

    Sounds like something from a horror movie! Think I’ll stay quiet about this one, family already overworried….

    • Re: “Sounds like something from a horror movie!”

      If you have seen a case of rabies, which I did has a house officer in South Africa, it is from a horror story. This is unlikely to be a major problem with COVID-19; if it was it would have emerged in the case series that have now been published from China. I suspect it is will be a very rare event, but unless we look for it and study it we won’t know.

  • I am an Ocrevus patient and have a question I haven’t been able to find the answer to. Could Ocrevus and similar DMTs make someone less likely to mount a fever in response to COVID-19 or another virus? I am just wondering because I am monitoring myself for COVID symptoms and wonder if the usual 3 symptoms MIGHT not apply. I know much is unknown but would be very grateful for any research info that would related to this. I am not seeking medical advice and know that you cannot provide any here. Thank you.

    • I am not sure why this would make you unable to mount a fever response.as this response is unlikely to B cell mediated. Fever is a response to infection as the high temperature can kill bugs

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