Author: Gavin Giovannoni

Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

Lukewarm – lifestyle & wellness

Barts-MS rose-tinted-odometer: ★★

How brain-healthy is your lifestyle?

Someone asked yesterday why did I give George Jelinek’s book ‘Overcoming MS’ a positive review and yet we don’t promote it openly on the blog? Very simple our policy is not to advertise commercial products on this blog and if we promoted OMS then what about the other MS-related lifestyle and wellness programmes? I am still pissed off with myself for not making it clear that I don’t support the OMS diet. Yes, I support the principles of OMS in terms of lifestyle interventions, but I simply can’t support the OMS diet. The diet is simply not evidence-based. In fact, there is no ‘MS diet’ that is evidence-based so anyone who claims their diet needs to be followed to treat MS can’t be doing this from any position of authority.

So why did I give OMS a positive review?

The principles that underpin OMS are scientifically sound, but a lot of them are not evidence-based, i.e. they are not supported by randomised controlled trials. Some of the lifestyle recommendations in OMS are also quite extreme and hence are very difficult to follow. I view George Jelinek as the lifestyle-wellness equivalent of the ‘ultra-distance marathon runner’. You don’t need to run ultra-distance marathons to derive the benefits from running, some people do just fine on subscribing to and running regular 5km park runs. It is horses for courses. I think the important messages in OMS and other lifestyle-wellness programmes are:

Lifestyle-wellness interventions are not alternative medicine, but complementary; i.e. you need to do them in addition to taking for example DMTs.
Lifestyle-wellness interventions need to be personalised. In particular, they need to be affordable, compatible with your culture, your worldview and your belief systems.
Lifestyle-wellness interventions fall on a continuum they are not all or nothing phenomenon. You can engage with some aspects of a programme and not others. In other words, doing something is better than doing nothing.
You need to be self-motivated to stick to a healthy lifestyle and wellness programme. I think herein lies the secret of the success of the programmes. Setting goals and sticking to them is self-rewarding. The rewards centres in the brain make you feel good about yourself and motivate you further. The downside is that when you slip you have a sense of self-loathing and guilt. These emotions are part of the package; they are the regulatory or negative emotional feedback loop. My personal opinion is that slipping occasionally is fine, but you need to earn the off-days.
Lifestyle wellness programmes take a holistic view of the management of the disease. Saying this is easy, but it is very difficult to set up a lifestyle-wellness service in the NHS. What is the evidence and how do we show that the programme will be cost-saving to justify the investment? In addition, adherence rates to lifestyle-wellness interventions are very poor. This is a conundrum that challenges HCPs and behavioural psychologists but is not an insurmountable obstacle. There are examples that when politicians, HCPs and the general public get behind a national lifestyle and wellness programme it can work. A good example of this is what Finland has done at a population level over the last 20 years.
Lifestyle-wellness interventions should be adopted by everyone regardless of whether, or not, you have MS. This is why we set up the Barts-MS Brain Health challenge and why I started the Think Brain Health initiative. Getting HCPs to personally engage with their own Brain Health would make them think about their patients’ health. In addition, patients are more likely to take the advice seriously from a Brain Healthy HCP than from an HCP who is unhealthy. If you smoke, are unfit, overweight and eat badly how can you tell your patients to stop smoking, to start exercising, change their diet and lose weight? Unless you walk the talk you are not credible.
Most lifestyle-wellness interventions are common sense with an evidence base from outside the field of MS. However, like any other field, the lifestyle-wellness space is full of quacks and charlatans so be careful to accept anything at face value. Do your research and ask questions. For example, what is the evidence that you need to follow a gluten-free diet? Plant-based diet? Etc? Unless you have documented gluten sensitivity there is no evidence. Similarly, the war on fats, and saturated fats, is built on a very poor evidence base. It is clear that fats, and saturated fats, are not bad for you if eaten in moderation. I am sure more evidence will emerge around this issue in the next few years. It is clear that at present processed and ultra-processed foods are in the dog house and justifiably so. I am adamant that what you eat needs to be compatible with your culture which is why I wrote a piece on Medium about Diet as a Philosophy.
Please let common sense rule the day and if you find you like, and enjoy, walking or running 1 km or 5 km, who knows you may gradually extend your walks and runs to 10 km, half-marathons, marathons and possibly ultra-marathons. The intensity and distance are not that important it is getting started and staying committed that is important.

So I yes I have gone lukewarm on OMS because it is not the be-all and end-all of MS management. I have also heard from many independent sources that George Jelinek promotes it openly as an alternative option for the management of MS. I have seen many tragic examples of patients under my care who are now very disabled as a result of using lifestyle and wellness programmes as an alternative option to DMTs to manage their MS. OMS should only ever be used as a complementary MS management tool.

#MSCOVID19: adenoviral vector vaccines

Barts-MS rose-tinted-odometer: ★

You may have heard that the FDA has suspended dosing of the J&J COVID-19 vaccine as they have identified 6 cases of thrombosis in young woman similar to that described below with the Oxford-AstraZeneca vaccine (see articles below). It looks like the complication may therefore be due to the vectors, i.e. adenoviruses, rather than the SARS-CoV-2 spike protein. If this is the case there is likely to be similar cases identified with the Russian Sputnik V vaccine, which uses two different adenoviral vectors.

Please remember that this thrombotic complication is still very rare, i.e. likely to be less than 1 person affected in over 100,000 vaccinated people, which is why the EMA, MHRA and WHO have made it clear that the potential benefit of the Ox-AX vaccine outweighs the risk of thrombosis. In other words, the risk of getting COVID-19 is far worse than the risks associated with the vaccine. So our message remains the same; #GetVaccinatedASAP.

Thrombotic (blood clots) thrombocytopaenia (low platelets) is an immune-mediated condition, in which your own immune system makes antibodies against a protein called platelet factor 4 expressed on platelets. In other words, it is an antibody-mediated autoimmune disease. This will allow haematologists and vaccinologists to study the condition and work out why it is happening and then manage the risk or hopefully prevent it from happening in the future. For example, it could simply be due to molecular mimicry to a protein or stretch of protein in one of the adenoviral proteins that could be engineered out of the next generation of vaccines.

With my preventive medicine hat on I am concerned that this rare complication of the adenoviral vaccines will feed the anti-VAXX lobby and turn people off having the COVID-19 vaccine. This would be a great tragedy as it is the adenoviral vaccines that are going to save the world from this pandemic; they are relatively cheap and easy to manufacture and don’t have to be stored at -20 or -80. All these attributes make them the vaccines of choice for low and middle-income countries.

Please note I would not have a problem being vaccinated with a COVID-19 adenoviral vaccine nor would I have a problem recommending these vaccines to my family members.

Greinacher et al. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. 2021 Apr 9. doi: 10.1056/NEJMoa2104840. Online ahead of print.

Background: Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca). More data were needed on the pathogenesis of this unusual clotting disorder.

Methods: We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19. We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)-heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions. Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4-heparin immunoassay.

Results: Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49). Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage. Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died. Five patients had disseminated intravascular coagulation. None of the patients had received heparin before symptom onset. All 28 patients who tested positive for antibodies against PF4-heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin. Platelet activation was inhibited by high levels of heparin, Fc receptor-blocking monoclonal antibody, and immune globulin (10 mg per milliliter). Additional studies with PF4 or PF4-heparin affinity-purified antibodies in 2 patients confirmed PF4-dependent platelet activation.

Conclusions: Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia. (Funded by the German Research Foundation.).

Schultz et al. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N Engl J Med. 2021 Apr 9. doi: 10.1056/NEJMoa2104882. Online ahead of print.

We report findings in five patients who presented with venous thrombosis and thrombocytopenia 7 to 10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against coronavirus disease 2019 (Covid-19). The patients were health care workers who were 32 to 54 years of age. All the patients had high levels of antibodies to platelet factor 4-polyanion complexes; however, they had had no previous exposure to heparin. Because the five cases occurred in a population of more than 130,000 vaccinated persons, we propose that they represent a rare vaccine-related variant of spontaneous heparin-induced thrombocytopenia that we refer to as vaccine-induced immune thrombotic thrombocytopenia.

Under&Over: we need your help

Since being hit by a motorbike travelling at high speed and nearly losing my life or independence I now have personal experience of the value of physical neurorehabilitation. When I say #UseItOrLoseIt I really mean it. So if you have more advanced MS and are using a walking stick (EDSS 6.0) we want you to enrol in a #CitizenScience type study in which we are testing a new hand and arm activity called Under&Over to see if it can improve or maintain upper limb function. The study is titled: “Under & Over: A controlled study to develop an upper limb rehabilitation tool for people with Multiple Sclerosis.”

The Under&Over project is an extension of our #ThinkHand campaign, i.e. you are never too disabled to be treated with DMT and we are doing the O’HAND (ORATORIO-HAND) and CHARIOT-MS studies to test ocrelizumab and oral cladribine in people with more advanced MS with the primary outcome being the 9-hole peg test; an outcome measure of upper limb function. Under&Over is simply a form of upper limb exercise. However, to get the MS community to accept arm and hand rehabilitation as a treatment we need evidence from a controlled study. So without volunteers, without you, we won’t be able to generate the evidence to prove that we can protect upper limb function with exercise.

This study is now recruiting – find out more information on the study website.

This is part of our ThinkHand project which addresses the need for more resources, research and services to support upper limb function.

What is the purpose of the study?

The research is designed to find out whether repeated use of the Under & Over tool (pictured above) can improve upper limb function in people with MS. It is also designed to gather information about the long term use of the tool based on participants’ experiences and the use of a digital platform and community integration to support this.

Who can take part?

Men and women over 18 years can take part if:

You have a diagnosis of MS (more than 6 months)
You have internet access
You have an Expanded Disability Status Scale (EDSS) score of ≥6 as measured using the online WebEDSS
You understand and able to communicate in English

You will not be Eligible to take part if:

You are unable to use your hands because of pain or any other reason that might interfere with your ability to complete the intervention using the Under & Over device.

It is a fully remote study, so there are no clinical visits or examinations. All study resources are online or will be posted to your home. You just need to live in the UK.

A number of baseline questionnaires will gather initial data that we will compare with the same data gathered at the end of the study (cardboard 9 Hole Peg test, WebEDSS, ABILHAND questionnaire, MSIF and MSIS-29).

Following baseline assessments, everyone who agrees to take part in this study will be randomly assigned to one of two groups; one group will receive immediate intervention and the other group will receive the delayed intervention; this is called the wait-list control group. This means that they will receive access to the rehabilitation programme after a 3-month period. This way everyone who participates in the study will eventually get access to the rehabilitation programme.

Contact for further information about the study:

If you would like further information, answer to any questions or queries and would like to express interest to take part please contact the Under & Over Research Team (underandover@qmul.ac.uk) and read the participant information on the study website.

The aftermath

Barts-MS rose-tinted-odometer: ★★

I am increasingly being asked about what is going to happen to MS research and clinical services post-COVID-19. The question is being asked as if I am some kind of futurist or prophet. I am not. My response is let’s focus on the here and now. The following on the issues that need to be addressed this year:

Untreated or under-treated MS. There is has been a drop-off of about 30% of new-starts on DMTs. This means people with MS are waiting in queues to be diagnosed and offered treatment.
Far too few people with PPMS and SPMS have been through the screening pathways for potential treatment with ocrelizumab or siponimod, respectively. Some MS centres have yet to start their progressive treatment pathways.
Vaccine hesitancy: too many pwMS are refusing our offer for a COVID-19 vaccine. Why? What do we need to address vaccine hesitancy? The message #GetVaccinatedASAP is maybe too flippant and doesn’t take into account the complexity of the issues.
Neuro rehab: so many of my patients have deteriorated because their rehab services are on hold. Does the NHS have the capacity to deal with the backlog?
Mental health: so many of my patients have mental health issues as a result of lockdown. Who is managing this avalanche of depression and anxiety? What can we do about social isolation and loneliness?
Symptomatic therapies: where do I begin? The biggest one is bladder and muscle botox services. So many of my patients are waiting for these services to restart; they are in a desperate state with bladder problems and spasticity. Wheelchair services? Orthotics? Falls prevention? Bone health? Continence services? Swallowing assessments? Dietary advice? Comorbidity screening and management? Etc. It is not that these services are not running, however, many are running at half capacity and need really need to be face-2-face to be done properly.
Monitoring: so many patients are waiting for annual MRIs to assess treatment response? How many have EDA (evident disease activity) that is being missed? Cervical smears as part of cancer screening? Blood monitoring etc.?
Social services: how many people with MS are waiting for housing assessments or adaptions? How are we going to address social determinants of health? Poverty? Inequality? Addiction? Alcohol consumption has soared during the pandemic; pwMS are not exempt.

The other elephant in the room is the manpower shortage. Many NHS workers are taking early retirement because of burn-out. Yes, many of us are simply tired, depressed and worn out. How are we going to do more, much more, with less staff? This is not unique to MS but applies to the NHS in general.

Clearly, there is MS research that needs addressing. Many trials were halted or even terminated early because of COVID-19. Can we resuscitate these studies? Who is going to cover the funding shortfall to cover the extension costs of these trials?

I am told that charities are down about 40% in their fundraising. Less fundraising less priming of research ideas, less innovation.

At least the pandemic has driven a rapid adoption and investment in new technologies, which is likely to increase productivity in the future. I see no reason why the productivity gains won’t have a positive impact on MS services and research output.

One of the advantages of the pandemic is that I have had quite a bit of time to reflect on things and will come out of the COVID-19 more focused. I have learnt to say no and will continue to say no to many things related to MS. My time left to make a difference to MS research is relatively short and I want to make a real difference, which is why my focus is going to be on EBV, the viral aetiology of MS and MS prevention.

Please don’t get blinkered about the impact of DMTs on COVID-19 and vaccines; these ‘micro issues’ are really tiny relative to the ‘macro issues’ highlighted above. We seem to be missing seeing the forest for the trees. Yes, the mountain looks big and impossible to scale, but unless we start climbing it today we will never reach its summit.

Should we abandon the ADIOS study?

Barts-MS rose-tinted-odometer: ★★★

If you have been on ocrelizumab for two years would you be prepared to participate in the ADIOS (adaptive dosing ocrelizumab study)? One of the study arms would mean that you would not receive any ocrelizumab until you had a relapse or new MRI activity. In other words, we would be using ocrelizumab like we use alemtuzumab or cladribine, i.e. as an immune reconstitution therapy (IRT).

Some of our colleagues doubt whether people with MS would volunteer for such a study. I personally think they being affected by their own preconceived biases. We don’t know if we can use ocrelizumab or other anti-CD20 therapies as an IRT, which means we have equipoise. It is clear that using anti-CD20 therapy in this way will be safer, i.e. you would be less likely to develop hypogammaglobulinaemia and infections as a complication of continuous therapy. Similarly, the risk of secondary malignancies should be lower and you will be vaccine ready. The latest paper below shows that the time from the last dose of an anti-CD20 therapy predicts seroconversion after a COVID-19 vaccination; i.e. the longer you wait after a dose of rituximab, and probably ocrelizumab, the more likely you are to seroconvert after having the COVID-19 vaccine. I suspect going forward people on anti-CDC20 therapy may have to take drug holidays anyway to make sure they respond to vaccines. In fact, I was on a Medscape recording yesterday with a colleague from UCSF and a vaccinologist and they both said that most MSologists and rheumatologists in North America are already doing this. At the moment I have been saying get #GetVaccinatedASAP and cross the vaccine-readiness bridge when the boosters arrive. We will also have evidence, such as below, to guide us in the future.

Deepak P et al. Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2. MedRxiv https://doi.org/10.1101/2021.04.05.21254656.

The following data from Anat Achiron will hopefully be out as a pre-publication this week.

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Disclaimer: Please note that the opinions expressed in this blog post are those of Professor Giovannoni and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.