Barts-MS rose-tinted-odometer: ★★★★★

A problem in modern medical practice is the assumption that there is a pill for everything. The one eye-opener for me after my recent trauma has been how easy it is for medics to reach for the prescription pad. When I was first discharged from hospital I was on 14 different medications. About half of the medications were prescribed to manage or prevent the side effects of the primary medications. It is easy to rationalise the use of each of the 14 medications, but were they all necessary? It is quite astounding how we have ‘pharmaceuticalised medicine’.

Initially, when my head was muzzled by morphine and gabapentin, I had an elaborate system in place to make sure I didn’t miss or forget any of my medications. This experience has given me a profound appreciation for how difficult it must be for some of my own patients, particularly those with cognitive impairment, to manage their own polypharmacy. The other question, which is the elephant in the room, is are all these medications really necessary. 

A good example in MS is the management of MS-related fatigue. MS neurologists prescribe a large number of different medications for MS fatigue when in reality none, yes zero, of these medications has been shown to make a difference in randomised controlled trials. A recent study from the US shows that amantadine, modafinil and methylphenidate make no difference. In comparison, mindfulness therapy has been shown to work in several MS fatigue trials. So why don’t neurologists prescribe mindfulness to more of their patients? There is also an expanding evidence-base that mindfulness therapy helps depression, anxiety and insomnia.

Maybe 2021 should be the year when the medical profession questions and challenges the ‘pharmaceutical-model of medicine’ and helps lobby the NHS so that all of our patients have access to mindfulness therapy.  

If you have a moment can I suggest you watch Gratitude, on the ‘Mindfulness 360 – Center For Mindfulness’ channel on YouTube. Are you surprised that this is better than a tablet?

I would be very interested if you could share your thoughts on this blog post and your own experiences with tablets versus mindfulness therapy for managing your symptoms. There are a lot of cynical HCPs out there who question the benefits of mindfulness, which is just one of the main barriers that prevent the wide adoption of this complementary therapy into routine MS practice. 

Nourbakhsh et al. Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: a randomised, placebo-controlled, crossover, double-blind trial. Lancet Neurol. 2021 Jan;20(1):38-48.

Background: Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue.

Methods: In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with, NCT03185065 and is closed.

Findings: Between Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0-53·6) at baseline, 40·6 (38·2-43·1) with placebo, 41·3 (38·8-43·7) with amantadine, 39·0 (36·6-41·4) with modafinil, and 38·6 (36·2-41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil).

Interpretation: Amantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis.

Ulrichsen et al. Clinical Utility of Mindfulness Training in the Treatment of Fatigue After Stroke, Traumatic Brain Injury and Multiple Sclerosis: A Systematic Literature Review and Meta-analysis. Front Psychol. 2016 Jun 23;7:912. doi: 10.3389/fpsyg.2016.00912. eCollection 2016.

Background: Fatigue is a common symptom following neurological illnesses and injuries, and is rated as one of the most debilitating sequela in conditions such as stroke, traumatic brain injury (TBI), and multiple sclerosis (MS). Yet effective treatments are lacking, suggesting a pressing need for a better understanding of its etiology and mechanisms that may alleviate the symptoms. Recently mindfulness-based interventions have demonstrated promising results for fatigue symptom relief.

Objective: Investigate the efficacy of mindfulness-based interventions for fatigue across neurological conditions and acquired brain injuries.

Materials and methods: Systematic literature searches were conducted in PubMed, Medline, Web of Science, and PsycINFO. We included randomized controlled trials applying mindfulness-based interventions in patients with neurological conditions or acquired brain injuries. Four studies (N = 257) were retained for meta-analysis. The studies included patients diagnosed with MS, TBI, and stroke.

Results: The estimated effect size for the total sample was -0.37 (95% CI: -0.58, -0.17).

Conclusion: The results indicate that mindfulness-based interventions may relieve fatigue in neurological conditions such as stroke, TBI, and MS. However, the effect size is moderate, and further research is needed in order to determine the effect and improve our understanding of how mindfulness-based interventions affect fatigue symptom perception in patients with neurological conditions.

Simpson et al. Effects of Mindfulness-based interventions on physical symptoms in people with multiple sclerosis – a systematic review and meta-analysis. Mult Scler Relat Disord. 2020 Feb;38:101493. 

Background: Physical wellbeing is commonly impaired in people with multiple sclerosis (PwMS). This study aims to update our previous systematic review (2014) and conduct a meta-analysis on the efficacy of Mindfulness-based interventions (MBIs) for improving physical symptoms in PwMS.

Methods: In November 2017 we carried out systematic searches for eligible randomised controlled trials (RCTs) in seven major databases, updating our search in July 2018. We used medical subject headings and key words. Two independent reviewers used pre-defined criteria to screen, data extract, quality appraise, and analyse studies. The Cochrane Collaboration risk of bias tool was used to determine study quality. Physical wellbeing was the main outcome of interest. We used the random effects model for meta-analysis, reporting effect sizes as Standardised Mean Difference (SMD). This study is registered with PROSPERO: CRD42018093171.

Results: We identified 10 RCTs as eligible for inclusion in the systematic review (including 678 PwMS), whilst seven RCTs (555 PwMS) had data that could be used in our meta-analyses. In general, comorbidity, disability, ethnicity and socio-economic status were poorly reported. MBIs included manualised and tailored interventions, treatment duration 6-9 weeks, delivered face-to-face and online in groups and also individually. For fatigue, against any comparator SMD was 0.24 (0.08 – 0.41), I2=0%; against active comparators only, SMD was 0.10 (-0.14 – 0.34), I2=0%. For pain SMD was 0.16 (-0.46 – 0.79), I2=77%. Three adverse events occurred across all studies.

Conclusions: MBIs appear to be an effective treatment for fatigue in PwMS. The optimal MBI in this context remains unclear. Further research into MBI optimisation, cost- and comparative-effectiveness is required.

Crowdfunding: Are you a supporter of Prof G’s ‘Bed-to-5km Challenge’ in support of MS research?

CoI: multiple

Twitter: @gavinGiovannoni                              Medium: @gavin_24211

Measles a known unknown

I was called to casualty to assess one of my patients with MS who was on natalizumab. She had been admitted with a temperature, confusion, seizures and a generalised skin rash. Within thirty minutes of seeing her, she went into status epilepticus and had to be sedated, intubated and admitted to ITU. Within 72 hours she was dead. At post-mortem, she had a measles pan-encephalitis. Four days before presentation she had unknowingly come into contact with a friend’s child who had measles. The friend was a staunch anti-vaxxer who believed that the measles vaccine caused autism and would corrupt her child’s immune system. 

The above scenario is fictitious, but could happen, or more likely will happen sometime in the near future. This is a ‘known unknown’.

Things have a tendency to happen in threes; I experienced two today let’s hope the third remains science fiction. 

(1) As I left home this morning on my daily commute to Whitechapel I finished listening to an Audm podcast “FEAR, MISINFORMATION, AND MEASLES SPREAD IN BROOKLYN” by Amanda Schaffer (Wired,  24-06-2019); scary stuff about the real impact of the anti-VAXX campaign on residents in Brooklyn, New York.

(2) I followed this by reading a review about measles in the latest NEJM (Strebel & Orenstein. Measles. N Engl J Med. 2019 Jul 25;381(4):349-357), which reminded me of medical school and my time on the medical wards in South Africa. 

I then had flashbacks to my days as a neurology registrar in South Africa seeing and managing many patients with SSPE (subacute sclerosing panencephalitis) a relatively rare, but fatal, complication of measles infection.

More recently there was a fatal case of measles inclusion body encephalitis presented at our Association of British Neurologists meeting; tragically this young woman had not been vaccinated against measles. 

Why is this important? We are living through a measles epidemic. The anti-VAXX campaigners have convinced enough parents over the last two decades to not vaccinate their children against measles, mumps and rubella (MMR). Once a certain proportion of the population is not immune to measles, so-called herd immunity becomes ineffective; i.e. the shield offered by a population of people immune to measles is too porous to isolate susceptible people from wild-type infection in the community. In fact, vaccination works because of herd immunity. 

Image from BioNinja

Another factor to consider is that unvaccinated people also get MS. If you are unvaccinated and have not been exposed to the wild virus you are now at relatively high-risk of acquiring measles as an adult. If you then decide to go onto longterm immunosuppression to treat your MS you are putting yourself at risk of serious complications from these infections, in particular measles. In addition, once you are on a longterm immunosuppressive therapy you can’t be vaccinated with the MMR vaccine as it is a live attenuated vaccine. 

Measles is also a neurotropic virus and hence seeds to the brain. If you are on natalizumab and contract measles you will be in serious trouble. Natalizumab works by blocking trafficking of lymphocytes to the CNS and hence will stop your lymphocytes detecting, attacking and clearing the virus from the brain. The consequences of an unimpeded measles virus infection of the brain will be in all likelihood be lethal. This is a similar scenario to what happens with PML. Although natalizumab is being fingered here there is a risk will all of our immunosuppressive DMTs.

Because of this known unknown, I am proposing that all MSers are screened at baseline, i.e. before initiating a maintenance immunosuppressive therapy, to make sure they have immunity to MMR. If they are antibody negative they should be offered the option of receiving the MMR vaccine, or at least the individual components of the vaccine if they are still available in your country, to make sure they are immune to these viruses before they start treatment with the DMT concerned. 

I sincerely hope my case scenario remains fiction and things don’t have to happen in threes. 

What is happening to my cortex?

A very common analogy is the comparison of MS to an iceberg. Why?

Only one-eighth of an iceberg is visible above the water; to see what is below the water line requires specialised technology. The MS iceberg analogy refers to several observations:

1. For each clinical relapse, 10 or more MRI visible lesions are seen on MRI.
2. For each visible white matter lesions on MRI, there are at least an equivalent number or more grey matter lesions. In fact, it is now estimated that more than half the MS pathology is in the grey matter.
3. For every visible white matter lesion, either on MRI or with the naked eye, there are 20 or more microscopic lesions present in the white matter.
4. Despite only a relatively small amount of brain or spinal cord atrophy, there is almost three times as much neuronal loss underlying the atrophy.
5. Despite a relatively good recovery of function in a particular pathway, for example, after a relapse, there is a substantial loss of axons and hence reserve capacity in that pathway.
6. People with MS have many more hidden symptoms and disabilities than visible physical disabilities; early MS is often a hidden disease.

When you use newer technologies, for example, a 7 Tesla MRI to look at cortical or grey matter lesions in MS you begin to see how large the iceberg really is. Please remember the vast majority of cortical MS lesions (>90%) or not seen with conventional MRI. The bad news in the study below is that almost all the pwMS studied had cortical lesions and these, not surprisingly, correlated with disability and cognitive impairment. What is interesting is that the lesions on the surface of the brain (subpial), but not those on the grey-white matter interface (leukocortical), correlated better with cortical volume. However, the grey-white matter interface, or leukocortical, lesions correlated most strongly with cognitive impairment.  

What is becoming increasingly important is to try and target the grey matter pathology and prevent cognitive impairment in pwMS. The problem is we don’t routinely monitor brain and in particular grey matter atrophy in routine clinical practice; in fact it is largely ignored. If we did we would probably find many more pwMS opting for the higher efficacy treatments that have the greatest impact on brain atrophy (alemtuzumab and HSCT).

It is important for you to realise that you can be NEDA-3, i.e. no clinical attacks and MRI activity, and still have progressive grey matter atrophy. Why this is happening is debatable. Some evidence points to immunoglobulins and complement activation, rather than cytotoxic T-cells, being the major driver of cortical pathology. This why Barts-MS is exploring add-on drugs that will hopefully target the B-cell follicles and plasma cells within the central nervous system to try and slow down this process. We plan to start recruiting for our add-on study later this year.

I have little doubt that slowing down and preventing progressive brain and grey matter atrophy will become one of the treatment targets for the next generation of MSologists. To make this a reality we need to have tools to measure these processes reliably in clinical practice.

Harrison et al. Association of Cortical Lesion Burden on 7-T Magnetic Resonance Imaging With Cognition and Disability in Multiple Sclerosis. JAMA Neurol. 2015 Jul 20. doi: 10.1001/jamaneurol.2015.1241.

IMPORTANCE: Cortical lesions (CLs) contribute to physical and cognitive disability in multiple sclerosis (MS). Accurate methods for visualization of CLs are necessary for future clinical studies and therapeutic trials in MS.

OBJECTIVE: To evaluate the clinical relevance of measures of CL burden derived from high-field magnetic resonance imaging (MRI) in MS.

DESIGN, SETTING, AND PARTICIPANTS: An observational clinical imaging study was conducted at an academic MS center. Participants included 36 individuals with MS (30 relapsing-remitting, 6 secondary or primary progressive) and 15 healthy individuals serving as controls. The study was conducted from March 10, 2010, to November 23, 2012, and analysis was performed from June 1, 2011, to September 30, 2014. Seven-Tesla MRI of the brain was performed with 0.5-mm isotropic resolution magnetization-prepared rapid acquisition gradient echo (MPRAGE) and whole-brain, 3-dimensional, 1.0-mm isotropic resolution magnetization-prepared, fluid-attenuated inversion recovery (MPFLAIR). Cortical lesions, seen as hypointensities on MPRAGE, were manually segmented. Lesions were classified as leukocortical, intracortical, or subpial. Images were segmented using the Lesion-TOADS (Topology-Preserving Anatomical Segmentation) algorithm, and brain structure volumes and white matter (WM) lesion volume were reported. Volumes were normalized to intracranial volume.

MAIN OUTCOMES AND MEASURES: Physical disability was measured by the Expanded Disability Status Scale (EDSS). Cognitive disability was measured with the Minimal Assessment of Cognitive Function in MS battery.

RESULTS: Cortical lesions were noted in 35 of 36 participants (97%), with a median of 16 lesions per participant (range, 0-99). Leukocortical lesion volume correlated with WM lesion volume (ρ = 0.50; P = .003) but not with cortical volume; subpial lesion volume inversely correlated with cortical volume (ρ = -0.36; P = .04) but not with WM lesion volume. Total CL count and volume, measured as median (range), were significantly increased in participants with EDSS scores of 5.0 or more vs those with scores less than 5.0 (count: 29 [11-99] vs 13 [0-51]; volume: 2.81 × 10-4 [1.30 × 10-4 to 7.90 × 10-4] vs 1.50 × 10-4 [0 to 1.01 × 10-3]) and in cognitively impaired vs unimpaired individuals (count: 21 [0-99] vs 13 [1-54]; volume: 3.51 × 10-4 [0 to 1.01 × 10-4] vs 1.19 × 10-4 [0 to 7.17 × 10-4]). Cortical lesion volume correlated with EDSS scores more robustly than did WM lesion volume (ρ = 0.59 vs 0.36). Increasing log[CL volume] conferred a 3-fold increase in the odds of cognitive impairment (odds ratio [OR], 3.36; 95% CI, 1.07-10.59; P = .04) after adjustment for age and sex and a 14-fold increase in odds after adjustment for WM lesion volume and atrophy (OR, 14.26; 95% CI, 1.06-192.37; P = .045). Leukocortical lesions had the greatest effect on cognition (OR for log [leukocortical lesion volume], 9.65; 95% CI, 1.70-54.59, P = .01).

CONCLUSIONS AND RELEVANCE: This study provides in vivo evidence that CLs are associated with cognitive and physical disability in MS and that leukocortical and subpial lesion subtypes have differing clinical relevance. Quantitative assessments of CL burden on high-field MRI may further our understanding of the development of disability and progression in MS and lead to more effective treatments.

CoI: multiple

To T or not to T (2)

Prof G what happens to MS disease activity if you stimulate T-cells?

About 2 years ago I attended a grand round during which a patient with a history of RRMS had had a catastrophic relapse after receiving ipilimumab for metastatic melanoma. The patient has a massive brain stem relapse and her MRI showed multiple Gd-enhancing lesions with several pseudotumoral lesions. She was in a bad way. Interestingly, this case was not unique as a very similar case had been published. In addition, there are series of other examples of ipilimumab and other immune checkpoint inhibitors exacerbating and/or triggering autoimmune diseases including an MS-like disease. I say MS-like because we don’t know for sure if these cases will turn out to have classic MS on biopsy, or at post-mortem, to prove they have definite MS according to a conventional definition of the disease.

Ipilimumab belongs to the class of drugs called ‘checkpoint inhibitors’ that are designed to remove one of the immunological brakes that control T-cell activation. Ipilimumab is one of many T-cell stimulants that have revolutionised the care of patients with various different cancers. Ipilimumab is a very smart drug it blocks CTLA-4, a cell surface molecule on T cells, which normally blocks or downregulates T cell activation when it binds to CD80 and CD86 on antigen-presenting cells. Ipilimumab enhances the anti-tumoral response while increasing the likelihood of autoimmunity.

So what has this really got to do with MS? Well, these cases are telling us in a not so subtle way that by stimulating T-cells we can exacerbate MS. In other words, T-cells are probably still active in established MS. What this experiment is not telling us is which population of T-cells is the culprit as CD4+, CD8+ and T-regulatory cells express CTLA-4 and are hence affected by Ipilimumab. Nor is it telling us about the APC side, which APC is stimulating the T-cells. Is it the B-cell, the macrophage/microglia or another APC?

The moral of this story is that it takes two to tango; the T-cell and its APC. The question is which APC is the preferred partner for the T-cell in MS. Based on the evidence the B-cell seems to be the dominant partner, but who knows in the presence of peripheral B-cell depletion other less dominant partners may take to the floor.

Gettings et al. Severe relapse in a multiple sclerosis patient associated with ipilimumab treatment of melanoma. Mult Scler. 2015 Apr;21(5):670.

56-year-old male, diagnosed in December 1997 with RRMS. Treated with glatiramer acetate in February 1998. Relatively good response to GA with only sensory relapses. In 2005 methotrexate was added. His MS stabilized and he was free of relapses from 2005 to 2013 with a slight increase in disability from an Expanded Disability Status Scale (EDSS) score of 1 to 1.5. In September 2009 diagnosed with melanoma. He had a recurrence in November 2012 with metastases to soft tissue and lymph nodes. He was started on ipilimumab. Methotrexate and glatiramer acetate were stopped prior to initiating ipilimumab. Within one month, he presented with subacute onset of left lower extremity hemiparesis, gait dysfunction and ataxia. An MRI revealed a new left centrum semiovale enhancing lesion consistent with active demyelination. His symptoms improved with high dose methylprednisolone. Ipilimumab was continued. In May 2013 he was readmitted for transient left-sided weakness and ataxia. MRI revealed an enhancing lesion in the right corona radiata. Follow-up imaging revealed a second enhancing lesion in the right frontal lobe and he was restarted on glatiramer acetate and steroids.

To B or not to B

Is targeting the B-cell sufficient to get on top of MS or do we need something extra?

I spoke at the MS Nurses’ MS@TheLimits2019 meeting at the Royal College of Physicians yesterday. My brief was to cover the role of B-cells in the pathogenesis of MS and to review the converging evidence that supports B-cells being the central player in the pathogenesis of MS.

It is clear that depleting B-cell therapies are very effective in controlling relapses and MRI activity. With a very favourable safety profile and relatively low treatment and monitoring burden, B cell therapies are likely to become one of the most widely prescribed classes of DMT. However, B-cell therapies don’t match HSCT, alemtuzumab and natalizumab when it comes to downstream end-organ damage markers, in particular, brain volume loss. Why? I wish I knew. But if I knew the answer to this question I would have a pretty good idea about the cause of MS.

A clue may be in the ‘Field Hypothesis‘. It is clear to me that relapses and focal MRI activity are not the primary events in MS. Focal inflammation is not MS. Focal inflammation is in response to what is causing MS and the cause is likely to be something in the CNS. Focal changes occur in the white matter weeks to months before you get a Gd-enhancing lesion. When you stop natalizumab and allow re-trafficking of lymphocytes you get rebound disease activity way and above what one would expect from pre-treatment baseline levels of disease activity. What is happening in the brain, or field, of these patients to trigger such a vigorous inflammatory response? Could it be a virus? Importantly, B-cells appear to be needed for the rebound response. Rituximab, and I suspect ocrelizumab, are very effective in preventing rebound. However, as both these agents target a small subset of T-cells you can’t claim categorically that the rebound is only driven by B-cells.

The difference between HSCT, alemtuzumab and natalizumab and the anti-B cell therapies (rituximab, ocrelizumab and possibly cladribine) is the former take out or inhibit trafficking of both T & B cells. As HSCT and Alemtuzumab have the best data in relation to long-term remission, or potential cures, you have to conclude that you need to target both B cell and T cells (substantial peripheral depletion) if this is your treatment aim.

Please note that I classify cladribine as a B-cell depelter and not a dual B and T cell depelter. The level of T-cell depletion with cladribine is modest at the licensed dose (~50%) which is not sufficient to put it into the same class as alemtuzumab and HSCT. This is one of the reasons why I refer to cladribine as being a SIRT (selective immune reconstitution therapy) and the others as NIRTs (non-selective immune reconstitution therapies).

I have always made the point that to treat MS you need much more than an anti-inflammatory and that you also have to have neuroprotective therapies and potentially remyelinating agents on board as well. If you have disabilities we need to be thinking about neurorestorative therapies and finally you need to target lifestyle and wellness to tackle the issue of comorbidities and ageing.

So in short, targeting B-cells is important, but not sufficient to get on top of the shredder.

You will see that a large part of my talk was covering the link between EBV, B–cells and MS. The B-cell hypothesis at least strengthens the case for EBV being the cause of MS and the need for an EBV vaccine for MS prevention trials. Please don’t forget that EBV lives inside memory B cells and hijacks the B cell’s biology in many ways that have potential relevance to MS and other autoimmune diseases.

My talk will be available online in a few weeks to help you interpret my presentation. In the interim you can download my talk from my slide sharing site.

Food coma: does it affect you?

This post explains why eating may exacerbate MS-related fatigue and what you can do to counteract it.

Do you suffer from food coma or excessive sleepiness and fatigue after eating a meal?

For ‘normal people’, we call this phenomenon postprandial somnolence or the siesta syndrome. Others refer to it as the ‘food coma’. It is my anecdotal experience that people with MS, in particular, people with more advanced MS, are particularly sensitive to postprandial sleepiness and fatigue. Why?

Postprandial somnolence (PPS) is a normal state of drowsiness or lassitude following a meal. PPS is a real phenomenon and has two components: (1) a state of perceived low energy related to activation of the parasympathetic nervous system in response to expansion of the stomach and duodenum from a meal. In general, the parasympathetic system slows everything down.  (2) A specific state of sleepiness, which is triggered by the hormone cholecystokinin (CCK) that is released in response to eating and changes in the firing and activation of specific brain regions. The reflexes responsible for PPS are referred to as neurohormonal modulation of sleep through the coupling of digestion and the brain. The signals from the gut to the brain travel via the vagus nerve.

My index patient is so affected by PPS that she now only eats one meal a day; her evening meal. She does this quite late so that she can crash and sleep about an hour after eating. She is a professional and needs to be functional during the day and finds if she eats anything substantial in the day she simply can’t work because of her overwhelming desire to sleep. We have tried caffeine, modafinil and amantadine to counteract PPS, but they only had a small effect in counteracting her PPS and allowing her to work productivel. Other patients reporting this have noticed some benefit from stimulants. Interestingly, my index patient, like a few others, finds carbohydrate-rich foods particularly potent at inducing ‘food coma’

Physiologists think that not all foodstuffs are made equal when it comes to causing PPS and it appears that glucose, or sugar, induced insulin is one of the drivers of this behavioural response. I suspect this why people who fast or eat very low carbohydrate or ketogenic diets describe heightened alertness and an ability to concentrate for much longer periods of time.

The reason for doing this post is to find out how common PPS is in the MS population and to give you some simple advice to counteract it. If you suffer from PPS can I suggest you review your diet and see if you identify ways to modify your eating habits and/or diets to coounteract PPS?

  1. You could adopt the above extreme solution and only eat one meal per day. Clearly, this not for everyone and is very difficult to implement. I say this, but many of my Muslim patients report feeling so much better during Ramadan when they essentially practice this type of eating pattern.
  2. You could reduce your meal size and cut out any carbohydrates from your daytime meals. You may find this difficult because it takes time for your metabolism to become optimised for ketosis. If any of you are interested in the science of ketosis I have written a Medium post on ketogenic and low-carbohydrate diets.
  3. Some of my patients find micro-meals helpful, i.e. instead of large meals you eat multiple small snacks during the day.
  4. The judicious use of stimulants. I tend to recommend caffeine, followed by modafinil and them amantadine. Please note you should probably not take stimulants later than about 3-4 pm as they have a long half-life and can cause insomnia.
  5. Some of my patients have also reported that exercise has helped them deal with PPS. I am not sure how exercise works except by possibly lowering glucose and insulin levels and improving insulin sensitivity. The latter will reduce hyperinsulinaemia that will not only cause PPS, but is an impotant driver and component of the metabolic syndrome.

Please note that PPS will be worse if you suffer from a sleep disorder and suffer from daytime sleepiness. Most pwMS have a sleep disorder so there is little point in focusing on PPS and ignoring the elephant in the room.

If you have a few minutes to spare can you please complete this survey and let us know if you come across any other effective treatments to manage your PPS.

What the eye doesn’t see?

I saw someone with possible MS earlier this week and he had been told that he couldn’t have MS because he only had one detectable lesion on his MRI. Is this correct?

The problem: ‘MS has become an MRIscopic disease’.

The diagnosis of MS remains clinical and is underpinned by the need to show (1) dissemination in time (typically new activity 4 weeks apart or the presence of locally produced oligoclonal IgG bands in the spinal fluid) and (2) dissemination is space (symptoms and/or signs affecting two different pathways in the CNS) and (3) the exclusion of other possible diagnoses. It is clear that based on these criteria you don’t necessarily need to have visible, or specific, MRI lesions to make a diagnosis of MS. However, neurologists feel uncomfortable making a diagnosis of MS or CIS if there are no visible lesions on MRI. In other words from a practical and clinical perspective, MS has become a macroscopic or MRIscopic disease. Therein lies the rub. 

MS is a biological disease that is characterised pathologically by multifocal inflammatory lesions that cause demyelination and variable degrees of axonal loss. Please note I have dropped using the term white matter. MS is clearly both a white and grey matter disease with more than half the lesion burden in the largely MRI-lesion-invisible grey matter component (see study below). Even in the white matter where it is easier to see lesions the resolution of an MRI scan is down to about 3-4 mm. Many more lesions are found pathologically than what is seen on MRI or the naked eye. Therefore, particularly early on in the course of the disease, there will be a small number of people with MS with one or no lesions who have MS. 

A very small lesion in a strategic pathway can cause typical symptoms and signs, but when you investigate many of these patients with an MRI scan you see no obvious lesion in the expected area. This happens more often than not with a so-called internuclear ophthalmoplegia (INO); a very specific eye movement problem that presents with double-vision on looking to the left or right. This is an example of a microscopic lesion causing an MS attack. This is why we shouldn’t be using MRI to confirm, or make, a diagnosis of relapse in pwMS.

The study below that is rapidly becoming a citation classic in the field of MS, shows you with elegant infographics how large the lesion burden is in areas that are MRI invisible using our standard clinical sequences. 

Kutzelnigg et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005 Nov;128(Pt 11):2705-12.

Focal demyelinated plaques in white matter, which are the hallmark of multiple sclerosis pathology, only partially explain the patient’s clinical deficits. We thus analysed global brain pathology in multiple sclerosis, focusing on the normal-appearing white matter (NAWM) and the cortex. Autopsy tissue from 52 multiple sclerosis patients (acute, relapsing-remitting, primary and secondary progressive multiple sclerosis) and from 30 controls was analysed using quantitative morphological techniques. New and active focal inflammatory demyelinating lesions in the white matter were mainly present in patients with acute and relapsing multiple sclerosis, while diffuse injury of the NAWM and cortical demyelination were characteristic hallmarks of primary and secondary progressive multiple sclerosis. Cortical demyelination and injury of the NAWM, reflected by diffuse axonal injury with profound microglia activation, occurred on the background of a global inflammatory response in the whole brain and meninges. There was only a marginal correlation between focal lesion load in the white matter and diffuse white matter injury, or cortical pathology, respectively. Our data suggest that multiple sclerosis starts as a focal inflammatory disease of the CNS, which gives rise to circumscribed demyelinated plaques in the white matter. With chronicity, diffuse inflammation accumulates throughout the whole brain, and is associated with slowly progressive axonal injury in the NAWM and cortical demyelination.

MMR to test or not to test?

Can I assume you know about Andrew Wakefield and the fake link between the MMR vaccine and autism?

Despite Wakefield being discredited and struck off the medical register in the UK he, and the ‘Anti-Vax’ brigade, is still having a profound impact on society, which is gradually beginning to filter down to how we manage MS. Why?

The number of children receiving the MMR vaccine in England is falling. A report from NHS Digital shows that coverage of the MMR vaccine for children reaching their 2nd birthday has fallen the fourth successive year. Uptake was 91.2% in England in 2017-18, down from 91.6% in 2016-17 and the lowest level since 2011-12 (BMJ). The downside of this is that we have seen an epidemic of measles, yes measles, in the UK. Between 1 January 2018 and 31 October 2018, there have been 913 laboratory-confirmed measles cases in England (Public Health England).

So what has this got to do with MS? Well, unvaccinated people also get MS. If you are unvaccinated and have not been exposed to the wild virus you are at risk of acquiring these infections as an adult. If you then decide to go onto longterm immunosuppression to treat your MS you are putting yourself at risk of serious complications from these infections. In addition, once you are on a longterm immunosuppressive therapy you can’t be vaccinated with the MMR vaccine as it is a live attenuated vaccine. 

Because of this, we will be starting to screen all our patients at baseline, i.e. before initiating a maintenance immunosuppressive therapy, to make sure they have immunity to MMR. If they are antibody negative we will be offering them the option of receiving the MMR or the individual components to make sure they are immune to these viruses. This practice is not new. When I was in Melbourne last year, where MMR antibody screening has been routine for several years, they had picked-up three pwMS who were MMR-negative in the last year. At our recent ABN conference in Birmingham, there was a presentation of a young woman who tragically died of inclusion-body encephalitis due to measles (please note she did not have MS). Tragically, her mother had stopped her having the MMR vaccine as a child. 

If you are an HCP prescribing DMTs do you want any of your patients to develop inclusion-body encephalitis on fingolimod, DMF, natalizumab, alemtuzumab, cladribine or ocrelizumab? Definitely not as it is a preventable infection. 

I also need to walk the talk. With my #PreventMS hat on and one of our strategies being an EBV vaccine to prevent MS, I have to support and promote vaccination as a very important public health initiative. This is why I urge you to read this week’s ‘5 minutes with…Peter Hotez‘ from the BMJ. 

Sophie Arie: Speaking up for vaccination: five minutes with…Peter Hotez. BMJ 2018. 


The professor and dean of the National School of Tropical Medicine at Baylor College of Medicine, in Texas, explains to Sophie Arie why he’s written a book about his daughter

“I became alarmed at the sharp drops in vaccine coverage. Children are now dying because of the “anti-vax” movement. Most of the children who died in the latest influenza epidemic in the US weren’t vaccinated.

“The anti-vax movement is extremely well organised, with huge funding and bandwidth. There are 480 anti-vaccine websites. Of course, people are challenging their paediatricians because of what they’ve read.

“But there is general silence on the pro-vaccine side. The US government has been conspicuously silent. Unicef and the World Health Organization are not recognising the threat this poses to low and middle-income countries.

“We have enabled this by refusing to recognise that public engagement is important for scientists. When I was doing my training the message was ‘you’re not supposed to engage the public.’ It was seen as self-promotion. It may be that it’s just not in the DNA of our profession. But if you are silent you won’t achieve your goals. We have to speak up.

“I’ve written my book, Vaccines Did Not Cause Rachel’s Autism, as a vaccine scientist, a paediatrician, and an autism dad. I’ve just spoken in simple, declarative language which is not what we scientists are taught to do. I’ve written about my personal experience and I’ve just said, ‘vaccines don’t cause autism’ and here’s why. The Institute of Medicine would say something like ‘the preponderance of evidence today cannot show any clear link between vaccines and autism.’ That sounds to a layperson like hedging.

“I’m hoping it can make as much difference as a book can make for parents who are sitting on the fence, for paediatricians who are feeling under siege, and journalists who still frame this as a ‘debate’ when there is no debate.

“Colleagues are supporting me privately but not speaking out themselves. The anti-vax movement is very aggressive. Who wants to receive an email while standing in line for their morning bagel to find themselves being compared to Hitler? It’s not very nice.
“We need to give physicians and scientists the tools and training to communicate. It’s good that some grants for funding now demand that you provide an advocacy plan for your science. This needs to become part of the way we think.”

CoI: multiple