#MSCOVID19: transverse myelitis is not a reason to avoid being vaccinated

Barts-MS rose-tinted-odometer: ★★★

I am getting an increasing number of emails and direct messages on social media platforms about the transverse myelitis (TM) risk and COVID-19 vaccines; in particular the Oxford-AstraZeneca (Ox-AZ) vaccine. Some of the people who have contacted me have decided to forgo the vaccine and take their chances with COVID-19 and its potential sequelae. 

I want to stress that at present the link between COVID-19 vaccination and TM is very tenuous and arguably not there. Contrary to what misinformation is out there 3 cases of TM did not occur in relation to the Ox-AZ vaccine. This is the data as presented by the EMA in their ‘COVID-19 Vaccine (ChAdOx1-S [recombinant]) RISK MANAGEMENT PLAN’:

“There were 3 serious adverse events (SAEs) of demyelinating disease: 2 cases in the Ox-AZ group (1 case of transverse myelitis, and 1 case of multiple sclerosis in a participant with pre-existing, but previously unrecognised, multiple sclerosis), and 1 case of myelitis in the control group.” (EMA-ChAdOx1-S RMP)

It is important to realise that the subject with MS had signs of MS disease activity that predated vaccination, i.e. the vaccine did not cause the MS. This means that the two cases of TM were balanced between the Ox-AZ and the control arm (meningococcal vaccine).  

So the cynical anti-Vaxxers will argue that the TM is simply due to vaccination and a strong argument not to be vaccinated. So how common is TMTM post-vaccination?  

“The association between vaccines and acute demyelinating events has been assessed in a range of studies and expert reviews, including a population-based analysis of nearly 64 million vaccine doses in the US, which concluded that if there is an association between transverse myelitis and vaccines, it is < 2 per million doses of live-zoster and live-attenuated influenza vaccines, and < 1 per million doses for other vaccines (Baxter et al 2016). Moreover, demyelinating diseases occur more frequently with infections than with vaccination (Miravalle et al 2010). Taken together, the evidence is inconclusive regarding a causal relationship between contemporary vaccines and acute demyelinating events (Principi and Esposito 2020, Mouchet et al 2018, Phillips et al 2018).” (EMA-ChAdOx1-S RMP)

I suspect that TM post-COVID-19 will turn out to be commoner than TM post-COVID-19-vaccination. I have already done a blog post about the former, i.e. TM occurring in people who have had SARS-CoV-2 infection.

The annual incidence of TM ranges from 1.34 to 4.60 cases per million but increases to 24.6 cases per million if acquired demyelinating diseases like MS and neuromyelitis optica (NMO) are included. The John Hopkins COVID-19 site states that worldwide over 300M people have already received at least one dose of a COVID-19 vaccine and over 30M have received two doses as of the 8th March 2021. I think this number of COVID-19 vaccinations would be sufficient to see a TM signal. The one signal that we thought may have emerged was Bell’s palsy, but the number of cases seems to be in keeping with the background rate in the general population. Bell’s palsy was seen in the phase 3 Ox-AZ trial, but again the number of events was balanced. 

“Nonserious AEs of facial paralysis occurred in 3 participants in the Ox-Az group and 3 participants in the control group.” (EMA-ChAdOx1-S RMP)

“The MHRA continues to review cases reporting Bell’s Palsy and to analyse case reports against the number expected to occur by chance in the absence of vaccination (the ‘natural rate’). The number of reports of facial paralysis received so far is similar to the expected natural rate and does not currently suggest an increased risk following the vaccines. We will continue to monitor these events, including through the evaluation of electronic healthcare record data.” (MHRA Coronavirus vaccine – weekly summary of Yellow Card reporting, 4th March 2021)

The MHRA safety data has not shown a TM signal with either of the vaccines and that is now with millions of doses of vaccine given. 

Please remember a lot of patients with TM go onto develop MS. Thousands of people with MS have now had one of the vaccines and the last I had heard only 6 relapses had been reported to the MHRA; a very low number considering how many MS relapses occur in the UK every year. No signal has emerged in Israel either with TM or MS relapses post COVID-19 vaccination. The one caveat about Israel’s data is that it is dominated by the Pfizer-BionTech vaccine. 

As the plan is to vaccinate the whole adult population there will be people who get TM post-vaccination. This will happen by chance. Unless there are large numbers of cases of TM, as what happened with Guillain-Barre Syndrom (GBS) after the H1N1 flu vaccine, it will be very difficult to prove causation. 

Nobody is being forced to be vaccinated. If you don’t want to be vaccinated just say no, but if you decided not to be vaccinated you need to realise that you are likely at some point to get COVID-19. SARS-CoV-2 is almost certain to become an endemic viral infection, i.e. the virus won’t disappear. So you need to think about the risks that getting COVID-19 entails. In general, most people who get COVID-19 are likely to get mild to moderate disease, but there are no guarantees that you won’t get the severe disease with the potential to die. Then there is the issue of long COVID-19, which affects about 10% of people who get COVID-19. So not having the vaccine has it own risks.

My advice remains the same: #GetVaccinated ASAP; TM is not a reason to avoid the vaccines and it is not a reason to avoid the Ox-AZ vaccine either. 

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211

#MSCOVID19: transverse myelitis

Barts-MS rose-tinted-odometer: ★★

How do you distinguish transverse myelitis that is not MS-related from spinal cord involvement in MS? 

Yesterday after reporting the possible and likely link between the Oxford-AstraZenca vaccine and transverse myelitis (TM) and possibly MS you asked how do neurologists differentiate TM from CIS or MS. 

Idiopathic or post-infectious/vaccine-related TM tends to be more extensive, i.e. involve multiple segments of the spinal cord compared to CIS/MS. This is often referred to as longitudinally-extensive TM. In addition, typical non-MS TM tends to involve the whole cord and not particular areas of the spinal cord. In comparison, CIS/MS tends to have discrete lesions that may involve the back or a segment of the spinal cord and extend over one or two segments. 

CIS/MS myelitis tends to fit the demographic profile of MS, i.e. more common in females, youngish age of onset (20-40 years) and is more common in regions of the world with a high MS prevalence. In addition, there are often other lesions in the brain and/or spinal cord that look like MS and CSF analysis usually shows oligoclonal IgG band and the cell counts in the spinal fluid are lower. 

Non-MS related TM can occur in any age group, occurs in both sexes and its quite common in Asian, African, Afro-Caribbean and African-American populations.  Brain imaging is usually normal; the exception being some patients with NMO. CSF analysis is OCB negative and the cell count is often raised. Interestingly, it is not uncommon in acute TM to find some neutrophils and occasionally eosinophils in the spinal fluid that does not happen in MS-related myelitis. 

An important clue is that non-MS related TM may have obvious precipitating factors of a recent viral or bacterial infection or vaccination. 

Saying all this it is sometimes very hard to differentiate the two and then time becomes the best diagnostician, i.e. you have to wait to see if someone goes onto to develop recurrent events. This is why medicine and neurology remain as much an art as a science. 

Worryingly the number of TM cases post-COVID-19 in the literature is quite high considering we are only 6-9 months into this pandemic. This would indicate that SARS-CoV-2 and its proteins may be the triggering factor for TM and/or MS and this will make this adverse event from this vaccine a real problem and we are likely to see more cases emerge. This does not mean the vaccine won’t be effective it simply means that some people with have to suffer harm to protect the many or the herd. This is the basic premise that population health is based on. 

CoI: multiple

Twitter: @gavinGiovannoni  / Medium: @gavin_24211

#MSCOVID19: coronavirus vaccine linked to MS-like complications

You will have heard by now that AstraZenca has paused its coronavirus vaccine study because of safety concerns. A study subject who received the vaccine developed transverse myelitis and had to be admitted to hospital. 

“The woman’s diagnosis has not been confirmed yet, but she is improving and will likely be discharged from the hospital as early as Wednesday”, said Soriot AstraZenca’s CEO (source STAT News).

From the same press conference, we also found out that another study subject had developed multiple sclerosis after receiving the vaccine. As most of you are aware transverse myelitis may be the initial manifestation of MS and sometimes it is very difficult to differentiate non-MS related transverse myelitis from CIS (clinically isolated syndrome compatible with demyelination or MS). 

Are two swallows enough to make a summer? I suspect not and I would be surprised if the data and safety monitoring committee recommends stopping the trials. However, they may do so if there is a third or fourth case. 

Transverse myelitis (TM)  is well described after vaccination as well as after viral and other infections. The yellow fever vaccine is probably the most common cause of vaccine associated TM. However, it was a common adverse event with the original rabies vaccine that was cultured and isolated from monkey neuronal cells. Fortunately, this is not how the rabies vaccine is made anymore and the incidence of TM is now much less common after rabies vaccination. Other vaccines that can trigger TM are influenzae, MMR, Japanese B encephalitis, hepatitis B and HPV vaccines. TM has also been associated with many infections, particularly viral and some bacterial infections. We neurologists refer to this type of TM as being vaccine-associated or post-infectious TM, respectively. 

Even if the AstraZenca vaccine trials restart, which in my opinion is likely, and the vaccine is shown to be effective, it is likely that the regulatory authorities will include TM as a potential adverse event. The latter will be based on the recent case and the historical perspective of other vaccines being known triggers of TM. What they will do about the case of MS is anyone’s guess, but I suspect they will include triggering MS disease activity as a potential adverse event as well. If they do this this will cause the MS community to probably err on the side of safety and hence this particular coronavirus vaccine will not be recommended for people with MS. 

Other implications is that there is a chance that the TM has not been induced by the Chimpanzee Adenovirus vector that is being used in this vaccine, but the actual coronavirus spike protein or immunogen. It is noteworthy that several cases of COVID-19 related TM have already been reported in the literature (see below), suggesting it may be the virus or the spike-protein that is the culprit.  If this proves to be the case then it is really bad news as TM will be a problem for the whole class of vaccines using the spike protein as the immunogen. 

So the implications of these observations are enormous for the field. However, there are things that can be done by neuroimmunologists to study the immune response to the SARS-CoV-2 spike protein and the Chimpanzee Adenovirus vector to see if there is any cross-reactivity with proteins and lipids in the spinal cord. The latter are standard molecular mimicry studies and this could help AstraZeneca and other vaccine manufacturers understand the TM risk in more detail.

You have to realise that this is what happens with vaccine and drug development and underscores why drug and vaccine development is so risky and expensive. The investment costs in terms of this vaccine have been largely derisked for AstraZenca by most of the preclinical development being funded and done by academia and the fact that the British and other governments have pre-ordered millions of doses of vaccine. 

We will update you on this story as it evolves. 

Addendum: the published case reports of TM-like conditions occurring in association with COVID-19.

1.Acute transverse myelitis after COVID-19 pneumonia.Munz M, Wessendorf S, Koretsis G, Tewald F, Baegi R, Krämer S, Geissler M, Reinhard M.J Neurol. 2020 Aug;267(8):2196-2197. doi: 10.1007/s00415-020-09934-w. Epub 2020 May 26.PMID: 32458198 Free PMC article. No abstract available.
2.Transverse Myelitis in a Child With COVID-19.Kaur H, Mason JA, Bajracharya M, McGee J, Gunderson MD, Hart BL, Dehority W, Link N, Moore B, Phillips JP, Rogers D.Pediatr Neurol. 2020 Jul 29;112:5-6. doi: 10.1016/j.pediatrneurol.2020.07.017. Online ahead of print.PMID: 32823138 Free PMC article. No abstract available.
3.Acute transverse myelitis in COVID-19 infection.Chow CCN, Magnussen J, Ip J, Su Y.BMJ Case Rep. 2020 Aug 11;13(8):e236720. doi: 10.1136/bcr-2020-236720.PMID: 32784242 Free PMC article.
4.COVID-19-associated acute transverse myelitis: a rare entity.Chakraborty U, Chandra A, Ray AK, Biswas P.BMJ Case Rep. 2020 Aug 25;13(8):e238668. doi: 10.1136/bcr-2020-238668.PMID: 32843475 Free PMC article.
5.Transverse myelitis related to COVID-19 infection.Zachariadis A, Tulbu A, Strambo D, Dumoulin A, Di Virgilio G.J Neurol. 2020 Jun 29:1-3. doi: 10.1007/s00415-020-09997-9. Online ahead of print.PMID: 32601756 Free PMC article. No abstract available.
6.COVID-19-associated acute necrotizing myelitis.Sotoca J, Rodríguez-Álvarez Y.Neurol Neuroimmunol Neuroinflamm. 2020 Jun 10;7(5):e803. doi: 10.1212/NXI.0000000000000803. Print 2020 Sep.PMID: 32522767 Free PMC article. No abstract available.
7.Acute necrotizing myelitis and acute motor axonal neuropathy in a COVID-19 patient.Maideniuc C, Memon AB.J Neurol. 2020 Aug 9:1-3. doi: 10.1007/s00415-020-10145-6. Online ahead of print.PMID: 32772172 Free PMC article.
8.A case of possible atypical demyelinating event of the central nervous system following COVID-19.Zoghi A, Ramezani M, Roozbeh M, Darazam IA, Sahraian MA.Mult Scler Relat Disord. 2020 Jun 24;44:102324. doi: 10.1016/j.msard.2020.102324. Online ahead of print.PMID: 32615528 Free PMC article.
9.Acute transverse myelitis associated with SARS-CoV-2: A Case-Report.Valiuddin H, Skwirsk B, Paz-Arabo P.Brain Behav Immun Health. 2020 May;5:100091. doi: 10.1016/j.bbih.2020.100091. Epub 2020 Jun 6.PMID: 32835294 Free PMC article.

CoI: multiple