Secondary progressive – Prof G's MS Blog Archive

Second opinion

Barts-MS rose-tinted-odometer: zero-★s (black Monday; playing roulette with your patients’ brains)

I recently saw a patient for a second opinion. He was about to start dimethyl fumarate (DMF), but his wife who had spent a lot of time reading about MS wanted him to be treated with something more effective. She had read the MS-Blog (formerly the Barts-MS Blog) and wanted him to have a higher efficacy DMT.

He is only 43 years of age and has had MS for at least 12 years. He had an episode of transverse myelitis when he was 31. At the time his MRI of the brain had no MS-like lesions, but in retrospect, there was subtle brain volume loss; his so-called Sylvian fissures were much too large for a 31-year-old and he had largish lateral ventricles (the fluid-filled spaces in the brain). The clue to the diagnosis of MS was in the spinal fluid analysis that showed the local synthesis of oligoclonal IgG bands; these can now be used in the diagnosis of MS to indicate dissemination in time. This patient was sent away and told to come back if he developed any new symptoms. He did come back with an episode of vertigo and unsteadiness of gait 12 years later. His MRI of the brain was full of MS lesions and he had gross brain volume loss. He was told by his neurologist that he now had relapsing-remitting MS and was eligible for treatment and been offered DMF.

When taking a neurological history this patient had had numerous symptoms that indicated he had had several attacks in the last 12 years. An episode of sharp shooting pains in legs, a period of urinary frequency and urgency, an episode when he had noticed difficulty running with a partial dropping of his right foot. All of these were clearly relapses, which he ignored. The onus of reporting these symptoms had been put on the patient. Maybe things would have turned out differently if he had been seen annually and had regular monitoring MRIs.

On our video consultation, he said he was fully functional, working full-time and had no problems with activities of daily living. This was in keeping with his neurologist’s clinic letter that didn’t mention any abnormal neurological signs and the letter actually played down the MRI findings, by not even mentioning the gross brain atrophy that had been reported by the neuroradiologist on the current MRI.

As I was doing this consultation via a video platform something told me I need to examine this patient. I arranged a face-2-face consultation and when I saw this patient a few weeks later his neurological examination was far from normal. He has jerky eye movement with square-wave jerks indicative of cerebellar involvement. He had bilateral optic disc pallor indicative of optic nerve involvement. He was unable to walk heel-to-toe due to an unsteady gait and he had a positive Romberg’s test, i.e. his body swayed from side to side when he closed his eyes and he would have fallen if I had not told him to open his eyes. He had mild triparesis; i.e. weakness in three out of four limbs. He also had clear cerebellar signs with incoordination in both upper limbs with a mild intention tremor. Finally, he had impaired joint position sensation in the joints of the big toe.

On taking his history again he now volunteered mild to moderate urinary frequency and sexual dysfunction. His wife who attended with him told me that he had had to stop running a few years ago because of exercise-induced left foot drop, which had been getting worse and now was visible after 2-3 km of walking. She also mentioned limb jerks in bed at night, nocturia and that he had become very forgetful and was having difficulty at work.

It is clear this gentleman has advanced MS with severe end-organ damage affecting all functional systems. Sadly he has been let down by the system. He should have been told upfront it is likely he had MS. Just maybe cognitive testing and a set evoked potential 12 years ago would have shown dissemination in space and he would have been diagnosed with MS and treated. Instead, his diagnosis of MS has been delayed by 12 years. Based on his history and examination this paint has secondary progressive MS (SPMS).

Should I label him as having active SPMS and offer him siponimod? Should I say he has highly active MS or rapidly evolving severe MS and try and manipulate the NHS England treatment guidelines to offer him a choice of several high efficacy DMTs? Should I just take the path of least resistance and offer him ocrelizumab or ofatumumab the two very high-efficacy DMTs that can be used first-line in the NHS? Should I not offer him a licensed DMT and refer him for possible enrollment into the high-dose simvastatin trial?

What this pandemic has taught me is that my real skill, which won’t be replaced soon by a robot, is doing a neurological examination and eliciting signs of end-organ damage and then integrating this information with the history, MRI and other investigations. I wonder if the many MS self-monitoring applications that are emerging would have detected and interpreted the clinical examination the way I have done with this patient?

Interestingly, when I examined this patient he told me that his neurologist, apart from getting him to walk and test his eye movements, had not done a detailed neurological examination. This is not unusual in clinical practice; in fact, one of our colleagues at the Royal London Hospital has even argued for us not doing the neurological examination at all as it doesn’t add much to either the diagnosis and/or management of his patients. Do you agree with him?

Christopher H Hawkes. I’ve stopped examining patients! Pract Neurol. 2009 Aug;9(4):192-4.

If you are interested in finding out about what changes to our MS services from the pandemic will stick I suggest you log into the webinar that I am doing later this week with Trishna Bharadia when we will be discussing the impact and changes the pandemic has had om MS services and what I think will change. What is clearly not going to go away is the need for face-2-face consultations and neurological examinations. But then this is referring to my take on things and I may not be correct.

Conflicts of Interest

Preventive Neurology

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

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

No patient with secondary progressive MS should be left behind

It was a privilege to be asked to write the foreword to a new policy document, “The Forgotten Many: A 2020 Vision for Secondary Progressive Multiple Sclerosis” dealing with more advanced MS. If you get a chance please read the document.

The ‘forgotten many’ is how people with secondary progressive or advanced multiple sclerosis (SPMS) describe themselves. SPMS has a significant impact on those with the disease, their families, the NHS and society overall.

The lack of efficacy of many of the licensed treatments for the relapsing forms of MS has left people with SPMS with the impression they have a second, different, untreatable disease. Telling someone they have SPMS is not too dissimilar to telling someone they have a terminal illness. For this reason, many healthcare professionals steer away from having this awkward conversation. For those people on a Disease-Modifying Therapy (DMT) for relapsing MS, disease progression conjures up fear that a diagnosis of SPMS will mean them having to stop their treatment.

A further issue is that many people with SPMS are discharged from regular neurological follow-up to local community-based services and their general practitioners to manage any problems. This is despite emerging evidence that aggressive management of MS-related comorbidities and lifestyle interventions can improve MS outcomes. So many people with progressive MS are smouldering away in the community thinking they have an untreatable, but relentlessly progressive disease.

A new report challenges this assumption and makes the case for actively managing and treating people with SPMS. However, to do this there is an urgent need to expand MS services and to develop new MS centres to accommodate these forgotten patients.

The emergence of treatments to treat and modify the course of progressive MS will require a retooling of MS centres and services; an increase in MS neurologists and specialist nurses, more dedicated MRI time for monitoring patients and additional ancillary services to address the massive unmet need associated with patients who have greater disabilities and associated comorbidities.

This report touches on the many facets of managing SPMS and the forgotten many and how we need to find them and offer them a holistic service to improve their quality of life, improve their neurological outcomes and at the same time reduce unnecessary and preventable utilisation of healthcare services. This report is a call to arms for parliamentarians, policy makers, NHS Providers, commissioners as well as the MS community to think differently, work differently and to now reconnect with the forgotten many.

No patient with secondary progressive MS should be left behind.

CoI: multiple

Premature Ageing

One of my colleagues, with whom I was co-authoring an editorial on smouldering MS, demanded I delete the section on premature ageing being a factor driving delayed worsening of disability in people with MS (pwMS). I refused so we had to pull the editorial. The fact that he is quite old and doesn’t like the hypothesis of brain & cognitive reserve being neuroprotective explains his position. He criticised my theory for being ageist.

I am more convinced than ever that premature ageing is a big driver of delayed worsening in MS.

A few years ago I was asked to see a patient from the North of England who has presented in her early 60’s with SPMS. She had had three spinal cord attacks in her late teens and had been in remission until her late 50’s when she noticed increasing weakness in her weaker leg with foot drop. In the intervening 40 years since her last attack, she had been relapse-free and fully functional apart from mild persistent weakness in her one leg that prevented her from running.

As part of her work-up, I repeated her MRI of the brain and spinal cord and we performed a lumbar puncture. Her CSF showed local synthesis of oligoclonal IgG bands consistent with her diagnosis of MS and her neurofilament levels were low. Her MRI showed no active or new lesions and apart from some brain and spinal cord atrophy, there was nothing extraordinary about her imaging. When I saw her in outpatients I explained to her that she did not have active MS and that her diagnosis was now non-relapsing or inactive secondary progressive MS; I now refer to this as smouldering MS.

She then volunteered that she didn’t think her worsening was due to MS, but rather ageing. I couldn’t disagree with her and explained that her previous MS attacks had probably reduced the number of axons or nerve fibres in the motor pathway to her leg, which was now ageing as the surviving nerve fibres were gradually dying off she was seeing increasing weakness in the leg. This is called the premature ageing theory of progressive MS. Is there any proof for it?

We know from other neurological diseases that ageing can cause delayed worsening. The most well know one is post-polio syndrome. This is when people who have had polio notice increasing weakness in previously affected muscles decades later as they start to age. In HIV we see age-related neurodegenerative diseases present decades earlier than one would expect. The theory being that HIV infection of the brain reduces reserve and triggers premature ageing mechanisms. Even with Alzheimer’s disease factors that are associated with reduced brain reserve result in an earlier age of onset of dementia.

I suspect MS is not and exception and that ageing, or premature ageing, is part of the disease. The problem we have is that disease duration and disability are strongly correlated with ageing. This makes it difficult to unentangle ageing from disease duration. One way to look at this is to use biomarkers of ageing. As you get older the ends of your chromosomes or telomeres get shorter. Telomere length is used as a biomarker of physiological and not chronological ageing. By using telomere length instead of your age we may be able to unpick the impact of ageing on disease worsening.

In this study below there was a clear gradient in terms of disability and telomere length. Shorter telomere length was associated with disability independent of chronological age, suggesting that biological ageing is contributing to neurological injury in MS.

The implications of this are enormous and imply that we should be targeting age-related mechanisms as a therapeutic strategy in MS. This is why I also include ageing in my holistic management of MS talks and why focusing on all of those lifestyle issues and comorbidities is so important in MS. Interestingly, I made this a major theme in my talk at ACTRIMS last year when I had to predict what was going to happen in MS in 5 years time (slides below).

So the time for biohacking (diet) and aggressive lifestyle interventions have arrived in the MS space. The million-dollar question is how to we get the MS community to buy into this as a therapeutic strategy.

Krysko et al. Telomere Length Is Associated With Disability Progression in Multiple Sclerosis. Ann Neurol, 86 (5), 671-682 Nov 2019.

Objective: To assess whether biological aging as measured by leukocyte telomere length (LTL) is associated with clinical disability and brain volume loss in multiple sclerosis (MS).

Methods: Adults with MS/clinically isolated syndrome in the University of California, San Francisco EPIC cohort study were included. LTL was measured on DNA samples by quantitative polymerase chain reaction and expressed as telomere to somatic DNA (T/S) ratio. Expanded Disability Status Scale (EDSS) and 3-dimensional T1-weighted brain magnetic resonance imaging were performed at baseline and follow-up. Associations of baseline LTL with cross-sectional and longitudinal outcomes were assessed using simple and mixed effects linear regression models. A subset (n = 46) had LTL measured over time, and we assessed the association of LTL change with EDSS change with mixed effects models.

Results: Included were 356 women and 160 men (mean age = 43 years, median disease duration = 6 years, median EDSS = 1.5 [range = 0-7], mean T/S ratio = 0.97 [standard deviation = 0.18]). In baseline analyses adjusted for age, disease duration, and sex, for every 0.2 lower LTL, EDSS was 0.27 higher (95% confidence interval [CI] = 0.13-0.42, p < 0.001) and brain volume was 7.4mm3 lower (95% CI = 0.10-14.7, p = 0.047). In longitudinal adjusted analyses, those with lower baseline LTL had higher EDSS and lower brain volumes over time. In adjusted analysis of the subset, LTL change was associated with EDSS change over 10 years; for every 0.2 LTL decrease, EDSS was 0.34 higher (95% CI = 0.08-0.61, p = 0.012).

Interpretation: Shorter telomere length was associated with disability independent of chronological age, suggesting that biological aging may contribute to neurological injury in MS. Targeting aging-related mechanisms is a potential therapeutic strategy against MS progression. ANN NEUROL 2019;86:671-682.

CoI: multiple

What is advanced MS?

Barts-MS rose-tinted-odometer – zero stars

Someone recently asked what is advanced MS? I suspect they have been getting frustrated with our use of this adjective without a clearer understanding of what it really means. To find out if you have advanced MS you need to put yourself through a battery of stress tests to find-out much reserve you have left to deal with MS and life in the future.

What is advanced MS is a very important topic and we at Barts-MS have tried not to define it using the EDSS as it entrenches the physically-disabling, particularly lower-limb function, worldview of MS.

Advanced MS is really when someone has lost reserve in a particular neuronal system and they are noticing worsening in that system that is impacting on their ability to function at a personal, social or occupational level and by inference is affecting their quality of life.

Using this definition someone can have advanced MS with very little physical disability. As you are aware the initial impact of MS may be cognitive, which is probably the main driver of the high early unemployment rates we see in MS.

A software engineer with MS who depends on her cognitive skills for writing code, concentrating for prolonged periods of time and multitasking may find it very difficult-staying at the top of her game. She will notice much earlier her progressive cognitive loss based on her performance or lack of performance in her work. In comparison, a professional athlete may not necessarily notice early cognitive impairment but will be more susceptible to the effects of MS on their coordination and endurance, for example, the marathon runner with a dropped foot.

These examples are the two extremes, but they illustrate why we need stress tests of the nervous system to be able to ascertain how much reserve there is which will give us some idea how advanced MS is in a particular domain. One thing that is not done very well in MS clinics is cognition. Most MS centres don’t have the resources to monitor cognition properly. This needs to change (#ThinkCognition).

In almost every MS clinic I do I see patients who complain of cognitive symptoms; increasing forgetfulness, difficulty multi-tasking, the inability to learn and use a new technology or cognitive fatigue.

One of my high functioning patients, who worked in a large City law firm, simply could not keep up and was forced to take early retirement because of her MS. She had been interferon-beta-1b for 12 years but had stopped treatment about 7 years ago when she had moved to London. Her MRI showed a highish lesion load and severe brain atrophy. She had had a few relapses on interferon-beta in the early years, but her neurologist decided to leave her on interferon-beta. Back then this was normal practice; we didn’t expect interferon-beta to render you relapse-free. Interferons were only meant to reduced attack rates by about a third and severe attacks, i.e. those requiring steroids and/or hospital admission, by about a half. The only alternative when this patient was having relapses on interferon-beta was glatiramer acetate; this was in the pre-natalizumab era.

Apart from her cognitive problems, this patient had mild unsteadiness of gait, but this had not affected her walking distance and she was still able to do yoga several times per week. To help with her unemployment insurance claim I requested a formal neuropsychological assessment and she was documented to have profound cognitive deficits across multiple domains. The conclusion based on these tests was that she would never be able to have meaningful employment again; at least not in the knowledge economy When I took a detailed history it was clear that she had had progressive cognitive impairment over at least 7-10 years. In other words, she had advanced (secondary progressive) MS manifesting as progressive dementia.

You must not underestimate the impact MS has on cognition. Cognitive problems can be there from the start; approximately a quarter of people with a radiologically isolated syndrome (RIS) or asymptomatic MS already have cognitive impairment. The proportion with cognitive impairment gets higher the longer you have the disease. What is driving cognitive impairment is almost certainly grey matter pathology, both in the cortex and deep grey matter, which is not detected with our current monitoring tools.

Until recently we the MS community used the Paced Auditory Serial Addition Test (PASAT) for monitoring cognition in clinical trials. The PASAT is a measure of cognitive function that assesses auditory information processing speed and flexibility, as well as calculation ability. The PASAT is presented using audiotape or disk to ensure standardization in the rate of stimulus presentation. Single digits are presented every 3 seconds and you have to add each new digit to the one immediately prior to it. Shorter inter-stimulus intervals, e.g., 2 seconds or less have also been used with the PASAT but tend to increase the difficulty of the task. The PASAT is very difficult and requires multitasking; it is a very good cognitive stress test.

One of the reasons we dropped the PASAT test is because of its learning effect, when you do the PASAT test your scores improve because of so-called ‘learning’ or ‘practice’ effects. In reality this is a general phenomenon of most neurological stress tests; our nervous systems are wired for learning.

In the FREEDOMS 1 and 2 pivotal phase 3 fingolimod trials, we showed that not being able to improve on the PASAT at baseline predicted a worse outcome. We hypothesised that pwMS who couldn’t learn, i.e. were unable to improve their PASAT scores at baseline, would do worse and this is exactly what we found and we noted it regardless of treatment allocation; i.e. whether you were on fingolimod or placebo.

Not surprisingly, the poor learners were older, had a higher disability score at baseline, smaller brains and higher lesions volumes on MRI; i.e. they had reduced cognitive reserve or resilience. In other words, they had more advanced MS. The depressing point about this analysis was that even the poor learners on fingolimod did badly; it was if they were already primed to do badly and that starting a DMT had a limited impact on the outcome. In reality, their MS disease activity in the past had primed their brains to continue to deteriorate despite being on a DMT; previous damage or smouldering MS was now driving their disease worsening. This is why the treatment response on DMTs drop off with ageing and disease duration. Please note this applies to all DMTs, including HSCT.

It is important to prevent the ravages of MS by treating as early and effectively as possible. Some pwMS are luckier than others; i.e. you may present very early in the course of your MS before too much end-organ damage has accrued. In others, the asymptomatic period of the disease may be longer, during which time you acquire a lot of end-organ damage. Regardless of what group you are in, you still need to seriously consider getting on top of your MS disease activity as soon as possible to prevent any further damage.

It is clear from several data sources that on average pwMS do best on DMTs that have the greatest impact on inflammatory activity (new MRI lesions and relapses) and those that reduce brain volume loss. In reality, these are the high and very high efficacy DMTs. This is why flipping the pyramid and going for the most effective DMTs first-line is a very appealing treatment strategy; particularly the DMTs that ‘normalise’ brain volume loss.

This post illustrates why we should be monitoring cognition in routine MS clinical practice. Although this topic gets discussed and debated all the time most neurologists don’t agree with doing routine cognitive testing, because of the lack of evidence in terms of treatments that impact on cognition. This, however, will change as data emerges that DMTs have positive effects on cognitive function, even in advanced MS. For example, siponimod has been shown to delay cognitive worsening compared to placebo in people with SPMS.

At Barts-MS we will continue to run our #ThinkCogniton campaign. By shifting the MS worldview from a physical one to a cognitive one we will hopefully get the MS community to manage MS more actively.

Maria Pia Sormani et al. Learning Ability Correlates With Brain Atrophy and Disability Progression in RRMS. J Neurol Neurosurg Psychiatry, 90 (1), 38-43 Jan 2019.

Objective: To assess the prognostic value of practice effect on Paced Auditory Serial Addition Test (PASAT) in multiple sclerosis.

Methods: We compared screening (day -14) and baseline (day 0) PASAT scores of 1009 patients from the FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) trial. We grouped patients into high and low learners if their PASAT score change was above or below the median change in their screening PASAT quartile group. We used Wilcoxon test to compare baseline disease characteristics between high and low learners, and multiple regression models to assess the respective impact of learning ability, baseline normalised brain volume and treatment on brain volume loss and 6-month confirmed disability progression over 2 years.

Results: The mean PASAT score at screening was 45.38, increasing on average by 3.18 from day -14 to day 0. High learners were younger (p=0.003), had lower Expanded Disability Status Scale score (p=0.031), higher brain volume (p<0.001) and lower T2 lesion volume (p=0.009) at baseline. Learning status was not significantly associated with disability progression (HR=0.953, p=0.779), when adjusting for baseline normalised brain volume, screening PASAT score and treatment arm. However, the effect of fingolimod on disability progression was more pronounced in high learners (HR=0.396, p<0.001) than in low learners (HR=0.798, p=0.351; p for interaction=0.05). Brain volume loss at month 24 tended to be higher in low learners (0.17%, p=0.058), after adjusting for the same covariates.

Conclusions: Short-term practice effects on PASAT are related to brain volume, disease severity and age and have clinically meaningful prognostic implications. High learners benefited more from fingolimod treatment.

CoI: multiple

Is siponimod the first cul-de-sac DMT?

Barts-MS rose-tinted-odometer ★

A big worry for neurologists and pwMS is the sequencing of DMTs. What DMTs can be used before and after each other and does the sequencing of DMTs change the risk profile of the individual DMTs concerned? These have been dealt with many times on this blog and I am in the final stages of completing phase 1 of my app that will address the specific issues around each DMT.

Another issue relates to the specifics of the label and how we classify patients; this is particularly problematic when it comes to the EMA’s label for siponimod, i.e. “treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease evidenced by relapses or imaging features of inflammatory activity (see section 5.1)”.

To prescribe siponimod we will have to (1) label the patient concerned as having secondary progressive MS and (2) provide evidence, at least in the UK, that the patient has active disease. The latter would be relapses and/or evidence of MRI activity (new or enlarging T2 lesions or Gd-enhancing lesions). The latest NICE guidance, which is trying to standardise the definition states that MRI activity is “1 T1 gadolinium-enhancing lesion at baseline MRI or a significant increase in T2-lesion load compared with a previous MRI”. Although we haven’t been given a specific time period it is likely to refer to the last 24 months.

Some questions. If the relapses and MRI activity occurred prior to the diagnosis of SPMS can they still be counted? Or does the diagnosis of SPMS rebaseline patients? I think the answer should be somewhere in between these two extremes. As the diagnosis of SPMS is retrospective the baseline or clock for assessing disease activity should be set when the first objective evidence of worsening was documented. In reality, this is typically 6 or 12 months in the past depending on the frequency of follow-up appointments. The definition of SPMS requires at least 6 months of worsening disability independent of relapse activity. The problem here is that to have active SPMS you also need to have had a relapse and/or MRI activity in this period as well. So it becomes very difficult to untangle worsening from relapses from worsening independent of relapses. These definitions are a mess!

In an ideal world, all the above may make sense, but this does not take into account the reluctance of neurologists and HCPs to document or label their patients as having SPMS. In some countries, a label of SPMS means the current DMTs may need to be stopped. Also the label SPMS has other negative connotations; it is often interpreted as having a second disease, importantly a disease that is not modifiable. I know this happens a lot. When we tried to recruit study subjects for our PROXIMUS study (add-on neuroprotection with oxcarbazepine) my colleagues were reluctant to refer their patients for the trial as it required them to diagnose early SPMS and nobody wanted to do that.

Another issue that arises is that once someone is labelled as having SPMS can you unlabel them and refer to them as having relapsing MS? Common wisdom says no. In other words, once you have transitioned (and I hate this term) to becoming SPMS you can’t go backwards. This has major implications for patients with active SPMS; once you are on siponimod it may close the door to the other DMTs as they are not licensed, at least in Europe, for SPMS. I suspect this will be one of the biggest hurdles for the widespread adoption of siponimod for active SPMS in the UK. In other words, siponimod will become the cul-de-sac or dead-end DMT until another DMT is licensed for SPMS. I can already see NHS England making it impossible to switch someone who is failing on siponimod, can’t tolerate it, or develops adverse events that require stopping siponimod, onto another high-cost DMT that is licensed for RRMS.

I think we as an MS community need to make the argument that you can flip-flop between MS subtypes. We have evidence buried in the trial data that a subset of patient labelled as having SPMS behave as having RRMS, i.e. their EDSS scores improve despite superimposed relapses. Similarly, there is a subgroup of patients with ‘inactive’ or ‘smouldering’ SPMS who have not had a relapse for years suddenly become active. The same thing happens with PPMS; approximately 25% of pwPPMS will go onto have superimposed relapses. Surely these people have relapsing MS rather than PPMS? Calling them progressive-relapsing MS does not deal with the biology of the disease in these patients nor their treatment. Leaving them as having a form of PPMS means that are only eligible for ocrelizumab, whereas relabeling them as having RMS opens up many more treatment options for these patients.

These arguments are more than just semantics they have real-life implications for individuals with MS and how we treat their disease.

At the end of the day, we can avoid all these arguments by defining MS as one disease and not two or three diseases (#MS_is_1_not_2_or_3_diseases). Until we do this siponimod, despite the hype and hope around its anticipated launch, is likely to not to be used as much as it should be used to avoid putting patients down a treatment pathway that is a cul-de-sac.

CoI: multiple

Slip-sliding away – do I have secondary progressive MS?

Barts-MS rose-tinted-odometer – zero stars

We have been running a campaign that #MS_is_1_not_2_or_3_diseases for sometime. This is based on the biology of MS and not what we see clinically. The pathology that underpins so-called progressive MS is the loss of axons, loss of neurons and loss of synapses, which are the chemical connections between neurons. All three of these processes begin very early in the so-called asymptomatic stage of MS. What dictates whether or not we see the effects of these subtle changes depends on how much we stress the neurological system concerned and how much resilience, or reserve, this system has to handle the stress.

A good example is a marathon runner with MS who develops a dropped foot after running for about an hour at race pace. A year earlier he would only notice that symptoms towards the end of the marathon. Does this marathon runner have SPMS? If this runner had not stressed his motor pathway with vigorous competitive exercise the issue of whether or not he has SPMS would not arise. In other words, the question of SPMS would only arise when his dropped foot would impact on normal activities of daily living, for example walking, which may have only occurred in 10 years time if he had not been a runner.

What this anecdote tells us that the diagnosis of SPMS is a moving target and depends on what system, or systems, MS has shredded, how you use that system and how much reserve is left in that system to compensate for the damage. We know progressive cognitive dysfunction is the driver of early unemployment in so-called knowledge jobs. Why aren’t these patients being labelled as having SPMS? That is because neurologists, first and foremost, view MS as a physically disabling disease rather than a cognitively disabling disease. This needs to change; #ThinkCognition.

The diagnosis of SPMS is therefore in the eye of the beholder. In my eyes, progressive MS is present from the beginning of the disease. Trying to identify a point in time when you can be diagnosed with SPMS is futile and to discuss transitioning MS is a misnomer. Neurologists think we are smart when we classify our patients as having relapsing-remitting MS, or relapsing SPMS, or non-relapsing SPMS. Let me tell you this is a fallacy.

For example, I am doing a relapse assessment on a patient later today who was thought to have non-relapsing SPMS. Four weeks ago she went off her legs with new-onset weakness in her good leg. Her MS nurse said this is likely to be progressive MS and asked her to sit it out. Over the last few weeks, she has been recovering function in that leg and has started to mobilise again. Based on her history it is likely she has had a relapse. I am seeing her, to document the likely relapse, to assess whether or not she needs a course of steroids and to counsel her about her future treatment options. At present, she is not on any DMT having completed two courses of off-label cladribine several years ago.

The problem the MS community faces is that we view MS through clinical and MRI spectacles and we don’t think about the biology of the disease. If we took a biological approach to MS all MS would be labelled as being inflammatory, all MS would be active and all MS would progressive. Based on this thinking all people with MS would need to be offered treatment with a combination therapy approach and treated holistically.

The following study below describes the development of a new HCP-completed questionnaire to support HCP-patient interactions in evaluating disease transition or progression to SPMS. Using a prompt like this in clinical practice will almost certainly lead to an earlier label change in the notes, i.e. SPMS being diagnosed earlier. Will this help the patient? In the UK once you are labelled as having SPMS you are meant to stop DMTs. Would things change if NICE approved siponimod for the treatment of active SPMS under the NHS? If siponimod was green-lighted by NICE the SPMS label had better be ‘active-SPMS’ and not ‘inactive-SPMS’. The latter label would make the patient ineligible for treatment.

Another problem around the corner is that what happens if you now are now labelled as active-SPMS and start on siponimod and you then have to stop taking it because of lack of efficacy, poor tolerance or an adverse event? Will we be able to relabel the patient as having relapsing MS and put them back on a DMT that is licensed for relapsing MS? I call this flip-flopping and it happens all the time in clinical practice. However, it is likely that NHS England will put in place systems to prevent this from happening. My solution is to get rid of labels and let the neurologist and the patient decide on what treatment they want.

I think all the licensed treatment for MS, including HSCT, work in patients with active MS but have very little impact on smouldering disease. Smouldering MS is really the next frontier in the management of MS.

I hope the above demonstrates the folly of our ways. We need to call-out MS for what it is; an inflammatory neurodegenerative disease from the outset. Our guiding treatment principle should be to diagnose and treat MS early and effectively to prevent end-organ damage. Our therapeutic aim should be to maximise brain health for the duration of our patients’ lives. Anything less would be doing them a disservice.

Ziemssen et al. A mixed methods approach towards understanding key disease characteristics associated with the progression from RRMS to SPMS: Physicians’ and patients’ views. Mult Scler Relat Disord. 2019 Nov 18;38:101861. doi: 10.1016/j.msard.2019.101861.

OBJECTIVES: The transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS) evolves over time and it can be challenging for physicians to identify progression early. Typically, SPMS is diagnosed retrospectively with a significant delay, based on a history of gradual worsening, independent of relapses, following an initial relapsing-remitting disease course. As such, SPMS is often associated with a considerable period of diagnostic uncertainty. This study aimed to explore and characterize key symptoms and impacts associated with transitioning from RRMS to SPMS and inform the content for a tool to support evaluation of early subtle signs suggestive of progressive disease.

METHODS: The qualitative study involved 60-min, face-to-face, concept elicitation (CE) interviews with 32 patients with MS (US = 16 and Germany = 16); and 30-min, telephone, CE interviews with 16 neurologists (US = 8 and Germany = 8). Multivariate analysis on data from a real-world observational study of 3294 MS patients assessed the differences between early-RRMS and early-SPMS, and identified factors that were significant drivers of this difference. These studies informed selection of the key variables to be included in a pilot tool. Sixteen physicians used the pilot tool, presented as a paper questionnaire, with a sample of patients whom they suspected were progressing to SPMS (n ≥ 5). Following this, the physicians participated in a 30-min cognitive debriefing (CD) interview to evaluate the relevance and usefulness of the tool. Qualitative analysis of all anonymized, verbatim transcripts was performed using thematic analysis.

RESULTS: Patients and physicians reported signs that indicated progression to SPMS including gradual worsening of symptoms, lack of clear recovery, increased severity and presence of new symptoms. No specific symptoms definitively indicated progression to SPMS, however a number of potential symptoms associated with progression were identified by SPMS patients and physicians, including worsening ambulation, cognition, balance, muscle weakness, visual symptoms, bladder symptoms and fatigue. Quality of life domains reported to be more severely impacted in SPMS than MS in general included: physical activity, work, daily activities, emotional and social functioning. Multivariate analysis of the observational study data identified several variables strongly associated with progression to SPMS including, requirement of assistance in daily living, presence of motor symptoms, presence of ataxia/coordination symptoms, and unemployment. Physicians reported that items included in the tool were easy to understand and relevant. Physicians also reported that there is an unmet need for a tool to help identify signs of SPMS progression and so the tool would be useful in clinical practice.

CONCLUSIONS: This was the first stage of development of a novel, validated, physician-completed tool to support physician-patient interactions in evaluating signs indicative of disease progression to SPMS. Qualitative and quantitative methods (involving physician and patients) were used to determine tool content. The usefulness and unmet need for such a tool in clinical practice was confirmed via CD interviews with physicians. Further work is now warranted to develop a scoring algorithm and validate the tool so that it can be reliably implemented in clinical practice.

CoI: multiple

Killjoys peddle fake news

For all the killjoys out there DMTs do work, i..e. they modify the course of MS and prevent you from reaching all disability milestones including the time to diagnosis of SPMS and EDSS 10.0 or death.

Please don’t listen to the zealots who are trying to spin fake news that the only treatment to prevent the development of progressive MS is HSCT; they are wrong. There are other options; the study below shows you can do it with currently licensed DMTs that are safer than HSCT. One message that is loud and clear with this data is that the earlier you treat the better and you have a much better outcome if you flip the pyramid and start on high-efficacy DMTs first-line.

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Brown et al. Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis. JAMA. 2019 Jan 15;321(2):175-187.

IMPORTANCE: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.

OBJECTIVE: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition.

DESIGN, SETTING, AND PARTICIPANTS: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years’ follow-up.

EXPOSURES: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017).

MAIN OUTCOME AND MEASURE: Conversion to objectively defined secondary progressive MS.

RESULTS: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1).

CONCLUSIONS AND RELEVANCE: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies’ risks, may help inform decisions about DMT selection.

CoI: multiple

Hopebird

The debate about what is active and inactive secondary progressive MS will not be settled by the EMA adopting a positive opinion, recommending the granting of a marketing authorisation for siponimod, which is now ‘licensed’ for the treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease. Siponimod reduces disability progression in people with active SPMS. The most common side effects are headache, hypertension and increased liver enzyme levels. The full indication is: “treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease evidenced by relapses or imaging features of inflammatory activity (see section 5.1)”.

This label will disappoint the many pwSPMS who don’t have active scans and therefore won’t be eligible for DMTs. I have commented on what is and is not active SPMS in the past. I think the siponimod label entrenches the MRIcentric worldview of what is active MS. We know that the majority of people dying with SPMS have ongoing inflammation in their brains and spinal cords at post-mortem. Try telling someone with SPMS who is getting worse that they don’t have active MS because they have no enhancing, or new or enlarging T2, lesions on MRI. And what about using CSF and/or peripheral blood neurofilament levels to assess activity? We clearly need to challenge the EMA’s and FDA’s definitions of what is active SPMS.

At least the licensing of siponimod for treating SPMS is a big positive for the field and indicates that we are beginning to address the unmet need in treating more advanced MS.

The impact that this will have on our MS services should not be underestimated. We are now going to have to monitor our SPMS patients with annual MRI scans. Do we have the resources for this? What about the extra follow-up clinic slots? This alongside ocrelizumab for active PPMS is going to put a major strain on our MS services. Will our managers give us more resources?

Siponimod may not be an eagle, phoenix or maven, but rather a hopebird which symbolises the importance of “an optimistic approach to what lies ahead” and why it is important to have a “glass half full” attitude. Less than a decade ago we were telling our patients with a progressive course that they were beyond hope, that has now changed.

CoI: multiple

Self-diagnosis

Dear Neuro,

You see me once a year for 15 minutes, you look at my MRI report and blood results, you ask me a lot of questions, you examine me and then you tell me that everything is fine. At my last visit, you said my MS was stable, you mentioned to me that I was NEDA, because I had had no relapses, no new lesions on my MRI and my EDSS was static at 3.0.

I have now looked up and read about NEDA (no evident disease activity) and I disagree with your assessment. I am clearly getting worse. The Christmas before last I remember going for a 5-mile walk with my family after lunch and managed it fine. When I tried the same walk last Christmas I had to turn back after a mile because my right leg was dragging.

I also have other problems that you didn’t pick up on during the consultation. I now have to get up 2 or 3 times at night to pass urine. My memory is much worse than it was last year. My head feels foggy all the time as if I have a permanent mild hangover. I now avoid any social occasions with colleagues after work. The truth is I am too tired to at the end of the day to do anything else than get home. I feel exhausted most of the time. I have stopped gardening.

I think I have developed secondary progressive MS. Do you agree? Would it be possible to see you sooner to discuss this? Is there anything you can do about my deterioration in functioning?

Yours sincerely

Patient Y

Does this story sound familiar?

At first glance, it is easy to say this person has SPMS. But do they?

Based on the definition of SPMS it seems likely, i.e. objective worsening of function for at least 6-12 months independent of relapse activity. Based on the latter it seems Patient Y is not having relapses. As for the objective worsening of function the interpretation is in the eye of the beholder. As far as the neurologist is concerned the patient is not deteriorating because the EDSS is stable. In comparison, the patient has documented, albeit rather crudely, a drop if in functioning. Who do you believe?

The scenario illustrates what will happen when MSers begin to self-monitor and prepare for clinic appointments in advance, i.e. they will potentially be self-diagnosing secondary progressive or worsening MS.

However, I want you to take a step back and ask could the deterioration be due to something else, something reversible? If it is due to something else it may be treatable and potentially reversible.

Does this patient have any reversible comorbidities that could be responsible for the deterioration? Smoking, hypertension, diabetes, metabolic syndrome, obesity, underactive or overactive thyroid function, renal, liver, heart or lung disease? If a woman, is she menopausal? What about mental health issues; depression and anxiety? Is this patient drinking too much alcohol? Is the patient malnourished? They may be eating a diet of toast and tea.

Is this patient sleeping well? Getting-up 2 or 3 times a night to pass urine means their sleep hygiene is very poor. Just improving this patient’s bladder problems will have a major impact on their daytime fatigue and work performance.

What about a chronic infection? Could this patient have a low-grade urinary tract infection? What about their oral health; could they have gingivitis or periodontitis? Sinusitis?

Is this patient exercising enough? I suspect not. The drop off in the walking distance could be deconditioning, i.e. losing fitness because of lack of exercise. In this particular patient, I suspect this, however, is unlikely because deconditioning is unlikely to result in a dragging leg on walking a mile.

What medication is this patient on? Are they are on an anti-spastic medication or anticholinergics for their bladder problems? Both these class of drugs affect cognition and may explain the memory loss and brain fog. I have commented on baclofen being particularly problematic in the past.

How well is patient Y? Patient Y seems to have become socially isolated and withdrawing from having social interactions with their work colleagues. The patient has stopped gardening, which helps improve mental health. What about the home environment? Is patient Y’s relationship with the family stable, etc? What are this patient’s finances like? Are they in debt? Are they struggling economically?

Could this patient have smouldering MS? Does this patient need an MRI of the spine and a lumbar puncture to measure CSF neurofilament levels? We know that brain MRI will not pick-up all disease activity. Does this patient need to start a DMT or have a DMT switched and escalated? I would be very interested to know how this patient’s cognitive function is and whether or not they have a swiss cheese brain (lots of black holes) and brain volume loss. Having this information makes a diagnosis of SPMS and/or smouldering MS more likely.

How old is patient Y? If they are over the age of 50 we may be seeing early ageing.

Making a diagnosis of SPMS is not simple and most neurologists would prefer not to do it. However, if we are to improve the lives of our patients we need to take a holistic approach to the management of MS. Clinical practice must not be a box-ticking exercise. We need to provide our patients with the tools to self-monitor, self-diagnose and self-manage. We need them to become partners on a life-long MS journey that will result in better outcomes and happier and more content MSers and HCPs.

To reiterate the philosophy of marginal gains “if you break down everything we can think of that goes into improving MS outcomes, and then improving it by 1%, we will get a significant increase when we put them all together”. This case vignette illustrates this very well.

I hope this post motivates you to start self-monitoring and to start preparing for your consultations with your HCP. You need to have a list of questions to ask. Don’t let your neurologist or HCP fob you off. You know yourself better than they do; please don’t forget this.

CoI: multiple