Reflections on 2020 and a quick look forward to 2021

During my physical rehabilitation exercise session yesterday I realised that I have not reflected on the New Year from an MS or personal perspective be it MS research, MS clinical practice or my personal life. I suspect I have been distracted by my injuries and recovery and that the COVID-19 pandemic has pushed the New Year transition into the future. The political mayhem across the world has also hijacked my attention and as a result, I have wasted many unproductive hours reading, listening to and watching the news. Putting these issues aside there are several MS-related questions that I have asked myself that we need to address in 2021.    

Do my posts still need a rose-tinted-odometer? 

We now live in a world where information is walled-in and that most people only consume information, which is consistent with their worldview – the so-called echo-chamber phenomenon. People with MS who read this blog should be able to handle any type of post; they come here to hear what we have to say, be it sugar-coated or not. I am therefore ditching the odometer. I hope you agree!

Should we continue to challenge the dogma? 

As with any specialist field, multiple sclerosis is wrapped in a cloak of dogma that largely dictates the research agenda. It is always important to challenge the prevailing dogma and to think laterally. The latter is particularly important when it comes to preventing MS. Yes, I do think MS is caused by EBV and there is now a groundswell of people within the MS community who think so as well. So this year will be one in which we focus on EBV and how we can target it to treat and prevent MS.

Another theory that we actively promote is the memory B-cell hypothesis, which overlaps with EBV biology. The B cell hypothesis is not new and underpins many of our current DMTs and a potential new class of treatment, namely the BTK inhibitors (BTKi). The CNS penetrant BTKi also inhibit activated microglia and macrophages and hence may help address the ‘hot microglial’ hypothesis of progressive MS. The latter hypothesis is based on the observation that people with progressive MS have extensive activation of the innate immune system in their brains and spinal cords, which may be responsible for the neurodegeneration that characterizes progressive MS. I have previously argued that this may not necessarily be the case as innate immune responses may be secondary to what is causing MS and may be part of repair response. The good news is that three phase-3 trial programmes of BTKi in MS have already started. This is also an acknowledgement by Big Pharma that we need to go beyond our current DMTs. In other words, there is still a lot to do when it comes to managing MS optimally. 

Smouldering MS is a rebranded old hypothesis that will continue to dominate MS debates this year. Essentially it states that focal inflammation is not MS, but rather the immune system’s response to what is causing MS and that our therapeutic targets should include the processes that are downstream of inflammation that have been identified to drive smouldering disease.

In 2021 we will continue to promote and investigate smouldering disease and help develop the therapeutic paradigm for testing add-on or combination therapies. The hurdles or obstacles to making this a reality are not insurmountable, but we clearly need a consensus from all MS stakeholders that this is what we want to do and to get the regulators on board. 

Will we be able to close the loop on several hypotheses we have been pushing? 

The short answer is yes for some and no for others. Getting funding, setting-up, starting and then completing clinical trials takes time. The good news is that as part of our #ThinkHand campaign the ORATORIO-HAND or O’HAND study (ocrelizumab in  PPMS) started last year and despite some delays in recruitment due to COVID-19 should fully recruit this year. Prof K  tells me that first-patient for the CHARIOT-MS trial should be randomised in the first quarter of this year. 

Some other good news is that our Under&Over remote hand rehabilitation trial will start in the next few weeks. This is will be testing whether a simple, but engaging, dexterity task can maintain or improve hand-function in people with late-stage MS. This study will be testing the ‘use it or lose it’ hypothesis, something I now know from personal experience to be true. 

Other studies that we are involved in that will start this year includes STAR-MS, which compare HSCT to alemtuzumab or ocrelizumab. This study may help address the B-cell versus T&B-cell hypothesis, which I support; i.e. it is not enough to target B-cells only. To manage MS you need to target both B and T cells. 

We will watch on the sidelines to see how the DELIVER-MS and TREAT-MS trials recruit. In DELIVER-MS (NCT03535298) subjects are being randomized either to a maintenance-escalation or an early high-efficacy treatment approach (flipping the pyramid). In comparison, TREAT-MS  (NCT03500328) is evaluating subjects with higher and lower risks of disability accumulation whether an escalation approach or early highly effective therapy (flipping the pyramid) influence disability. TREAT-MS is also comparing disability risk between individuals who switch from a first-line medication to a highly effective medication (escalation) versus those who switch to another first-line therapy (horizontal switching or cycling).  

We designed a NEDA trial back in 2014 to test treat-2-target of NEDA versus standard of care but soon realised that at Barts-MS we didn’t have equipoise and felt it would not be ethical to randomise our patients to a trial of this nature, which is why we personally didn’t progress the trial. We think the data is so compelling in relation to rapid vertical escalation or flipping-the-pyramid, compared to the ‘standard step-care’ approach, that pwMS should be given a choice in how they want their MS to be treated. 

In 2021 I would argue that in most MS centres the ‘step-care’ or ‘slow-escalation’ approach to DMTs is not standard of care anymore. Rapid vertical escalation or flipping-the-pyramid in the context of informed- and/or guided-choice is the new ‘standard-of-care’ when it comes to treating active MS. 

Clearly, as our ideas have evolved since 2014 I would argue that the new frontier is going beyond NEIDA (no evident inflammatory disease activity) and targeting the end-organ. Normalising brain and spinal cord volume loss and protecting the reserve capacity of the CNS for healthy normal ageing should become our new treatment target. This is why we have extended our MS Brain Health campaign to the general population, i.e. #ThinkBrainHealth.

Why did MS remyelination trials fail? 

2020 saw the failure of three remyelintion strategies; high-dose biotin, bexarotene and opicinumab (anti-LINGO-1). Most people have dismissed the high-dose biotin trial as targeting people with MS in whom the MS pathology was too advanced to modify; most of the subjects in the trial had an EDSS or 6.0 (unilateral support to walk 100m) or 6.5 (bilateral support to walk 10m). The bexarotene trial was negative, but a per protocol subgroup analysis showed a positive treand, but was underpowered. Despite this weak efficacy signal the drug had too many adverse events to be taken forward. The opicinumab or anti-LINGO-1 trial was the most dissappointing as it was backed by good science, a positive proof of biology and a phase 2 study that suggested a sweet spot for remyelination, i.e. patients who were disabled by MS, but not too disabled, and had MRI evidence of demyelination. We really need to look at the opicinumab study results in greater detail to find out why the study failed. Was it the biology (wrong target), the molecule (non-CNS penetrant), the population (too old or not disabled enough) or the trial design (wrong outcome measure)? If we don’t learn from these negative studies we won’t progress the field and are likely to make the same mistakes again in the future. 

The question we need to ask ourselves in the MS community is whether or not persistent demyelination is a problem in MS? Just maybe the dogma is wrong and remyelination is not necessary in MS. When you suppress ongoing inflammation in people with active MS the lesions remyelinate spontaneously. Yes, we know that the remyelination processes slow down and eventually fail with increasing age.

Ageing is the next biological frontier in MS and other fields; we may have to reverse the biology of senescence with dietary manipulations or drugs (e.g. metformin) and to then repeat the remyelination experiment. So this year we will hopefully see a phase 2 combination therapy trial of metformin (anti-ageing)  and clemastine a centrally-acting anticholinergic remyelination therapy start.

We will also see phase 2 results of the elezanumab (ABT-555)  trial reported this year.  Elezanumab is a monoclonal antibody that inhibits or blocks the repulsive guidance molecule A (RGMa). Inhibiting RGMa promotes remyelination, axonal sprouting and synapse formation. The basic science underlying RGMa, particularly from spinal cord injury models, is very compelling. Will the elezanumab trial be able to answer the fundamental question about whether or not remyelination and neurorestoration are realistic treatment target in MS? I would give the odds of this trial being positive at slightly over 50%; maybe 55%.

Why are social determinants of health so important?

I have personally been interested in the social determinants of health (SDoH) for several years and I am convinced they affect MS outcomes. To that effect, we have produced some preliminary evidence from our own centre showing that social capital, one of the SDoH, improves MS outcome. We have therefore been fortunate to get funding for a PhD student to study the impact that our public engagement programme has on social capital in our own patients. I see a future when social prescribing will be part of the service we provide to pwMS to improve their longterm disease outcomes. 

It is clear that inequality, one of the major SDoH, explains a lot when it comes to health outcomes and mortality. It is worth noting that COVID-19 pandemic has exposed the brutality of inequality in our societies and this will hopefully be a turning point for politicians to do something about this scourge. When the dust settles post-COVID-19 and the data comes in I am confident that we will see the impact inequality has had on pwMS during the pandemic. 

So yes, 2021 will be the year when our #ThinkSocial campaign will be given some teeth.

Can we listen, watch, experience or do and learn?

I think most readers have heard enough about my accident, resuscitation, acute management, inpatient stay, rehabilitation and now my recovery. The reason for publising my story was to help raise money for our Barts-MS COVID-19 antibody study. To this aim the information campaign was a great success and I would like to thank you once again for generously donating money towards our study. 

However, my brush with mortality and exposure to the NHS as a patient has taught me that healthcare services need to learn from each other. What can we adopt from acute medicine and surgery services and their service design to improve what we have to offer pwMS? This is something I will try and do once I am back at work next month. 

My COVID-19 prehabilitation programme was one of the reasons I got so lucky and I am convinced is one of the reasons why I am recovering so well after the accident. I am confident that by the end of the month my physical rehabilitation will be sufficient enough for me to go back to work in February. 

When I wrote about prehabilitation early during the COVID-19 pandemic it was to try and get the wider MS community to improve their general health so as to maximize their chances of doing well in the event of them getting COVID-19. As a result of my prehabilitation post, I decided to walk-my-talk. This motivated me to get physically fit, yes marathon fit, lose weight and in general optimise my sleep, diet, blood pressure, etc. I even experimented with biohacking, i.e. trying a low carbohydrate ketogenic diet and intermittent fasting. I am now a biohacking convert and think we need to study ketogenesis as a potential DMT in pwMS.

Finally, what has allowed me to do this was time; not travelling, spending quality time at home and thinking. Hopefully, my musings and reflections will allow me to focus on the research questions above and make the many changes I have made to my life during the pandemic a habit. 

Thank you

I also want to thank the Barts-MS team who have been quite amazing in rising the unique clinical and research challenges last year threw at us. We have not come out unscathed, but I think we will be leaner and wiser when we tackle the challenges of 2021.

Happy New Year. 

Twitter: @gavinGiovannoni                                     Medium: @gavin_24211

MSIF updates its international COVID-19 advice

The new MSIF International COVID-19 guidelines have just been published.

CoI: multiple

Re Private Healthcare Workers and Carers

There has been a lot of comments on this blog about private carers and private healthcare workers not been eligible for COVID-19 vaccination under the current NHS England vaccine priority system.

I have just discovered that government guidelines don’t distinguish between public or private employees. So if you are an active healthcare worker, working in the private sector, you are eligible for the vaccine. All you need to do is call your GP and book an appointment for a vaccination. I assume if your GP doesn’t know you very well you may need to provide some form proof of your type of employment.

I would expect the same rules to apply to carers of very vulnerable people with MS. So if you are a carer and look after vulnerable people with MS and are employed privately you also need to contact your GP to make an appointment to be vaccinated. You don’t want to be responsible for potentially infecting the person you care for with coronavirus.

It is important to stress that the whole purpose of the priority vaccination programme is to protect vulnerable people from COVID-19, to protect the NHS and to save lives. It is now obvious to me that this applies to both public and private sector workers.

If your GP refuses to offer you a vaccine I suggest reiterating the above and letting us know how it goes.

How is your end-organ functioning?

Barts-MS rose-tinted-odometer: ★

My prediction or dream for 2021 is that smouldering MS will be accepted by the wider MS community as being the ‘real MS’ and that simply suppressing the immune response to what is causing MS, i.e. relapses and/or focal MRI activity, will be accepted as folly. What matters most to pwMS will be their end-organ, i.e. the size, reserve capacity and function of their brains and spinal cords. 

In the same way as patients with a chronic heart or kidney disease ask their cardiologists or nephrologists what is my cardiac ejection fraction or creatinine clearance, markers of end-organ function of the heart and kidneys, respectively, I suspect pwMS will be asking what is the current state of their brains and spinal cords and how has the measures changed from last year. To answer our patients’ questions we are going to have much better functional and structural outcome measures or just maybe patients will be telling us how they are doing via their own self-monitoring initiatives.

The two studies below one looking at the thickness of retinal layers in the eye and the other the size of the thalamus, or deep grey matter structures, in the brain, show that loss of neurons or atrophy predicts future disability.  The problem I have with anatomical studies is that by the time you measure and show loss of neurons or atrophy it is too late, i.e. the damage is done and is irreversible. There is data out there that shows loss of function precedes the loss of neurons and that some of the early loss of function may in fact be reversible. Therefore we are going to need to measure function as well as structure. 

It is clear that our current clinical outcome measures are too insensitive to change, which is why we are going to need more sensitive and frequent monitoring of function to get on top of smouldering MS. The question is ‘so what if you detect subclinical worsening of function in MS what are you going to do about it?’. In the future, we will be adding-on new therapies to existing anti-inflammatory DMTs that will allow us to go beyond NEIDA (no evident inflammatory disease activity) to tackle smouldering MS. I am acutely aware that we are not there yet when it comes to combination therapies, but that is clearly the direction of travel the MS community is heading. Let’s hope the regulators agree and support the emerging development framework for combination therapies and allow us to start as many trials as soon as possible.

So if you are an MSologist and are reading this post don’t be too surprised if your patients start demanding more detailed functional and structural monitoring of their brains and spinal cords. Wouldn’t you if you had MS?

Retinal thinning in MS

Maria Cellerino et al. Relationship Between Retinal Layers Thickness and Disability Worsening in Relapsing-Remitting and Progressive Multiple Sclerosis. J Neuroophthalmol. 2020 Dec 29. 

Background: Data regarding the predictive value of optical coherence tomography (OCT)-derived measures are lacking, especially in progressive multiple sclerosis (PMS). Accordingly, we aimed at investigating whether a single OCT assessment can predict a disability risk in both relapsing-remitting MS (RRMS) and PMS.

Methods: One hundred one patients with RRMS and 79 patients with PMS underwent Spectral-Domain OCT, including intraretinal layer segmentation. All patients had at least 1 Expanded Disability Status Scale (EDSS) measurement during the subsequent follow-up (FU). Differences in terms of OCT metrics and their association with FU disability were assessed by analysis of covariance and linear regression models, respectively.

Results: The median FU was 2 years (range 1-5.5 years). The baseline peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell + inner plexiform layer (GCIPL) were thinner in PMS compared with RRMS (P = 0.02 and P = 0.003, respectively). In the RRMS population, multivariable models showed that the GCIPL significantly correlated with FU disability (0.04 increase in the EDSS for each 1-μm decrease in the baseline GCIPL, 95% confidence interval: 0.006-0.08; P = 0.02). The baseline GCIPL was thinner in patients with RRMS with FU-EDSS >4 compared with those with FU-EDSS ≤4, and individuals in the highest baseline GCIPL tertile had a significantly lower FU-EDSS score than those in the middle and lowest tertile (P = 0.01 and P = 0.001, respectively). These findings were not confirmed in analyses restricted to patients with PMS.

Conclusions: Among OCT-derived metrics, GCIPL thickness had the strongest association with short-medium term disability in patients with RRMS. The predictive value of OCT metrics in the longer term will have to be further investigated, especially in PMS.

Thalamic atrophy in MS

Burggraaff et al. Manual and automated tissue segmentation confirm the impact of thalamus atrophy on cognition in multiple sclerosis: A multicenter study. Neuroimage Clin. 2020 Dec 25;29:102549.

Background and rationale: Thalamus atrophy has been linked to cognitive decline in multiple sclerosis (MS) using various segmentation methods. We investigated the consistency of the association between thalamus volume and cognition in MS for two common automated segmentation approaches, as well as fully manual outlining.

Methods: Standardized neuropsychological assessment and 3-Tesla 3D-T1-weighted brain MRI were collected (multi-center) from 57 MS patients and 17 healthy controls. Thalamus segmentations were generated manually and using five automated methods. Agreement between the algorithms and manual outlines was assessed with Bland-Altman plots; linear regression assessed the presence of proportional bias. The effect of segmentation method on the separation of cognitively impaired (CI) and preserved (CP) patients was investigated through Generalized Estimating Equations; associations with cognitive measures were investigated using linear mixed models, for each method and vendor.

Results: In smaller thalami, automated methods systematically overestimated volumes compared to manual segmentations [ρ=(-0.42)-(-0.76); p-values < 0.001). All methods significantly distinguished CI from CP MS patients, except manual outlines of the left thalamus (p = 0.23). Poorer global neuropsychological test performance was significantly associated with smaller thalamus volumes bilaterally using all methods. Vendor significantly affected the findings.

Conclusion: Automated and manual thalamus segmentation consistently demonstrated an association between thalamus atrophy and cognitive impairment in MS. However, a proportional bias in smaller thalami and choice of MRI acquisition system might impact the effect size of these findings.

CoI: multiple

Twitter: @gavinGiovannoni                                       Medium: @gavin_24211

#MSCOVID19: antigenic sin

Barts-MS rose-tinted-odometer: zero-★s

The scale and intensity of the 2nd or 3rd wave of COVID-19 in London, the SouthEast of England and now in the remainder of the UK is worrying. It is being blamed on a new more infectious ‘British’ variant of SARS-CoV-2. This variant has many more mutations in its RNA genome and resulting changes in its protein structure. Most pundits are confident that this variant is not an immune-escape variant, i.e. that anti-viral immunity to the original SARS-CoV-2 via wild-type natural infection or a vaccine will work against the new variant. Their position is based on the observation that only one epitope (area of the spike protein) has been altered and that immunity to the remainder of the spike protein will be sufficient to provide immunity. 

Until basic lab work is done using animal and cell culture models we can’t assume the above as fact. Therefore, I am going to propose a contrary position that until proven otherwise we need to entertain the possibility that this new variant of SARS-CoV2 is an immune-escape variant. What I mean is that pre-existing immunity, and by implication vaccine immunity, to the original SARS-CoV-2 spike protein may not be sufficient to stop its spread or being reinfected with the new variant. 

The immune system is a remarkable thing. It has mainly evolved to protect us from infections and has multiple intricate systems to detect and respond to novel infections. However, coronaviruses are low fidelity viruses and don’t have mechanisms for checking how accurately their genomes are copied. As a result, they are highly mutagenic. Within the body, there is this evolutionary race between the virus and the immune system. As the body neutralises a specific variant of the virus, new variants or mutants that are able to avoid being neutralised escape and multiply and are selected to dominate. This is almost certainly how the new more infectious British and South African variants emerged. The latter process is much more likely to happen in people who are immunocompromised and have defects in innate or adaptive immunity that allow the virus to persist. We know this happens with SARS-CoV-2 it has recently been written up as a case report in the New England Journal of Medicine (see below). Please note how rapidly the virus mutated in this individual. 

The reason why I am proposing a contrary view is the fact that we were supposed to be getting towards some kind of herd immunity in London and this 2nd/3rd wave of COVID-19 seems oblivious to herd immunity and there are increasing anecdotal reports, which I am hearing via the grapevine, of people being infected twice. 

Another factor that needs more air time is the immunological phenomenon called antigenic sin. This is when the immune response to one variant or strain of a virus increases your chance of symptomatic infection and/or severe infection with a second variant or strain. The best example of this is Dengue fever, which is caused by an arbovirus (transmitted by mosquito bite). There are different subtypes of dengue virus. If you are infected with one subtype and develop antibodies to first subtype these antibodies (original antigenic sin) prevent an adequate immune response to subsequent infection with a different subtype of the virus. This results in subsequent dengue virus infections being more likely to be symptomatic and severe. 

Is it possible that immunity to the original SARS-CoV-2 wildtype virus is selecting for infection with (preexisting antibodies may actually enhance infection) and shedding of the new strain and driving the 2nd/3rd wave of COVID-19? This infection and shedding do not necessarily have to be occurring in people with symptomatic COVID-19; this could be asymptomatic shedding. I am aware that public health officials are simply saying the new strain has a higher R-number and hence is more infectious, which is their explanation for the new rise in COVID-19 cases numbers. However, until we have lab-based hardcore virology data we need to entertain the possibility that the new variants may be immune-escape variants and/or original antigenic sin is neutralising or cancelling-out pre-existing herd immunity. In the latter context, herd-immunity may actually be acting as a catalyst for the new wave of infections. 

This is why we need to take this third lock-down seriously and wait for the data to emerge to refute these hypotheses or to confirm them. This clearly has major implications for how we manage the pandemic going forward. In hindsight, we should have been much more vigilant about the management of immunocompromised patients with COVID-19 as they are likely to be the source of these new variants. 

P.S. I estimate that likelihood of the above hypotheses being correct is low (<10%) and hence this post is a low-likelihood scenario and is simply a counterbalance to the current public health dogma.

Choi et al. Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host. N Engl J Med. 2020 Dec 3;383(23):2291-2293. doi: 10.1056/NEJMc2031364. Epub 2020 Nov 11.

Figure 1. SARS-CoV-2 Whole-Genome Viral Sequencing from Longitudinally Collected Nasopharyngeal Swabs. Shown is a maximum-likelihood phylogenetic tree with patient sequences (red arrow) at four-time points with high levels of SARS-CoV-2 viral loads.

Weisblum et al. Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants. Elife. 2020 Oct 28;9:e61312. doi: 10.7554/eLife.61312.

Neutralizing antibodies elicited by prior infection or vaccination are likely to be key for future protection of individuals and populations against SARS-CoV-2. Moreover, passively administered antibodies are among the most promising therapeutic and prophylactic anti-SARS-CoV-2 agents. However, the degree to which SARS-CoV-2 will adapt to evade neutralizing antibodies is unclear. Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, we show that functional SARS-CoV-2 S protein variants with mutations in the receptor-binding domain (RBD) and N-terminal domain that confer resistance to monoclonal antibodies or convalescent plasma can be readily selected. Notably, SARS-CoV-2 S variants that resist commonly elicited neutralizing antibodies are now present at low frequencies in circulating SARS-CoV-2 populations. Finally, the emergence of antibody-resistant SARS-CoV-2 variants that might limit the therapeutic usefulness of monoclonal antibodies can be mitigated by the use of antibody combinations that target distinct neutralizing epitopes.

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211

What is your ACB?

ACB = anticholinergic burden

Barts-MS rose-tinted-odometer: ★

“I had no idea oxybutynin and other anticholinergics affected cognition to such an extent” is the standard response I get when I discuss the impact of the most commonly prescribed drugs for MS-related bladder problems (urgency and frequency). The older the bladder drug the more likely it is to cross the blood-brain barrier and affect cognition. Oxybutynin, for example, reduces IQ or cognition by a half a standard deviation, or approximately 7 points on the standardised IQ scale. Although I stopped prescribing oxybutynin decades ago it is often still prescribed.

And it is not only common bladder medications that have anticholinergic effects the list, which is long, also includes tricyclic antidepressants and over the counter anti-histamines. Tricyclic antidepressants are often prescribed to help pwMS with pain and are used as sedatives. It is remarkable how often neurologists and pain doctors reach from the prescription pad to prescribe amitriptyline to their patients. I think it is time for us to step back from this practice as we now have other options or better medication with less off-target anticholinergic effects. 

It is also worth noting that exposure to anticholinergics increases your risk of developing dementia. There have been several population case-control studies showing this. As MS affects cognition I suspect the MS brain is more vulnerable to the effects of anticholinergics and hence we may have inadvertently been exacerbating MS dementia. It is time for us to reevaluate how we manage bladder dysfunction and other symptomatic problems in MS and avoid prescribing drugs with anticholinergic effects. 

The study below compared a relatively new class of drug represented by mirabegron that works on the so-called beta-3 adrenergic receptor and showed it was as effective as anticholinergic drugs in controlling bladder symptoms in MS. However, as it is a newer drug it is more expensive than the commonly prescribed anticholinergics and GPs, therefore, are often reluctant to prescribe mirabegron. The question I ask is if they had MS and bladder dysfunction, which agent would they like to be on. I bet mirabegron would be their choice. ‘Prescribe for your patients what you would want to be prescribed to you’ is a maxim that should be commonly used by doctors.

Anticholinergics also make MS-related constipation worse and cause dryness of the mouth that is often the most common adverse effect that causes patients to stop taking their medication. 

Another trend has been the off-label prescribing of anticholinergic agents to promote remyelination, in particular, the drug clemastine. The clinical data on clemastine is at present rather weak and we need to wait for further trials to try and confirm preliminary results in pwMS. In addition, you may not need to take clemastine for prolonged periods of time to promote remyelination as once the demyelinated areas are remyelinated the drug could theoretically be stopped. So I don’t advocate the off-label use of clemastine or benztropine, another remyelinating anticholinergic, in pwMS because of the downside of cognitive impairment for questionable benefits in relation to remyelination. 

Can I suggest you review your symptomatic medications and ask yourself what your anticholinergic burden (ABC) is and if it is high you should review your medication with your MS team to see if anything can be done to reduce the burden on your brain? There is an online ACB (anticholinergic burden calculator)  that makes this task relatively easy and provides you with a risk score. Although this calculator was created for confusion, falls and death in the elderly it is still useful to give you an idea of your anticholinergic burden. Any score of 3 or higher is undesirable. 

I would be interested to know if any of you have stopped taking and anticholinergic and noticed an improvement in your cognition? 

Glykas et al. B3 agonists or anticholinergics in the treatment of the lower urinary tract dysfunction in patients with multiple sclerosis?-A randomized study. World J Urol. 2021 Jan 2. doi: 10.1007/s00345-020-03555-8. 

Introduction and objective: Multiple sclerosis (MS) is the most frequent autoimmune demyelinating disease of the central nervous system. MS patients usually present with lower urinary tract dysfunction (LUTD). Objective of this study is to evaluate and compare the efficacy and safety of treating MS patients with LUTD with either a b3 agonist (mirabegron) or anticholinergics. The study’s primary outcome is the LUTD symptom improvement.

Material and methods: This is a multi-center, single-blinded, comparative study including 91 MS patients with LUTD. At baseline, patients underwent thorough clinical examination, urine cultivation and abdominal ultrasound and completed urination diaries and specific, validated questionnaires (NBSS, MusiQoL). At second visit, patients were administered either mirabegron or anticholinergics. Treatment was always carried out alongside with MS treatment. Reevaluation was performed 3 months after first visit. Patients underwent the same clinical and imaging tests that were carried out at first visit.

Results: We compared several clinical and imaging parameters between the two groups at first visit and month 3 after treatment. Νo statistical difference was noted between the mirabegron group and the anticholinergic group in terms of LUTD improvement. In both groups, improvement from baseline regarding LUTD was recorded. Statistical analysis was performed using the paired and unpaired t test method. No patient discontinued either medication due to side effects.

Conclusions: MS patients receiving either mirabegron or anticholinergic therapy for LUTD showed improvement. Nevertheless, no statistical difference was noted between the two cohorts at 3 months in terms of drug efficacy in all the statistically significant parameters.

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211

A time to cry and a time to laugh

Barts-MS rose-tinted-odometer: ★

When I met her for the first time she was in her early fifties. She had had multiple sclerosis for over 20 years. Her family now kept her at home; isolated from the wider world. Her behaviour would embarrass them. Why? She suffered from pathological laughter and occasionally inappropriate crying and her husband and children could not deal with this in public. It was clear she was very disabled when I met her in the clinic; she was unsteady on her feet, had a slurred speech and dancing eyes from cerebellar problems. She had gross cognitive impairment. When I had introduced myself to her she had burst into tears. Within in two to three months of starting sertraline, a selective serotonin reuptake inhibitor (SSRI), her husband informed me that her laughing and crying episodes had improved by over 50% and the family were now taking her out on a regular basis. He was very grateful that I had been able to educate them about her symptoms and more importantly been able to help her and them as a family deal with this problem.

Pathological or inappropriate laughing and crying are common in pwMS; it is defined as an emotional expression that is exaggerated or incongruent with underlying mood. From my experience, it is much commoner than studies suggest it is and if you ask about the symptom many pwMS suffer from a mild form of it. 

In short inappropriate laughing and crying is due to frontal lobe or brainstem damage as a result of MS and in my experience is associated with cognitive and mood problems. It is important to realise that inappropriate laughing and crying are symptoms of MS as that they respond to tricyclic and SSRI antidepressants and a combination pill that includes dextromethorphan/quinidine (Nuedexta®). 

The medical or neurological name for inappropriate laughing and crying is a ‘pseudobulbar affect’ and is diagnosed using standardised scales or questionnaires, which can be self-administered. 

I would be interested to know how many of you have inappropriate laughing and crying and how disruptive these symptoms are to your life? Does your MS team ask about these symptoms and have you been offered a screening questionnaire for this problem? If you have been diagnosed as having a pseudobulbar affect have you been treated for it, what treatments did you receive and how have you responded to these treatments? 

You may realise that inappropriate laughing and crying in pwMS are another two neglected symptoms that often go undetected and untreated in many pwMS. This doesn’t have to be the case.

Hanna et al. The association of pathological laughing and crying and cognitive impairment in multiple sclerosis. J Neurol Sci. 2016 Feb 15;361:200-3.

Background: Pathological laughing and crying (PLC) is common in multiple sclerosis (MS), defined as emotional expression that is exaggerated/incongruent with underlying mood. In other neurological disorders, PLC is associated with cognitive impairment (CI). Few studies have examined this relationship in MS.

Objective: To determine the association between PLC and CI in an MS population.

Methods: Retrospective chart review study of 153 MS subjects assessed in an outpatient clinic for CI. Data was collected on the minimal assessment of cognitive function in MS (MACFIMS), the Center for neurological study-lability scale (CNS-LS), a screening measure for PLC symptoms and the hospital anxiety and depression scale (HADS). Analyses of covariance compared performance on the MACFIMS between PLC (CNS-LS score ≥ 17, HADS-D ≤ 7) and non-PLC groups.

Results: MS subjects positive for PLC on the CNS-LS but without depression had lower scores on the controlled oral word association test, a measure of verbal fluency, and the California verbal learning test – 2 immediate recall score, a verbal memory measure.

Conclusions: This study demonstrates a connection between CI, specifically verbal fluency and verbal learning, and PLC in MS subjects. Further studies are warranted to explore the causative relationship between CI and PLC.

CoI: multiple

Twitter: @gavinGiovannoni                               Medium: @gavin_24211

#MSCOVID19: yes, have the vaccine

Barts-MS rose-tinted-odometer: ★★★★★

Despite the long blog post that I called CATCH-22 I am still getting numerous emails and questions from patients with MS about whether or not they should have a COVID-19 vaccine.

YES, you should have the vaccine when it is offered to you. Clearly, timely access to the vaccine will depend on where you live, how vulnerable you are and the local, regional and national guidelines in place in your own country. 

The benefits of COVID-19 vaccination is time-sensitive and if you wait to be vaccine-ready you may inadvertently acquire the coronavirus infection and become really ill or when you are vaccine-ready the pandemic and the at-risk period may have passed. 

In my opinion, some immunity is better than no immunity and the blunted vaccine immunity on some DMTs may be sufficient to prevent you from becoming infected with SARS-CoV-2, developing COVID-19 and more importantly developing severe COVID-19. 

Are the vaccines safe? No vaccine is 100% safe, but the fact that the regulatory authorities have licensed these vaccines indicates that the benefits of the vaccine far outweigh the risks associated with the vaccine in the general population. At the moment the only relative contraindication to the Pfizer-BioNTech RNA vaccine is a history of severe atopy or allergies, i.e. people who carry around an epi-pen to prevent anaphylaxis in response to an environmental allergen.  

If you have any questions please read the CATCH-22 blog post, and our new advice here. If these don’t answer your question(s) we will try and address them below.

Crowdfunding: Are you a supporter of Prof G’s ‘Bed-to-5km Challenge’ in support of MS research?

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211

Unsteadiness

Barts-MS rose-tinted-odometer: ★★★★★

How many of you people who have MS (pwMS) have balance problems; i.e. when you stand and close your eyes or try and stand on one leg you tend to fall? 

Since my accident, I have been having problems with balance. I first noticed it when I tried to stand on one leg and I would feel unsteady. When walking to and from the bathroom at night I tend to veer to one side. I suspect my balance problems are due to vestibular problems as a result of my head injury and possibly due to my neck injuries. I say possibly due to my neck injury as the concept of cervical vertigo or cervicogenic unsteadiness is very controversial in neurology. But as there are specialised receptors in the neck that pick-up neck rotation it is possible that these have been affected by the injury and surgery.  

Despite my balance problems not affecting most things I do, it makes it difficult to complete what I call routine or standard daytime tasks. For example, getting dressed in the morning; when I put on underpants or trousers I have often have to sit down. Leaning forward to pick-up things off the floor is now very difficult I as I tend to tip forwards. I can’t stand on my tiptoes to get things off a high-shelf; I now have to use a chair. These things add up and are a sign that things are not right. 

I have never specifically focused on subtle balance issues in my MS clinic, which must be very common in pwMS. I would be interested to know if any of you suffer from balance problems? Have you been referred for a physical assessment? Have you has specific rehabilitation exercises to address the issue? Has the rehab helped?

It is clear that since I became aware of my balance issues and I have started doing specific exercises to address the issue, things have improved. I can now stand on either leg unsupported for over a minute when just a few weeks ago I could only manage to do this for a few seconds. Whether this will translate in better functioning remains to be seen. 

There are a number of well-established rehabilitation programmes that have been shown to help with balance problems. So my advice to you is rather than suffering in silence ask for an assessment and a referral for vestibular or balance rehabilitation. If you don’t try and correct the problem it is likely to get worse. And don’t accept no for an answer. There are also a lot of online tools available to help you with self-assessments and self-rehabilitation if you are that way inclined.

Kalron et al. The effect of balance training on postural control in people with multiple sclerosis using the CAREN virtual reality system: a pilot randomized controlled trial. J Neuroeng Rehabil. 2016 Mar 1;13:13. doi: 10.1186/s12984-016-0124-y.

Background: Multiple sclerosis (MS) is a multi-focal progressive disorder of the central nervous system often resulting in diverse clinical manifestations. Imbalance appears in most people with multiple sclerosis (PwMS). A popular balance training tool is virtual reality (VR) with several advantages including increased compliance and user satisfaction. Therefore, the aim of this pilot RCT (Trial registration number, date: ISRCTN14425615, 21/01/2016) was to examine the efficacy of a 6-week VR balance training program using the computer assisted rehabilitation environment (CAREN) system (Motek Medical BV, Amsterdam, Netherlands) on balance measures in PwMS. Results were compared with those of a conventional balance exercise group. Secondary aims included the impact of this program on the fear of falling.

Methods: Thirty-two PwMS were equally randomized into the VR intervention group or the control group. Each group received balance training sessions for 6 consecutive weeks, two sessions per week, 30 min sessions. Clinical balance tests and instrumented posturography outcome measures were collected upon initiation of the intervention programs and at termination.

Results: Final analysis included 30 patients (19 females, 11 males; mean age, (S.D.) = 45.2 (11.6) years; mean EDSS (S.D.) = 4.1 (1.3), mean disease duration (S.D.) = 11.0 (8.9) years). Both groups showed a main effect of time on the center of pressure (CoP) path length with eyes open (F = 5.278, P = .024), sway rate with eyes open (F = 5.852, P = .035), Functional Reach Test (F = 20.841, P = .001), Four Square Step Test (F = 9.011, P = .031) and the Fear of Falls self-reported questionnaire (F = 17.815, P = .023). In addition, significant differences in favor of the VR program were observed for the group x time interactions of the Functional Reach Test (F = 10.173, P = .009) and fear of falling (F = 6.710, P = .021).

Conclusions: We demonstrated that balance training based on the CAREN device is an effective method of balance training for PwMS.

Crowdfunding: Are you a supporter of Prof G’s ‘Bed-to-5km Challenge’ in support of MS research?

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211

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