Gavin Giovannoni

Double-whammy

Sleep glorious sleep! Walking, or sleeping, the talk. Over the last two years, I have tried to increase the duration and quality of my sleep. On reflection, it seems to be working for me. I feel so much better for it.

It is now clear that shift work, reduced sleep and poor quality sleep are risk factors for developing dementia. We need to maximise my chances of not developing dementia. Sleep is therefore important for one’s brain health. During sleep, your brain clears out cellular and intracellular debris and it consolidates memories. The study below, using MRI, shows that in ‘normal young adults’ those with reduced sleep have an MRI signature of poor brain health.

Six years ago we did a survey on this blog and found that 71% of MSers, or respondents, had symptoms suggestive of sleep apnea. This is probably too high, but in other more systematic studies, approximately 50% of MSers have sleep apnoea. I suspect the reason for such a high prevalence of this comorbidity is due to MS affecting the brain stem and upper spinal cord. Sleep apnoea in MS is a problem and we should be screening all our patients for it.

In the same survey, 64% of respondents complained of insomnia, a persistent inability to fall asleep or stay asleep. Almost 50% of MSers volunteered symptoms suggestive of narcolepsy or daytime hypersomnolence and two-thirds had periodic limb movements or uncontrollable leg or arm jerks during sleep. The latter two are what I refer to as MS-related restless leg syndrome.

Not mentioned here is poor sleep due to nocturia; many MSers have to get up many times at night to pass urine. Other sleep problems more prevalent in MSers include poor sleep due to excessive alcohol consumption or overuse of daytime stimulants, the pernicious effect of anxiety and depression on sleep and pain.

I have little doubt that poor sleep in MS contributes to worsening disability, fatigue and poor cognition. People who are sleep deprived don’t function well the next day. I suspect that the latter is worse in MSers who have reduced brain reserve and have to not only compensate for reduced reserve but sleep deprivation as well. A double-whammy!

As poor quality sleep contributes to MS-related fatigue; unless you sort out your sleep you won’t get on top of your fatigue.

Has your neurologist or HCP asked about your sleep? It may be worth downloading a sleep app for your smartphone as a screening tool to see how well you are sleeping at night. If it shows that you sleep duration and quality is poor your HCP may be able to refer you for a formal sleep study. In the interim, however, you need to improve your sleep hygiene and see if it makes a difference to how you are feeling.

The following are some simple tips to improve your sleep hygiene:

Make sure you spend an appropriate amount of time asleep in bed; a minimum of 6 hours. Some people need more than this to feel refreshed.

Limit daytime naps to 30 minutes. Please note that napping does not make up for inadequate nighttime sleep.

Avoiding stimulants such as caffeine, modafinil and nicotine close to bedtime.

Only drink alcohol in moderation. Alcohol is well-known to help you fall asleep faster, but too much disrupts sleep.

Exercise helps improve sleep quality. As little as 10 minutes of aerobic exercise per day can improve sleep quality.

Don’t eat before going to bed. Heavy foods and fizzy drinks can trigger indigestion or heartburn/reflux that disrupts sleep.

Ensure you get adequate exposure to natural light; exposure to sunlight during the day, as well as darkness at night, helps to maintain a normal sleep-wake cycle.

Establish a regular relaxing bedtime routine, which helps the body to recognise that it is bedtime. This could include taking a shower or bath or reading. However, avoid reading or watching emotionally upsetting content before attempting to sleep.

Making sure that your sleep environment is pleasant. Your mattress and pillows should be comfortable. The bedroom should be cool for optimal sleep (16-20°C). The bright light from lamps, smartphones and television screens can make it difficult to fall asleep, so turn those lights off or adjust them when possible. Use the blue filter mode on your smartphone and other devices that reduces the inhibition of melatonin from light. Consider using blackout curtains, eyeshades, earplugs, white noise machines and other devices that can make the bedroom more relaxing.

And if you have pain, nocturia, restless legs, sleep apnoea, etc. get these adequately managed via your HCP.

Please let us know what strategies work for you to improve your sleep. An important role of this blog is to share best practice and alternative practices as well. We like it when our patients hack their own physiology to come up with solutions that work.

Don’t forget our treatment aim is to maximise your brain health and part of this philosophy is the holistic management of MS including sleep.

Yaffe et al. Sleep Duration and White Matter Quality in Middle-Aged Adults. Sleep. 2016 Sep 1;39(9):1743-7.

STUDY OBJECTIVES: Sleep duration has been associated with risk of dementia and stroke, but few studies have investigated the relationship between sleep duration and brain MRI measures, particularly in middle age.

METHODS: In a prospective cohort of 613 black and white adults (mean age = 45.4 years) enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study, participants reported typical sleep duration, dichotomized into moderate sleep duration (> 6 to ≤ 8 h) and short sleep duration (≤ 6 h) at baseline (2005-2006). Five years later, we obtained brain MRI markers of white matter including fractional anisotropy, mean diffusivity, and white matter hyperintensities.

RESULTS: Compared to moderate sleepers, short sleepers had an elevated ratio of white matter hyperintensities to normal tissue in the parietal region (OR = 2.31, 95% CI: 1.47, 3.61) adjusted for age, race/sex, education, hypertension, stroke/TIA, depression, smoking status, and physical activity. White matter diffusivity was also higher, approximately a 0.2 standard deviation difference, in frontal, parietal, and temporal white matter regions, among those reporting shorter sleep duration in (P < 0.05 for all).

CONCLUSIONS: Short sleep duration was associated with worse markers of white matter integrity in midlife. These mid-life differences in white matter may underlie the link between poor sleep and risk of dementia and stroke.

#ThinkCognition

If you have MS-related cognitive impairment would you want a treatment to improve your cognitive function?

The study below shows that dalfampridine, or fampridine, improves cognition in particular processing speed in MSers with cognitive impairment. Importantly the improvement on the SDMT (Symbol Digit Modalities Test) was greater than 4 points, which is considered clinically meaningful in that it is anchored to improved day-to-day functioning and quality of life.

Dalfampridine has a complex mode of action and is thought to increase the so-called safety factor of conduction and synaptic function and improves the functioning of demyelinated or thinly remyelinated axons.

Dalfampridine is currently licensed to improve walking speed in MSers. As it has not been green-lighted by NICE for use on the NHS most MSers can’t access this treatment. In London, some NHS hospitals have put in place a limited access scheme and therefore can prescribe fampridine for some of their patients. Despite this most MSers who take fampridine in the UK are having to pay for it privately, which I find totally unacceptable. Why should your ability to pay and access private healthcare dictate your access to a treatment that is being used extensively across the world?

This cognitive study below suggests that similar mechanisms underlie both motor and cognitive performance in MS. What is important about this study is that it demonstrates the principle that MS-related cognitive impairment is a potentially treatable problem. It also raises the question of whether, or not, we should be doing routine cognitive testing in clinical practice and telling our patients they have cognitive impairment and hopefully in the future being able to offer them an effective therapy to improve their cognition or processing speed.

De Giglio et al. Effect of dalfampridine on information processing speed impairment in multiple sclerosis. Neurology. 2019 Jul 22. pii: 10.1212/WNL.0000000000007970.

OBJECTIVE: To test a possible benefit of dalfampridine on information processing speed (IPS), a key function for cognitive impairment (CogIm) in multiple sclerosis (MS).

METHODS: In this randomized, double-blind, placebo-controlled trial, we included patients with a score on the Symbol Digit Modalities Test (SDMT) under the 10th percentile of the reference value. Patients were randomized in a 2:1 ratio to receive dalfampridine 10 mg or placebo twice daily for 12 weeks. They underwent a comprehensive neuropsychological evaluation at screening (T0), at the end of treatment (T1), and after a 4-week follow-up (T2). The primary endpoint was improvement in SDMT.

RESULTS: Out of 208 patients screened, 120 were randomized to receive either dalfampridine (n = 80) or placebo (n = 40). At T1, the dalfampridine group presented an increase of SDMT scores vs placebo group (mean change 9.9 [95% confidence interval (CI) 8.5-11.4] vs 5.2 [95% CI 2.8-7.6], p = 0.0018; d = 0.60 for raw score; and 0.8 [95% CI 0.6-1] vs 0.3 [95% CI 0.0-0.5], p = 0.0013; d = 0.61 for z scores; by linear mixed model with robust standard error). The improvement was not sustained at T2. A beneficial effect of dalfampridine was observed in the Paced Auditory Serial Addition Test and in cognitive fatigue.

CONCLUSION: Dalfampridine could be considered as an effective treatment option for IPS impairment in MS.

TRIAL REGISTRATION: 2013-002558-64 EU Clinical Trials Register.

CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with MS with low scores on the SDMT, dalfampridine improves IPS.

CoI: multiple

Inactive MS; does it exist?

I had an interesting discussion with some like-minded colleagues recently about active and inactive MS. We seemed to agree on what active MS is, be it in the relapsing or progressive phases of MS. However, we couldn’t really agree on what inactive MS is. Take this following case scenario; many said he was inactive, but others felt he had active MS and should have his treatment switched. Would you agree?

When you look at post-mortem studies of people dying with endstage MS they all have active inflammation within their brains. Active inflammation refers to both adaptive (memory responses) and innate (hard-wired) immune responses. MSers at death still have T-cells, B-cells and plasma cells in their brains in addition to astrocyte and microglial activation.

If we extrapolate these pathological findings to life then all MSers have active MS. What is the solution in terms of forming a common nomenclature? Surely MS is a biological disease rather than a clinical disease? If this is the case we need to come up with a biological classification system to describe active and inactive MS.

On reflection, I think we need to get rid of the terms active and inactive and describe what we mean pathologically using metrics. For example,

This patient has evidence of ongoing focal inflammation (relapses, new and/or enlarging T2 lesions and/or Gd-enhancing lesions and/or raised CSF NFL levels) in the last 12 or 24 months.
This patient has no evidence of ongoing focal inflammation in the last 24 months but has worsening disability (physical and/or cognitive) and evidence of smouldering MS with increased brain/spinal cord atrophy and/or an increasing T1 black volume.
This patient has no evidence of ongoing focal inflammation in the last 24 months, is stable clinically (physical and cognitive) and has no evidence of smouldering MS, i.e. no increased brain/spinal cord atrophy and a stable T1 black volume.

I suspect that we will have very few MSers in category 3, simply because with an MS-centric view of the world we are forgetting that MSers are human and will age and will get comorbidities. Therefore, how do we include ageing and comorbidities, which affect these biomarkers, into this classification system? In addition, none of our metrics is black-and-white so there is scope for miss-classification. What is clear that if you take this approach then MS is one, and not two or three, diseases. A person with PPMS with new lesions will be treated in the same way as someone in the relapsing-remitting phase of the disease. Do you have a problem with this?

Thoughts, please?

CoI: multiple

Goalposts

We need to keep pushing the envelope and moving the goalposts in terms of our treatment targets in MS.

As MS advances innate immune activation with microglial and astrocyte activation occurs. However, the latter may be adaptive in response to damage and hence a good thing, which is why I am sceptical about treatments aimed at targeting these cells in advanced MS.

In comparison, B-cells and plasma cells are a different story. These cells are part of the adaptive immune system and are likely producing pathogenic, or damaging, antibodies. B cells and plasma cells set-up shop in the brain and spinal cords of MSers and churn out these heat-seeking missiles that are likely to be responsible for smouldering MS; i.e. the cortical lesions and the slowly expanding lesions or (SELs), which cause disease worsening even in those MSers who are NEDA (no relapses or no new or enhancing MRI lesions). The problem we have is that our current DMTs don’t appear to target these cells with the possible exception of cladribine that is a small molecule and gets into the brain and spinal cords of MSers. Konrad Rejdak and colleagues in Poland have shown that about 50% of cladribine treated MSers lose their oligoclonal IgG bands (OCBs) from their CSF and that the patients who lose their OCBs tend to be stable compared to those who don’t lose their OCBs. We need to replicate these findings and supports our hypothesis to target CNS-resident plasma cells in MS.

Please note spinal fluid OCBs and immunoglobulin free light chains are at the bottom of our treat-2-target pyramid. This is our new goalposts.

This is why we are starting two studies in parallel, and want to start more studies with additional agents, to see if we can get rid of OCBs in MSers.

Our first study will look at oral cladribine’s effect on B-cell and plasma cell activity within the brain and spinal cords of MSers. Does cladribine reduce OCBs and immunoglobulin production? This study is called the “Oral Cladribine B-cell study” or CLAD B.

The following are the inclusions criteria for CLAD B:

Patients with RRMS who are being treated with oral cladribine at Barts Health NHS Trust
Patients must be willing and able to undergo lumbar punctures
Patients who are OCB positive in their CSF (from previous diagnostic lumbar puncture)

In our second study, we are testing a myeloma drug called Ixazomib in MS. Ixazomib is a second-generation proteasome inhibitor that works against malignant plasma cells. This study is called “Safety of targeting plasma cells in Multiple Sclerosis: A phase 1b randomised, double-blind, placebo-controlled trial” or SIZOMUS.

The following are the SIZOMUS inclusion criteria:

Each participant must meet all of the following inclusion criteria to be enrolled in the SIZOMUS study:

Male and female patients 18 to 65 years old at screening.
Must have a diagnosis of MS, and:
1. Patients with RRMS must be on DMT
2. Patients with progressive MS must not be on DMT
Participants with RRMS must be on stable DMT (i.e. must not have had a relapse within 1 month prior to the screening visit)
OCB positive CSF either from a previous CSF analysis or from the screening CSF analysis
Patients must be willing and able to undergo lumbar punctures
Agree to use of effective contraception

For those interested in proteasome inhibitors there is an emerging evidence base of them working in autoimmune diseases in general, in particular with the 1st-generation drug called Bortezomib.

Do you think we are crazy? We have been working on getting these trials off the ground for over 3 years and the ideas, and hypotheses, underpinning these trials goes back more than 15 years. I originally wanted to do a thalidomide trial, targeting plasma cells, way back in 1997. However, I was advised against it by Professor W. Ian McDonald who thought it would be too risky.

If you live in London, or the home counties, and are interested in participating in these trials, and you think you are eligible, let your HCP know and they can contact us.

Baker et al. Plasma cell and B cell-targeted treatments for use in advanced multiple sclerosis. Mult Scler Relat Disord. 2019 Jun 26;35:19-25

There is increasing evidence that agents that target peripheral B cells and in some instances plasma cells can exhibit marked effects on relapsing multiple sclerosis. In addition, B cells, including plasma cells, within the central nervous system compartment are likely to play an important role in disease progression in both relapsing and progressive MS. However, current B cell-targeting antibodies may not inhibit these, because of poor penetration into the central nervous system and often oligoclonal bands of immunoglobulin persist within the cerebrospinal fluid despite immunotherapy. Through targeting B cells and plasma cells in the CNS, it may be possible to obtain additional benefit above simple peripheral depletion of B cells. As such there are a number of inhibitors of B cell function and B cell depleting agents that have been developed for myeloma and B cell leukaemia and lymphoma, which could potentially be used off-label or as an experimental treatment for advanced (progressive) MS.

CoI: multiple

Sugar crash

My recent blog post on food coma (14-Jan-2019) not only uncovered another hidden symptom in MSers but has led us to start exploring this phenomenon in our patients and, hopefully, to some evidence-based advice on how to manage the problem.

In our short web survey on food coma, I was surprised to find that 86% of MSers report this phenomenon with 28 of the 81 respondents (35%) reporting their food coma as being severe or severe-and-incapacitating. When exploring the science I was surprised to uncover that insulin, the hormone that the pancreas releases in response to carbohydrates or sugar, is one of the main mediators of food coma. How could this be when my mother always used to accuse me of having a sugar rush as a child? A sugar rush is a so-called period of hyperactivity that occurs after ingesting too much sugar in a short period of time.

I was therefore not surprised to read the following well-done metanalysis debunking this piece of dogma. On the contrary, sugar does not cause a sugar rush, but a sugar crash, another term for food coma.

This and other evidence keeps mounting against sugar and the sugar industry. There seems to be very little reason for anyone to consume sugar or processed carbohydrates in any form. This is why nutritionists have started to refer to processed carbohydrates as empty calories.

So I am going to repeat myself again if you want to select a diet that is healthy for you can I suggest a real-food diet low in carbohydrates, i.e. free of all processed carbohydrates. This means you may need to get most of your calories from fats and proteins. The carbohydrates you eat on the real-food diet will be unprocessed with a low glycaemic index. As a result of this diet, you will keep your insulin levels low and hence you will reduce your postprandial hypersomnolence or ‘food coma’.

Keeping your insulin levels low will have other positive effects on your health; i.e. it will help you maintain a healthy weight, counteract insulin resistance and hence your chances of developing the metabolic syndrome (insulin resistance, diabetes, hypertension, hyperlipidaemia and obesity) and it should reduce your risk of developing common cancers.

What is there to lose? How easy is it to stick to the real-food diet? You tell me.

Mantantzis et al. Sugar rush or sugar crash? A meta-analysis of carbohydrate effects on mood. Neurosci Biobehav Rev. 2019 Jun;101:45-67.

The effect of carbohydrate (CHO) consumption on mood is much debated, with researchers reporting both mood improvements and decrements following CHO ingestion. As global consumption of sugar-sweetened products has sharply increased in recent years, examining the validity of claims of an association between CHOs and mood is of high importance. We conducted a systematic review and meta-analysis to evaluate the relationship between acute CHO ingestion and mood. We examined the time-course of CHO-mood interactions and considered the role of moderator variables potentially affecting the CHO-mood relationship. Analysis of 176 effect sizes (31 studies, 1259 participants) revealed no positive effect of CHOs on any aspect of mood at any time-point following their consumption. However, CHO administration was associated with higher levels of fatigue and less alertness compared with placebo within the first-hour post-ingestion. These findings challenge the idea that CHOs can improve mood, and might be used to increase the public’s awareness that the ‘sugar rush’ is a myth, inform health policies to decrease sugar consumption, and promote healthier alternatives.

PML carryover onto ocrelizumab

I have just received the following information from Roche, which is reassuring in that

As of July 3rd 2019, the Roche can confirm there have been no new carry-over cases of PML in MS patients treated with ocrelizumab since their last update in April 2019. The seventh case was reported in March 2019.
As of April 2019, over 100,000 people have been treated with ocrelizumab globally, within a combination of clinical trial and post-marketing settings.
No unconfounded cases of PML with ocrelizumab have been reported to date.
Of the seven cases of carry-over PML, none were reported as fatal at the last point of follow up (Feb 2019).

Information relating to all carry-over cases has been reported to regulatory agencies in compliance with agreed pharmacovigilance processes.

The recommendations relating to PML in the approved product labelling for ocrelizumab remain unchanged. HCPs should be vigilant for early signs and symptoms of PML, which can include any new-onset, or worsening of neurological signs or symptoms, as these can be similar to an MS relapse. If PML is suspected, withhold dosing with ocrelizumab.

Summary of carry-over PML cases to date (July 2019):

Carry-over case	Country	Reported	Setting	Carry-over from
1	Germany	May 2017	Compassionate Use programme	Natalizumab
2	Canada	April 2018	Post-marketing	Fingolimod
3	USA	May 2018	Post-marketing	Natalizumab
4	USA	June 2018	Post-marketing	Natalizumab
5	USA	July 2018	Post-marketing	Natalizumab
6	Luxembourg	September 2018	Post-marketing	Natalizumab
7	USA	February 2019	Post-marketing	Natalizumab

Roche are sharing this information for full transparency and hope you find this useful.

#ThinkSocial

At our second MS Services Variance meeting, ‘Raising the Bar’, in Birmingham last week my colleague Helen Ford and I co-chaired the workstream on the social determinants of health (SDoH).

What are the SDoH?

The SDoH are life-enhancing resources, such as food supply, housing, economic and social relationships, transportation, education and health care, whose distribution across populations effectively determines length and quality of life. As MS is such a disabling disease with poor quality of life it is likely to impact on the SDoH, which in turn will feedback and make MS outcomes worse. This vicious cycle needs to be broken if we want to optimise MS outcomes; i.e. when applying the philosophy of marginal gains we can’t ignore the SDoH when managing someone with MS.

The following is a selection of slides we put together around the SDoH theme.

Do you have an example of how the SDoH can impact on a person with MS?

The study highlighted below from Sweden is an example of how MS reduces your earnings. Interestingly, the reduction in earnings even begins before MS diagnosis and clearly increases thereafter. I suspect some people who have prodromal MS have difficulty working, which impacts on the average outcome or earnings. Besides sickness absence and disability pension, educational level and type of occupation are influential determinants of earnings in pwMS. In other words, inequality plays a role in determining your earnings once you have MS. Are you surprised? I am not.

When we asked whether or not MS HCPs routinely screen for the SDoH very few hands went up in the room. The hands that went up tended to belong to occupational therapists; they clearly need to look at SDoH as part of their treatment plans. No neurologists put up their hands and therein lies a problem or a solution depending on how you look at things.

The following is a short list of some of the SDoH that may impact on MS outcomes, which we discussed.

Level of education and health literacy
Poverty (absolute or relative)
Employment / unemployment
Access to social services (personal independent payments, etc.)
Home environment (heating, cleanliness, amenities, etc.)
Local environment (safety, green spaces, amenities, etc.)
Food poverty (absolute or relative)
Transport (access and costs)
Childcare (access and costs)
Social isolation (social networks, access to the internet, mobile phone, data, etc.)
Lifestyle factors (sedentary vs. active, smoking, alcohol and other addictions)
Need to be looked after by a child (child carer) or ageing parents or other family members (aged carers)
Cognitive impairment and hidden psychiatric comorbidities (depression and anxiety)
Physical and emotional abuse

How do we address these issues in an MS clinic without upsetting our patients by being too overbearing? We did agree that there was a lot we could potentially do about some of these SDoH and that we had an obligation to at least consider these as part of our routine management of our patients and their families. Some ideas that emerged in our session include the following:

Provide information about IT solutions to help pwMS.
Start a high-risk register of patients within our service; patients on this list would need to be seen and contacted more frequently, ideally on pre-planned and regular basis.
Start a home visit programme. Most services have had to stop home visits because of resource and staffing issues.
Make sure our patients know that they can get hospital transport so they don’t go out of pocket or reimburse their travel costs.
Convert were possible physical face-2-face visits with telemedicine options.
To do a complex needs assessment similar to what is done in other disease areas to identify high-risk or vulnerable patients.
Lobby the government to waive prescription costs for pwMS and other disabilities.
Lobby government to create a healthy food voucher system for pwMS and other disabilities.
Lobby government to improve social services for pwMS and other disabilities.
Engage pwMS and include them in your service; for example, using an MS Health Champions model.
Explore social prescribing to increase social capital.
Enrol all patients into a lifestyle and wellness programme.

Wiberg et al. Earnings among people with multiple sclerosis compared to references, in total and by educational level and type of occupation: a population-based cohort study at different points in time. BMJ Open. 2019 Jul 11;9(7):e024836.

OBJECTIVES: To investigate earnings among people with multiple sclerosis (PwMS) before and after MS diagnosis compared with people without MS, and if identified differences were associated with educational levels and types of occupations. Furthermore, to assess the proportions on sickness absence (SA) and disability pension (DP) in both groups.

DESIGN: Population-based longitudinal cohort study, 10 years before until 5 years after MS diagnosis.

SETTING: Working-age population using microdata linked from nationwide Swedish registers.

PARTICIPANTS: Residents in Sweden in 2004 aged 30-54 years with MS diagnosed in 2003-2006 (n=2553), and references without MS (n=7584) randomly selected by stratified matching.

OUTCOME MEASURES: Quartiles of earnings were calculated for each study year prior to and following the MS diagnosis. Mean earnings, by educational level and type of occupation, before and after diagnosis were compared using t-tests. Tobit regressions investigated the associations of earnings with individual characteristics. The proportions on SA and/or DP, by educational level and type of occupation, for the diagnosis year and 5 years later were compared.

RESULTS: Differences in earnings between PwMS and references were observed beginning 1 year before diagnosis, and increased thereafter. PwMS had lower mean earnings for the diagnosis year (difference=SEK 28 000, p<0.05), and 5 years after diagnosis, this difference had more than doubled (p<0.05). These differences remained after including educational level and type of occupation. Overall, the earnings of PwMS with university education and/or more qualified occupations were most like their reference peers. The proportions on SA and DP were higher among PwMS than the references.

CONCLUSIONS: The results suggest that the PwMS’ earnings are lower than the references’ beginning shortly before MS diagnosis, with this gap increasing thereafter. Besides SA and DP, the results indicate that educational level and type of occupation are influential determinants of the large heterogeneity of PwMS’ earnings.

Zombie

Are you an anticholinergic zombie?

A few months ago a 63-year-old MSer was admitted to hospital because of faecal impaction and overflow diarrhoea. She had had worsening constipation for years and was having intermittent diarrhoea due to liquification of stool from an overgrowth of bacteria in her colon, above a massive faecolith (a faecal rock). Her neurologist had her on a long-acting formulation of solifenacin for her neurogenic bladder and 50mg of amitriptyline to help her sleep at night. She had restless legs due to myelopathic pain and spasticity, which was helped by the amitriptyline. Could this be you? Or if you are an HCP do you recognise this patient?

Her daughter had noticed that she had become increasingly forgetful over the last few months and had missed appointments and had started to repeat herself during casual conversation; often asking the same question during a short conversation. She also could not recall the name of her granddaughter, which was out of character and quite worrying. Her family had started to worry about whether, or not, she was developing dementia.

During her admission to hospital, her solifenacin was replaced with mirabegron, a new class of drugs that work by stimulating the beta-3 receptor in the bladder wall, that is not associated with CNS side effects. Her amitriptyline was also stopped. Both of these were done to reduce the anticholinergic effects of these drugs on her bowels, which is constipation and on rare occasions faecal impaction. A day or two after these changes to her medication and the clear out of her bowels she woke up cognitively; she became animated and began to interact with her daughter and family members in a way that she had not done for years. She also stopped repeating herself. I identify this syndrome as the ‘Anticholinergic Zombie Syndrome’. Centrally acting anticholinergics have major cognitive side effects and in people with MS, who have reduced reserve, these can be severe.

I have been developing the argument over the last few months that we should approach the management of MS holistically using the marginal gains philosophy developed by Sir Dave Brailsford when he initially started to manage the Team GB cycling team.

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

If you apply this to MS, i.e. 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 also means avoiding things that make MS worse.

One particular factor that we know makes MS worse is exposure to anticholinergics. We use this class of drug mainly for bladder dysfunction, i.e. to reduce bladder irritability. The older the bladder drug the more likely it is to cross the blood-brain barrier and affect cognition. Oxybutynin, for example, reduces IQ or cognition by a half a standard deviation or 7 points. This is enough to make someone with MS-related cognitive impairment demented.

However, many of the other drugs we prescribe to help MSers have anticholinergic effects off-target. These include the tricyclic antidepressants. As a class, these are used to help MSers with myelopathic pains and as sedatives. It is quite remarkable how often neurologists reach from the prescription pad to prescribe amitriptyline for their patients. I think it is time for us to step back from this practice. We now have other options.

The remarkable thing is that in the general population exposure to anticholinergics increases your risk of developing dementia. The most recent population case-control study confirming this has just been published in JAMA. I suspect the MS brain is more vulnerable to the effects of anticholinergics and hence we may have inadvertently been exacerbating MS dementia. It is time for us to rethink how we manage the MS bladder and other symptomatic problems and avoid drugs with anticholinergic effects?

Dare I suggest we should have zero-tolerance for anticholinergics and try and avoid them altogether?

Coupland et al Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study. JAMA Intern Med. Published online June 24, 2019. doi:10.1001/jamainternmed.2019.0677

Question: Is the risk of dementia among persons 55 years or older associated with the use of different types of anticholinergic medication?

Findings: In this nested case-control study of 58 769 patients with a diagnosis of dementia and 225 574 matched controls, there were statistically significant associations of dementia risk with exposure to anticholinergic antidepressants, antiparkinson drugs, antipsychotic drugs, bladder antimuscarinics, and antiepileptic drugs after adjusting for confounding variables.

Meaning: The associations observed for specific types of anticholinergic medication suggest that these drugs should be prescribed with caution in middle-aged and older adults.

Importance: Anticholinergic medicines have short-term cognitive adverse effects, but it is uncertain whether long-term use of these drugs is associated with an increased risk of dementia.

Objective: To assess associations between anticholinergic drug treatments and risk of dementia in persons 55 years or older.

Design, Setting, and Participants: This nested case-control study took place in general practices in England that contributed to the QResearch primary care database. The study evaluated whether exposure to anticholinergic drugs was associated with dementia risk in 58 769 patients with a diagnosis of dementia and 225 574 controls 55 years or older matched by age, sex, general practice, and calendar time. Information on prescriptions for 56 drugs with strong anticholinergic properties was used to calculate measures of cumulative anticholinergic drug exposure. Data were analyzed from May 2016 to June 2018.

Exposures: The primary exposure was the total standardized daily doses (TSDDs) of anticholinergic drugs prescribed in the 1 to 11 years prior to the date of diagnosis of dementia or equivalent date in matched controls (index date).

Main Outcomes and Measures Odds ratios (ORs) for dementia associated with cumulative exposure to anticholinergic drugs, adjusted for confounding variables.

Results: Of the entire study population (284 343 case patients and matched controls), 179 365 (63.1%) were women, and the mean (SD) age of the entire population was 82.2 (6.8) years. The adjusted OR for dementia increased from 1.06 (95% CI, 1.03-1.09) in the lowest overall anticholinergic exposure category (total exposure of 1-90 TSDDs) to 1.49 (95% CI, 1.44-1.54) in the highest category (>1095 TSDDs), compared with no anticholinergic drug prescriptions in the 1 to 11 years before the index date. There were significant increases in dementia risk for the anticholinergic antidepressants (adjusted OR [AOR], 1.29; 95% CI, 1.24-1.34), antiparkinson drugs (AOR, 1.52; 95% CI, 1.16-2.00), antipsychotics (AOR, 1.70; 95% CI, 1.53-1.90), bladder antimuscarinic drugs (AOR, 1.65; 95% CI, 1.56-1.75), and antiepileptic drugs (AOR, 1.39; 95% CI, 1.22-1.57) all for more than 1095 TSDDs. Results were similar when exposures were restricted to exposure windows of 3 to 13 years (AOR, 1.46; 95% CI, 1.41-1.52) and 5 to 20 years (AOR, 1.44; 95% CI, 1.32-1.57) before the index date for more than 1095 TSDDs. Associations were stronger in cases diagnosed before the age of 80 years. The population-attributable fraction associated with total anticholinergic drug exposure during the 1 to 11 years before diagnosis was 10.3%.

Conclusions and Relevance: Exposure to several types of strong anticholinergic drugs is associated with an increased risk of dementia. These findings highlight the importance of reducing exposure to anticholinergic drugs in middle-aged and older people.

CoI: multiple

Resilience

Down, but definitely not out!

The WHO rejected our application to get glatiramer acetate, fingolimod and ocrelizumab/rituximab onto the Essential Medicined List. Why?

The following is the relevant section from Executive Summary:

“The Expert Committee recognized the public health need for effective and affordable treatments for multiple sclerosis (MS) but did not recommend the addition to the EML and EMLc of glatiramer acetate, fingolimod and ocrelizumab at this time. The Committee acknowledged the application’s approach to increasing access to MS treatments by prioritizing selected treatment options. However, the Committee noted that some relevant therapeutic options for MS were not included in the application (azathioprine and natalizumab) or were not given full consideration (rituximab). The superiority of presented medicines over other therapeutic options in the outcomes considered (benefits, harms, affordability) did not clearly emerge. The Committee would, therefore, welcome a revised application which comprehensively reviews the relative roles of relevant available medicines for MS. “

For the committee to recommend we look at azathioprine again, when the WHO themselves rejected azathioprine in 2015, is odd. To the best of my knowledge, nothing has changed in terms of new data since 2015 to change Azathioprines position as a potential off-label treatment for MS.

As for natalizumab, we did not add it to the EML application because it is still on patent, i.e. expensive, it needs to be given as a monthly infusion, which adds to its expense, and is associated with a high monitoring burden for PML. The latter is would be very difficult in resource-poor environments. At the moment the PML JCV serology assay is controlled by Biogen so when natalizumab comes off-patent, and say natalizumab biosimilars emerge, what will happen to the international JCV serology monitoring system that currently exists? Would the WHO take it over from Biogen? Would it be distributed to national labs? Will resource-poor countries be able to incorporate this into their already over-stretched systems?

We went through all these factors in our deliberations and came to the conclusion that 6-monthly ocrelizumab, and rituximab if ocrelizumab is not available, would be a better alternative to natalizumab. Another factor was that ocrelizumab is now licensed to treat PPMS. If we excluded ocrelizumab from the list what message would this send out to PPMSers in the world? In addition, the monitoring requirements for anti-CD20 therapies are much less burdensome than natalizumab.

So we take the punch on the chin, get up and start working on the next application that will be due in 2021. We are a resilient group and we owe it to people with MS all over the world to get them access to effective DMTs.

The following is the MSIF’s press release and the agenda for their meeting in London this Thursday and Friday. Instead of a celebratory mood, I suspect the atmosphere will be more sombre.

We may have lost a battle, but we have not lost the war.

#OffLabel

I am speaking at the Multiple Sclerosis International Federation (MSIF) Access to Treatment and Healthcare meeting next week in London. My talk is on “Off-label opportunities, barriers and risks in availability and affordability”.

My journey to this point goes back 5-years and started when I was on sabbatical and was visiting countries all over the world and seeing how MS was managed. I soon realised that MSers living in resource-poor environments had poor access to MS disease-modifying therapies and other MS services. This led us to formulate an Essential Off-Label DMT list and to start a social media campaign using the hashtag #OffLabel to get people to adopt off-label prescribing of DMTs. We also developed a protocol for off-label cladribine use and have distributed it widely.

These activities and other factors nudged the MSIF to make ‘access to treatment’ one of their priorities and led to the MSIF submitting an application to the WHO to get three DMTs, albeit licensed DMTs, onto the essential medicines list (EML). If successful (hopefully we will hear next week – fingers-crossed) we will be able to use this as a springboard to raise awareness of untreated or under-treated MS across the world. It will also raise awareness about MS in low prevalence areas and challenge the prevailing dogma that MS is a rich-world problem.

Please note our essential off-label DMT list is ‘evidence-based’ or at least anchored to licensed DMTs. The following is a new version of the list.

Azathioprine*
Dimethyl fumarate (generic, licensed for psoriasis)
Cladribine
Cyclophosphamide*
Fludarabine*
Leflunomide
Methotrexate*
Mitoxantrone
Rituximab*
HSCT

*drugs that are on the 19th WHO Model List of Essential Medicines (April 2015)

I am particularly interested to hear stories about off-label treatments in your countries and if any of you are receiving off-label treatments.

Apart from rituximab use, particularly in Sweden, off-label prescribing is simply not being adopted. Why? I think it takes more than a few people standing on a soap-box to make it happen; what is required is a systems change and a whole lot of nudges to get HCPs to start doing it. This is why I have become so interested in behavioural psychology and behavioural economics, which teaches us why information is simply not enough to change HCP behaviour.

CoI: multiple