#MSCOVID19: the new lepers?

Barts-MS rose-tinted-odometer: ★★★

Early this week my wife came down with a cold. Did she have coronavirus was the immediate question? She asked me for advice and I said she had better get herself swabbed and in the interim we should isolate ourselves. All she had was a mild headache (sinus-type), runny nose, sneezing and a sore throat. She did not have a temperature and only developed a mild cough after a few days. Her nasopharyngeal swab for coronavirus done via the post took almost 72 hours to come back and was fortunately negative. 

Interestingly despite a blocked and runny nose, she did not develop loss of smell or her taste; I tested it with coffee, chocolate and some fine white wine. Although loss-of-taste (ageusia) and smell (anosmia) occur in about 40-60% of subjects with COVID-19 it is really not specific enough to exclude coronavirus infection so don’t rely on it. In addition, it may not occur until several days into the infection, prior to which you could be highly infectious and spreading the virus.

Fortunately, my wife is now much better. I suspect she had rhinovirus infection, a common cause of rhinitis or the ‘common cold’, which is now circulating as it normally does this time of year.

In response to the emerging rhinovirus problem, the BBC and most of the newspapers have run articles or special features to highlight the differences between COVID-19, influenzae and the common cold. If you look at this list of symptoms below it is simply not possible to differentiate mild infections from each virus apart. Surely, it is not about diagnosing which infection you have but making sure you don’t act as a source of coronavirus and spread the infection. 

Therefore everyone with symptoms suggestive of an upper respiratory tract infection, including the common cold, should really consider themselves infected with coronavirus until proved otherwise. This means they need to get themselves swabbed and tested. Therein lies the problem. The UK at the moment does not have enough testing capacity outside of the NHS Trust’s to deal with this emerging problem. Hence anyone with a cold will probably have to self-isolate including their immediate contacts.  

The other thing is the new ‘COVID-19 leper syndrome’. Even if you go outdoors or travel, for example, to work, with a blocked nose and cold-like symptoms people will treat you like a leper and run a mile. This has been happening already before the rhinovirus problem; if anyone sneezes or coughs on the underground they immediately attract dirty looks and space clears around them as if they are radioactive. 

Things are only going to get worse the further we move into Autumn and Winter. In addition, young children are back in school and they are hothouses for acquiring and spreading viruses. The perfect storm is having two highly infectious viruses, which cause overlapping symptoms, circulating at the same time when we are trying to get society moving again. I can only imagine the chaos this going to cause in schools, universities and the workplace. The only solution is for the government to massively increase testing capacity ideally with the emerging point-of-care diagnostics, which can provide an answer within 60-90 minutes whether or not you have COVID-19. 

It is clear to me that an effective coronavirus vaccine can’t come soon enough. 

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#MSCOVID19: European COVID-19 Cup Quarterfinals

There has been a lot of debate about which country has had the best strategy at dealing with their coronavirus epidemic. It is clear based on the epidemiology of pandemics that countries needed to play with the mid and end game in mind. We are now quite a way into the COVID-19 pandemic and have reached the quarterfinals stage. Which countries do you think are going to win the quarterfinals and get to the next round?

Quarter Final 1: Sweden vs. Denmark

Quarter Final 2: United Kingdom vs. Germany

Quarter Final 3: Italy vs. Spain

Quater Final 4: France vs. Switzerland

If you need some help in understanding the epidemiology of pandemic you can refer to my infographic below.

CoI: multiple

#MSCOVID19: round 2

Barts-MS rose-tinted-odometer: ★

Every now again it is worth covering a topic that is important for people living with MS (pwMS) a second time. Today’s topic is COVID-19 prehabilitation.

Today when I got on the  London Underground to come to work the carriages were ~75% full, i.e. very few empty seats and not much standing room. In other words, adequate social distancing was not possible. This was at 7.05 am, which means it will only be getting worse as we head to peak time. In an attempt to get the economy back on its feet and society working the government is encouraging people back to work, which is why we are seeing a second surge in COVID-19. The difference this time is the demographic is different. The average age of those with COVID-19 is younger and hence fewer people are needing hospitalisation and intensive care admission. However, this is likely to change as more and more people come down with COVID-19 in the next wave of infections. 

I sincerely hope that you are doing everything you can do to prepare for when you get COVID-19?

In the event of you getting severe COVID-19, there are a lot of things you can do to maximise your chances of surviving the infection and its immune complications. Prehabilitation is the term I have used to describe this programme. 

The following is a list of things I recommend you do:

  1. Smoker? If you are a smoker stop smoking. 
  2. If you have comorbidities make sure their management is optimised.
  3. Hypertension? Check your blood pressure yourself. If it is high see your GP. If you have established hypertension make sure your medications have been adjusted to render you normotensive.
  4. Diabetic? Make sure you adhere to your diabetic medication and be extra-vigilant with your glucose monitoring. You may need to check in with your diabetic nurse or diabetologist for advice if your blood glucose levels are all over the place. 
  5. Obese? Maybe it is time to get back on that diet and lose some weight? I would recommend looking into intermittent fasting and avoiding processed and ultra-processed foods. There are no magic diets. You need to find one that is suitable for your lifestyle, culture and metabolism. 
  6. Alcohol misuse? If you drink more than the national guidelines try and cut back on your excessive drinking? If you have a drinking problem and need help please speak to your GP. 
  7. Asthmatic? How is your asthma control? If you have bronchospasm you may need to get your meds/inhalers changed. You don’t want to have poorly controlled asthma when you get COVID-19. 
  8. Sleep-deprived or sleep disorders? It is important you optimise the amount of sleep you are getting. Sleep deprivation is associated with multiple poor health outcomes. PwMS are more likely than the general population to have a sleep disorder. If you use sedatives to sleep you may want to try and wean these as they can affect respiratory function if and when you get COVID-19.
  9. Exercise? There is no doubt that being deconditioned or unfit is a risk factor for a poor outcome from many serious diseases. If you are unfit this would be an opportune time to start exercising with the aim of increasing your fitness. For those of you who are mobile, I have suggested the couch-to-5 programme in the past. If you are not mobile there are upper body exercises that you can do. Ideally, an exercise programme should be personalised with a physiotherapist, but if this is not possible there are pragmatic ways of getting going on your own.
  10. Breathing exercises: A lot of clinicians are instructing the general population to start doing deep breathing exercises to increase the ventilation of the little-used parts of the lung. This can be done before or more importantly after you develop COVID-19. 
  11. Mental health: Anxiety and depression are stressors in themselves and will affect how your body responds to infection. It is important that if you are anxious and/or depressed you get this treated. Exercise, mindfulness (meditation) and cognitive behavioural therapy have all been shown to reduce anxiety and improve depression. These are things you can do yourself. I am aware that it may be hard to address depression and anxiety during the lockdown, but there are things you can do to help yourself; but, if you think you need help can please reach out to your general practitioner and/or MS team.
  12. Pulse oximeter: if you live alone and get COVID-19 I would recommend having access to a pulse oximeter to monitor the oxygen levels in your blood in the case you get COVID-19 pneumonia and are asked to stay at home. It is clear that many people with COVID-19 drop their blood oxygen levels without being aware of it.
  13. Advanced directives / Living wills: It is important to prepare for things in advance. If you did get severe COVID-19 and needed to go to ITU, possibly be ventilated and receive advanced life support. Is that what you would want? If it is not, make sure this is documented formally with your general practitioner and is included in your medical records. Also, let your family know what your wishes are. It may be a good time to update your will and instructions for your family in the event of you getting severe COVID-19 and passing away. You may want to prepare a folder summarising your medical condition, including your advanced directive, with all the necessary contact details of your next of kin. If you do get COVID-19 and are admitted to the hospital. Also, make a list of things you will need to take to hospital in the event of you getting COVID-19; please don’t forget your mobile charger. Please remember visitors are not allowed for COVID-19 patients so having a functioning mobile phone is an important way of keeping in contact with your family and friends.

CoI: multiple

Twitter: @gavinGiovannoni 

Medium: @gavin_24211

#MSCOVID19: has coronavirus cancelled the flu season?

Barts-MS rose-tinted-odometer: ★★★★★

I think COVID-19 has just cancelled the flu season. 

I and many public health officials were very concerned that we were heading for a double-whammy this winter with a second and third surge of COVID-19 and a bad influenzae pandemic superimposed on it. It is looking like this may not happen. In the Southern hemisphere,  including my country South Africa, it seems as if the flu season was cancelled. Incredibly the number of documented annual cases has dropped by over 99% (see table below). 

Country201820192020
Argentina1517462353
Chile2439500712
Australia925993333
South Africa71110946
Documented cases April through mid-August. Source Science 28-Aug-2020

It is clear that the behavioural changes we have put in place, such as social distancing and wearing of masks, has prevented the spread of influenzae virus. Will these behaviours become the new norm during future flu seasons? I am not sure if people realise that influenzae is one of the biggest infectious disease killers each year so preventing the spread of the virus via behavioural change makes sense. 

Saying this the UK Government has just ordered many more doses of influenzae vaccines than it normally does and is extending the so-called at-risk adult group who can get the vaccine free on the NHS this year. 

Does this change our recommendations regarding getting the annual flu-jab? No, it doesn’t. All pwMS should take up the offer by the NHS to get the annual flu vaccine.

Please note, if you are severely immunosuppressed and have small children, please make sure they don’t get the live intranasal flu vaccine at school. There is a risk that this attenuated vaccine strain, which they may bring home, will cause disease in severely immunocompromised subjects. If you want your children to be vaccinated against influenza they will need to be given the component vaccine by injection. The latter is done via GP practices and some pharmacists. Please note it is only patients recently treated with alemtuzumab and HSCT that fall into this category.

I suspect that after reading the post on complications in the Oxford-AstraZeneca coronavirus vaccine study many of you are nervous about vaccinations in general. Please don’t be. The regulatory authorities assess the efficacy and safety of all vaccines and make an informed decision that at a population level the risks justify the benefits. Influenzae vaccination is the most studied vaccine in pwMS and it has been shown to be safe, i.e. it does not appear to trigger relapses and/or MRI activity. 

CoI: multiple

Twitter: @gavinGiovannoni 

Medium: @gavin_24211

#MSCOVID19: transverse myelitis

Barts-MS rose-tinted-odometer: ★★

How do you distinguish transverse myelitis that is not MS-related from spinal cord involvement in MS? 

Yesterday after reporting the possible and likely link between the Oxford-AstraZenca vaccine and transverse myelitis (TM) and possibly MS you asked how do neurologists differentiate TM from CIS or MS. 

Idiopathic or post-infectious/vaccine-related TM tends to be more extensive, i.e. involve multiple segments of the spinal cord compared to CIS/MS. This is often referred to as longitudinally-extensive TM. In addition, typical non-MS TM tends to involve the whole cord and not particular areas of the spinal cord. In comparison, CIS/MS tends to have discrete lesions that may involve the back or a segment of the spinal cord and extend over one or two segments. 

CIS/MS myelitis tends to fit the demographic profile of MS, i.e. more common in females, youngish age of onset (20-40 years) and is more common in regions of the world with a high MS prevalence. In addition, there are often other lesions in the brain and/or spinal cord that look like MS and CSF analysis usually shows oligoclonal IgG band and the cell counts in the spinal fluid are lower. 

Non-MS related TM can occur in any age group, occurs in both sexes and its quite common in Asian, African, Afro-Caribbean and African-American populations.  Brain imaging is usually normal; the exception being some patients with NMO. CSF analysis is OCB negative and the cell count is often raised. Interestingly, it is not uncommon in acute TM to find some neutrophils and occasionally eosinophils in the spinal fluid that does not happen in MS-related myelitis. 

An important clue is that non-MS related TM may have obvious precipitating factors of a recent viral or bacterial infection or vaccination. 

Saying all this it is sometimes very hard to differentiate the two and then time becomes the best diagnostician, i.e. you have to wait to see if someone goes onto to develop recurrent events. This is why medicine and neurology remain as much an art as a science. 

Worryingly the number of TM cases post-COVID-19 in the literature is quite high considering we are only 6-9 months into this pandemic. This would indicate that SARS-CoV-2 and its proteins may be the triggering factor for TM and/or MS and this will make this adverse event from this vaccine a real problem and we are likely to see more cases emerge. This does not mean the vaccine won’t be effective it simply means that some people with have to suffer harm to protect the many or the herd. This is the basic premise that population health is based on. 

CoI: multiple

Twitter: @gavinGiovannoni  / Medium: @gavin_24211

#MSCOVID19: coronavirus vaccine linked to MS-like complications

You will have heard by now that AstraZenca has paused its coronavirus vaccine study because of safety concerns. A study subject who received the vaccine developed transverse myelitis and had to be admitted to hospital. 

“The woman’s diagnosis has not been confirmed yet, but she is improving and will likely be discharged from the hospital as early as Wednesday”, said Soriot AstraZenca’s CEO (source STAT News).

From the same press conference, we also found out that another study subject had developed multiple sclerosis after receiving the vaccine. As most of you are aware transverse myelitis may be the initial manifestation of MS and sometimes it is very difficult to differentiate non-MS related transverse myelitis from CIS (clinically isolated syndrome compatible with demyelination or MS). 

Are two swallows enough to make a summer? I suspect not and I would be surprised if the data and safety monitoring committee recommends stopping the trials. However, they may do so if there is a third or fourth case. 

Transverse myelitis (TM)  is well described after vaccination as well as after viral and other infections. The yellow fever vaccine is probably the most common cause of vaccine associated TM. However, it was a common adverse event with the original rabies vaccine that was cultured and isolated from monkey neuronal cells. Fortunately, this is not how the rabies vaccine is made anymore and the incidence of TM is now much less common after rabies vaccination. Other vaccines that can trigger TM are influenzae, MMR, Japanese B encephalitis, hepatitis B and HPV vaccines. TM has also been associated with many infections, particularly viral and some bacterial infections. We neurologists refer to this type of TM as being vaccine-associated or post-infectious TM, respectively. 

Even if the AstraZenca vaccine trials restart, which in my opinion is likely, and the vaccine is shown to be effective, it is likely that the regulatory authorities will include TM as a potential adverse event. The latter will be based on the recent case and the historical perspective of other vaccines being known triggers of TM. What they will do about the case of MS is anyone’s guess, but I suspect they will include triggering MS disease activity as a potential adverse event as well. If they do this this will cause the MS community to probably err on the side of safety and hence this particular coronavirus vaccine will not be recommended for people with MS. 

Other implications is that there is a chance that the TM has not been induced by the Chimpanzee Adenovirus vector that is being used in this vaccine, but the actual coronavirus spike protein or immunogen. It is noteworthy that several cases of COVID-19 related TM have already been reported in the literature (see below), suggesting it may be the virus or the spike-protein that is the culprit.  If this proves to be the case then it is really bad news as TM will be a problem for the whole class of vaccines using the spike protein as the immunogen. 

So the implications of these observations are enormous for the field. However, there are things that can be done by neuroimmunologists to study the immune response to the SARS-CoV-2 spike protein and the Chimpanzee Adenovirus vector to see if there is any cross-reactivity with proteins and lipids in the spinal cord. The latter are standard molecular mimicry studies and this could help AstraZeneca and other vaccine manufacturers understand the TM risk in more detail.

You have to realise that this is what happens with vaccine and drug development and underscores why drug and vaccine development is so risky and expensive. The investment costs in terms of this vaccine have been largely derisked for AstraZenca by most of the preclinical development being funded and done by academia and the fact that the British and other governments have pre-ordered millions of doses of vaccine. 

We will update you on this story as it evolves. 

Addendum: the published case reports of TM-like conditions occurring in association with COVID-19.

1.Acute transverse myelitis after COVID-19 pneumonia.Munz M, Wessendorf S, Koretsis G, Tewald F, Baegi R, Krämer S, Geissler M, Reinhard M.J Neurol. 2020 Aug;267(8):2196-2197. doi: 10.1007/s00415-020-09934-w. Epub 2020 May 26.PMID: 32458198 Free PMC article. No abstract available.
2.Transverse Myelitis in a Child With COVID-19.Kaur H, Mason JA, Bajracharya M, McGee J, Gunderson MD, Hart BL, Dehority W, Link N, Moore B, Phillips JP, Rogers D.Pediatr Neurol. 2020 Jul 29;112:5-6. doi: 10.1016/j.pediatrneurol.2020.07.017. Online ahead of print.PMID: 32823138 Free PMC article. No abstract available.
3.Acute transverse myelitis in COVID-19 infection.Chow CCN, Magnussen J, Ip J, Su Y.BMJ Case Rep. 2020 Aug 11;13(8):e236720. doi: 10.1136/bcr-2020-236720.PMID: 32784242 Free PMC article.
4.COVID-19-associated acute transverse myelitis: a rare entity.Chakraborty U, Chandra A, Ray AK, Biswas P.BMJ Case Rep. 2020 Aug 25;13(8):e238668. doi: 10.1136/bcr-2020-238668.PMID: 32843475 Free PMC article.
5.Transverse myelitis related to COVID-19 infection.Zachariadis A, Tulbu A, Strambo D, Dumoulin A, Di Virgilio G.J Neurol. 2020 Jun 29:1-3. doi: 10.1007/s00415-020-09997-9. Online ahead of print.PMID: 32601756 Free PMC article. No abstract available.
6.COVID-19-associated acute necrotizing myelitis.Sotoca J, Rodríguez-Álvarez Y.Neurol Neuroimmunol Neuroinflamm. 2020 Jun 10;7(5):e803. doi: 10.1212/NXI.0000000000000803. Print 2020 Sep.PMID: 32522767 Free PMC article. No abstract available.
7.Acute necrotizing myelitis and acute motor axonal neuropathy in a COVID-19 patient.Maideniuc C, Memon AB.J Neurol. 2020 Aug 9:1-3. doi: 10.1007/s00415-020-10145-6. Online ahead of print.PMID: 32772172 Free PMC article.
8.A case of possible atypical demyelinating event of the central nervous system following COVID-19.Zoghi A, Ramezani M, Roozbeh M, Darazam IA, Sahraian MA.Mult Scler Relat Disord. 2020 Jun 24;44:102324. doi: 10.1016/j.msard.2020.102324. Online ahead of print.PMID: 32615528 Free PMC article.
9.Acute transverse myelitis associated with SARS-CoV-2: A Case-Report.Valiuddin H, Skwirsk B, Paz-Arabo P.Brain Behav Immun Health. 2020 May;5:100091. doi: 10.1016/j.bbih.2020.100091. Epub 2020 Jun 6.PMID: 32835294 Free PMC article.

CoI: multiple

#MSCOVID19: Fundraising

Two months ago we floated the concept of doing a UK-wide seroprevalence study in UK residents with MS to see how many had seroconverted to become anti-SARS-CoV-2 antibody positive and to see if there are differences in seroconversion rates between people on different DMTs. 

The motivation was based on a prediction that people with MS on ocrelizumab would have lower titres of anti-SARS-CoV-2 antibody titres, be more likely to be seronegative despite a history of COVID-19 and less likely to have neutralizing anti-spike protein RBD (receptor binding domain) antibodies compared to patients on other DMTs.

It looks like we may be correct; some early case reports suggest pwMS on ocrelizumab may not seroconvert. 

In addition to the cross-sectional analysis, we proposed following the seronegative pwMS over time to study how the COVID-19 pandemic evolves and monitor the development of herd immunity. 

We have designed the study and in parallel, to applying for funding we got the study approved by our University and Ethics committee. We thought we had the funding approved, but at the last minute due to a funding crisis, our funder said no. We are now sitting with a dilemma; an approved study with no funding. So we are having to revert to plan B; crowdfunding

Forms response chart. Question title: Do you think it is worth doing a national COVID-19/coronavrius seroprevalence study?. Number of responses: 88 responses.

When we did our survey you all agreed that crowdfunding would be one potential solution to our funding crisis. However, we can’t simply ask you to donate money. We have to put our money where our mouths are. So I have decided to come out of marathon running retirement to raise money for this study that will be managed by Dr Ruth Dobson and Dr Angray Kang. 

I have signed up for the virtual New York City Marathon in the medal-winning category. My aim is to complete a 26.2-mile run in London between October 17 and November 1. I will be joining runners from around the globe to make this the world’s largest virtual marathon. The question is does my right hip have enough cartilage left in it for me to complete the run? 

In addition, to me attempting to complete a marathon with a failing hip I am gently prodding other members of Bart-MS to do something as well. I may have one taker already, but more on this later. 

Our objective is to raise £25,000 to cover the costs of posting out blood spots to study participants. As this study is time sensitive we need to raise the money ASAP.

If you want to help us raise the funds please do not hesitate to contact us. 

Barts-MS JustGiving Fund Raising Site

Prof G with his virtual New York City Marathon bib on. Does he have what it takes to complete 26.2 miles?

CoI: multiple

#T4TD colour vision

When your neurologist looks in your eyes with an ophthalmoscope he/she is looking for the telltale signs of previous damage to the optic nerve. The sign we look for is optic disc pallor. The optic disc is made up of nerve fibres from the retina, which then pass out of the back of the eye to form the optic nerve. If you have had optic neuritis in the past and have lost nerve fibres this can be detected with an ophthalmoscope, OCT (optical coherence tomography) or with retinal photography. Nerve fibre loss from optic neuritis makes the optic disc look pale (see figure below).

The optic disc receives its blood supply from small arteries from the back of the eye; the amount of blood is proportional to the number of nerve fibres in the optic disc. The lower the number of nerve fibres the fewer blood vessels there are the paler the disc looks. Please remember red blood cells are red and give a health optic disc a pinkish colour (see top images above).

Did you know that with a typical attack of optic neuritis you lose about 20% of the nerve fibres in the eye? If you lose so many nerve fibres why isn’t your vision so badly affected in that eye? That is simply because your visual system is able to compensate for the damage; it has spare capacity. Despite this most pwMS who have optic neuritis will know that although their visual acuity, or gross vision, may have recovered they have subtle deficits that we don’t routinely test for. For example, colour vision is often abnormal; colours appear washed out. Contrast sensitivity is abnormal; you may have difficulty distinguishing between shades of grey. Depth perception is all over the place; you need binocular (both eyes) vision for accurate depth perception. If you have poor depth perception you may see things in 3D when they should be in 2D and you may have difficulty judging distances. You may also find that you are hypersensitive to bright lights or lights with certain wavelengths; I find a lot of pwMS become intolerant of fluorescent lights after an attack of optic neuritis. 

The problem with the COVID-19 induced changes in our MS service is that with remote consultations I can do this aspect of the neurological examination. Is it important? Yes, firstly it allows one to determine what neuronal systems have been affected by MS, which is required for diagnosis, i.e. dissemination of disease in space, and secondly for assessing your EDSS or Expanded Disability Status Scale. 

I am telling you all this as we developed a web-EDSS that requires you to know if your neurological examination is normal or abnormal. Having optic disc pallor is one clinical sign that may affect the EDSS. If you can’t get this information from your neurologist you can get a reasonable idea if your optic nerve has been affected by MS by downloading and using one of the many colour vision applications on your smartphone; we recommend using ‘eye handbook’ as it is free. So before completing your webEDSS you will need to know if you have abnormal colour vision in your left or right eye; this could be used as a proxy for optic nerve involvement. Please note if you have congenital colour blindness, which is more common in males, you can’t use this sign as a proxy for optic nerve involvement.

#T4TD = Thought for the Day

CoI: nil in relation to this post

#MSCOVID19: the storm

I have been asked many times about how COVID-19 is affecting our MS research programme. The short answer is massively and its true impact is yet to be realised because we are a far way off from anything that feels and looks like normal. We are still paralysed by the threat of a second wave of COVID-19; the social distancing requirements within the NHS means everything is going to be at half-mast and then the knock-on effects on research funding have yet to be felt. 

I am having sleepless nights about the covert threats of upcoming redundancies, whether or not our soft money will dry up, which we rely on to support administrative staff and prime research, how would one goes about declaring that you are academically bankrupt and then the massive increase in the teaching workload as we reconfigure all our teaching courses to go online. I have never worked harder and felt more unsettled than I do now. 

A good example of COVID-19’s knock-on effects is our #ThinkHand campaign. For those of you who have been following this blog for years should remember it well.  The central theme of the campaign ‘is not to write-off people with MS who have lost their lower limb function and are now having to use a wheelchair’. We have hypothesised and put forward a theory that MS is modifiable throughout its course and want to do clinical trials in people with advanced MS who are wheelchair users. The article by Timmermans and colleagues below shows that leg function declines earlier and quicker than arm function in MS, which supports our so-called ‘length-dependent axonopathy model of MS’.

Our #ThinkHand campaign started about 6 years ago and has resulted in the design and funding of two clinical trials targeting advanced MS. ORATORIO-HAND will be testing ocrelizumab in advanced PPMS (i.e. up to an EDSS of 8.0) and CHARIOT-MS that will be testing oral cladribine in advanced MS, including subjects with either SPMS and PPMS with an upper EDSS cut-off of 8.5. In both these trials, we will be using the 9-hole peg test as the primary outcome. The initiation and/or recruitment of subjects for both these trials have been suspended for the last 4 months and is unlikely to restart for another 2-3 months and maybe longer. We are talking about 6 months or more in COVID-19-related delays. If ‘Time is Brain’ or in the case of these trials ‘Time is Loss of Hand Function’ then these delays may mean that many pwMS will have progressed beyond the eligibility cutoffs for these trials.

We are not the only ones that have been affected and maybe it doesn’t help complaining. A very good friend of ours has cancer that is potentially terminal; as a result of COVID-19, her potentially life-saving surgery has been delayed by over 3 months. This week’s BMJ highlights the plight of cancer patients in the NHS and suggests that COVID-19 may result in 45,000 excess cancer deaths. What is the equivalent figure for people with MS? Will it be 10,000 people with MS lose their independence because of the progression of their MS and loss of upper limb function? Or 8,000 people with MS become unemployed because of worsening disability are a result of subclinical worsening cognition?

My philosophy is to simply get up each morning and try and get on with the task at hand. My motivation comes from an unusual source; a book “The Boy, the Mole, the Fox and the Horse” that my wife gave me at the beginning of lockdown. The quote that sums up the right attitude is the one about storms. 

“What is the best thing you’ve learnt about storms?”

“That they end”, said the horse.

Timmermans et al.  Ten-year disease progression in multiple sclerosis: walking declines more rapidly than arm and hand function. Mult Scler Relat Disord. 2020 Jun 26;45:102343.

Background and aims: From a clinical perspective there is a difference in the decline of arm and hand function and leg function in patients with multiple sclerosis (PwMS). Therefore, this study investigated the course of walking and arm and hand functions in PwMS over the first 10 years after diagnosis, including whether any function declined earlier or faster.

Methods: A long-term prospective follow-up study of an incidence cohort of 156 patients with a definite diagnosis of MS, either non-relapse onset (n=28) or relapse onset (n=128) type. Participants were systematically examined immediately after definite diagnosis, at 6 months, and at 1, 2, 3, 6 and 10 years. Walking was determined with the fast 10-meter timed walk test (10mTWT), arm and hand function with the Action Research Arm test (ARAT) and the nine-hole peg test (9HPT). The 10-year trajectories of walking and arm and hand functions were compared using standardized z-scores.

Results: From 3 years onwards the z-scores of the arm and leg function were visually diverging, with a trend towards significance at 6 years, and at 10 years the 10mTWT z-score is significantly higher than the 9HPT. This difference is more pronounced in non-relapse onset patients than in patients with relapse onset type MS, but present in both groups over the first 10 years. In the non-relapse onset group a difference in z-scores at 10 years post-diagnosis between the 10m TWT and 9HPT was found of -12.94 (95% confidence interval (CI) -20.2 to -5.73) for the right and -10.14 (95% CI -17.3 to -2.93) for the left hand. In the relapse onset group there was a difference at 10 years post-diagnosis of -2.17 (95% CI -3.75 to -0.59) for the right and a difference of -2.29 (95% CI -3.87 to -0.71) for the left hand.

Conclusion: This is the first longitudinal study that shows that walking declines earlier and more rapidly than arm and hand function in patients with MS. These results give important insights that can be linked to the pathophysiological disease process regarding the ascending order of deterioration in patients with MS.

Giovannoni et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Mult Scler Relat Disord. 2017 Feb;12:70-78.

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials.

CoI: multiple

#MSCOVID19: vaccine readiness

Will Prof G have to eat his proverbial hat?

I have been telling people that an effective SARS-CoV-2 vaccine is a long way away and that we shouldn’t expect a commercially available vaccine for another 12-18 months. Maybe I am wrong. The Moderna phase 1 results were published by the NEJM yesterday and are more impressive than I expected. These results are so important because the vaccine is based on RNA technology, which is relatively easy to scale-up in terms of production, unlike recombinant protein vaccines or inactivated viral vaccines. Therefore this vaccine may be with us before the end of the year.

The Moderna RNA vaccine carries the code for S-2P antigen, consisting of the SARS-CoV-2 glycoprotein. The vaccine is given as two doses (Day 1 and Day 29) into the deltoid or shoulder muscle. The RNA then uses the molecular machinery of the deltoid muscle to make the immunogen that then stimulates the immune response to the antigen, which will hopefully prevent wild-type SARS-CoV-2 infection and prevent COVID-19. 

This has potential implications for how we treat MS. It increases the likelihood of a successful vaccine to prevent COVID-19 and increases the chances of pwMS having to be vaccine-ready in a 6-9 month time scale rather than a 12-18 months period. Clearly this has implications for how we manage patients on DMTs that have been shown to blunt or prevent protective vaccine responses, in particular, pwMS on anti-CD20 therapy (rituximab, ocrelizumab, ofatumumab) or S1P-modulators (fingolimod, siponimod, ozanimod, ponesimod). 

Will Prof G have to eat humble pie or his hat? The market response to the data below suggests he will. What will be the implications for the MS DMT market? I suspect an effective coronavirus vaccine will hit the anti-CD20 market the most, which means ofatumumab’s MS launch will be a damp squib. 

Jackson et al. An mRNA Vaccine against SARS-CoV-2 — Preliminary Report. NEJM July 14, 2020 DOI:10.1056/NEJMoa2022483

BACKGROUND:  The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein.

METHODS: We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group.

RESULTS: After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti–S-2P antibody geometric mean titer [GMT], 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events.

CONCLUSIONS: The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461

CoI: multiple