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.
As you are aware, MS is an iceberg, with most of the MS disease activity and resultant damage being hidden. The study below expands the concept of the MS iceberg to the cerebral cortex or grey matter. Most lesions (~80%) found at post-mortem in the grey matter are not detected using specialised MR imaging. Please note that post-mortem MRI imaging in more standardised than that which happens in clinical practice and I suspect even more lesions will be missed in real-life.
Is this study important? You bet. We know that these grey matter lesions are associated with cognitive impairment, loss of brain volume and in particular progressive grey matter atrophy and are associated with poor longterm outcome and reduced quality of life.
Do you want to know what your true MS disease burden is? Based on this data and other studies it looks as if MRI is not the best way of doing this. I suspect a better marker will be ‘deep phenotyping’, i.e. interrogating the function of your nervous system using stress tests to see how you perform. Knowing you have cognitive impairments, for example, slow cognitive reaction times, difficulty with concentration and attention, poor memory or other specific deficits may be more meaningful to you. Or not? I say ‘or not’ as not all pwMS want to know that have cognitive impairment; they argue if nothing can be done about it is best to ignore it. This is called the ‘ostrich syndrome’.
Knowing you have cognitive deficits will allow you to take specific actions to address the problem and to potentially make important real-life decisions about your future. It also allows your HCP to take action to address some medical issues that are linked to cognitive impairment, i.e. poor adherence to treatments, physical accidents and comorbid depression and anxiety to name a few. One could argue that pwMS who have cognitive impairment should be put on a high-risk register for more proactive management and care.
It is clear that the burden of MS is not only physical but cognitive as well. This is another reason to diagnose, treat and manage MS effectively and as early as possible to prevent end-organ damage and preserve your grey matter. Can I please remind you that no all DMTs are made equal when it comes to preserving brain volume or grey matter.
This post reminds me of an infographic I put together about 5 years ago called ‘Grey Matter, Matters’, which I used to support a campaign I started to redefine MS as a ‘preventable dementia’.
Cortical demyelinating lesions are clinically important in multiple sclerosis, but notoriously difficult to visualize with MRI. At clinical field strengths, double inversion recovery MRI is most sensitive, but still only detects 18% of all histopathologically validated cortical lesions. More recently, phase-sensitive inversion recovery was suggested to have a higher sensitivity than double inversion recovery, although this claim was not histopathologically validated. Therefore, this retrospective study aimed to provide clarity on this matter by identifying which MRI sequence best detects histopathologically-validated cortical lesions at clinical field strength, by comparing sensitivity and specificity of the thus far most commonly used MRI sequences, which are T2, fluid-attenuated inversion recovery (FLAIR), double inversion recovery and phase-sensitive inversion recovery. Post-mortem MRI was performed on non-fixed coronal hemispheric brain slices of 23 patients with progressive multiple sclerosis directly after autopsy, at 3 T, using T1 and proton-density/T2-weighted, as well as FLAIR, double inversion recovery and phase-sensitive inversion recovery sequences. A total of 93 cortical tissue blocks were sampled from these slices. Blinded to histopathology, all MRI sequences were consensus scored for cortical lesions. Subsequently, tissue samples were stained for proteolipid protein (myelin) and scored for cortical lesion types I-IV (mixed grey matter/white matter, intracortical, subpial and cortex-spanning lesions, respectively). MRI scores were compared to histopathological scores to calculate sensitivity and specificity per sequence. Next, a retrospective (unblinded) scoring was performed to explore maximum scoring potential per sequence. Histopathologically, 224 cortical lesions were detected, of which the majority were subpial. In a mixed model, sensitivity of T1, proton-density/T2, FLAIR, double inversion recovery and phase-sensitive inversion recovery was 8.9%, 5.4%, 5.4%, 22.8% and 23.7%, respectively (20, 12, 12, 51 and 53 cortical lesions). Specificity of the prospective scoring was 80.0%, 75.0%, 80.0%, 91.1% and 88.3%. Sensitivity and specificity did not significantly differ between double inversion recovery and phase-sensitive inversion recovery, while phase-sensitive inversion recovery identified more lesions than double inversion recovery upon retrospective analysis (126 versus 95; P < 0.001). We conclude that, at 3 T, double inversion recovery and phase-sensitive inversion recovery sequences outperform conventional sequences T1, proton-density/T2 and FLAIR. While their overall sensitivity does not exceed 25%, double inversion recovery and phase-sensitive inversion recovery are highly pathologically specific when using existing scoring criteria and their use is recommended for optimal cortical lesion assessment in multiple sclerosis.
If you thought having MS was bad enough the Swedish study below confirms that people with MS are more likely to have a raft of other diseases, which include cardiovascular disease (CVD), stroke, heart failure, venous thromboembolism, other autoimmune conditions, bowel dysfunction, depression and fractures. These results replicate what we see from other studies and are not dissimilar what we see in other autoimmune diseases such as rheumatoid arthritis (RA).
It is clear that some comorbidities, in particular, venous thromboembolism, bowel problems, depression and fractures, are probably due to MS. However, the other comorbidities are associated with MS. Why pwMS are at increased risk of CVD, stroke and heart failure is interesting and needs more study. Is it because pwMS live an unhealthy lifestyle; poor diet, less exercise and a higher rate of smoking? Or is the systemic inflammation that occurs in MS driving the vascular disease? Should we be doing trials to test preventive strategies to address this problem? I suspect the answer to all of these questions is YES.
#ClinicSpeak
What are the clinical implications of these findings? We know from other studies that pwMS with vascular and other comorbidities become disabled more quickly. A person with MS with vascular comorbidity will on average need a walking stick 6 years earlier than a pwMS who does not have vascular comorbidity. This 6-year gap is larger than the treatment effect of our platform therapies. Six years is a long time in the life of someone with MS.
Therefore, if you want to manage MS holistically pwMS need to be screened for comorbidities and have them managed. This is part of my marginal gains strategy. Who should do the comorbidity screening? In the UK it usually falls to the family doctor or GP to do this screening, but I have found many pwMS simply don’t see their GP regularly enough for health checks. This is why it may be important for you as individuals with MS, and a stake in your own health, to take control and have yourself screened.
More importantly, prevention is better than cure. So if you have MS you should do everything you can to prevent yourself from developing comorbidity. This means adopting a heart- and brain-healthy lifestyle; stop smoking, improving your diet, maintaining a healthy weight, exercising regularly, reducing your alcohol consumption to safe limits, having your blood pressure, cholesterol and sugar levels checked. In addition, you need the inflammation due to your MS controlled; this may require DMTs and a highly-effective DMT.
I am aware this advice is easier said than done, but at the end of the day, there is only so much that your HCP can do and a lot of the advice above is about self-management and empowering yourself to take responsibility for your own health.
Background: Comorbidity is of significant concern in multiple sclerosis (MS). Few population-based studies have reported conditions occurring in MS after diagnosis, especially in contemporary cohorts.
Objective: To explore incident comorbidity, mortality and hospitalizations in MS, stratified by age and sex.
Methods: In a Swedish population-based cohort study 6602 incident MS patients (aged ≥18 years) and 61,828 matched MS-free individuals were identified between 1 January 2008 and 31 December 2016, using national registers. Incidence rates (IRs) and incidence rate ratios (IRRs) with 95% CI were calculated for each outcome.
Results: IRs of cardiovascular disease (CVD) were higher among MS patients than MS-free individuals, (major adverse CVD: IRR 1.42; 95% CI 1.12-1.82; hemorrhagic/ischemic stroke: 1.46; 1.05-2.02; transient ischemic attack: 1.65; 1.09-2.50; heart failure: 1.55; 1.15-2.10); venous thromboembolism: 1.42; 1.14-1.77). MS patients also had higher risks of several non-CVDs such as autoimmune conditions (IRR 3.83; 3.01-4.87), bowel dysfunction (2.16; 1.86-2.50), depression (2.38; 2.11-2.68), and fractures (1.32; 1.19-1.47), as well as being hospitalized and to suffer from CVD-related deaths ((1.91; 1.00-3.65), particularly in females (3.57; 1.58-8.06)).
Conclusion: MS-patients experience a notable comorbidity burden which emphasizes the need for integrated disease management in order to improve patient care and long-term outcomes of MS.
In clinic yesterday a patient told me that a vaccine post they read on the blog was very confusing. After reading it they didn’t know what to do. It is important to emphasise that this blog is primarily about MS research and not necessarily about clinical advice. I always tag my clinical posts with the hashtag #ClinicSpeak. In future, I will also colour code them. Will this help?
The following vlog is some off the cuff advice about vaccines. I hope this clears up some of the confusion.
Adding to this Post By ProfG and relevant to todays post.
Genetic evidence for a case of re-infection with SARS-CoV-2. Tillett et al. SSRN-id3680955.pdf Here is a case where re-infection can be shown to occur as the person had two different strains of the virus. Perhaps the bad news whilst the first infection was mild was that the second round of infection was associated with hospitalization showing that infection with the virus does not give 100% protection. This could be uncommon but we cannot say this and it may not be.
Informing patients about their potential coronavirus risks associated with anti-CD20 therapy is complicated and resulting in our patients being given different advice depending on who they see. The reason for this is that we don’t have the direct evidence to be able to dissect out why people on anti-CD20 therapy are at higher risk of COVID-19 and at higher risk of being admitted to hospital with severe COVID-19.
I doubt this increased risk relates to increased exposure to the coronavirus. Why should someone on ocrelizumab who attends their healthcare facility be at increased risk of acquiring SARS-CoV-2 infection compared to someone for example on natalizumab who attends for their infusion every 4-6 weeks?
The clue to the increased risk is in the detail of the data. It is apparent that the longer you have been on an anti-CD20 therapy the greater your risk; the risk of COVID-19 is particularly high if you have been on an anti-CD20 therapy for more than 3 years. This means that it must be due to prior exposures, i.e. exposures before the COVID-19 pandemic started.
In the general population, it is now clear that some people have T-cells and antibodies that cross-react with SARS-CoV-2 and that these protect these people from developing COVID-19 or severe COVID-19. These cross-reactive immune responses are likely to have developed in response to infection or exposure to other circulating coronaviruses; the viruses that cause the common cold.
My theory is that if you are on an anti-CD20 therapy with no B-cells and a poorly functioning antibody response and you get the common cold your immune system will not be able to make these protective cross-reactive anti-coronavirus antibodies. This would then reduce your chances of being protected from getting COVID-19 or getting only mild COVID-19 when you are infected with SARS-CoV-2.
I have tried to illustrate this in the following slide showing that people on long-term anti-CD20 therapies are more likely to get symptomatic SARS-CoV-2 infection, i.e. COVID-19, and when they do get COVID-19 it is likely to be more severe. Severity in this context is requiring hospitalisation and potential intensive care and ventilation.
What does this mean for you? It means that if you are about to start ocrelizumab, rituximab or ofatumumab then your chances of getting COVID-19 are unlikely to be different to another DMT, with the exception of interferon-beta that lowers your risk because of its antiviral effects.
If you happen to be on ocrelizumab, rituximab or ofatumumab already there is little you can do, because these agents are not rapidly reversible and even if you stop the treatment and allow your B-cell compartment to reconstitute you are unlikely to develop the cross-reactive immunity from common coronaviruses. However, by stopping your anti-CD20 and allowing your B-cells to reconstitute you will be allowing your immune system to prepare itself for a coronavirus vaccine in the future.
At the beginning of the pandemic, I was a bit cynical about the chances of a successful coronavirus vaccine emerging, but the preliminary phase 2 results of several vaccines and the immunological insights above have made me much more optimistic that we will have an effective coronavirus vaccine quite soon. When I say soon I suspect we will have one ready for general consumption early next year. In all likelihood, one of the first vaccines will be the Oxford-AstraZeneca vaccine that happens to involve a live virus, which itself will have implications for some of the MS DMTs.
If my predictions are correct the MS community may need to start getting vaccine ready or they can simply rely on herd immunity. With anti-CD20 therapy, this needs to be planned ahead and patients will need to miss one, two or possibly three infusions depending on their body size and individual B-cell reconstitution kinetics in order to prepare their immune systems for the vaccine.
Some critics of this strategy are saying that patients on an anti-CD20 therapy will still make T-cell responses to the vaccine that will in all likelihood protect them. Yes, this may be the case, but then how do you explain the above observations that people on anti-CD20 therapy are at increased risk of COVID-19 and severe COVID-19? I would interpret this as them having blunted T-cell responses to cross-reactive common coronaviruses. If this is the case pwMS on an anti-CD20 will have blunted T-cell response to the vaccine. In support of the latter is the observation that several pwMS on ocrelizumab who have had swab-positive COVID-19 have failed to make an antibody response to the virus. Please remember that good quality antibody responses are T-cell dependent. These observations are telling me that in all likelihood being on anti-CD20 therapy will prevent you from developing protective immunity to coronavirus from a vaccine.
Clearly getting more detailed population-level COVID-19 data in people with MS is very important. This is why we are trying to crowdfund our study to identify people who have antibodies to SARS-CoV-2. We will be able to use this resource to do nested immunological studies on pwMS on different DMTs to understand the cross-reactive immunology at both the T and B cell level to coronaviruses in general and test the hypotheses above. It will also allow us to study vaccine responses if and when the vaccines arrive.
If you are prepared to help with a small donation it would be much appreciated. Thank you.
Two months ago we floated the concept of doing a UK-wide seroprevalence study in UK residents with MS to see how many had seroconverted to become anti-SARS-CoV-2 antibody positive and to see if there are differences in seroconversion rates between people on different DMTs.
The motivation was based on a prediction that people with MS on ocrelizumab would have lower titres of anti-SARS-CoV-2 antibody titres, be more likely to be seronegative despite a history of COVID-19 and less likely to have neutralizing anti-spike protein RBD (receptor binding domain) antibodies compared to patients on other DMTs.
It looks like we may be correct; some early case reports suggest pwMS on ocrelizumab may not seroconvert.
In addition to the cross-sectional analysis, we proposed following the seronegative pwMS over time to study how the COVID-19 pandemic evolves and monitor the development of herd immunity.
We have designed the study and in parallel, to applying for funding we got the study approved by our University and Ethics committee. We thought we had the funding approved, but at the last minute due to a funding crisis, our funder said no. We are now sitting with a dilemma; an approved study with no funding. So we are having to revert to plan B; crowdfunding.
When we did our survey you all agreed that crowdfunding would be one potential solution to our funding crisis. However, we can’t simply ask you to donate money. We have to put our money where our mouths are. So I have decided to come out of marathon running retirement to raise money for this study that will be managed by Dr Ruth Dobson and Dr Angray Kang.
I have signed up for the virtual New York City Marathon in the medal-winning category. My aim is to complete a 26.2-mile run in London between October 17 and November 1. I will be joining runners from around the globe to make this the world’s largest virtual marathon. The question is does my right hip have enough cartilage left in it for me to complete the run?
In addition, to me attempting to complete a marathon with a failing hip I am gently prodding other members of Bart-MS to do something as well. I may have one taker already, but more on this later.
Our objective is to raise £25,000 to cover the costs of posting out blood spots to study participants. As this study is time sensitive we need to raise the money ASAP.
If you want to help us raise the funds please do not hesitate to contact us.
I recently did a post that I called ZOOMED-OUT that was in response to spending too much time online in endless meetings, on webinars with information overload and preparing and watching too many didactic lectures. Therefore, we have changed the format of our next triMSx-online meeting into a Q&A session. If you are interested please register to find out more and to make the meeting more interactive and worthwhile.
For those who missed our online journal club on radiologically isolated syndrome (RIS) or asymptomatic MS, which was held online this afternoon, you can catch-up with the banter on YouTube.
Over 70% of pwMS have a sleep disorder with about 40-45% having obstructive sleep apnoea. The latter is massively underdiagnosed and needs to be actively screened for to be detected. I suspect having MS increases one’s chances of developing OSA by affecting the tone and function of the so called bulbar or throat muscles. This problem is that OSA affects quality of sleep and leaves most people with daytime sleepiness, which exacerbates MS-related fatigue and cognitive impairment. This is why if you have daytime sleepiness, fatigue or cognition problems you need to be screened for one of the many sleep disorders that affect pwMS.
The simplest screen for OSA is the Epworth Sleepiness Scale, which takes about 2 minutes to complete. The following symptoms are also clues to having OSA:
Snoring
Stopping breathing or struggling to breathe
Feeling of choking
Tossing and turning
Sudden jerky body movements
Needing to go to the toilet in the night
Sometimes your partner might be more aware of your snoring and pauses in your breathing than you are. If you don’t have a partner you can download one the many sleep apps that monitors your sleep and records snoring. Some of my patients are surprised when they actually hear how bad their snoring is at night.
The good news is that OSA is treatable and many patients come back and say that their lives are transformed after getting a good night’s sleep. The study below documents that pwMS with OSA also improve their cognitive function when their OSA is treated.
Cognitive impairment (CI) and fatigue are common in people with multiple sclerosis (MS), with well-known profound effects on quality of life. Sleep disorders, including obstructive sleep apnoea (OSA), are also common in MS patients. The presence of CI has previously been shown to strongly correlate with OSA diagnosed using polysomnography in MS. Treatment of OSA has not previously been investigated as a potential modality to improve cognition in MS patients. Therefore, we sought to investigate the potential effects of OSA treatment on both cognitive function and fatigue in MS patients. Twenty-three participants with MS reporting significant fatigue were enrolled. CI was assessed by the Brief International Cognitive Assessment in MS and the 3-second Paced Auditory Serial Addition Test. All participants underwent overnight polysomnography to assess for possible OSA. Cognitive and fatigue measures were repeated in those subsequently treated for OSA and in a comparative untreated sample. Seven participants (30%) had a diagnosis of OSA based on an apnoea-hypopnea index greater than 5 per hour, with no correlation between the presence of CI and OSA. Verbal learning at follow-up assessment was seen to improve significantly in those treated for OSA, compared with those who were not treated for a sleep disorder. This small study demonstrates the potential for OSA treatment to improve verbal learning in people with MS, larger studies are indicated to further investigate the potential for cognitive and fatigue improvement in people with MS through treatment of comorbid OSA.
