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.
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.
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.
