As you are aware we, or I depending on your perspective, have recently have hit a brick wall trying to convince the MS community that the big unmet need in MS is smouldering disease.
The central hypothesis is that smouldering MS is the real MS. The following YouTube presentation summarises some of the main arguments for the hypothesis.
Your comments will help me make a decision to giving-up working on established MS and to focus on preventive neurology; in particular, preventing MS.
Yesterday I had the experience of a patient with highly active MS pull out of being treated with ocrelizumab (Ocrevus) because of concerns around being infected with the coronavirus COVID19. I suspect this will be the first of many patients with multiple sclerosis to do so.
It is clear that COVID19 epidemic is now a pandemic, i.e. it has involved enough continents and countries to be considered a major and very serious global health emergency. This was predicted to happen many weeks ago. Several basic epidemiological factors indicated that this would occur:
A long asymptomatic period during which infected people shed the virus and are infectious
Asymptomatic shedders who don’t get ill
An estimated R0 (r-zero) of 3-5, which is an estimate of how many people or contacts that an infected person infects
The identification of superspreaders; individuals who seem to be able to infect a large number of people
Excessive national and international travel; the initial epidemic in Wuhan happened to coincide with the largest annual human migration of people (see graph below). Approximately 400 million people migrate in relation to the Chinese New Year and a lot of that migration was international, which explains why the virus has spread so rapidly to other countries
Ubiquitous air travel, involving large airports and hubs, which has the ability to spread viruses very rapidly to people on the same aircraft and then to disperse them to all corners of the world before they get symptomatic disease
COVID19 is also a new human pathogen having jumped to humans from animals and as a result of this, we have no pre-existing herd immunity that could buffer or reduce its rate of spread.
At the moment the mortality or death rate form the virus is approximately 2%, or 1 in 50, with the majority of deaths affecting the elderly or infirm. The mortality is likely to fall as case ascertainment and reporting gets better. This occurs because the less ill get counted into the so-called denominator. At a population level, this death rate has major implications for healthcare systems. The majority of the deaths are due to pneumonia and these sicker patients require intensive care support. All countries simply don’t have enough ITU beds to support large numbers of ventilated patients. In fact, Britain has too few ITU beds already, without having to deal with the coronavirus pandemic.
What to look out for?
Coronavirus infection presents very non-specifically with flu-like symptoms, i.e. fever, a cough, or difficulty breathing. Most cases are mild. Those who have died in often have pre-existing health conditions and this is where the problem lies for pwMS. If you have advanced MS, a history of recurrent chest infections and/or you are on immunosuppressive therapies you are considered at high risk of complications from coronavirus infection. The latter risk extends to other infections as well, which is why, for example, it is our policy to recommend the annual flu vaccine to all of our patients with MS.
What to do?
If you have symptoms following travel to a high-risk area or after coming into contact with someone who has had coronavirus infection you should contact the NHS hotline so that appropriate samples can be submitted to Public Health England for testing. In addition, you will need to self-isolate or be treated in isolation.
I would not recommend stopping your disease-modifying therapy. The immunosuppression associated with MS DMTs is relatively mild-moderate and hence most pwMS can handle infections relatively well. The exception being alemtuzumab (Lemtrada), and possibly cladribine (Mavenclad), during the lymphocyte depletion phase. Cladribine is less of a problem as T-cells are on average depleted by ~50%, whereas with alemtuzumab the T- and B-cell depletion is typically greater than 90%. The good thing about IRTs (immune reconstitution therapies) is that once your immune systems have reconstituted they are competent to deal with infections.
Although fingolimod (Gilenya) causes lymphopaenia it is not an absolute lymphopaenia as lymphocytes are sequestered or trapped in lymph nodes. Therefore, pwMS on fingolimod can in general deal with viral infections, although they have more frequent and possibly more severe infections. This also applies to other S1P modulators (siponimod, ponesimod, ozanimod, etc.), in other words it is a class effect.
Viral response on anti-CD20 therapies (rituximab, ocrelizumab and ofatumumab) should also be maintained, but maybe blunted as B-cell and antibody responses may be necessary to help clear the virus. The infections that people on anti-CD20 therapies have a problem with are encapsulated bacteria (pneumococcus, meningococcus, Haemophilus, etc.).
Coronaviruses can rarely cause and encephalitis, typically in severely immunocompromised patients. This would indicate that as a class coronaviruses are neurotropic. I am not aware of any data on whether or not COVID19 causes encephalitis. If COVID19 is neurotropic encephalitis would be a risk for people on natalizumab (Tysabri). As natalizumab blocks immune surveillance of the CNS, a person on natalizumab who develops a COVID19 encephalitis would be in danger of succumbing to the infection. The latter is analogous to PML, which is also viral encephalitis.
DMF (Tecfidera) is only mildly immunosuppressive and in my opinion, is unlikely to be a major worry in the event of you acquiring a COVID19 infection. The one caveat being patients on DMF with a significant lymphopaenia, i.e. with a total lymphocyte count of less than 0.8 x 109/L or 800/mm3.
Teriflunomide (Aubagio), glatiramer acetate (Copaxone) and interferon beta (Betaferon, Avonex, Rebif, Plegridy) are not immunosuppressive agents and hence should not increase your chances of having a severe COVID19 infection.
Whilst the risk of COVID19 infection to the general public, and hence pwMS, is very low I would not recommend changing your DMT or avoiding starting any planned infusions. I would, however, recommend that if you are immunosuppressive to be extra-vigilant about hygiene (handwashing, etc.) and to avoid travelling to high-risk areas. If you are travelling through high-risk areas, for example, China, Hong Kong or Singapore you need to be more vigilant.
I am also getting asked for advice about face masks. The evidence that cheap surgical masks work for coronaviruses is limited. Coronaviruses are spread in a different way to the flu virus. Coronaviruses are not aerosolized in the same way as the flu virus and hence are not breathed in, but are rather spread by droplets. These stick to surfaces and hence the need to wash your hands. So masks are likely to work both ways for coronavirus, where they are not very effective for flu. One thing masks do is they make you wearer change your behaviour in other ways.
If you are travelling to a high-risk area and are going to use a face mask can I suggest using a good quality one, i.e. an FFP3 mask that filters out small particulate matter? These work for larger organisms such as TB and may help reduce transmission of COVID19. It is important that you have the masks fitted and you know how to use them properly. Within the NHS the latter is typically done by a healthcare professional with the necessary training on how to assess adequate mask fitting and usage.
As we are not infectious disease experts or virologists I would recommend following the NHS’ and Public Health England’s website for up to date advice.
What did I recommend for my patient above?
As there was no way he was going to be treated with ocrelizumab I ended-up recommending teriflunomide. The advantage of teriflunomide is that it is not immunosuppressive and has pan anti-viral activity against many viruses.
Clearly the advice given above applies to pwMS living in the UK. In COVID19 hotspots, e.g. China, it may be safer to delay treatment with immunosuppressive therapies until the epidemic has passed and there is herd immunity to protect you. In addition, a COVID19 vaccine may become available within the next 6-12 months. Therefore, it may be worthwhile initially choosing an immunomodulatory DMT that won’t interfere with future vaccine responses.
P.S. (27-Feb-2020): Please be aware that the advice above may be time-limited. Once the coronavirus becomes established in the community and person-to-person spread becomes more common and the source of infection can’t be traced, which is happening in China and Italy at the moment, then the public health advice may change. In this situation reverse quarantine may be necessary, i.e. to ask high-risk individuals to self-isolate themselves so as not expose themselves to the virus. At the moment this is not necessary in the UK as all the cases have been linked to a clearly identifiable source.
I am in Milan at the International Progressive MS Alliance Industry Forum Meeting. The aims of the meeting are to:
Discuss challenges understanding and measuring progression and its impact on drug labels
Discuss regulatory issues, opportunities and implications for drug labels and regulatory approvals
Discuss links and opportunities for industry and the Alliance to contribute feedback to the International Advisory Committee on Clinical Trials in Multiple Sclerosis activities on phenotype classification and clinical trials
Share lessons from recent clinical trials/development programs and how they impact the challenges of developing drugs for progression in MS
I have been asked to speak on the implications of disease classification for drug development, regulatory approval and drug labelling. This topic is fine, but it is far removed from people with the disease, which is why I am going to base my talk on case scenarios to illustrate how absurd the current status quo is for pwMS and the wider MS community.
As a pre-read to these case scenarios, I suggest you read a previous post of mine about progressive MS.
Case scenario 1
48-yr old woman MS x 22 year Last relapse 8 years ago – lower limb weakness and exacerbation of bladder problems
Annual MRI scans: Last scan 3 years ago Marked brain and spinal cord atrophy
Poor gait, now needs to use walking sticks outdoors and can manage only 10-20m; uses scooter outdoors Bladder and bowel problems with recurrent UTIs Significant cognitive impairment
EDSS = 6.5
DMTs: Interferon-beta-1a stopped 3 years
Does this patient have active SPMS? Does she have active SPMS?
Case scenario 2a
36-yr old male MS x 12 years Previously treated with Rebif-44 x 6 years; failed due to ongoing relapses Switched to fingolimod 3 years ago Last relapse 4 years ago / MRI stable
EDSS = 3.0 (stable)
Difficulty running and walking long distance; Fitbit data over the last 3 years showing objective reduction in daily activity
Does this patient have SPMS? Is the patient eligible for a DMT switch? Is the patient eligible siponimod?
Case scenario 2b
36-yr old male MS x 12 years Previously treated with Rebif-44 x 6 years; failed due to ongoing relapses Switched to fingolimod 3 years ago Last relapse 4 years ago / MRI stable
EDSS = 3.0 (stable)
Difficulty running and walking long distance; Fitbit data over the last 3 years showing objective reduction in daily activity
Labeled as having inactive SPMS Under NHSE guidelines fingolimod is stopped and 10 weeks later he presents with new onset paraplegia MRI shows longitudinally extensive myelitis and >30 new Gd-enhancing lesions over the neuraxis
Does this patient have SPMS? Is the patient eligible siponimod? What happens if his treatment response is suboptimal on spinoimod?
Case scenario 2c
36-yr old male MS x 12 years Previously treated with Rebif-44 x 6 years; failed due to ongoing relapses Switched to fingolimod 3 years ago Last relapse 4 years ago / MRI stable except progressive brain volume loss (0.78% per year over the last 3 years; Icometrix)
EDSS = 3.0 (stable)
Does this patient have SPMS? Is the patient eligible for a DMT switch? Is the patient eligible siponimod?
Case scenario 2d
36-yr old male MS x 12 years Previously treated with Rebif-44 x 6 years; failed due to ongoing relapses Switched to fingolimod 3 years ago Last relapse 4 years ago
EDSS = 3.0 (stable), but has noticed increasing forgetfulness at work and difficulty using a new software system T25W & 9HPT stable SDMT worsening: 2017 = 48 2018 = 45 2018 = 41 2019 = 39
Does this patient have SPMS? Is the patient eligible for a DMT switch? Is the patient eligible siponimod?
If you work through the logic of each of these case scenarios that are based on real-life examples you will quickly see that the current status quo is not compatible with the biology of the disease and makes very little sense; in other words, classifying MS as three diseases is absurd.
We ran our third triMS-online this week and apart from a technical problem in the satellite symposium it went reasonably smoothly. The participants were very engaged and asked lots of questions. The topic of vaccination was particularly well received. Which vaccine? Component or live vaccines? When to give the vaccines and whether or not to delay starring a DMT to complete the schedule.? Interestingly and importantly MMR, or mumps, measles and rubella, was not on the radar.
It is my impression that the MS community assume these childhood infections and vaccinations are done and dusted. However, with the rise of the anti-vaccine movement, there is an increasing number of people not being vaccinated in childhood with the MMR. This means that an undefined number of pwMS will be MMR seronegative. Is this a problem? You bet it is!
To explain the consequences of getting measles infection as an adult on immunosuppression I penned this fictional case scenario. According to the “Donald Rumsfeldometer”, this is an unknown known.
Rumsfeldometer
Known-knowns – there are things we know that we know
Unknown-knowns – these are the things we know will occur
Known-unknowns – there are things that we now know we don’t know
Unknown-unknowns – there are things we do not know we don’t know
“There are known knowns; there are things we know that we know. There are known unknowns; that is to say, there are things that we now know we don’t know. But there are also unknown unknowns – there are things we do not know we don’t know.”
Donald Rumsfeld, former United States Secretary of Defense.
Fictional Case
When she finally arrived on the ward she was unable to speak and was clearly confused and disorientated. All four of her limbs were twitching and would jerk when touched; i.e. she had generalised myoclonus. She was drooling from the mouth. Her latest MRI showed hyperintense signal change in the cortical ribbon or the grey matter on the surface of her brain.
Since her last MRI 8 days ago, the involvement of cortex had spread from the left parietal lobe to involve the entire left frontal lobe, the medial surface of the right frontal lobe, the left occipital lobe and the left temporal lobe. There was new signal change in the left thalamus and pulvinar and the white matter of the left hemisphere was diffusely involved. Interestingly, the post-contrast scans showed no obvious gadolinium-enhancement. Her EEG showed diffuse slowing over the left hemisphere with occasional sharp waves. The neurophysiologist did not think the pattern was a burst suppression pattern.
She was only 24 years of age and had been on natalizumab for 37 months. She was JC virus seronegative and her most recent CSF examination was negative on PCR for JC virus DNA. Apart from a mildly raised protein, the CSF was acellular. Her referring neurologist thought the most likely diagnosis was a secondary CNS lymphoma and had referred to our centre for a brain biopsy.
What the neurologist had missed was that this patient had recently come into contact with her friend’s 4-year old daughter who had been diagnosed with measles. In fact, there had been a cluster of eight cases of measles in the nursery school her friend’s daughter had attended. The tragedy is that this patient had not received her MMR vaccine as a child because her mother had been concerned about the safety of the MMR vaccine after the now retracted and fraudulent Andrew Wakefield study linking MMR vaccine to autism.
Once we had this history our working diagnosis was that of a measles inclusion body panencephalitis and our diagnosis was confirmed once we got back the CSF measles PCR result from her repeat lumbar puncture. Sadly the patient passed away 5 days after admission. A post-mortem examination confirmed the diagnosis of measles inclusion-body panencephalitis.
Interestingly, despite being on natalizumab there were was quite a heavy CD8+ T-cell infiltrate, which would indicate that natalizumab does not necessarily block all trafficking of lymphocytes into the brain of someone with viral encephalitis.
So if you have MS and are about to start an immunosuppressive DMT please review your vaccine history. If you discover you have not had the MMR vaccine or other vaccines you may need, please discuss this with your neurologist or MS nurse. Once you are on specific DMTs live vaccines such as the MMR are contraindicated.
I am sure some of you will be saying that I am scaremongering, but I know that it is only a matter of time before we see MMR-naive patients with MS succumb to wild-type or community-acquired infection with one or more of these viruses (see case study below).
Please note measles and mumps are circulating at present in the community and because of lower rates of MMR vaccine uptake you can’t necessarily rely on herd immunity to shield you from infection.
Isn’t prevention better than managing the consequences of these infections?
Measles inclusion body encephalitis (MIBE) is a disease of the immunocompromised host and typically occurs within 1 year of acute measles infection or vaccination. We report a 13-year-old boy who had chronic granulomatous disease and presented 38 days after stem cell transplantation with afebrile focal seizures that progressed despite multiple anticonvulsants. After an extensive diagnostic evaluation, brain biopsy was performed, revealing numerous intranuclear inclusion bodies consistent with paramyxovirus nucleocapsids. Measles studies including reverse transcriptase-polymerase chain reaction and viral growth confirmed measles virus, genotype D3. Immunohistochemistry was positive for measles nucleoprotein. Despite intravenous ribavirin therapy, the patient died. MIBE has not been described in stem cell recipients but is a disease of immunocompromised hosts and typically occurs within 1 year of measles infection, exposure, or vaccination. Our case is unusual as neither the patient nor the stem cell donor had apparent recent measles exposure or vaccination, and neither had recent travel to measles-endemic regions. The patient had an erythematous rash several weeks before the neurologic symptoms; however, skin biopsy was consistent with graft-versus-host disease, and immunohistochemistry studies for measles nucleoprotein were negative. As measles genotype D3 has not been seen in areas where the child lived since his early childhood, the possibility of an unusually long latency period between initial measles infection and MIBE is raised. In addition, this case demonstrates the utility of brain biopsy in the diagnosis of encephalitis of unknown cause in the immunocompromised host.
Have you registered for our third global triMS.online virtual conference on 13 February 2020?
The conference platform will open at 13:00 GMT, to allow delegates to explore the exhibit and poster halls. Those new to the area of MS may wish to join an educational session commencing at 13:30 GMT; the main scientific programme follows at 14:00 GMT.
I predict online conferences are the future. The environmental impact of large face-2-face conferences will not be justifiable within a decade.
If you can’t attend the live meeting the talks will be recorded and will remain online for you to watch in your own time. Please let your colleagues know about the meeting. Thanks.
I remember her so well. She was malnourished, bordering on anorexic. When I examined her she was literally skin and bone with abrasions over the bony protrusions, or spinous processes, on her back and an infected pressure sore on the heel of her right foot. She used to bum-hop down the stairs in her house and occasionally would slip and slide down the stairs, hence the carpet burns on her back Her husband had abandoned her and her 12-year-old son two years previously. Too proud to ask for help she had been struggling with an increasing disability; she was off her legs with bowel and bladder problems. She was depressed and in a bad way; she was simply not coping.
The tragedy is that her son had become her defacto carer and was responsible for doing the shopping, domestic chores and looking after her including bathing her and taking care of her intimate bodily needs. As a result of the burden of taking on the role as a primary carer he had become socially withdrawn and had no friends. Firstly, he had no time for play and, secondly, who want to bring home friends when his mother was in such an awful state. As a result of having to get his mother up in the morning, dressed and fed, he was often late for school and had had several warnings from the school. The tragedy is that when his mother failed to attend parents evenings and meetings with his teachers nobody bothered to ask the right questions. Nobody had noticed his social isolation and I suspect his demeanour.
All it took was one phone call from me to her GP, who arranged for a social worker to do an urgent home visit that same day. She was admitted to a local hospital the following day for rehabilitation and management of her pressure sore that required surgical intervention. Her sister came down from the midlands to look after her son and the rest is history. I don’t work at that hospital anymore, but I suspect this woman will either have very advanced MS or will by now have passed away from the complications of MS. Her son will by now, be in his late twenties. I sincerely hope he is okay and managed to reconnect to wider society and has many friends. Just maybe he has reconnected with his father.
This lady’s story is exceptional in that these dire social circumstances don’t happen very often. Saying this there is still an army of young carers in Britain looking after parents, grandparents or siblings with disabling neurological conditions, including many with MS. Young carers, are part of the underbelly of austerity Britain and the harsh consequences of our government’s massive cuts in social spending.
The article below covers the experiences of young people living in a family affected by a disabling neurological condition. In reality, the condition, in this case MS, shapes them, throws them into the deep end and creates an intense need for them to talk about things and highlights the obvious that they usually don’t understand what is going on. This is one of the reasons why Barts-MS created and runs Digesting Science; to teach children about the disease their mother or father has and to give them an environment to ask questions.
If you have young children between the ages of 6 and 12 you should ask your MS nurse if there is a Digesting Science course being run near you and you should take them along. Some of my patients tell me the experience for the family is transformational. Knowledge is empowering even if you are only 6 years old.
If you are a young carer and this post has affected you can get help from the Carers Trust.
In this case study research, we investigated the impact that having a parent with a neurological condition can have on young adults’ experiences of growing up and the nature of their support networks. The work was informed by models of the interface of chronic conditions and the family. Stroke (n = 6), multiple sclerosis (n = 14), and dementia (n = 11) were selected as discrete cases. Within each case, the researcher (a) carried out semi-structured interviews with young adults (16-25 years) living in families affected by this condition and (b) organized a workshop in which all participants reviewed preliminary themes and reflected on their support networks. A thematic analysis identified four themes: the condition has shaped me, thrown into the deep end, I need to talk about this, and they don’t understand. A model of networks and support for these young adults was generated reflecting the need to increase their visibility and their access to support.
How close are we to offering some people with MS a cure?
I am speaking at the Imperial College Neuroscience Society this morning on ‘how close we are to curing MS’. I think we are very close; in fact some of the longterm follow-up data of IRT (immune reconstitution therapies), in particular, alemtuzumab, non-myeloablative HSCT and myeloablative HSCT looks very promising. I suspect that when we complete our long-term follow-up of cladribine -treated patients we will find a similar story.
If you want to have any chance of potentially curing yourself of MS you have to be treated early, as early as possible, with an IRT preferably with one of the big guns. The problem you will have is finding a neurologist who agrees with this treatment strategy.
The Barts-MS team is heavily engaged with the 2020 MS@theLimits meeting at the Royal College of Physicians. Two things to note is the gender bias in favour of female speakers. This was in response to criticism about the male dominance at the last MS@theLimits meeting in 2018.
I am speaking today about some of my ideas around ‘the real MS’ or ‘smouldering MS’. I hope to challenge the current clinico-MRI worldview of MS and to get the MS community to think about MS as a biological disease.
I am hoping to make a compelling case for tackling smouldering MS with combination therapies and will be giving several examples in the presentation. Please note my talk includes Brain Health that will become increasingly important in the future.
Today the EU licensed siponimod for the treatment of active secondary progressive MS. It has been a very long and winding road to get here.
Siponimod is not an eagle, phoenix or maven, but rather a hopebird which symbolises the importance of “an optimistic approach to what lies ahead”. Less than a decade ago we were telling our patients with a progressive course that they were beyond hope, that has now changed.
Being able to offer treatment to people with SPMS will be a challenge to the NHS, because of the way our services are configured, but it is doable. If there is a will to make it happen it will happen.
The next task is to challenge the term ‘active’ SPMS. What does it really mean? How can you tell someone with worsening SPMS they don’t have active SPMS. I think it is time to challenge the old dogmas that thave crept into our field. I also hope siponimod will be a segway into a new era of combination therapy.
CoI: multiple; in particular, I sit on the Siponimod SPMS trial steering committee
As you know high-dose simvastatin 80-mg per day is being tested in a phase 3 trial in the UK (MS-STAT2). I have referred several patients to participate in this study. Despite this, there has always been a worry about this treatment strategy because statins have been associated with changes in cognition, which is why I have always said that if I needed a statin I would take one that was non-CNS penetrant, for example, pravastatin.
The publication below is reassuring in that it shows that statin therapy in a population of elderly Australians was not associated with any greater decline in memory or cognition over 6 years compared to non-statin users. In fact, statin usage actually attenuated the decline in specific memory test performance in participants with heart disease and the genetic dementia risk factor apolipoprotein Eε4.
You may ask what has this got to do with MS? I think a lot. One of the theories of delayed or late worsening in MS is related to early ageing mechanisms. This is why it will become important in the future to tackle ageing as a potential add-on treatment for MS (please see my previous blog post, ageing, on this topic).
Background: There is widespread consumer concern that statin use may be associated with impaired memory and cognitive decline.
Objectives: This study sought to examine the association between statin use and changes in memory and global cognition in the elderly population over 6 years and brain volumes over 2 years. Interactions between statin use and known dementia risk factors were examined.
Methods: Prospective observational study of community-dwelling elderly Australians age 70 to 90 years (the MAS [Sydney Memory and Ageing Study], n = 1,037). Outcome measures were memory and global cognition (by neuropsychological testing every 2 years) and total brain, hippocampal and parahippocampal volumes (by magnetic resonance) in a subgroup (n = 526). Analyses applied linear mixed modeling, including the covariates of age, sex, education, body mass index, heart disease, diabetes, hypertension, stroke, smoking, and apolipoprotein Eε4 carriage. Interactions were sought between statin use and dementia risk factors.
Results: Over 6 years there was no difference in the rate of decline in memory or global cognition between statin users and never users. Statin initiation during the observation period was associated with blunting the rate of memory decline. Exploratory analyses found statin use was associated with attenuated decline in specific memory test performance in participants with heart disease and apolipoprotein Eε4 carriage. There was no difference in brain volume changes between statin users and never users.
Conclusions: In community-dwelling elderly Australians, statin therapy was not associated with any greater decline in memory or cognition over 6 years. These data are reassuring for consumers concerned about statin use and risk of memory decline.
