#MSCOVID19: vaccine hesitancy

Barts-MS rose-tinted-odometer: ★★★

She is in her early thirties and is a first-generation ethnic minority immigrant to the UK. She was diagnosed as having MS 6 months ago after presenting with optic neuritis and a subsequent spinal cord syndrome. She is due to start on ocrelizumab in the next few weeks, but we want to delay her start until she has her first dose of one of the COVID-19 vaccines. However, she doesn’t want the COVID-19 vaccine. She is worried that it will ‘affect her DNA and any children she may have in the future’. I spent a lot of time explaining to her that what she has been told about the vaccine affecting her DNA is incorrect and simply not possible biologically and therefore the vaccine will not affect any children she has in the future. Fortunately, a 30-minute phone call to this particular patient seems to have worked. She has now agreed to take-up one of our early Barts-MS vaccination slots next week.

The above scenario represents just one of the conspiracy theories doing the rounds on social media concerning different COVID-19 vaccines. It is clearly incorrect. Similarly, there are many other conspiracy theories about the vaccines that also need to be dispelled. 

The survey below done quite early in the pandemic shows that in the USA only two-thirds of pwMS were willing to have a COVID-19 vaccine. This figure is over 90% in the UK but is highly variable globally. Just across the channel in France, a recent Ipsos survey showed that just over 40% of people said they would have a COVID-19 vaccine. A recent Lancet study (see below) highlights the variation in attitudes to vaccinations across the world.

In the US survey below vaccine willingness, is associated with education level, perceived risk for COVID-19 infection, and trust in COVID-19 information sources. 

Among less-educated communities trust, like knowledge, is built socially. People are more inclined to believe what their friends tell them, either in person or on social media. Clearly, the downside of this is that conspiracy and anti-science theories spread. However, this also provides us with an opportunity to build trust where it is lacking. What we need are local vaccine influencers from ethnic minorities and other communities to come forward to have the vaccine and spread the word that they are safe and that by having them you are not only protecting yourself but the wider community from getting severe COVID-19 and potentially dying from it.

COVID-19 vaccination is about public health, saving lives, protecting the NHS and getting society and the economy back to normal or let’s hope a more compassionate new normal. 

Scientists, pharma companies, regulators, governments and the NHS have delivered us effective, safe and accessible vaccines, which is the only realistic way out of this pandemic. It is now up to the population to take up the offer of having the vaccine. We in the UK are in a very privileged position when it comes to COVID-19 vaccinations; you only have to watch the shenanigans going on politically in terms of ‘vaccine nationalism’ to appreciate the significance of this. 

So if you want to become a local COVID-19 vaccination champion please contact us (bartsmsblog@gmail.com)  we can provide you with the necessary information to educate your friends and family. I and my colleagues are also prepared to set-up and run online meetings to answer any questions you may have about COVID-19 and the available vaccines. 

Please feel free to share any conspiracy theories about COVID-19 vaccines that you have heard about. The point is not to just dismiss them but to discuss them and hopefully convince people that they are not a good reason not to have the vaccine.

We are in this mess together and we need to get of this mess together and that means not leaving people behind and vulnerable to COVID-19.

Global trends in perceptions towards the safety of vaccines in November, 2015, and November, 2018 (Figure from the Lancet)

Ehde et al. Willingness to obtain COVID-19 vaccination in adults with multiple sclerosis in the United States. Mult Scler Relat Disord. 2021 Jan 22;49:102788. 

Background: As vaccines for the coronavirus become available, it will be important to know the rate of COVID-19 vaccine acceptability in adults with multiple sclerosis (MS), given that vaccination will be a key strategy for preventing SARS-CoV-2 infections. Using a national sample of adults with MS in the United States obtained early in the COVID-19 pandemic, the current study aimed to: (1) assess willingness to get a COVID-19 vaccine when available; (2) determine demographic, MS, and psychosocial correlates of vaccine willingness; and (3) measure where people with MS get their COVID-19 information and their perceived trustworthiness of such sources, which may influence COVID-19 vaccine willingness.

Methods: Adults with MS (N = 486) living in the United States completed a cross-sectional online survey (between 10 April 2020 and 06 May 2020) about their willingness to receive a COVID-19 vaccination once available. Participants also completed measures to describe the sample and to assess factors potentially related to vaccine willingness, including demographics, MS-specific variables, psychological measures, COVID-19 information sources, and perceived trustworthiness of their information sources.

Results: Approximately two-thirds of the participants (66.0%) reported a willingness to obtain a future COVID-19 vaccine, whereas 15.4%of the sample was unwilling. Greater willingness to receive the vaccine was associated with having a higher level of education and holding a higher perception of one’s risk of catching COVID-19. Participants reported accessing COVID-19 information from many different sources. Approximately a third (31.6%) of the sample reported getting their information from healthcare providers. Healthcare providers and the National MS Society had the highest perceived trustworthiness for COVID-19 information. The perceived trustworthiness of information sources was highly associated with vaccine willingness.

Conclusion: Early in the pandemic, willingness to get a COVID-19 vaccine was not universal in this large sample or people living with MS. Vaccine willingness was associated with a few variables including education level, perceived risk for COVID-19 infection, and trust in COVID-19 information sources. These results have important implications for guiding healthcare providers and the MS community as COVID-19 vaccines become widely available.

Figueiredo et al. Mapping global trends in vaccine confidence and investigating barriers to vaccine uptake: a large-scale retrospective temporal modelling study. Lancet. 2020 Sep 26;396(10255):898-908.

Background: There is growing evidence of vaccine delays or refusals due to a lack of trust in the importance, safety, or effectiveness of vaccines, alongside persisting access issues. Although immunisation coverage is reported administratively across the world, no similarly robust monitoring system exists for vaccine confidence. In this study, vaccine confidence was mapped across 149 countries between 2015 and 2019.

Methods: In this large-scale retrospective data-driven analysis, we examined global trends in vaccine confidence using data from 290 surveys done between September, 2015, and December, 2019, across 149 countries, and including 284 381 individuals. We used a Bayesian multinomial logit Gaussian process model to produce estimates of public perceptions towards the safety, importance, and effectiveness of vaccines. Associations between vaccine uptake and a large range of putative drivers of uptake, including vaccine confidence, socioeconomic status, and sources of trust, were determined using univariate Bayesian logistic regressions. Gibbs sampling was used for Bayesian model inference, with 95% Bayesian highest posterior density intervals used to capture uncertainty.

Findings: Between November, 2015, and December, 2019, we estimate that confidence in the importance, safety, and effectiveness of vaccines fell in Afghanistan, Indonesia, Pakistan, the Philippines, and South Korea. We found significant increases in respondents strongly disagreeing that vaccines are safe between 2015 and 2019 in six countries: Afghanistan, Azerbaijan, Indonesia, Nigeria, Pakistan, and Serbia. We find signs that confidence has improved between 2018 and 2019 in some EU member states, including Finland, France, Ireland, and Italy, with recent losses detected in Poland. Confidence in the importance of vaccines (rather than in their safety or effectiveness) had the strongest univariate association with vaccine uptake compared with other determinants considered. When a link was found between individuals’ religious beliefs and uptake, findings indicated that minority religious groups tended to have lower probabilities of uptake.

Interpretation: To our knowledge, this is the largest study of global vaccine confidence to date, allowing for cross-country comparisons and changes over time. Our findings highlight the importance of regular monitoring to detect emerging trends to prompt interventions to build and sustain vaccine confidence.

CoI: multiple

Twitter: @gavinGiovannoni                               Medium: @gavin_24211

#MSCOVID19: backing another winner

Good news! Another UK-backed COVID-19 vaccine, developed by Novavax, proves to be a winner with a point estimate of vaccine efficacy of 89.3% and no cases of severe COVID-19 in those who received the actual vaccine. The vaccine also works against the UK and South African variants of the virus.

This vaccine is important because it is based on using a recombinant form of the spike protein produced in insect cells and not bacterial or mammalian cells, and uses a brand new adjuvant to boost the immune response.

Insect cells are interesting because they are really easy to grow and don’t necessarily require the same expensive infrastructure as other recombinant protein manufacturing platforms. This vaccine also needs very small amounts of the recombinant protein, making scale-up production easier. This new vaccine technology, similar to the RNA vaccines, will lower the entry-level for other vaccines in the future; for example, new SARS-CoV-2 variants and strains and just possibly EBV?

The UK Government has pre-purchased 60 million doses of the Novavax vaccine, which means the UK now have more than enough pre-ordered vaccine purchased for the UK’s population.

Importantly, the Coalition for Epidemic Preparedness Innovations (CEPI) funded the manufacturing of the vaccine for the phase 2b South African clinical trial (see below), which was supported in part by a $15 million grant from the Bill & Melinda Gates Foundation. This vaccine may therefore prove just as important as the Oxford-AstraZeneca vaccine for low and middle-income countries.

When historians write the history of the COVID-19 pandemic I have little doubt that Bill and Melinda Gates, as indiviudals, will be seen to have done more than any other individuals to tackle the pandemic globally. They are trying to ensure the vaccines are distributed across the world as equitably as possible. The same can’t be said for politicians in the rich world.

NOVAVAX PRESS RELEASE

UK Phase 3 Results: 89.3% Efficacy

The study enrolled more than 15,000 participants between 18-84 years of age, including 27% over the age of 65. The primary endpoint of the UK Phase 3 clinical trial is based on the first occurrence of PCR-confirmed symptomatic (mild, moderate or severe) COVID-19 with onset at least 7 days after the second study vaccination in serologically negative (to SARS-CoV-2) adult participants at baseline.

The first interim analysis is based on 62 cases, of which 56 cases of COVID-19 were observed in the placebo group versus 6 cases observed in the NVX-CoV2373 group, resulting in a point estimate of vaccine efficacy of 89.3% (95% CI: 75.2 – 95.4). Of the 62 cases, 61 were mild or moderate, and 1 was severe (in placebo group).

Preliminary analysis indicates that the UK variant strain that was increasingly prevalent was detected in over 50% of the PCR-confirmed symptomatic cases (32 UK variant, 24 non-variant, 6 unknown). Based on PCR performed on strains from 56 of the 62 cases, efficacy by strain was calculated to be 95.6% against the original COVID-19 strain and 85.6% against the UK variant strain [post hoc].

The interim analysis included a preliminary review of the safety database, which showed that severe, serious, and medically attended adverse events occurred at low levels and were balanced between vaccine and placebo groups.

“These are spectacular results, and we are very pleased to have helped Novavax with the development of this vaccine. The efficacy shown against the emerging variants is also extremely encouraging. This is an incredible achievement that will ensure we can protect individuals in the UK and the rest of the world from this virus,” said Clive Dix, Chair, UK Vaccine Taskforce.

Novavax expects to share further details of the UK trial results as additional data become available. Additional analysis on both trials is ongoing and will be shared via prepublication servers as well as submitted to a peer-reviewed journal for publication. The company initiated a rolling submission to the United Kingdom’s regulatory agency, the MHRA, in mid-January.

South Africa Results:   Approximately 90% of COVID-19 cases attributed to South Africa escape variant

In the South Africa Phase 2b clinical trial, 60% efficacy (95% CI: 19.9 – 80.1) for the prevention of mild, moderate and severe COVID-19 disease was observed in the 94% of the study population that was HIV-negative. Twenty-nine cases were observed in the placebo group and 15 in the vaccine group. One severe case occurred in the placebo group and all other cases were mild or moderate. The clinical trial also achieved its primary efficacy endpoint in the overall trial population, including HIV-positive and HIV-negative subjects (efficacy of 49.4%; 95% CI: 6.1 – 72.8).

This study enrolled over 4,400 patients beginning in August 2020, with COVID-19 cases counted from September through mid-January. During this time, the triple mutant variant, which contains three critical mutations in the receptor binding domain (RBD) and multiple mutations outside the RBD, was widely circulating in South Africa. Preliminary sequencing data is available for 27 of 44 COVID-19 events; of these, 92.6% (25 out of 27 cases) were the South Africa escape variant.  

Importantly in this trial, approximately 1/3 of the patients enrolled (but not included in the primary analyses described above) were seropositive, demonstrating prior COVID-19 infection at baseline. Based on temporal epidemiology data in the region, the pre-trial infections are thought to have been caused by the original COVID-19 strain (i.e., non-variant), while the subsequent infections during the study were largely variant virus. These data suggest that prior infection with COVID-19 may not completely protect against subsequent infection by the South Africa escape variant, however, vaccination with NVX-CoV2373 provided significant protection.

“The 60% reduced risk against COVID-19 illness in vaccinated individuals in South Africans underscores the value of this vaccine to prevent illness from the highly worrisome variant currently circulating in South Africa, and which is spreading globally. This is the first COVID-19 vaccine for which we now have objective evidence that it protects against the variant dominating in South Africa,” says Professor Shabir Maddi, Executive Director of the Vaccines and Infectious Diseases Analytics Research Unit (VIDA) at Wits, and principal investigator in the Novavax COVID-19 vaccine trial in South Africa. “I am encouraged to see that Novavax plans to immediately begin clinical development on a vaccine specifically targeted to the variant, which together with the current vaccine is likely to form the cornerstone of the fight against COVID-19.”

CoI: none

#T4TD: pneumonia

Barts-MS rose-tinted-odometer: zero-stars

#T4TD (thought for the day)

How bad is your breathing and lung function?

Every year a few of our patients with advanced MS die. During the first COVID-19 lockdown I received an email from the husband of one of my patients I had been looking after for over a decade. Thankfully she died peacefully in her sleep. Her MS had affected her swallowing to such an extent that she had to have a feeding tube inserted into her stomach for feeding. Prior to the feeding tube, she was getting recurrent chest infections. Her speech was also very poor and at times I couldn’t really understand what she was saying. Her other complications included intermittent pressure sores and frequent bladder infections. 

A common cause of unscheduled hospital admissions and sadly death is aspiration pneumonia. This is when people with MS have poor coordination of their swallowing mechanism and instead of swallowing saliva and/or food properly some of it travels down the trachea or windpipe into their lungs and causes pneumonia. 

At the same time, people with swallowing difficulties may have weakness of their muscles of respiration, in particular, the diaphragm. The cause of diaphragmatic weakness is usually lesions in the upper cervical spine. However, it is often made worse by poor posture. For the diaphragm to work properly it needs to be able to move downwards into the abdominal cavity without being impeded; sitting upright and not hunched over help. Seeing a physiotherapist is important to correct your posture and to make sure your wheelchair if you are using a wheelchair, has the correct postural supports.  There has been a lot of wheelchair innovation recently with the production of bespoke moulded body supports to keep you sitting straight and upright.

When the diaphragm is weak the so-called accessory muscles of respiration help a person breath. The accessory muscles lift the thorax or chest as the weak diaphragm pushes downwards. The accessory muscles actually work as a pulley and then rely on gravity to lower the chest. So for the accessory muscles to work well you need to be sitting upright; as soon as you lean back or lay down you reduce the effect of gravity and the accessory muscles’ ability to function as a pulley. 

When we look at how well your breathing capacity is we often measure your so-called vital capacity, i.e. how much air you can move in and out of your lungs. A normal vital capacity is around 60-70 mL/kg; so a 70kg person has a vital capacity of about 4.5-5.0 litres. When the vital capacity drops below about 20-30ml/kg it is associate with a reduced ability to cough and move mucus plugs out of your lungs. When your cough reflex is weak it puts you at risk of segments of the lung collapsing (atelectasis) and becoming infected. 

When your vital capacity drops below 15mL/kg you are in serious trouble and are likely to be in or close to respiratory failure and your blood gases (oxygen and carbon dioxide) may be affected.

When I was a trainee neurologist in South Africa we used to carry around a vital capacity flow metre on our ward consult rounds. This was to assess respiratory function in patients admitted with paralysis from nerve or muscle disease. These vital capacity meters were expensive and in short supply and we didn’t own them and some hospitals didn’t have them. Nowadays you can purchase relatively cheap vital capacity meters that connect to a smartphone.

At Baragwanath hospital, now called the Chris Hani hospital, in Soweto (South Western Township) outside Johannesburg, we used to use low tech clinical signs. The first was how many numbers could someone count at a rate of one number per second on a single breath-hold, whilst sitting-up.  If the person couldn’t get to 12 they needed to be seen by the respiratory intensive care team. The other test was whether or not the patient could blow out a lit match or candle held 30cm from their face. The use of a lit match or candle was not really allowed on the wards because of the fire risk, particularly if patients were on oxygen therapy, but the Baragwanath consultants ignored health and safety and used the test anyway. It is important to realise that if someone can’t blow out a lit match or candle at 30cm then their ability to cough is likely to be compromised and they are therefore likely to at risk of collapsing part of their lung and getting a serious lung infection. 

Another important clinical sign is simply to listen to a person speak. If their speech is not smooth, but soft and broken up with frequent pauses to take a breath, also indicates a problem with their breathing. You can also ask the person to cough; if the quality of the cough is poor and weak that can also be taken as a sign of weak respiratory muscles. 

A mistake that many people make is to use a so-called peak flow meter and pulse oximeter to monitor lung function. These two devices are not suitable for pwMS. The peak flow is really best for people with asthma and bronchospasm and the peripheral blood oxygenation as measured with a pulse oximeter only becomes abnormal very late. Although a pulse oximeter is good to monitor lung function when you have an infection, such as COVID-19 pneumonia, or when someone has a pulmonary embolus (blood clot in the arteries to the lung) it is not a good measure of your respiratory reserve. 

If you have advanced MS with swallowing or breathing problems you may want to self-monitor yourself. You need to see a speech therapist to have your swallowing assessed. If your swallowing is compromised you may need to change your diet; for example, if you are choking or coughing when drinking liquids you may need to use thickened liquids. It is also important to have regular home chest physiotherapy to prevent sections of your lung collapsing and to lung muscle exercises. The physiotherapists use so-called incentive spirometers to make the lung exercises fun. I know all about these devices; I had to do incentive spirometry four times a day in the first few weeks after my accident to prevent lung atelectasis. 

incentive spirometer

It is also important that your family and carers have basic first aid training and can do a pharyngeal sweep and/or Heimlich manoeuvre to dislodge food stuck in your throat. Portable pharyngeal suction or vacuum devices can also be purchased and kept at home to clear the throat. If you go this route then your carers and family will need to be trained in how to use them.

If this post is relevant to you because you have advanced MS or you have a family member or patient with advanced MS it is important to ask them if they have an advanced directive. An advanced directive is a legally binding document setting-out how you want to be managed if you ever end up with life-threatening medical complications of having MS. For example, do you want advanced life support or not? It is important that your family doctor, hospital team, family members and carers have a copy of this directive so that they can ensure your wishes are carried out if ever the need arises. 

Finally, please make sure you have had your vaccine requirements reviewed. You need your annual flu vaccine, the pneumococcal vaccine if you have not had one on the last 5 years and a COVID-19 vaccine.

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211

#MSCOVID19: alcohol

Barts-MS rose-tinted-odometer: ★

She recently turned 32 and has had multiple sclerosis for just shy of 4 years. She previously described herself as a moderate drinker having 2 to 3 glasses of wine per day in the week and maybe a bottle of wine per day on weekends. She would have typically her first drink of the day in the early evening when she got home from work. However, with COVID-19 and being forced to work from home she started drinking earlier, typically midafternoon. She has started drinking wine out of a mug to disguise it from her work colleagues on her zoom calls. 

Now in the second lockdown, she has her first glass of wine with lunch. Her wine consumption has increased to more than a bottle per day. She admits to being unable to stop drinking and feels hungover on most mornings. She admits that her drinking has become a crutch. She feels lonely as she lives on her own and has not been able to visit family and friends, which is one of the reasons she is now drinking so heavily. 

Does this scenario sound familiar? Alcohol consumption data during COVID-19 is worrying; recent studies have shown a large increase in alcohol purchases and consumption.

Data and image from Nielsen

Alcohol is an anxiolytic and is probably the most used drug on the planet. Its adverse event profile is well described and long-term chronic use is associated with neurological and systemic toxicity. Neuroscientists now say there is no safe level of alcohol consumption when it comes to your brain health. 

There is limited data showing that alcohol and drug misuse is higher in people with MS (pwMS) than the general population. The latter is not surprising given anxiety is so common in pwMS. Similarly, social isolation and loneliness, which are strongly associated with alcohol misuse, are endemic in pwMS. A recent survey by the MS Society indicates that 3 out of 5 pwMS describe themselves as lonely.

If you are reading this and feel your alcohol consumption has got out of hand as a result of COVID-19 please contact your  HCPs and let them know. There are things that can be done remotely to help you. Don’t be ashamed to admit you have a problem; HCPs are trained to be non-judgemental and understand the issues.

As part of the holistic or marginal gains approach to the management of MS reducing alcohol consumption is one of the lifestyle interventions we promote. I am aware that it is easier said than done, but unless you try you won’t optimise your potential longterm outcome.

If you have any personal experiences you want to share with us about alcohol and how it has affected your MS, we would appreciate hearing about them. Your stories may help your fellow readers. 

Bombardier et al. Alcohol and drug abuse among persons with multiple sclerosis. Mult Scler. 2004 Feb;10(1):35-40.

Objective: To examine the one-month prevalence and impact of substance abuse in a large community sample of persons with multiple sclerosis (MS).

Method: Members of the Multiple Sclerosis Society of King County were surveyed by mail. This multifaceted health survey included questions pertaining to substance abuse. Seven hundred and thirty-nine out of 1374 potential participants (54%) returned the survey, while 708 reported a medically confirmed diagnosis of MS and provided sufficient data.

Results: Fourteen per cent of the sample screened positive for possible alcohol abuse or dependence, and 7.4% reported misusing illicit drugs or prescription medications within the previous month. Possible alcohol abuse and drug misuse were associated with younger age, less severe MS-related disability and being employed, as well as greater self-reported depressive symptomatology. Most persons with alcohol problems indicated an interest in learning more about ways to stop or cut down.

Conclusions: Substance abuse may be present in up to 19% of this sample and contribute to high rates of depression. There may be greater risk of harm due to substance abuse in people with MS because of the potential magnification of motor and cognitive impairments. Comprehensive MS care should include substance abuse screening and advice to cut down or abstain.

CoI: multiple

Twitter: @gavinGiovannoni                                      Medium: @gavin_24211

#MSCOVID19: moral distress

Barts-MS rose-tinted-odometer: zero stars

A dear and very close friend of my wife and I tragically passed away from inoperable cancer two weeks ago.  She sadly died alone in hospice with no family members by her side to comfort her. She is one of the many collateral deaths that have occurred due to COVID-19. From the time she got symptoms to suggest her cancer had returned in late April last year, it took almost four months before she was examined under anaesthesia when it was found her tumour had grown and spread to such an extent that it was then inoperable. Three to four months is a long time in the natural history of highly malignant and invasive cancer. The delays in her management were directly due to the COVID-19 lockdown and reconfiguration of oncology services to cope with the first wave of the pandemic. Pre-COVID-19 she would have been seen and managed within weeks and would almost certainly be still alive today; maybe not cured, but with enough life in her to witness her youngest daughter turn twenty-one.  

In cancer the outcome is black and white; survival or death. In MS the outcomes are more subtle and nuanced. How long is too long in the course of a disease that last decades? Saying this I have a collection of patients who I follow when relatively small delays in diagnosis and treatment have major and rarely catastrophic consequences for the individual. Occasionally a spinal cord relapse can leave someone wheelchair-bound or result in loss of bowel, bladder or sexual function. 

Image from the Catholic Health Association

It is clear that fewer new patients are being referred to our MS service. Where are they? I doubt COVID-19 is preventing MS. A better explanation is that people are sitting on neurological symptoms that in normal times would prompt a referral to a neurologist and a diagnostic work-up. Even if patients are being referred into neurology services they are being seen and assessed virtually and are waiting for MRI scans, evoked potential and other non-urgent diagnostic investigations. These have been suspended until the current COVID-19 surge settles and neurology staff are de-deployed back to neurology. Even if some patients are seeing private neurologists and being diagnosed with MS outside the NHS they still have to wait to access DMTs on the NHS. 

This is why a commentary in this week’s BMJ on ‘moral distress’ hit a nerve when I read it. Moral distress is ‘psychological harm’ arising when people are forced to make, or witness, decisions or actions that contradict their core moral values. I can relate to the sense of powerlessness and feelings of guilt, shame and anger that are associated with moral distress. These are some of the feelings we neurologists are having when we can’t diagnose and treat our patients with MS in a timely and appropriate way. 

If you are reading this and are one of these people waiting in the COVID-19 induced NHS bottle-neck for either diagnostic or therapeutic decisions about MS, or any other non-urgent problem, you need to understand what your NHS HCPs are actually going through. Unfortunately, there is no alternative but to wait it out and hope that not too much time passes before you get diagnosed and appropriately managed. Writing this is particularly hard for me as I am the chair of the ‘MS Brain Health: Time Matters’  steering committee with the primary objective to ‘maximise your brain health’; to achieve this time really does matter. 

If you have 5 minutes I would recommend you read the full BMJ commentary on moral distress; if not, I have pasted a few excerpts that will give the gist of commentary and how HCPs working in the NHS are being affected. 

Coming back to our friend; the most we can do for her in death is to attend her socially distanced and very delayed funeral and help support her grieving husband and children. It is going to take a long time for us to digest, understand and accept the full impact COVID-19 will have on our society. I am going to be optimistic and predict that we will come out of this pandemic better for the experience; more in touch with each other’s and the environments’ needs, more tolerant, more willing to share the spoils of our education and careers, and a better understanding of the limits and promises of modern healthcare. 

Julian Sheather. Covid-19 has amplified moral distress in medicine. BMJ 2021; 372:n2 (Published 08 January 2021)

Excerpts

….. Simply working harder cannot resolve the conflicts caused by responsibility without autonomy

…… Doctors are accustomed to difficulty, to long hours, high stress, heavy responsibility. The job involves helping people navigate life’s gravest challenges: death and dying, suffering, loss and grief. 

…. But as the profession draws deeply on its resources to respond to covid-19, a new concept is entering the mainstream: moral distress. 

…. Moral distress is psychological harm arising when people are forced to make, or witness, decisions or actions that contradict their core moral values. While exposure to the suffering of others can lead to distress, it is not necessarily moral distress. But if serious and sustained resource constraints mean doctors cannot meet patients’ needs, it can open the door to moral distress. If you know that delays to treatment will likely lead to serious harms, consider the effect of repeatedly being forced to place patients on ever-lengthening waiting lists. Moral distress arises in the gap between what professional judgment dictates should be done and what healthcare systems permit. It is also associated with powerlessness—the impossibility of altering the situation so that professional acts can accord with professional values.

…. Understandably, moral distress has been strongly linked to the psychological harms of combat. The term entered health through nursing ethics: lack of professional agency meant that nurses felt unable to challenge behaviour at odds with their core values. 

…. Typical emotional responses to moral distress include feelings of guilt, shame, anger, and, in extreme form, disgust. If moral distress is sustained it can lead to moral injury—a deeper or more enduring harm that can lead to burnout and psychological trauma.#

…. Covid has highlighted how essential the NHS is to our collective wellbeing. It is beyond time to fund it effectively—and to make clear the costs of not doing so. Until then, all health professionals need support in managing moral distress—before its effects become too toxic.

CoI: multiple

Twitter: @gavinGiovannoni                                    Medium: @gavin_24211

Swiss-cheese

Barts-MS rose-tinted-odometer: zero-stars

What do you say when I colleague chastises you for stating the fact that MS is potentially a ‘preventable dementia’? This particular colleague was clear that there is no need to draw any parallels between MS and other neurodegenerative diseases because of the negative connations that the term dementia has. I had to remind him that MS ticks all the boxes for being classified as a dementia; i.e. (1) MS is an acquired and not a congenital disorder; (2) MS is a chronic progressive disease; (3) MS impacts on multiple cognitive domains and (4) MS impacts on social and occupational functioning. Have I missed something?

I also had to remind this colleague that almost every neurology or psychiatry textbook included MS on its list of causes of dementia. I am not prepared to peddle alternative facts because pwMS may find it distressing to find out that if MS is left to its own devices it will shred their brains and cause dementia. Please note the rose-tinted-odometer is set to zero for this post. 

The small study below reiterates what we already know that both relapsing and progressive patients have cognitive problems that correlate with physical disability. This study also confirms that T1 hypodensities or blackholes on MRI, particular in the thalamus (a deep grey matter structure in the brain) predicts cognition problems. T1 hypodense MS lesions or black holes, or at least a proportion of them, have been shown to be very destructive and include lesions with so-called phase-rims (iron around them) and a subset we call SELs (slowly expanding lesions). Some neuroradiologists often describe an MS brain with a high volume of black holes as being similar to Swiss cheese in reference to Emmental cheese. 

By Ekg917 – Own work, CC BY-SA 4.0,

Now for the good news is that these studies below are on patients with significant end-organ damage and if we can diagnose and treat MS effectively early on we can prevent or at least delay the end-organ damage and the progressive loss of cognition. This is why we have spent years promoting the concepts of ‘Time-is-Brain’, ‘Treat-2-Target of NEDA’, ‘Rapid escalation’, ‘Flipping-the-Pyramid’, ‘Brain Health’, ‘Beyond-NEDA preventing end-organ damage’, ‘Holistic Management’, ‘Marginal Gains’, etc. Buried in all of these concepts is the use of effective DMTs to prevent end-organ damage and to prevent dementia. 

I am very pleased that my pwMS in Australia have taken this one step further and launched their own awareness campaign, albeit sponsored by Biogen, to raise awareness about early effective treatment (www.msmotion.com.au). The campaign is been run by a group of MS social media influencers. I met them all virtually last year and spoke to them about the concepts that underpin our  ‘Brain Health: Time Matters’ policy document. It would be great if pwMS across the world could do a similar thing. 

Do you agree with my colleague above that we should try and protect pwMS from the harsh realities of MS and what can happen to their brains if we don’t manage their MS appropriately? Or should we peddle false facts and a rose-tinted view of the world?

de Paula Gois et al. Associations between cognitive and clinical disability across MS subtypes: The role of the underlying brain damage. Mult Scler Relat Disord. 2020 Dec 19;48:102701. 

Background: Cognitive impairment (CI) is present in all stages and subtypes of multiple sclerosis (MS). However, the majority of studies examined relapsing-remitting (RRMS) patients, and did not address cognitive phenotyping. Is still not clear whether patients with progressive MS (PMS) have a distinct pattern of CI compared to RRMS. In addition, there is conflicting data regarding the correlation between clinical and cognitive disability.

Objective: To investigate the differences of CI between PMS and RRMS patients, evaluating cognitive phenotypes. We also aimed to analyze the association between physical and cognitive disability with MRI measures of grey-matter atrophy and lesion burden.

Methods: Thirty patients with PMS and twenty-four with RRMS underwent neurological, neuropsychological (BRB-N, Boston Naming, and Tower of London), and MRI assessments (3T). Brain volume evaluations were performed using FreeSurfer. Principal Components Analysis on neuropsychological yielded six principal cognitive domains. Cognitive deficits were classified according to three categories: no CI, impairment in isolated cognitive domain, or impairment in combined domains.

Results: In the overall sample, the most frequently impaired cognitive domains were information processing speed (IPS) and visual memory. PMS patients had a higher prevalence of verbal memory and verbal fluency deficits, and more frequent impairment in combined cognitive domains compared to RRMS individuals. After multivariable regression analysis with clinical variables, EDSS was associated with most cognitive domains. Nevertheless, after including T1-lesion volume in the model, it was the most consistent predictor of cognitive performance. To further analyze the interaction between EDSS and T1-lesions, we performed GLM analysis with EDSS and T1-hypointense lesion volume as covariates, and T1-lesion volume adjusted better the model for verbal memory (p = 0.013), IPS (p = 0.021) and total number of impaired cognitive domains (p = 0.021).

Conclusions: RRMS and PMS patients tend to have a similar neuropsychological profile in general, but the extent of CI was greater in PMS patients. Worse cognitive performance was associated with increased physical disability, but this correlation was no longer significant after controlling for T1-lesion volume, suggesting that the underlying MS pathology might be involved in this relationship. Thalamic and T1-lesion volumes were the most consistent MRI predictors associated with cognitive disability.

CoI: multiple

Twitter: @gavinGiovannoni                                         Medium: @gavin_24211

How is Prof G doing?

Barts-MS rose-tinted-odometer: ★★★★★

#UseItOrLoseIt 

I am receiving an increasing number of emails and messages via my social media channels asking me for an update on how I am doing. 

I am continuing to improve slowly. I still have pain in my pelvis as a result of the fractures I sustained. However, the pain is manageable and I have stopped all my analgesics except a once-daily dose of an anti-inflammatory that I take before I go for my daily Rehab Walk. The good news is the Prof K and I are walking together on a weekly basis; typically on a Sunday. Last Sunday I almost managed 10km, which is my target for the end of January. 


Worryingly I have reduced movement in my right hip; mainly hip flexion and internal and external rotation. I am hoping this is not due to permanent hip damage as a result of the impact, as I am desperate to run again. Yes, I have ambitions of running another marathon. For my cardio workouts, I started using an exercise bike three or four times a week. However, sitting on a saddle is very uncomfortable with a fractured pelvis, albeit it a healing pelvis. 

My neck is improving, but I find it difficult to stand or sit for more than about 3-4 hours before needing to rest. The latter is due to my paraspinal muscles being weak after my neck surgery. The paraspinal muscles are the postural muscles that support the spine and work as an integrated column. Because the function of the paraspinal muscle column has been affected I have to rely on using my accessory muscles to support my neck and head. These muscles are only meant to be used intermittently so when they have to work continuously for hours they get tired and very sore. Although I am doing dedicated paraspinal muscles exercises as part of my rehab programme, which is helping, these muscles are not up to the task of supporting my head on their own. I have been told it can take up to a year for the paraspinal muscles to recover and work as a unit. This is why I have had to get a new reclining chair with neck support so that when I return to work I will be able to rest my neck muscles in my office. 

The real improvement is that my radicular or nerve pain has gone. This has allowed me to stop all my sedating medication and has allowed me to start thinking clearly again. As a result of the damage I sustained to my C7 and C8 nerve roots in the neck I still have mild to moderate weakness and wasting in my left C7 and C8 innervated muscles. I am told this may improve but is likely to permanent. It is interesting to see how some of my left shoulder muscles, particularly my trapezius muscle, has enlarged to compensate for my weak serratus anterior muscle. My weakest muscle by far is my left triceps muscle, but as I am right-handed I hope this won’t cause too many problems in the future. 

My balance is still not back to normal. I can’t really stand on one leg unsupported and have problems heel-toe walking. I am assuming the balance problem is vestibular from the mild head injury I sustained in the accident. Although I am doing balance exercises, my recovery in this domain seems to have plateaued. For those of you have issues with balance I can now understand how irritating it is and how it impacts on your ability to do simple tasks, such as walk in the dark and dressing. Being unsteady on your feet adds time to many tasks and prevents you from multi-tasking; all these small-time deficits add up and simply slow you down. 

My energy levels and attention span remain low. I still spend a lot of time on my back listening to podcasts and can only work for a few hours at a stretch. In the past, I would typically read a journal on the tube, the Economist Espresso app feed, skim the online Guardian website and read a few Guardian articles of interest, clear my other daily news and journal feeds and walk 2 km as part of my commute to work. I would typically achieve this all by 8 am, the time I usually get into my office to start work.  It now takes me several more hours to achieve the same level of productivity; not to mention the impact on the rest of my day’s work. The loss of my productivity is quite profound, which is why I am going to have to have a graded return to work.

This low level of mental productivity gives me a deep and profound understanding of what it must be like to have MS or have had a major head injury, which clips your cognition and attention span. Thankfully the brain fog I had whilst on gabapentin has lifted. Being a knowledge worker requires you to be able to concentrate for prolonged periods of time. I am very anxious about whether or not I will get back to my normal level of cognitive productivity.  I am also finding it difficult to get into the flow, i.e. a state of intense concentration when you are super-productive. I now tend to flit from one low impact task to the next. I really need to get a grip on this.

Despite the negative tone above, I am still very positive. My accident could have been much worse. I am sticking to my rehab programme religiously, but it is very time-consuming. I literally spend 3 or more hours a day on my physical rehabilitation, which is why going back to full-time work is going to be difficult as it would mean clearing time on either side of my workday to do my exercises. 

A very close colleague and friend of mine who has worked in a neurorehabilitation unit made the observation that physical therapy and rehabilitation often don’t achieve their outcomes because of poor adherence. The latter is clearly driven by the intensity and duration of the exercises. He even implied that I would also give up on my rehab at some stage. However, I am determined to prove him wrong. 

I am not complaining. I am very lucky and privileged to have the resources to pay for the services of a private neurophysiotherapist who has made such a difference to my recovery. I have a newfound appreciation for the added-value therapists bring to the table, both in the acute setting and in the community, in helping patients with physical impairments. It is a great pity the NHS doesn’t invest more in therapy services so that everyone can access what they need.  If I had gone the NHS route for community-based rehabilitation I would be having my first zoom or remote appointment about now.  When I contacted them they told me there was a 12-week wait for rehab services.

The orthopaedic and neurosurgery teams who have been looking after me are satisfied with the progress I have made, which is also positive. 

So, in summary, it is looking good. I am fine and good general health and will be back behind my desk in the near future.  

I want to thank you all for your kindness and support over the last few months; it is much appreciated. It is good to know that there are people out there who care about you.

CoI: multiple
Twitter: @gavinGiovannoni                                    Medium: @gavin_24211

Virus, virus where art thou hiding?

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

Would you volunteer to participate in a clinical trial of an antiviral drug cocktail to suppress MS disease activity, in particular smouldering MS?

There is reasonable evidence in the literature that HERVs (human endogenous retroviruses) may play a role in autoimmunity, in particular MS. HERVs are viruses (genetic code) that have been incorporated into the human genome over deep time. Some HERV genetic elements have taken on important functional roles, for example, they are involved in the development of the mammalian placenta and hence are part of our human biology. 

When HERVs elements are transcribed they may be capable of forming replication-competent viruses, which can reinfect cells and integrate back into the genome. These reintegration sites may be important in themselves and may drive the selection of cells with enhanced functions and may also result in cancer. Other HERV elements are replication-incompetent and although they can produce functional transcripts can’t form an infectious virus. 

Some HERV proteins act as danger signals activating so-called toll-like receptors and other danger-signalling pathways. These pathways then upregulate innate immunity and provide the immunological nudge that drives autoimmunity. This is why there have been some attempts to try and suppress HERV activation with antiviral drugs or to neutralise some of the HERV proteins that may activate the immune system, or are directly toxic to myelin-producing cells and/or neurones, as a treatment for MS. 

These HERV-related hypotheses are supported by several studies showing upregulation of HERVs transcripts and HERV proteins in the brains of people with MS. The study below uses a new technology called next-generation RNA sequencing to show that some HERV-W (a specific type of HERV) transcripts are exclusively present in MS brains and as they are located on chromosome 7 close to one of the MS genetic risk loci may be relevant to MS. Could this finding be part of the proof we need to show that HERV-W may be in the causal pathway that leads to the development of MS? Importantly, HERV transcripts (RNA message) close to the MS risk locus on chromosome 7 were overrepresented in MS brains. 

Although some would interpret these findings as being potentially causal, i.e. HERV transactivation and expression is driving the pathology that is MS, another interpretation is that whatever causes MS transactivates HERVs, which is then simply a bystander phenomenon. The only way to separate ‘causation’ from ‘association’ is to do an experiment to suppress HERV transactivation to see if it improves MS outcomes. This is a conclusion that Prof. Julian Gold and I came to several years ago and is why we have been trying to get funding to do a CNS penetrant combination antiretroviral trial in MS.

Some of the cynics will ask ‘well what about your EBV hypothesis’? Interestingly, EBV and some of the other herpes viruses are potent transactivators of HERVs, i.e. infection with EBV wakes-up HERVs in our genome and results in their transcription. Therefore, increased HERVs may be a marker of EBV infection. This may be important, but recent data indicates that some HAART (highly active antiretroviral therapies) components are also effective against EBV. Therefore, clinical trials of HAART may actually target both EBV and HERVs. This is why I am so excited about the news that a small HAART trial in MS will be starting soon in the US.  However, Prof. Julian Gold and I, as part of our Charcot Project, will still continue to prod and encourage big Pharma companies (ViiV-GSK, Gilead, Merck, etc.) with a footprint in the antiretroviral space, to come to the table with their products (HAART) and money to fund a large adequately powered study to test the hypothesis in a definitive MS study. 

It would be a travesty if in 20 years time the next generation of MS researchers discover that HAART is a very effective treatment for MS when we have the tools to answer this question now, i.e. in the next 4 to 5 years? In fact, we have a clue that this may be the case already. Having HIV infection protects one from getting MS. This may be due to the therapy (HAART) that is used to treat HIV and not due to the HIV virus itself. 

As you know outside-the-box ideas or paradigm shifts often take generations to occur. So you shouldn’t be surprised if the MS community continues to reject these hypotheses and nothing happens for decades.   

Maria L Elkjaer et  al. Unbiased examination of genome-wide human endogenous retrovirus transcripts in MS brain lesions. Mult Scler. 2021 Jan 19;1352458520987269. doi: 10.1177/1352458520987269. 

Background: Human endogenous retrovirus (HERV) expression in multiple sclerosis (MS) brain lesions may contribute to chronic inflammation, but the expression of genome-wide HERVs in different MS lesions is unknown.

Objective: We examined the HERV expression landscape in different MS lesions compared to control brains.

Methods: Transcripts from 71 MS brain samples and 25 control WM were obtained by C and mapped against HERV transcripts across the human genome. Differential expression of mapped HERV-W and HERV-H reads between MS lesion types and controls was analysed.

Results: Out of 6.38 billion high-quality paired-end reads, 174 million reads (2.73%) mapped to HERV transcripts. There was no difference in HERVs expression level between MS and control brains, but HERV-W transcripts were significantly reduced in chronic active lesions. Of the four HERV-W transcripts exclusively present in MS, ERV3633503 located on chromosome 7q21.13 close to the MS genetic risk locus had the highest number of reads. In the HERV-H family, 75% of transcripts located to nearby 7q21-22 were overrepresented in MS, and ERV3643914 was expressed more than 16 times in MS compared to control brains. 

Conclusion: Novel HERV-W and HERV-H transcripts located at chromosome 7 regions were uniquely expressed in MS lesions, indicating their potential role in brain lesion evolution.

CoI: multiple

Twitter: @gavinGiovannoni                                    Medium: @gavin_24211

What has my age got to do with having MS?

Barts-MS rose-tinted-odometer: ★★★ (some readers have asked for this feature to stay)

How old are you? It depends. You may be aware that there can be a disconnect between your chronological or actual age and your biological age. As ageing or senescence is a biological process driven by metabolic, genomic and environmental factors you can see how there can be a disconnect between the two. As a result, many of us in medicine are beginning to think about unhealthy or accelerated ageing as a disease process. Making ageing a disease will create incentives for pharmaceutical and nutraceutical companies to invest in ageing R&D with the hope of producing medications or dietary supplements to slow-down or reverse the effects of ageing. 

Ageing is important in MS as there is emerging evidence that MS causes premature ageing of the CNS (central nervous system), which means that pwMS are more likely to experience age-related neurodegeneration sooner than they have to and this almost certainly contributes to delayed disability worsening in pwMS. 

It is clear that ageing impacts one’s ability to recover from CNS damage. It has been known for some time from clinical and animal studies that remyelination and neuronal plasticity are less efficient as you get older, which is why older pwMS recover from relapses less well than younger people. The animal studies below show that there is real biology behind these observations. Oligodendrocyte (myelin-producing) progenitor cells (OPCs) isolated from the brains of neonate, young and aged female rats show an approximately 50% difference in the levels of proteins they make. Differences were noted in both myelin-associated proteins and proteins that control several metabolic pathways. This study has clinical implications and can act as a read-out for finding drugs that could be used as anti-ageing agents. 

There are several interesting biological targets and drugs that already exist for targeting ageing. Metformin, a drug for treating diabetes, is one of the lead compounds going in an MS clinical trial at the moment. It is believed that its antiageing effects of performing are mediated via the so-called NRF2 or programmed cell survival pathway. Interestingly, fumarates (e.g. dimethyl fumarate) and ketogenesis also activate this pathway. Could DMF, and the other fumarates, be the panacea antiageing drug we need for tackling progressive or more advanced MS? Yes, I think so but to convince Biogen to follow the money is proving more difficult than we anticipated. We approached them recently to do a combination DMF-plus trial with another class of drug to augment DMF’s response and they said no. Pity because I think they are missing a trick and an opportunity to create new intellectual property.

Physiological ketosis from caloric restriction, intermittent fasting or low-carbohydrate diets is another way of activating the NRF2 pathway. The biology behind this is probably via β-hydroxybutyrate, a ketone body, which works via the hydroxycarboxylic acid receptor 2 (HCA2). Interestingly, this is the same receptor DMF activates.

Other anti-ageing treatments and strategies include exercise and avoiding getting comorbidities, which accelerate ageing, in particular, the metabolic syndrome (obesity, hypertension, glucose intolerance or diabetes) and smoking. The driver of the metabolic syndrome seems to be hyperinsulinaemia and the diets referred to above are all very effective in suppressing or reducing circulating insulin levels. 

So in 2021 if you have MS you need to think seriously about what you can do to tackle early and accelerated ageing. Most of the things you can do now involve lifestyle changes, which are often hard to implement. My advice would be to implement the changes slowly and you may find over time that the behavioural changes you make will stick. There is a lot of evidence for this from the field of behavioural psychology.

The above advice is part of the holistic approach to the management of MS I have been pushing for several years and my adoption of the ‘marginal gains philosophy’ for managing MS. 

“If we break down everything we can think of that goes into improving MS outcomes, and then improving each by 1%, we will get a large improvement in MS outcome when we put them all together.”

“Ask not what your neurologist and HCP can do for you, but what you can do yourself to optimise your own MS management and long-term MS outcome.”

de la Fuente et al. Changes in the Oligodendrocyte Progenitor Cell Proteome with Ageing. Mol Cell Proteomics. 2020 Aug;19(8):1281-1302.

Following central nervous system (CNS) demyelination, adult oligodendrocyte progenitor cells (OPCs) can differentiate into new myelin-forming oligodendrocytes in a regenerative process called remyelination. Although remyelination is very efficient in young adults, its efficiency declines progressively with ageing. Here we performed proteomic analysis of OPCs freshly isolated from the brains of neonate, young and aged female rats. Approximately 50% of the proteins are expressed at different levels in OPCs from neonates compared with their adult counterparts. The amount of myelin-associated proteins, and proteins associated with oxidative phosphorylation, inflammatory responses and actin cytoskeletal organization increased with age, whereas cholesterol-biosynthesis, transcription factors and cell cycle proteins decreased. Our experiments provide the first ageing OPC proteome, revealing the distinct features of OPCs at different ages. These studies provide new insights into why remyelination efficiency declines with ageing and potential roles for aged OPCs in other neurodegenerative diseases.

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211

How healthy is your Brain?

As 2021 rapidly speeds up and COVID-19 leaves its trail of destruction it is clear to see how important general and brain health is for resilience against disease and its broader impact. These lessons go beyond COVID-19 and apply to any disease. This is why our #BrainHealth #TimeMatters campaign is so important for people with MS (pwMS) and the general public and why prehabilitation needs to become a way of life. I know this is easier said than done, but start small and gradually expand your horizons. 

It is often said to make good habits stick start doing one thing at a time and try and do it for 2-3 weeks and then the behaviour becomes sticky and you are more likely to persist with it longterm. 

I am so pleased that the messages from our  ‘Brain Health: Time Matters in MS’  policy document are finally getting traction and buy-in from the wider MS community. Shortly before my accident, I spoke to a group of Australian MS social media influencers about the principles of Brain Health and they went away and produced some online materials that will help spread the philosophy and nudge other pwMS and the wider MS community to take MS Brain Health more seriously. 

It was quite clear that when we developed the MS policy document that the message of maximising Brain Health was as relevant to the general population as to pwMS, which is why we went on to write a new and separate policy document ‘Time matters A call to prioritize Brain Health’  and launched the ‘Think Brain Health’ campaign, which targets the general population. Although this focuses on preventing age-related cognitive impairment and neurodegeneration the messages are very similar to one we promote to pwMS. 

I was, therefore,  thrilled to see that Alzheimer’s Research UK have copied our slogan and have launched their own Think Brain Health campaign. May be Oscar Wilde was correct when he said: “Imitation is the sincerest form of flattery”. For me, the important take-home message is that Brain Health is becoming a treatment target and putting preventive neurology centre stage. 

If you are reading this blog post can I suggest you pause and considering reading our ‘Brain Health: Time Matters in MS’ and ‘Time matters A call to prioritize Brain Health’ policy documents, they may change your life. 

CoI: multiple

Twitter: @gavinGiovannoni                                       Medium: @gavin_24211