Gavin Giovannoni

To get a booster or not

Barts-MS rose-tinted-odometer: ★★★ (a red-eyed Tuesday #FF0000)

I was doing a Q&A webinar with some US clinicians last night and they were asking whether or not pwMS should have a booster COVID-19 vaccine or not. The answer is simple, YES. The study below in 60+-year-old Israelis shows that people who had a booster or third dose of the Pfizer-BionTech RNA vaccine were 11.3x less likely to be infected with SARS-CoV-2 compared to people who had been double vaccinated. The more impressive finding is that severe COVID-19 was reduced by a factor of 19.5 in the boosted group compared to the non-boosted group.

The question is whether or not this study’s findings are relevant to pwMS. Of course, they are. Older people have immunosenescence which is a form of immunosuppression and hence if you have MS and are on immunosuppressive therapy you need to boost your immunity. The principles are very similar.

In the UK pwMS on immunosuppressive therapies are being called up for a third dose. Please go ahead with the booster. People on anti-CD20 therapy should be aware that if they have no B-cells in their peripheral blood they are unlikely to make an antibody response, but the booster should theoretically improve their anti-SARS-CoV-2 T-cell responses. If they want to make an antibody response they can ask their team if they can delay their next infusion to allow some B-cell reconstitution before being vaccinated. The question is whether or not this is necessary is a moot point.

Hopefully, real-life data will emerge comparing COVID-19 outcomes in pwMS who are seropositive post-vaccine with those who are seronegative.

If you are on an S1P-modulator, such as fingolimod, you don’t really have the luxury of delaying dosing. Therefore I suggest going ahead with the booster in the hope that it works. Stopping fingolimod, and or other S1P modulators, for a vaccine is risky because of rebound disease activity.

Booster responses for all other DMTs should be fine.

Bar-On et al. Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel. NEJM September 15, 2021 DOI: 10.1056/NEJMoa2114255

BACKGROUND: On July 30, 2021, the administration of a third (booster) dose of the BNT162b2 messenger RNA vaccine (Pfizer–BioNTech) was approved in Israel for persons who were 60 years of age or older and who had received a second dose of vaccine at least 5 months earlier. Data are needed regarding the effect of the booster dose on the rate of confirmed coronavirus 2019 disease (Covid-19) and the rate of severe illness.

METHODS: We extracted data for the period from July 30 through August 31, 2021, from the Israeli Ministry of Health database regarding 1,137,804 persons who were 60 years of age or older and had been fully vaccinated (i.e., had received two doses of BNT162b2) at least 5 months earlier. In the primary analysis, we compared the rate of confirmed Covid-19 and the rate of severe illness between those who had received a booster injection at least 12 days earlier (booster group) and those who had not received a booster injection (non-booster group). In a secondary analysis, we evaluated the rate of infection 4 to 6 days after the booster dose as compared with the rate at least 12 days after the booster. In all the analyses, we used Poisson regression after adjusting for possible confounding factors.

RESULTS: At least 12 days after the booster dose, the rate of confirmed infection was lower in the booster group than in the non-booster group by a factor of 11.3 (95% confidence interval [CI], 10.4 to 12.3); the rate of severe illness was lower by a factor of 19.5 (95% CI, 12.9 to 29.5). In a secondary analysis, the rate of confirmed infection at least 12 days after vaccination was lower than the rate after 4 to 6 days by a factor of 5.4 (95% CI, 4.8 to 6.1).

CONCLUSIONS: In this study involving participants who were 60 years of age or older and had received two doses of the BNT162b2 vaccine at least 5 months earlier, we found that the rates of confirmed Covid-19 and severe illness were substantially lower among those who received a booster (third) dose of the BNT162b2 vaccine.

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

#MSCOVID19: to delay anti-CD20 dosing or not

Barts-MS rose-tinted-odometer: ★ (It’s a Black-and-White Friday #000000 & #FFFFFF)

At the beginning of the COVID-19 pandemic, we made the case that B-cells and antibodies against SARS-CoV-2 were not necessary to clear the coronavirus and protecting you from severe disease. However, almost all emerging data challenges this position, therefore I have changed my position.

It is now clear that cross-reactive immunity from common coronavirus infections provides some protection from COVID-19. IVIG (intravenous immunoglobulin) formulations collected prior to COVID-19 contain neutralizing anti-SARS-CoV-2 antibodies and may have contributed to the survival of agammaglobulinaemic patients who had COVID-19.

Neutralizing monoclonal anti-SARS-CoV2 antibodies have been shown to be effective against COVID-19 and severe COVID-19 and are now part of our therapeutic armamentarium for treating COVID-19.

People on anti-CD20 therapy are more likely to get COVID-19, severe COVID-19, are more likely to need ITU and hence more likely to die from COVID-19.

The study below shows that antibody neutralization levels against SARS-CoV-2 and the observed protection from SARS-CoV-2 infection are clearly related. In other words, anti-SARS-CoV-2 antibodies are important.

They estimate the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20% of the mean antibody level in convalescent serum from people who have recovered from COVID-19. The estimated neutralization level required for 50% protection from severe infection was significantly lower at 3% of the mean convalescent level. This means you need fewer antibodies to protect you against severe disease. Another interpretation, which I think is more likely, is that antibodies are a marker of protective T-cell immunity.

Worryingly the modelled decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained as you need less antibody. Again the latter may be due to T-cell immunity that must be present in the background. Despite this, it is quite clear that antibody neutralization level is highly predictive of immune protection be it via the antibodies themselves or the associated T-cell immunity.

This study implies that if you don’t have antibodies you won’t be protected. The question that needs to be urgently answered is ‘ is T-cell immunity in the absence of antibody immunity sufficient to protect you against SARS-CoV-2 infection and severe disease?’. Unfortunately, we don’t have real-life data on this at the moment.

My interpretation of this – based on the observation that people who are on anti-CD20 therapy have a higher risk of severe COVID-19 and hence have on average less cross-reactive anti-SARS-CoV-2 neutralizing antibodies – is that if possible it would be better to have anti-SARS-CoV-2 antibodies than not to have them. The is really important for pwMS on anti-CD20 therapies or S1P modulators who have blunted antibody responses to the COVID-19 vaccines. This is why I have moved my position from getting vaccinated ASAP to let’s time your vaccine to give you the best chance of seroconverting. This means waiting for B-cell reconstitution post-anti-CD20 before vaccinating.

An adaptive vaccination/vaccine-booster strategy is logistically challenging for the simple reason that B-cell reconstitution post anti-CD20 therapy is quite variable. This means that after a certain period of time, say 9 months after your last dose of ocrelizumab, 6 months after your last dose of rituximab and 4 months after your last dose of ofatumumab you will have to have monthly B-cell counts to make sure your peripheral B-cell count is above 10 B-cells/mm3 before you can get vaccinated. I also suspect we will then have to check if you seroconvert and if not re-vaccinate you before redosing with the relevant anti-CD20.

What this strategy won’t answer is even if these patients make an antibody response will the antibody and associated T-cell responses are good enough to protect you from infection or reinfection with the emerging variants?

So until we have more evidence I am sitting on the fence. It is only fair to tell pwMS about the problem and the uncertainty around this issue and give them the choice to delay or miss their next dose of anti-CD20 therapy. So far some patients are delaying their next course of treatment and others are not on the grounds that they are not prepared to take a chance of undertreating their MS. A lot of the former group of patients are older with more comorbidities and hence are at higher risk of dying from COVID-19. In contrast, the latter group tend to be younger and hence are more willing to take their chances if they get COVID-19. As with all decisions around managing MS during the COVID-19 pandemic, there are no easy black-and-white answers.

What is clear from this study below is that there is a clear hierarchy when it comes to vaccine potency with the mRNA vaccine, Moderna in particular, being superior to the other vaccines in inducing protective immunity. So if you have a choice I would go with one of the mRNA vaccines when it comes to maximising your antibody levels.

Khoury et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med. 2021 Jul;27(7):1205-1211.

Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4-28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level; 95% CI = 0.7-13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.

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Preventive Neurology

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Derisking anti-CD20: the ADIOS-IM study

Barts-MS rose-tinted-odometer: ★★★★★ (a London Grey day #666677)

Can we use an anti-CD20 therapy as an immune constitution therapy (IRT), i.e. 2 years of treatment followed by no treatment unless there is EIDA (evidence of inflammatory disease activity)? This strategy is not new to the field of MS; this is how we use alemtuzumab, cladribine and AHSCT. So why not with ocrelizumab, ofatumumab or rituximab?

The anti-CD20-IRT question really needs an answer. However, many of my colleagues are nervous about not treating pwMS continuously and would therefore prefer to use adaptive dosing of anti-CD20s based on B-cell, or memory B-cell, reconstitution. This is why we proposed doing the ADIOS study (adaptive ocrelizumab dosing study) in 2019 and were in the process of getting this study designed and funded prior to COVID-19.

However, since COVID-19 and the introduction of COVID-19 vaccines have spotlighted the long-term safety signals associated with continuous anti-CD20 therapy and their associated poor vaccine responses we now want to redesign the study. We now want the study to be focused on safety and to add another arm to test using anti-CD20 therapy as induction therapy for 2 years and then following it with a derisking strategy using one of the licensed immunomodulatory or low-risk maintenance therapies, i.e. interferon-beta, glatiramer acetate, teriflunomide or dimethyl fumarate (DMF). This is the so-called IM or induction-maintenance arm.

The proposed primary outcome will be serious Infections, which are those requiring hospitalisation. Secondary outcomes will include the development of hypogammaglobulinaemia, antibiotic and antiviral drug usage as a surrogate for infections, vaccine responses, days off work and healthcare utilisation. With regard to efficacy, we propose assessing change in T2-lesion volume or number and relapses for inflammation and brain volume change and disability progression as end-organ damage markers.

This study will need to be pragmatic and run through a registry, for example, the UK’s OPTIMISE pharmacovigilance platform. We also propose doing some nested or add-on studies in cohorts to do specific vaccine, biomarker, immunology and virology studies. These add-on studies will provide more data on each of the arms being used in the ADIOS-IM study.

Some questions for any readers who are anti-CD20 therapies. Would you volunteer to participate in this study? If there are any HCPs reading this post do you think we have clinical equipoise to do this study or have you already adopted one or more of these strategies to derisk anti-CD20 therapy already in your clinical practice?

Another potential advantage of this study, apart from making your MS treatment safer, is the potential cost-saving in the long term for the NHS or your health insurance provider.

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More evidence to support the smouldering MS hypothesis?

Barts-MS rose-tinted-odometer: ★★★★★ (neon tennis ball green #dfff4f)

Yet another study showing that there are abnormalities in the so-called normal-appearing white matter (NAWM) that precede the development of new MS lesions.

This supports the hypothesis that there is something in the brain tissue that triggers the development of lesions and relapses. Could this be a virus, like an isolated seed or flower in a field of wheat? Why do I say this? Firstly, when pwMS were treated with interferon-gamma, a cytokine that stimulates immune responses, they all had relapses. The interesting thing about these interferon-gamma-induced relapses is that they occurred in sites previously affected by MS. When I discussed this observation with the late Hillel Panitch, who was the principal investigator on the gamma-interferon trial, he thought that this observation was a fundamental observation and was telling us something important about MS.

Another observation that supports the abnormal field hypothesis is the rebound post-natalizumab. This suggests that whilst you keep T and B cells out of the nervous system with natalizumab the field (brain and spinal cord) becomes more abnormal and when you let these cells back in they detect the abnormal field and run amok trying to clear the field of the offending agent. This is what happens with IRIS (immune reconstitution inflammatory syndrome) and PML. When natalizumab is washed out the immune system finds the JC virus and tries to clear it by initiating an inflammatory process. Some of us think that rebound post natalizumab is simply IRIS in response to the virus that causes MS.

Other serial MRI studies have shown subtle changes in the white matter many weeks or months before a gadolinium-enhancing lesion appears.

These studies all suggest that the primary pathology is smouldering MS and is due to something in the nervous system that takes weeks or months to trigger a focal inflammatory lesion. The inflammation is secondary to what is causing the disease. The challenge for us all is to find out what the abnormality is that is causing these changes in the NAWM. I think the best chance we have of doing this is to study the brains of pwMS on natalizumab. To do this we will need someone with MS to die whilst on natalizumab treatment and to donate their brain to a unit with the necessary techniques to look for viruses. I think this will work because the viral load is likely to be higher in the absence of inflammation. This is why it is so important for pwMS to donate their brains for medical research.

If you are interested in more musing about the field hypothesis please read a previous post of mine from 2012 on this subject.

Well done to Emma Raducanu, whose US Open victory was a joy to watch. But best of all is her Twitter bio which contains just four words “london|toronto|shenyang|bucharest”. Another example of the pros of diversity, similar to the author list of the paper below “Colm Elliott, Parya Momayyezsiahkal, Douglas L Arnold, Dawei Liu, Jun Ke, Li Zhu, Bing Zhu, Ilena C George, Daniel P Bradley, Elizabeth Fisher, Ellen Cahir-McFarland, Peter K Stys, Jeroen J G Geurts, Nathalie Franchimont, Arie Gafson, Shibeshih Belachew”.

Elliott et al. Abnormalities in normal-appearing white matter from which multiple sclerosis lesions arise.

Brain Communications, Volume 3, Issue 3, 2021, fcab176.

Normal-appearing white matter is far from normal in multiple sclerosis; little is known about the precise pathology or spatial pattern of this alteration and its relation to subsequent lesion formation. This study was undertaken to evaluate normal-appearing white matter abnormalities in brain areas where multiple sclerosis lesions subsequently form, and to investigate the spatial distribution of normal-appearing white matter abnormalities in persons with multiple sclerosis. Brain MRIs of pre-lesion normal-appearing white matter were analysed in participants with new T2 lesions, pooled from three clinical trials: SYNERGY (NCT01864148; n = 85 with relapsing multiple sclerosis) was the test data set; ASCEND (NCT01416181; n = 154 with secondary progressive multiple sclerosis) and ADVANCE (NCT00906399; n = 261 with relapsing-remitting multiple sclerosis) were used as validation data sets. Focal normal-appearing white matter tissue state was analysed prior to lesion formation in areas where new T2 lesions later formed (pre-lesion normal-appearing white matter) using normalized magnetization transfer ratio and T2-weighted (nT2) intensities, and compared with overall normal-appearing white matter and spatially matched contralateral normal-appearing white matter. Each outcome was analysed using linear mixed-effects models. Follow-up time (as a categorical variable), patient-level characteristics (including treatment group) and other baseline variables were treated as fixed effects. In SYNERGY, nT2 intensity was significantly higher, and normalized magnetization transfer ratio was lower in pre-lesion normal-appearing white matter versus overall and contralateral normal-appearing white matter at all time points up to 24 weeks before new T2 lesion onset. In ASCEND and ADVANCE (for which normalized magnetization transfer ratio was not available), nT2 intensity in pre-lesion normal-appearing white matter was significantly higher compared to both overall and contralateral normal-appearing white matter at all pre-lesion time points extending up to 2 years prior to lesion formation. In all trials, nT2 intensity in the contralateral normal-appearing white matter was also significantly higher at all pre-lesion time points compared to overall normal-appearing white matter. Brain atlases of normal-appearing white matter abnormalities were generated using measures of voxel-wise differences in normalized magnetization transfer ratio of normal-appearing white matter in persons with multiple sclerosis compared to scanner-matched healthy controls. We observed that overall spatial distribution of normal-appearing white matter abnormalities in persons with multiple sclerosis largely recapitulated the anatomical distribution of probabilities of T2 hyperintense lesions. Overall, these findings suggest that intrinsic spatial properties and/or longstanding precursory abnormalities of normal-appearing white matter tissue may contribute to the risk of autoimmune acute demyelination in multiple sclerosis.

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Kind of Blue

Barts-MS rose-tinted-odometer: zero-★s (Feeling ‘Kind of Blue’ for a Saturday, midnight blue #191970)

We have known for some time now that pwMS on DMTs who get COVID-19 seem to be at no greater risk of severe COVID-19 and death compared to the general population with the exception of pwMS on anti-CD20 therapies. This implies that anti-CD20 therapies either impact preexisting cross-reactive protective immunity from other community-acquired coronavirus infections and/or antibody responses during COVID-19, which have been now shown to prevent severe infection and death. I think there is now ample evidence to support both of these explanations.

People who had the original SARS in 2003 have been shown to have broad anti-coronavirus immunity and make very good neutralising antibodies to SARS-CoV-2, which is boosted to very high levels in response to COVID-19 vaccination. Similarly, immunoglobulin formulations made from the plasma of blood donors prior to COVID-19 is able to neutralise SARS-CoV-2. Therefore preexisting immunity to other coronaviruses is helpful and this will be blunted by being on an anti-CD20 therapy, particularly if you have been on the anti-CD20 therapy for a prolonged period of time. This observation goes beyond COVID-19 and explains why the risk of infections in people on long-term anti-CD20 therapy increases over time.

It has also recently been shown that the delayed development of neutralising anti-SARS-CoV-2 antibodies is strongly associated with death in patients with COVID-19 in intensive care (Lucas et al. Nat Med. 2021 Jul;27(7):1178-1186). Therefore contrary to original hypotheses that B-cell responses were not necessary for recovery from COVID-19, it is now clear that antibody responses to SARS-CoV-2 are important in protecting you against a poor COVID-19 outcome. This now explains why people on anti-CD20 therapies are more likely to have severe COVID-19 and I suspect more likely to succumb to the infection.

I discuss the clinical implications of this and other findings for the management of MS in my latest MS-Selfie Newsletter ‘Anti-CD20 Kool-Aid and COVID-19 vaccines’ (9-Sept-2021).

Kind of Blue: Please take some time off today to remember and reflect on the people who lost their lives in the 11-September-2001 attacks in New York and Washington and subsequently in the world’s response to these attacks. I am going to listen to Mile Davis’ album, ‘Kind of Blue’ when I do this.

Lucas et al. Delayed production of neutralizing antibodies correlates with fatal COVID-19. Nat Med. 2021 Jul;27(7):1178-1186.

Recent studies have provided insights into innate and adaptive immune dynamics in coronavirus disease 2019 (COVID-19). However, the exact features of antibody responses that govern COVID-19 disease outcomes remain unclear. In this study, we analyzed humoral immune responses in 229 patients with asymptomatic, mild, moderate and severe COVID-19 over time to probe the nature of antibody responses in disease severity and mortality. We observed a correlation between anti-spike (S) immunoglobulin G (IgG) levels, length of hospitalization and clinical parameters associated with worse clinical progression. Although high anti-S IgG levels correlated with worse disease severity, such correlation was time dependent. Deceased patients did not have higher overall humoral response than discharged patients. However, they mounted a robust, yet delayed, response, measured by anti-S, anti-receptor-binding domain IgG and neutralizing antibody (NAb) levels compared to survivors. Delayed seroconversion kinetics correlated with impaired viral control in deceased patients. Finally, although sera from 85% of patients displayed some neutralization capacity during their disease course, NAb generation before 14 d of disease onset emerged as a key factor for recovery. These data indicate that COVID-19 mortality does not correlate with the cross-sectional antiviral antibody levels per se but, rather, with the delayed kinetics of NAb production.

Conflicts of Interest

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I’m so sorry

Barts-MS rose-tinted-odometer: zero-★’s (Black Monday #000000)

I heard last week that one of my patients sadly succumbed to COVID-19. This is not the first person with MS to die of COVID-19 but is a reminder of how fickle life can be. I have contacted my patient’s partner to say how sorry I am. The question I am asking myself is; could this death have been prevented? Yes, almost certainly. However, I suppose this answer applies to all COVID-19 related deaths.

Although the official global death toll from COVID-19 is 4.6m the unofficial estimate is 15.2m (95%CI 9.4m-18.2m), which means most of us will know someone who has died of COVID-19 (see The Economist; The pandemic’s true death toll, 5th Sept. 2021).

We should count ourselves lucky in the UK because we have a very high vaccination rate that has clearly reduced the number of people getting severe COVID-19 and dying from COVID-19. Sadly, however, being double-vaccinated is no guarantee of protection. Data from Public Health England (PHE) reveals that of all the people who died within 28 days of testing positive for the delta variant between 1 February and 19 July, 49% (224) had had two vaccine doses; almost all of these people, 220, were aged 50 or older (Public Health England. Investigation of SARS-CoV-2 variants of concern: technical briefings. 23 July).

What does this mean for pwMS? This means we are not out of the woods yet. Please remain vigilant and careful. This particularly applies to those of you who have not been vaccinated and those on an anti-CD20 or S1P-modulator, in whom vaccine responses are likely to be blunted. People with MS are being classified by the government as being vulnerable and hence you will be offered a booster dose later this year.

For those of you who have lost a loved one to COVID-19, there is a very good series of articles in this week’s BMJ on grief and grieving, which I recommend you read. Lucy Selman’s essay touched a raw nerve when I read it and many of the issues she discusses are particularly pertinent to how I am feeling this morning. It is hard, harder than you think, being a healthcare professional during the pandemic.

Lucy Selman. Covid grief has cracked us open: how clinicians respond could reshape attitudes to bereavement. BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1803 (Published 10 August 2021)

Excerpts:

……. For people working in healthcare, grief brings home the ultimate futility of medicine as a lifesaving endeavour. Despite the best efforts of doctors, we all eventually die. Grief teaches us that medicine is about so much more than extending life.

…… Accommodating the ubiquity of sadness, loss, and grief makes some separation and compartmentalisation seem inevitable, even a useful coping strategy, for those who practise medicine.

……. Clinicians are often encouraged or required, overtly or implicitly, to disregard and not talk about their own grief in the name of efficient patient care. Despite evidence of significant grief among clinicians, patient deaths are often not discussed.

…… But sequestering grief into the “private” realm outside of medical practice can have unintended negative consequences for clinicians and patients and their families, rendering us all more alone. Denying grief, hiding it away, hiving it off to a personal self, distinct from the professional, is to deny its place in life and to deny our humanity. In the context of a pandemic in which colleagues, patients, and loved ones have died, leaving no room at the table for grief renders life inauthentic.

…… Working with death and grief elides professional barriers. It urges us to bring our vulnerability with us, meeting the patient as a person but also, crucially, bringing our own person with us. That does not mean burdening patients with our own suffering or failing to maintain helpful boundaries. Rather, responding with compassion towards patients requires us to understand and respect our own need to process emotions.

……. Grief prompts us to consider how we treat ourselves as well as how we treat the person in front of us professionally. Being open about our own experiences of grief, and showing the strength of vulnerability, is a powerful statement to patients, carers, and colleagues that can help shift society’s attitude to grief. Individually, this can bring about a deepening and maturity of medical practice. Bringing the insights that grief affords into our professional and personal lives could have huge personal and societal benefits.

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Teleneurology fatigue

Barts-MS rose-tinted-odometer: ★★ (Fatigue Friday has to be a midnight blue day #191970)

Everyone is asking me what COVID-induced changes to your MS NHS service will you keep? What will be the new normal, etc.?

What I don’t want to keep is not being able to examine my patients, in particular, new patients.

To diagnose MS you need to show dissemination in space; i.e. does this person have clinical signs in two neuronal pathways or two different areas of the central nervous system? For an adequate prognosis, you need to assess if there are any subtle signs of damage to the nervous system. The latter can’t be done on a video link very accurately.

Yesterday, I saw a patient for a relapse assessment who had clear signs that were missed on a video consult two weeks ago. She is on fingolimod and has clearly had a relapse or may have an opportunistic CNS infection and now requires an urgent MRI. What happens if she turns out to have PML? A two-week delay in diagnosing PML could have potential consequences for this patient.

Although we now use our online EDSS calculator to assess EDSS scores, to do it properly you need to do a neurological assessment, which takes about 20 minutes and you need to walk the patient. You can do neither by telephone or video. With remote work, we will never be assessing our patients level of disability accurately. This is particularly important to assess subtle signs for example pallor of the optic disc in the back of the eye. You can’t do ophthalmoscopy remotely; at least not yet.

In more disabled patients I like to get them on the couch and examine their buttocks for signs of early pressure sores. This can’t be done by telephone. Similarly, the smell of being unkempt and the assessment of foot and mouth hygiene can’t be done remotely. These provide clues about who is vulnerable and not. Many pwMS in the UK are extremely vulnerable and one of our tasks is to help these patients. If you can’t identify them how can you help them.

A pressure sore, which can’t be assessed remotely.

Subtle clues of physical abuse, which is very common in pwMS, can’t be detected remotely. How many patients who are being physically and mentally abused are being let down by remote work?

Diagnosing and managing depression in someone with MS is hard remotely. The subtle body language and demonstrating empathy often need presence, i.e. a physical presence and not a remote presence. One of my patients who I saw this week remotely is desperate for physical contact. She is socially isolated and working from home. She just wants an excuse to get away from home and see people. Coming up for her outpatient appointment is a day trip for her. We seem to forget that interacting with the NHS and its staff can be a needed social event. This is lost with remote work.

I can go on and on but will stop here. It is clear that remote work, despite having some advantages, has severe limitations. Do you have any personal experiences you want to share with us about how remote consultations have let you down?

This open-access letter below voices some of the concerns these HCPs have about their teleneurology service. If you are an HCP and are reading this please share your experiences with us.

Thank you.

Thomas et al. Integration of Teleneurology within the Health System to Manage Patients of Multiple Sclerosis and Other CNS Demyelinating Disorders During COVID-19 Pandemic. Ann Indian Acad Neurol. May-Jun 2021;24(3):443-445.

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triMS.online wins top award

Barts-MS rose-tinted-odometer: ★★★★★★ (A golden 6-star Thursday, #d4af37)

The great news, our triMS.online conference won the industry Communiqué Award for ‘Excellence in Global Education Meetings/Stand-Alone Events’ last night. What started as an idea on this blog back in October 2016 became a reality in 2018 and is now hopefully a permanent fixture in the MS calendar. This was a real team effort and it is thanks to the dedication and commitment of the teams at Oxford Health Policy Forum and Oxford Pharmagenesis that this was possible. The common denominator to everything that I have been involved in that has been successful is good project management and the team at Oxford Pharmagenesis are by the far the most talented and professional team I have worked with. Thank you and well done. This is also the team behind the success of the ‘Brain Health: Time Matters‘ policy initiative.

A big thank you to the triMS.online steering committee who help with designing and implementing the different programmes. The founding principles of triMS.online were to increase global access to MS meetings, particularly for HCPs living in low and middle-income countries and at the same time to increase the diversity of speakers, particularly women, young people and people from ethnic minorities. This was acknowledged by the judges and I suspect was the main reason behind us winning the award.

I also want to thank our Pharmaceutical partners who have sponsored these meetings. Without your support triMS.online would not have become a reality.

Where to next? Because of the pharmaceutical code of conduct that does not allow pwMS to attend triMS.online we are creating a separate meeting for pwMS called PRISMS (patient reflections and insights in MS). Our first meeting is called ‘Shining a light on MS learnings from the COVID-19 pandemic’ and will be on Thursday 23 September 2021m 19:30 – 20:30 BST (14:30 – 15:30 EDT / 20:30 – 21:30 CEST). If you have not registered yet please do.

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C-sections: how common are they in women with MS?

Barts-MS rose-tinted-odometer: ★★ (Indian summer orange #FF7722)

I have always said that women with early MS who start and extend families should have no reason to worry about additional problems with their pregnancy and childbirth because. It may be different for women with more advanced MS who are disabled. Maybe I should revise this general advice based on the study below.

In this study, 15 women with MS had 16 children. The cesarean section rate was 14 out of 16 deliveries or a staggering 87.5% of pregnancies. The main reason for C-sections was given as chronic fatigue and neurological deficits. The latter is interesting in that the mean disease duration of this cohort was less than 10 years with an average EDSS of 2.0. I suspect this cohort is biased and recruited women with MS via a high-risk clinic or an obstetric unit.

These results are incongruent with my experience as an MSologist. What about you? If there are any women with MS reading this post who have had children after being diagnosed with MS did you have a natural vaginal delivery, assisted delivery or a C-section?

Biringer et al. Fatigue as the limiting factor for vaginal birth in patients with multiple sclerosis. Neuro Endocrinol Lett. 2021 Aug 28;42(4):222-228.

Objectives: Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disease. This study evaluated pregnancy-related issues in patients with MS in one perinatological centre.

Material and methods: A single-centre, retrospective study of the perinatal period in patients with MS admitted at the Dpt. of Gynaecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University and the University Hospital in Martin, Slovak Republic, European Union from January 1, 2015 to December 1, 2020 was performed. Selected parameters from personal, obstetric, and neurological histories were analysed.

Results: A cohort of 15 patients (32.5±5.3 years) with a relapsing-remitting form of MS gave birth to 16 children. The mean length of MS at the time of delivery was 9±3.6 years. The severity of the Expanded Disability Status Scale score was 2.0±1.5. Caesarean section (CS) was indicated in 14 deliveries (87.5%). It was elective CS in 10 patients. The most common indication for elective CS was a combination of significant chronic fatigue syndrome and neurological deficit (paresis).

Conclusions: The basis for the management of pregnancy, childbirth, and the postpartum period in women with MS is a planned pregnancy based on close cooperation among patients, gynaecologists, and neurologists. Vaginal delivery is not primarily contraindicated. Indications for CS should be considered individually. One way to minimise the indications for CS is a more accurate diagnosis and personalised treatment of fatigue in pregnant women with MS. Presumably, both obstetricians and neurologists prefer vaginal delivery as the first choice in patients with fatigue syndrome.

Conflicts of Interest

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Preventive Neurology

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Is metformin a super-drug?

Barts-MS rose-tinted-odometer: ★★★★★ (skoda baby pink Wednesday #cca49a)

Should we all be taking metformin? As you know metformin is being tested in a remyelination therapy trial in MS; it rejuvenates senescent oligodendrocyte precursors making them more likely to make myelin.

The biology of metformin is fascinating as it also activates NRF2 the master transcription factor for programmed cell survival, which downregulates NFKappa-B the master pro-inflammatory transcription factor. I was surprised to find this paper below which shows the anti-ageing effects of metformin are not only limited to the brain but the thymus and the immune system as well.

Please note that ketogenic diets and fumarates (dimethyl fumarate and diroximel fumarate) also transactivate NRF2 and are potentially anti-ageing. It is a great pity Biogen pulled the plug on the DMF secondary progressive MS trial. I think we should revisit fumarates in progressive MS in combination with other potential agents that target mechanisms that drive smouldering MS.

The question I have is that in addition to a ketogenic diet should we all start taking metformin like so many other biohackers* are doing?

*Biohacking, also known as human augmentation or human enhancement, is do-it-yourself biology aimed at improving performance, health, and wellbeing through strategic interventions.

Fahy et al. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell. 2019 Dec;18(6):e13028. doi: 10.1111/acel.13028. Epub 2019 Sep 8.

Epigenetic “clocks” can now surpass chronological age in accuracy for estimating biological age. Here, we use four such age estimators to show that epigenetic aging can be reversed in humans. Using a protocol intended to regenerate the thymus, we observed protective immunological changes, improved risk indices for many age-related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (-2.5-year change compared to no treatment at the end of the study). The rate of epigenetic aging reversal relative to chronological age accelerated from -1.6 year/year from 0-9 month to -6.5 year/year from 9-12 month. The GrimAge predictor of human morbidity and mortality showed a 2-year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment. This is to our knowledge the first report of an increase, based on an epigenetic age estimator, in predicted human lifespan by means of a currently accessible aging intervention.

Conflicts of Interest

MS-Selfie Newsletter / MS-Selfie Microsite

Preventive Neurology

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