Prof G's MS Blog Archive

St Elsewhere

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

St Elsewhere is a euphemism in medicine for a fuck-up done under someone else’s watch, i.e. at St Elsewhere’s hospital. In this week’s NEJM there is a tragic case of a 22-year old Pakistani man who was misdiagnosed as having MS at St Elsewhere, started on natalizumab, which was ineffective, before being switched to interferon beta. By the time he was admitted to UCSF he was in extremis. A relatively standard workup revealed this gentleman had a tumour; a CNS germinoma that had spread to the meninges or coverings of the brain and spinal cord. On reviewing his initial presentation there were so many ‘red flags’ it is hard to understand why he was misdiagnosed. Tragically this poor man now has ‘substantial neurologic disability, for which he received assistance with all activities of daily living’. This case is a tragedy because CNS germinomas when caught early and treated have a reasonable prognosis with a 10-year survival rate of about 70%.

Minter et al. Stalking the Diagnosis. N Engl J Med. 2021 Apr 1;384(13):1262-1267.

If only this patient had had a lumbar puncture and CSF analysis done as part of his initial diagnostic work-up the correct diagnosis would have been made. The question arises whether or not this gentleman had medical insurance or not? He was a delivery driver and had only recently immigrated to the USA. To be fair to the neurological team looking after him a diagnostic short-cut may have had to be made because he simply didn’t have the financial resources to pay for the diagnostic tests. I suspect the latter is likely to have happened and maybe the title of this post should have been St Poor.

I want to remind you that if you have been diagnosed with MS you may not have MS. In the study below approximately 1 in 5 people diagnosed with MS don’t have MS. This figure is much higher than previous studies. I have always quoted the Danish post-mortem studies that suggest that about 1 in 20 patients are misdiagnosed. Maybe Danish neurologists are simply better at diagnosing MS compared to their American colleagues?

There is no one test that can be done to diagnose MS. MS is diagnosed by combing a set of clinical and MRI findings, electric or neurophysiological investigations and laboratory tests. If these tests fulfil a set of so-called MS diagnostic criteria the Healthcare professional (HCP) or neurologist makes a diagnosis of MS.

The underlying principle of making a diagnosis of MS is showing dissemination of lesions in space and time and excluding other possible diagnoses that can mimic MS. The diagnostic criteria have evolved over time from being based purely on clinical attacks to those including electrical and spinal fluid tests to the modern era in which we use MRI to help confirm dissemination in time and space.

Dissemination in time means at least two attacks or two MS lesions occurring at least 30 days apart.

Dissemination in space means lesions occurring in different locations, for example, the optic nerve and spinal cord.

The electrical or neurophysiological tests are called evoked potential (EPs) and test electrical conduction in a particular neuronal pathway. They can be useful to show the effects of lesions in pathways that are not evident on neurological examination or seen on MRI. The EPs can also show slow electrical conduction which is one of the hallmarks of diseases that affect myelin, the insulation of nerves that are responsible for speeding up electrical conduction.

The laboratory tests are typically done to exclude other diseases that can mimic MS. One test that is useful in helping to make the diagnosis of MS is examining the spinal fluid for the presence of oligoclonal immunoglobulin G or IgG bands (OCBs), which are the fingerprint of a specific type of immune activation within the central nervous system (CNS). The OCB fingerprint is relatively specific for the diagnosis of MS in the correct clinical context. Please note OCBs can are found in infections of the nervous system and other autoimmune diseases, therefore, the presence of OCBs are not diagnostic on their own.

When CSF is sent to the laboratory they also measure the protein, glucose, lactose and do a cell count. An often the spins the cells out of the CSF and examine them to make sure they are abnormal. I suspect if this patient had had a CSF examination it may have been abnormal, which would have led the clinicians to the correct diagnosis, which will have allowed him to be treated differently; importantly, treated early and he may not have become profoundly disabled.

Why is getting the correct diagnosis of MS so important? Firstly, some of the treatments for MS have life-threatening complications; you don’t want to expose people without MS to these complications. Some diseases that mimic MS can be made worse by MS DMTs. This latter is particularly relevant for NMO or neuromyelitis optic. Patients with NMO misdiagnosed as having MS get worse on many of the MS DMTs. Finally, a diagnosis of MS has many psychological, social, financial and economic implications for people. Just having a diagnosis of MS, even if you turn out to have benign MS in the future, has implications for the person concerned. For example, it may affect your life choices and may impact your ability to get insurance cover to name to obvious examples. I would, therefore, advise you to make sure you have MS and not an MS mimic.

The most common MS mimics:

The evolving definition of MS based on diagnostic criteria:

Clinical criteria only:

Schumacher, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y Acad Sci 1965;122:552-68.

Clinical, EPs and CSF analysis:

Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-31.

Clinical, EPs, CSF analysis and MRI:

Kaisey et al. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. Mult Scler Relat Disord. 2019 May;30:51-56.

BACKGROUND: Multiple Sclerosis (MS) specialists routinely evaluate misdiagnosed patients, or patients incorrectly assigned a diagnosis of MS. Misdiagnosis has significant implications for patient morbidity and healthcare costs, yet its contemporary incidence is unknown. We examined the incidence of MS misdiagnosis in new patients referred to two academic MS referral centers, their most common alternate diagnoses, and factors associated with misdiagnosis.

METHODS: Demographic data, comorbidities, neurological examination findings, radiographic and laboratory results, a determination of 2010 McDonald Criteria fulfillment, and final diagnoses were collected from all new patient evaluations completed at the Cedars-Sinai Medical Center and the University of California, Los Angeles MS clinics over twelve months.

RESULTS: Of the 241 new patients referred with an established diagnosis of MS, 17% at Cedars-Sinai and 19% at UCLA were identified as having been misdiagnosed. The most common alternative diagnoses were migraine (16%), radiologically isolated syndrome (9%), spondylopathy (7%), and neuropathy (7%). Clinical syndromes and radiographic findings atypical for MS were both associated with misdiagnosis. The misdiagnosed group received approximately 110 patient-years of unnecessary MS disease-modifying therapy.

CONCLUSION: MS misdiagnosis is common; in our combined cohort, almost 1 in 5 patients who carried an established diagnosis of MS did not fulfil contemporary McDonald Criteria and had a more likely alternate diagnosis.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Black with MS? This one’s for you

#GetVaccinatedASAP

Please help I am getting worse

Barts-MS rose-tinted-odometer: ★

After my clinic last week I was emotionally drained and probably more than usual. Patient after patient was telling me the same story and asking the same questions.

“Since lockdown last year things have gotten worse, what can I do about it?”

My superficial interpretation is that most of these patients had gotten worse because of relative physical and mental inactivity. Working from home or not working, self-isolation to prevent getting COVID-19 and less physical exercise are taking their toll. I am increasingly making the point that unless you use it you will lose it (#UseItOrLoseIt). Put simply less physical exercise (self-isolation), less mental exercise (reduced work or no work) and less emotional exercise (social interactions) are having a devastating impact on people with MS. Then there is the shredder, i.e. ongoing MS disease activity be it new focal inflammatory lesions or the dreaded smouldering MS. As we have not been able to monitor pwMS with regular MRIs and change and escalate treatments a large number of pwMS are paying the price of having their MS undertreated.

One of the patients I spoke to via a video consult wanted to know why she was getting worse and why she was not eligible for siponimod treatment. She had not had a relapse in over 10 years and had no new lesions when we imaged her last year January 2020. She has gone from EDSS 6.0, i.e. being able to walk several hundred metres with a cane, to being wheelchair-bound in just 12 months. This rapidity of her secondary progression is faster than what we usually see. Most people spend at least 3 to 4 years at EDSS 6.0 and EDSS 6.5. The question I have is there be another reason for the rapid progression? Had she developed a new lesion in the spinal cord? The only way to sort this out is with an MRI and possible lumbar puncture and CSF analysis to measure neurofilament levels. The problem we have is that we are not doing non-urgent MRIs or lumbar punctures at present. However, I suspect the repeat MRI and CSF analysis will show no obvious new inflammation, which will make her ineligble for siponimod.

Many of these patients don’t understand that beyond relapses and focal MRI activity the real MS lurks. I explain why disease worsening or disability progression occurs in MS under 4 headings:

1. SS (scissors and stripper): The acute focal inflammatory lesion acts like molecular scissors and strippers, cutting axons and stripping myelin off axons. The cut and naked axons are blocked from conducting signals and result in a neurological deficit. The neurological deficit from this acute conduction block will vary depending on the pathway affected, for example, if the lesions affect the optic nerves it will cause loss of vision. The way to prevent the SS from causing conduction block is to prevent new lesions from forming. If this patient has a new lesion it would offer her hope and make her eligible for siponimod.

2. EF (energy failure): The demyelinated axons may recover function by a process called axonal plasticity or remyelination. Axonal plasticity is the process by which the neuron inserts new ion channels into the demyelinated axonal segments and restores conduction. Remyelination may also occur, but the new myelin is never as thick and as efficient as the old myelin and is susceptible to intermittent failure. These demyelinated and thinly remyelinated sections of axons are susceptible to temperature and fatigue. If the temperature rises these sections block and if the axons are used too much, for example with exercise, they run out of energy and also block. Sometimes the type of ion channel that is inserted into the axons fire spontaneously can cause intermittent symptoms, for example, pins and needles, pain, neuralgia and muscle spasms. As these ion channels are sodium channels it explains why these intermittent symptoms respond to drugs that block sodium channels, for example, carbamazepine, oxcarbazepine, phenytoin and lamotrigine.

I suspect a large amount of progressive disability in this patient is due to these mechanisms; sadly, we don’t have any add-on treatments we can offer her at present.

Another process that helps with recovery is that the surviving axons form sprouts to reconnect disconnected pathways and create new synapses, which are the connections between nerve fibres. All these processes increase the energy requirements of the axon, which makes it vulnerable to die-off later. At the same time the ‘MS lesion’ remains inflamed and some of the chemicals produced as part of the inflammation poison the mitochondria, which are energy factories of the axons. A further reduction in energy production puts further stress on the system. As a result of these processes, there is a delayed dying off of axons that takes place over months to years after the initial MS lesion has formed. This delayed dying off of axons explains why despite effective treatments stopping new MS lesions from forming some people with MS still notice a slow deterioration in their functioning. This is why we have added this patient to our prescreening log for the upcoming Chariot-MS trial in which we will be testing whether or not oral cladribine will slow down the worsening of upper limb function.

There is mounting evidence that exercise encourages plasticity, i.e. axonal plasticity and sprouting and synaptogenesis and recovery or maintenance of function. Sadly due to lockdown this patient had not been having physiotherapy and was unable to attend her regular aqua aerobics. Could she be losing function because of this? I suspect this could explain some of her deterioration.

3. SB (slow burn): Some MS lesions never recover and become slowly expanding lesions or SELs. SELs have a rim of hot microglia at their edges and continue to swallow up the myelin and axons of the surrounding ‘normal-appearing’ tissue. These lesions don’t have much acute inflammation left in them, i.e. there are very little T and B cells in these lesions. SELs continue to expand over years to decades and are responsible for the slow accumulation of damage over many years. SELs can be seen on MRI; they typically cause black holes on so-called T1-weighted MR images and have a dark rim of iron around them when viewed with special MR sequences (susceptibility imaging). The iron rim is a marker of these so-called ‘hot microglia’.

I would not be surprised if this patient had a SEL in a critical position in her cervical spinal cord. At present we have no idea what causes some MS lesions to regress and recover and for others to expand and become SELs. What we do know is that our standard anti-inflammatory DMTs have very little or no effect on SELs once they have developed. It is important to realise that SELs are found throughout the course of MS and are even seen in people with a radiologically isolated syndrome (RIS) or asymptomatic MS. In other words, the so-called ‘progressive MS pathology’ is found very early in the MS disease course. We do know that the number and size of the SELs increase with disease duration, i.e. the more MS lesions that develop the more SELs will be formed. Another important observation that has recently emerged is that a single strategically located SEL can cause an extraordinary amount of damage; for example, a single SEL in the so-called pyramidal tract or motor pathway can cause progressive weakness down one side of the body. I have a few patients like this and it is very disheartening when their weakness fails to respond to standard anti-inflammatory therapies.

An interesting debate is whether or not the ‘hot microglial’ response is abnormal, i.e. pathological, or is occurring in response to something in the surrounding tissue. I support the latter view and hypothesise that there is something in the surrounding tissue that is activating the microglia and they are just doing their job and trying to clear-up the inciting agent. Others have suggested these microglia are responding to the back-end, or Fc-end, of antibodies and activated complement components as a result of these antibodies reacting with their target or in a non-specific manner. Other hypotheses include viruses, e.g. EBV and HERVs, are driving the expansion of these lesions. The way to test these two competing hypotheses is to use drugs that switch off or suppress microglia. If the ‘hot microglia’ are the problem these drugs will work and stop SELs getting bigger. If the microglia are just doing their ‘job’ these agents are unlikely to work. It is also important to remind you that myelin debris inhibits remyelination so these microglia may be needed to help with the repair. The problem is that without being able to switch off the abnormal processes that are causing SELs to enlarge trying to stimulate repair mechanisms may be futile.

Another factor that can’t be ignored is recurrent infections, which sometimes affects a lot of people with advanced MS. Recurrent urinary tract infections (UTIs) are the biggest problem. This is why we take UTIs so seriously. Every time you get an infection it causes your immune system to produce cytokines, or inflammatory messengers, that travel to the brain and boosts the activity of the microglia. The hot microglia then exacerbate the damage that MS is doing to your brain and spinal cord. This is why many of you tolerate infections so poorly and often don’t recover back to baseline after a severe infection. There is a lot we can do to reduce recurrent bladder infections. For example, the judicious use of intermittent self-catheterisation, drinking lots of liquids to flush the bladder, using urinary antiseptics to suppress the growth of bacteria in the bladder and screening for asymptomatic UTIs using self-monitoring home dipsticking and prompt treatment.

This patient has had several UTIs in the last 12 months. To manage this I recommended she starts taking daily urinary antiseptics and she starts self-monitoring her urine twice weekly with dipstix and to start antibiotics ASAP as she picks up an early UTI. I hope the GP will do what I recommend; not all GPs are prepared to allow their patients to self-monitor and manage their bladders in this way.

The upshot of ‘slow burn’ is that we need additional therapies to add on top of DMTs that stop new lesions, and in particular chronic expanding or SELs, from forming. These treatments may be drugs to purge the CNS of antibody-producing B cells and plasma cells, drugs that inhibit complement activation and/or the activation of Fc receptors on microglia, anti-virals that target EBV and HERVs, and/or drugs that inhibit activated microglia. In other words, there are many therapeutic targets that still need to be explored as add-on therapies in MS.

4. PA (premature ageing): Most of you are aware of the effects of ageing on the nervous system. The brain and spinal cord were never designed by evolution to last longer than about 35 years. It is only relatively recently that as a species we have extended our lifespans. Once you go beyond approximately 35 years of age there is a gradual loss of nerve cells and axons. This explains why as you get older you notice the effects of ageing; reduced vision, loss of hearing, poor balance and sadly age-related cognitive impairment. In short, life is an age-dependent neurodegenerative disease. If we all live long enough we will all develop cognitive impairment. What protects us from age-related changes is so-called brain reserve capacity, i.e. the size of the brain and spinal cord, and cognitive reserve, which relates to education level and environmental enrichment (social capital, adult learning, cognitive exercises, etc.). We know that MS reduces both brain and cognitive reserve and as a result people with MS experience the impact of ageing much earlier. I refer to this as premature ageing. Can we do anything about this? Yes, we can. We know from studies in the general population there are many things that you can do to maximise your brain and cognitive reserve. This is called Brain Health and involves lifestyle factors such as exercise, diet, sleep and avoiding smoking and excessive alcohol consumption. It is also important to be screened for comorbidities or other diseases and have them treated; these include smoking, hypertension, diabetes, obesity and abnormal lipids. As for diet, there have not been any that have been studied specifically in MS. However, data from animal and other studies indicate that calorie restricted, intermittent fasting and ketogenic diets have the most promise with regard to brain health. However, we need more evidence of their beneficial effects before promoting these to pwMS.

Yes, this patient is in late 50’s and ageing mechanisms are clearly contributing her loss of function.

Ageing is also a biological process and as we decode the molecular programmes that cause ageing we may be able to develop treatments that reverse ageing. An example of this is metformin, a drug for treating diabetes that has recently been shown to reprogramme oligodendrocyte precursors in older animals to behave as if they were young cells and become more efficient at remyelinating axons. I envisage in the future using anti-ageing drugs as add-on therapies to treat MS.

At the moment we don’t have enough evidence to recommend an add-on treatment for this patient. However, trials are happening so maybe in the next decade of so we will have add-on treatments to slow down or reverse these premature ageing mechanisms.

Finally, we know from other diseases that mood and other social determinants affect outcomes in other diseases and likely play a role in MS. This patient was clearly socially-isolated and depressed. The social-isolation was self-inflicted due to her anxiety about getting COVID-19. Now that she has been vaccinated and with national cases numbers falling she start to get-out and meeting her family and friend again. I suspect she will improve, maybe not back to her pre-COVID-19 baseline, once she starts exercising and reconnencting with the world.

Does this patient’s story sound familiar to you? Have you managed to cope with the lockdown? What have you done to keep going?

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Why does fingolimod affect antibody responses?

Barts-MS rose-tinted-odometer: ★

The Twittersphere is abuzz with the preliminary seroconversion rates in Israelis patients with MS on various DMTs in response to the Pfizer-BionTech COVID-19 vaccine (see below). As expected the antibody seroconversion rates in response to anti-CD20 therapies and S1P modulators are blunted and in most cases inhibited. The backstory or biology around anti-CD20 therapy is well-rehearsed; anti-CD20 therapy depletes B-cells and annihilates germinal centres in lymph nodes and the spleen.

The question I have just been asked is why does fingolimod block antibody responses? To answer this we need to go back to the basics of immunology.

Fingolimod and other S1P modulators work by internalising the S1P receptor making lymphocytes unresponsive to the S1P signalling or chemotaxis gradient in secondary lymph organs such as lymph nodes. In lay language, this causes lymphocytes to park-up in a long-term car park with a wheel lock-on. Even if you wanted to drive your car out of the car park by starting it up you wouldn’t be able to move it without removing the wheel-lock (fingolimod). By blocking lymphocyte mobility helper T-cells can’t migrate to the so-called germinal centres in the lymph nodes and spleen to help B-cells switch from IgM to IgG antibody production and to then help the B-cells to affinity mature their antibodies, i.e. to make good quality antibodies. Normally these affinity matured B-cells would leave the germinal centre to become memory B-cells or plasmablasts. The plasmablasts then mature to become plasma cells and produce high-quality antibodies, which in the case of anti-spike protein protect you from getting COVID-19 in particular severe COVID-19. Fingolimod and other S1P modulators prevent this normal immunology from happening hence the low or absent anti-COVID-19 antibody response after COVID-19 vaccination.

I like to think of the germinal centres as being the immune system’s university; this is where the immune system sends its primed T-cells to help educate B-cells. After a brutal natural selection process in the germinal centres, a few B-cells survive and graduate with a PhD, i.e. a highly specialised degree or class-switched high-affinity IgG antibodies. This then allows the B-cells to become memory B cells and go into semi-retirement or to set-up their own production company as plasma cells and to produce high-quality antibodies. Anti-CD20 therapies work by blowing up the B-cell university and S1P modulators stop the teachers (T-cells) from educating their students (B-cells). Having no university or no teacher-student interactions have the same effect and result in no educated B-cells and hence no IgG antibody responses.

Please note the above information does not change my personal advice regarding vaccination, whether you are on an anti-CD20 therapy, fingolimod or another S1P modulator (siponimod, ozanimod, ponesimod) #GetVaccinated ASAP; some immunity is better than no immunity. Please note having no anti-SARS-CoV-2 antibodies doesn’t necessarily mean you have no immunity. These antibody studies don’t tell us anything about T-cell responses, which are likely to be as important as antibodies in providing protecttive immunity against SARS-CoV-2.

Han et al. FTY720 suppresses humoral immunity by inhibiting germinal center reaction. Blood. 2004 Dec 15;104(13):4129-33. doi: 10.1182/blood-2004-06-2075. Epub 2004 Aug 19.

FTY720 is a novel immunosuppressant that is highly effective in inhibiting rejection of allografts and autoimmunity in various animal models. It has been shown that the sphingosine 1 phosphate (S1P) receptors are the direct molecular targets of FTY720. However, the mechanisms responsible for inhibiting specific immune responses by FTY720 are not well resolved. In particular, there is no available information on whether or how this compound affects humoral immunity. We have investigated the effect of FTY720 treatment on B-cell response during the immune response to a well-defined T-dependent antigen. Our data demonstrated that germinal center reaction was significantly reduced in peripheral lymphoid tissues of mice treated with FTY720. In addition, FTY720 treatment inhibited the production of high-affinity, class-switched antibodies, but not the production of low-affinity, immunoglobulin M (IgM) antibody. Consistently, FTY720 did not have a significant effect on antibody response to a T-independent antigen. Our results may have important implications in application of FTY720 in immune regulation.

Also see the post by MD from a few days ago. Fingolimod also stops B cells moving within the follciles and and stops them contacting areas where they the B cells are likely to be stimulated.

https://multiple-sclerosis-research.org/2021/03/another-eagle-has-landed/

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Rehab update: taking back control

Barts-MS rose-tinted-odometer: ★★★★★

After my life-threatening accident last year I returned to work on the 1st of February against the advice of many people. I thought getting back to work would help with my overall rehabilitation. Yes, in the sense that commuting to work and adapting my exercise programme to fit in with my workday would help my recovery. But no in the sense that my energy levels, both physical and mental, are nowhere near back to normal and hence my productivity or outputs remain low. As a result of my early return to work, I have not been focusing on my rehabilitation as much as I should have been; I have gone from doing 3 hours a day of rehab to maybe 3 hours a week. This is simply not enough for me to get back to normal.

It also became apparent to me that I can’t simply continue with the same-old and therefore something had to give. When I looked at my diary last week I realised I had no white space in it, i.e. big chunks of time for thinking, writing and taking on big projects such as our preventive neurology initiative.

I have therefore decided to reconfigure my academic work-life to re-engage with my physical and mental rehabilitation and to focus primarily on preventive neurology, in particular, MS prevention. So far I have resigned from 14 (and counting) MS-related initiatives I was involved in. My resignation from each is not about the individual initiatives but the gestalt and creating the necessary white space in my life for big projects.

As I will be focusing less on clinical issues and more on basic science and MS prevention I will be writing far fewer blog posts and answering fewer questions. I will keep you posted on how things evolve. The good news is that I have managed to start jogging albeit up-and-down the corridor outside my office. My ambition is to complete a parkrun, which is 5km, before the 21st of June.

Rehab in action. Hoping to run a #parkrun before the 21st June. pic.twitter.com/Yq8rRikFZI
— Gavin Giovannoni (@GavinGiovannoni) March 23, 2021

https://platform.twitter.com/widgets.js

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Russian Roulette

If you were invited to play Russian roulette would you do it with COVID-19 or the COVID-19 vaccine?

Russian roulette is a lethal game of chance; you place a single round in a revolver, you spin the cylinder, place the muzzle of the gun against your head before pulling the trigger in hope that the loaded chamber does not align with the firing pin, which would cause the revolver to fire and kill you.

Most people would argue Russian roulette is a voluntary game and that you can opt-out of playing it if you want. This is not the case with COVID-19 Russian roulette. You can either become immune by being infected with the SARS-CoV-2 virus or by having one of the COVID-19 vaccines. As this virus is going nowhere soon and is likely to mutate and become endemic, i.e. remain circulating in the human population forever, you will at some stage get infected with this coronavirus or one of its variants. Yes, at some point everyone who is not self-isolating as a hermit on a deserted island will get some form of COVID-19. So you need to decide: do you want to take your chances with COVID-19 and the morbidity (sickness) and mortality (death) associated with it or have one of the COVID-19 vaccines. In other words, you need to choose your poison.

For example, if you are between 40 and 50 years of age you have about 1 in 1000 chance of dying from COVID-19, a 1 in 300 chance of needing a ventilator or ITU admission, a 1 in 100 chance of needing to be hospitalised and 1 in 10 chance of getting long-COVID. On the other hand, if you have the vaccine you have about an 80% chance of getting a sore arm and some minor flu-like symptoms for a few days after the vaccine and if you have advanced MS you may notice a transient worsening of symptoms, similar to what happens when you have an infection and a temperature. These symptoms can largely be prevented or made milder by taking paracetamol and/or ibuprofen prophylactically. But the risk of the vaccine revolver firing and you developing a major rare potential complication from one of the vaccines is so small (probably in the order of 1 in 100,000 or even 1 in a million) that it can’t be compared to the risks of COVID-19.

Please remember that the very rare reported adverse events such as blood clots, disseminated coagulation. immune thrombocytopenia, transverse myelitis, sudden death, etc. have not necessarily been caused by the vaccine, they may simply be what is happening as part of the background rate of these disorders in the general population. You have to realise that when you are vaccinating the whole adult population shit will still be happening in the background; i.e. people will be getting DVTs, pulmonary emboli, myocardial infarctions, pneumonia, Bell’s palsy, etc. Life and biology continue as normal and all that has changed is that a vaccine is added to the mix. So when the EMA and MHRA say the benefits of these vaccines outway the risks; their advice is based on safety data from tens of millions of vaccinated adults. Their message can’t be any clearer: #GetVaccinated these #VaccinesAreSafe.

The European politicians have been irresponsible and simply stoked the fears people already have about these and other vaccines. This will not only cost European lives but will impact the uptake of vaccines in low and middle-income countries as well. This is tragic as the Astra-Zenica vaccine is the one that is going to play a major role in stopping the pandemic in these countries. Why do politicians employ and pay experts to work for the European Medicines Agency when they simply ignore their advice? Is there a more cynical or political reason to explains their motivation?

Now getting back to the point I made at the beginning of this post; if you are forced to play Russian roulette would you do it with COVID-19 or the COVID-19 vaccine?

I promised myself not today any more COVID-19 blog posts, but one of our MS nurses asked me to write this post. Hopefully, this will be the last one I do ;-(

Age-specfic mortality:
Levin et al. Assessing the age specificity of infection fatality rates for COVID-19: systematic review, meta-analysis, and public policy implications. European Journal of Epidemiology volume 35, pages1123–1138(2020).

COVID-19 Severity and ITU admissions:
Pijls et al. Demographic risk factors for COVID-19 infection, severity, ICU admission and death: a meta-analysis of 59 studies. BMJ Open. 2021 Jan 11;11(1):e044640.

Long COVID-19:
ONS. The prevalence of long COVID symptoms and COVID-19 complications. 20-Dec-2020
Around 1 in 5 respondents testing positive for COVID-19 exhibit symptoms for a period of 5 weeks or longer
Around 1 in 10 respondents testing positive for COVID-19 exhibit symptoms for a period of 12 weeks or longer

Oxford-AstraZeneca adverse event profile:
Voysey et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021 Jan 9;397(10269):99-111.

Ocrelizumab: DODO vs. ADIOS, who will win?

Barts-MS rose-tinted-odometer: ★★

In response to a question over the weekend about what has happened to the DODO and ADIOS studies. Both are alive and kicking. The more insightful question would be ‘how can I support both the DODO (double-dose ocrelizumab study) and the ADIOS (adaptive dosing ocrelizumab study) studies?’.

Surely, the DODO and ADIOS studies are incompatible with each other scientifically? How can I, on the one hand, support a higher dose of ocrelizumab and on the other hand suggest reducing the dose in the longterm. The hypothesis is all about timing and how you use anti–CD20 therapies.

You need higher doses of anti-CD20 therapy initially as an induction strategy to purge the various B-cell compartments of memory B-cells, which house latent EBV and the highly autoreactive population of B-cells that drive and maintain the MS-state. This population of cells may reside in the deep tissues and/or the central nervous system, which is why we are also testing CNS penetrant anti-B-cell strategies, simultaneously. Time is short so we need to run trials in parallel.

However, once you have purged these compartments say after 2 years of treatment you don’t need to maintain such high-doses of anti-CD20 therapies that are then suppressing normal B-cell biology and immune responses, which result in longterm complications. This is why we want to use ocrelizumab as an immune reconstitution therapy, i.e. high-dose upfront followed by no treatment and wait to see if MS remains in remission or disease-activity returns requiring additional courses. The latter is one of the arms of our proposed ADIOS study.

In reality, if we could convince a national funding agency, a pharma company or a wealthy philanthropist I would use anti-CD20 therapy as part of an induction-maintenance protocol. After two years of induction therapy with high-dose ocrelizumab, I would test different maintenance strategies in parallel. My agents of choice would be teriflunomide, leflunomide, IMU-838 (vidofludimus) or ASLAN003 (selective second-generation DHODH inhibitors), HAART (highly active antiretrovirals), famciclovir or another anti-EBV viral agent. The hypothesis is to allow B-cell reconstitution after anti-CD20 therapy in the presence of an anti-viral agent to prevent EBV reactivation and reinfection of new memory B cells. By doing this you will also be derisking the long-term immunosuppression associated with anti-CD20 therapies and prevent the development of hypogammaglobulinaemia. In addition, you will be allowing patients to respond to vaccines.

The problem with this trial proposal is the outcome measure; the power calculations are not trivial and the study would have to be very long. I also have reservations about whether or not the regulators will accept the induction maintenance strategy. Maybe we can sell it to them on safety, i.e. to prevent the development of hypogammaglobulinaemia and infections rather than on efficacy? If we go this route then there is only one agent we can use and that is teriflunomide, which is licensed to treat MS. As teriflunomide is coming off patent there is a chance the NHS may be interesting in funding such a trial; i.e. it would save them money. This is something I am exploring as a proof-of-concept trial.

The good news is that Roche-Genentech is testing the principles of the DODO study and announced at MSVirtual2020 two high-dose ocrelizumab trials (see below). These trials up the stakes in the anti-CD20 wars and I am confident that we need higher doses upfront to purge deep tissue and possibly CNS pools of B-cells. Please note that you don’t need higher doses of anti-CD20 therapy to suppress relapses and focal MRI activity you can do that with current or lower doses. I am confident both these studies will show that higher-dose ocrelizumab is superior to standard dose ocrelizumab on disability progression or smouldering MS, but not on focal inflammatory events. In relation to the latter, we have hit the ceiling already.

You need higher doses up-front to target the drivers of smouldering MS; i.e. disease progression independent of relapses, accelerated brain volume loss, slowly expanding lesions (SELs) and the subpial cortical lesions. If these higher-dose studies are positive it will put clear daylight between ocrelizumab and the other anti-CD20 therapies and it would mean the ofatumumab and rituximab are currently being underdosed, at least initially in the first two years. But don’t we have a hint of this already? Ofatumumab was not better than teriflunomide at slowing down brain volume loss in year two of the ASCLEPIOS I and II clinical trials (NCT02792218 and NCT02792231) despite being superior to teriflunomide on relapses and MRI activity. The latter is more proof that focal inflammatory disease (relapses and MRI activity) is not MS but in response to what is causing the disease. The real MS is what causes smouldering pathology and end-organ damage.

DODO vs. ADIOS vs. iTeri: which one would I prioritise? Almost certainly iTeri; the iTeri trial makes the most sense in terms of our current understanding of the pathogenesis of MS, mode of action of anti-CD20 therapies and the long-term risks of chronic B-cell depletion.

Hauser et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med. 2020 Aug 6;383(6):546-557.

Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.

Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.

Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, -0.15; 95% CI, -0.20 to -0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P = 0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P = 0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P = 0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups.

Conclusions: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231.).

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Are you tired of COVID-19 blog posts? If yes, then this letter is for you

Dear Blog Reader

I spent 15 minutes on the phone with one of my patients who has secondary progressive multiple sclerosis. She was an avid blog reader but has stopped reading the blog because she can’t stand the constant barrage of posts about COVID-19 and vaccinations and she doesn’t understand the posts anymore. I think some other readers may share her views.

This patient’s real concerns are about her MS and why she has deteriorated so much over the last 12 months. Is it neglect? Is it because she has stopped her weekly physiotherapy and pilates sessions? Is her MS active? The last time we imaged her in late 2019 there were no new lesions on her brain MRI. For your information, she was treated with off-label subcutaneous cladribine 4 years ago having failed interferon-beta and fingolimod in the past.

Has she deteriorated because of her worsening depression? She is lonely and lives alone. Prior to COVID-19, she used to work 2-3 days a week for a charity, with lots of contact with the public; this brought purpose to her life. Now she has face-time calls with her ageing parents once a day.

Is her deterioration due to her poor sleep? Her recurrent UTIs? Or is due to premature ageing?

Has she lost confidence in walking because of repeated falls? She now uses her wheelchair almost all day indoors.

I spent some time explaining to her that as soon as we can we will repeat her MRI and if she has new lesions she may become eligible for siponimod treatment. In the interim, I have referred her for screening for the MS-STAT-2, or high-dose simvastatin, trial and I sent her a link to the following blog post which tries to explain to pwMS why they are getting worse despite being NEDA or ‘inactive’.

EXPLAINING WHY YOU GET WORSE DESPITE BEING NEDA

Does this lady’s story sound familiar to you? Have you also noticed your MS worsening over the last 12 months during lockdown? In addition, are you also COVIDed-out? If yes, any recommendations on what content you want us to cover on the blog would be much appreciated?

Hang in there if you can, the storm is beginning to subside. If you are feeling low I would recommend reading or listening to Charlie Mackesy’s book, ‘The Boy, the Mole, the Fox and the Horse’; it has kept me sane over the last 12 months.

I am thinking of all of you. I know how hard it is but we will get through this together.

Thank you.

Prof G

Houston we have a problem

Barts-MS rose-tinted-odometer: ★

I did a post a few weeks ago about the secondary malignancy risk associated with longterm continuous immunosuppression and included a survey. The following are the results of the survey, which are quite disturbing. It is clear that a significant number of readers of this blog, although aware of the secondary cancer risk, are not been given standardised information about cancer risk and cancer screening. This is another piece of work that needs to be done and done well. Some of the comments are quite telling as well, including some personal critcism.

Who is interested in working on an evidence-based calculator of secondary malignancy risk in relation to MS DMTs? It will at least need to include the following variables:

Gender
Ethnicity
Age
Family history
Environmental risk factors, e.g. sun exposure, HPV vaccination status
Type of immunosuppression, i.e. continuous (anti-CD20, S1P modulators) vs. short-term (alemtuzumab, cladribine)
Intensity of immunosuppression
Duration of immunosuppression
Prior treatment history
Prior cancer history

I suspect many health and life insurance companies have actuarial data on this already and could potentially create a risk calculator using real-life data.

Would you use such a calculator? Comments please.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Is that revolver loaded?

Barts-MS rose-tinted-odometer: ★★

Are you lonely? Have you lost a loved on during COVID-19? Have you lost your job or had to reduce your income because of COVID-19? Can you make ends meet at the end of the month? Are you worried about your future? How is your relationship with your partner? Are you depressed? Anxious? Are you sleeping well? Are you drinking too much alcohol? Are you feeling guilty? Self-loathing? Failed ambitions? …..

These sorts of questions rarely come up in a standard MSology consultation because most classically trained HCPs working in a secondary or tertiary care environment haven’t been trained to deal with what we refer to as the Social Determinants of Health (SDoH). However, it is clear the SDoH have an outsized impact on health outcomes, which is likely to include MS outcomes. This is why we launched our #ThinkSocial campaign several years ago and have started several activities to see if there is anything we can do to help tackle the SDoH.

A story: Recently one of my patients chastised me for telling her off for her poor diet, which consisted mainly of bread. She lives alone, which may explain why she eats so poorly. She has marmite or jam on toast for breakfast, a sandwich for lunch and if she feels hungry another piece of toast for dinner…..

What should Prof G do to manage this patient?….. find out.

I can clearly see the cynics saying ‘focus on what you are trained to do and leave the SDoH to general practice, social care and the charitable sector’. Yes and no. Yes, it is easy to say this is not my responsibility, but when you are trying to do your best medically to improve MS outcomes only to get trumped by the SDoH it makes it look like your service is failing. Our patient population in the east end of London is one of the most deprived populations in England. When we recently analysed deprivation data from HES (hospital episode statistics) the only area worse off than us in England was Liverpool. On the other end of the scale were Cambridge and Oxford. So if we compared outcomes of the MS patient populations in Liverpool and east London and note they are doing worse than pwMS living in Oxford and Cambridge it may not have anything to do with our MS and other services, but simply represent levels of deprivation and its associated poorer outcomes.

How SDoH result in poor outcomes is likely to be due to the effects of chronic stress on the brain. Stress is a well-defined biological or physiological response of the body. Stress results in high levels of so-called stress hormones. These stress hormones have a direct and negative effect on the brain and other organ systems, which causes them to age prematurely and malfunction. Ask anyone who is stressed and they will tell they don’t feel well. Stressed people and stressed populations are more forgetful, more tired, have poorer sleep and tend to engage in unhealthy behaviours (smoking, alcohol, poor diet, sedentary) and have much higher mental health problems (depression, anxiety, addiction, suicide). In general, pwMS are more stressed and the reasons for this are not only obvious but potentially modifiable.

The main stress hormone is cortisol. Cortisol works via glucocorticoid receptors, which are found all over the body including the hippocampus, amygdala and frontal cortex, three brain regions involved in memory and emotions. Chronic stress is associated with reduced volume and malfunction of these areas. In pwMS, these areas may already be damaged from MS lesions, which increases the MS brain’s vulnerability to chronic stress. So if you want to improve MS outcomes you can’t ignore the SDoH and chronic stress. Do you agree?

This is why I have been promoting the marginal gains philosophy to the management of MS, which is based on Sir David Brailsford approach to competitive cycling and is the reason why the British cycling teams has been so dominant in the last two decades.

“The whole principle came from the idea that if you broke down everything you could think of that goes into riding a bike, and then improved it by 1%, you will get a significant increase when you put them all together.”

Sir David Brailsford

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

Prof. Gavin Giovannoni

So when we launched our ‘no patient left behind’ motto at the first MS Academy ‘Raising-the-Bar’ meeting to address variation and inequalities in access to MS healthcare in the UK we included a workstream to tackle the SDoH. How we do this is currently being defined, but we have an ambitious programme of work. Whatever happens, we will need to involve the whole MS community, which includes readers of this blog. So if you have any ideas to tackle the SDoH please share them with us.

Lupien et al. The effects of chronic stress on the human brain: from neurotoxicity, to vulnerability, to opportunity. Frontiers in Neuroendocrinology April 2018, 49:91-105.

For the last five decades, science has managed to delineate the mechanisms by which stress hormones can impact on the human brain. Receptors for glucocorticoids are found in the hippocampus, amygdala and frontal cortex, three brain regions involved in memory processing and emotional regulation. Studies have shown that chronic exposure to stress is associated with reduced volume of the hippocampus and that chronic stress can modulate volumes of both the amygdala and frontal cortex, suggesting neurotoxic effects of stress hormones on the brain. Yet, other studies report that exposure to early adversity and/or familial/social stressors can increase vulnerability to stress in adulthood. Models have been recently developed to describe the roles that neurotoxic and vulnerability effects can have on the developing brain. These models suggest that developing early stress interventions could potentially counteract the effects of chronic stress on the brain and results going along with this hypothesis are summarized.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211