Lab Lessons – Page 5 – Prof G's MS Blog Archive

Virus, virus where art thou hiding?

Barts-MS rose-tinted-odometer: ★★★★★★★★★★

Would you volunteer to participate in a clinical trial of an antiviral drug cocktail to suppress MS disease activity, in particular smouldering MS?

There is reasonable evidence in the literature that HERVs (human endogenous retroviruses) may play a role in autoimmunity, in particular MS. HERVs are viruses (genetic code) that have been incorporated into the human genome over deep time. Some HERV genetic elements have taken on important functional roles, for example, they are involved in the development of the mammalian placenta and hence are part of our human biology.

When HERVs elements are transcribed they may be capable of forming replication-competent viruses, which can reinfect cells and integrate back into the genome. These reintegration sites may be important in themselves and may drive the selection of cells with enhanced functions and may also result in cancer. Other HERV elements are replication-incompetent and although they can produce functional transcripts can’t form an infectious virus.

Some HERV proteins act as danger signals activating so-called toll-like receptors and other danger-signalling pathways. These pathways then upregulate innate immunity and provide the immunological nudge that drives autoimmunity. This is why there have been some attempts to try and suppress HERV activation with antiviral drugs or to neutralise some of the HERV proteins that may activate the immune system, or are directly toxic to myelin-producing cells and/or neurones, as a treatment for MS.

These HERV-related hypotheses are supported by several studies showing upregulation of HERVs transcripts and HERV proteins in the brains of people with MS. The study below uses a new technology called next-generation RNA sequencing to show that some HERV-W (a specific type of HERV) transcripts are exclusively present in MS brains and as they are located on chromosome 7 close to one of the MS genetic risk loci may be relevant to MS. Could this finding be part of the proof we need to show that HERV-W may be in the causal pathway that leads to the development of MS? Importantly, HERV transcripts (RNA message) close to the MS risk locus on chromosome 7 were overrepresented in MS brains.

Although some would interpret these findings as being potentially causal, i.e. HERV transactivation and expression is driving the pathology that is MS, another interpretation is that whatever causes MS transactivates HERVs, which is then simply a bystander phenomenon. The only way to separate ‘causation’ from ‘association’ is to do an experiment to suppress HERV transactivation to see if it improves MS outcomes. This is a conclusion that Prof. Julian Gold and I came to several years ago and is why we have been trying to get funding to do a CNS penetrant combination antiretroviral trial in MS.

Some of the cynics will ask ‘well what about your EBV hypothesis’? Interestingly, EBV and some of the other herpes viruses are potent transactivators of HERVs, i.e. infection with EBV wakes-up HERVs in our genome and results in their transcription. Therefore, increased HERVs may be a marker of EBV infection. This may be important, but recent data indicates that some HAART (highly active antiretroviral therapies) components are also effective against EBV. Therefore, clinical trials of HAART may actually target both EBV and HERVs. This is why I am so excited about the news that a small HAART trial in MS will be starting soon in the US. However, Prof. Julian Gold and I, as part of our Charcot Project, will still continue to prod and encourage big Pharma companies (ViiV-GSK, Gilead, Merck, etc.) with a footprint in the antiretroviral space, to come to the table with their products (HAART) and money to fund a large adequately powered study to test the hypothesis in a definitive MS study.

It would be a travesty if in 20 years time the next generation of MS researchers discover that HAART is a very effective treatment for MS when we have the tools to answer this question now, i.e. in the next 4 to 5 years? In fact, we have a clue that this may be the case already. Having HIV infection protects one from getting MS. This may be due to the therapy (HAART) that is used to treat HIV and not due to the HIV virus itself.

As you know outside-the-box ideas or paradigm shifts often take generations to occur. So you shouldn’t be surprised if the MS community continues to reject these hypotheses and nothing happens for decades.

Maria L Elkjaer et al. Unbiased examination of genome-wide human endogenous retrovirus transcripts in MS brain lesions. Mult Scler. 2021 Jan 19;1352458520987269. doi: 10.1177/1352458520987269.

Background: Human endogenous retrovirus (HERV) expression in multiple sclerosis (MS) brain lesions may contribute to chronic inflammation, but the expression of genome-wide HERVs in different MS lesions is unknown.

Objective: We examined the HERV expression landscape in different MS lesions compared to control brains.

Methods: Transcripts from 71 MS brain samples and 25 control WM were obtained by C and mapped against HERV transcripts across the human genome. Differential expression of mapped HERV-W and HERV-H reads between MS lesion types and controls was analysed.

Results: Out of 6.38 billion high-quality paired-end reads, 174 million reads (2.73%) mapped to HERV transcripts. There was no difference in HERVs expression level between MS and control brains, but HERV-W transcripts were significantly reduced in chronic active lesions. Of the four HERV-W transcripts exclusively present in MS, ERV3633503 located on chromosome 7q21.13 close to the MS genetic risk locus had the highest number of reads. In the HERV-H family, 75% of transcripts located to nearby 7q21-22 were overrepresented in MS, and ERV3643914 was expressed more than 16 times in MS compared to control brains.

Conclusion: Novel HERV-W and HERV-H transcripts located at chromosome 7 regions were uniquely expressed in MS lesions, indicating their potential role in brain lesion evolution.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

What has my age got to do with having MS?

Barts-MS rose-tinted-odometer: ★★★ (some readers have asked for this feature to stay)

How old are you? It depends. You may be aware that there can be a disconnect between your chronological or actual age and your biological age. As ageing or senescence is a biological process driven by metabolic, genomic and environmental factors you can see how there can be a disconnect between the two. As a result, many of us in medicine are beginning to think about unhealthy or accelerated ageing as a disease process. Making ageing a disease will create incentives for pharmaceutical and nutraceutical companies to invest in ageing R&D with the hope of producing medications or dietary supplements to slow-down or reverse the effects of ageing.

Ageing is important in MS as there is emerging evidence that MS causes premature ageing of the CNS (central nervous system), which means that pwMS are more likely to experience age-related neurodegeneration sooner than they have to and this almost certainly contributes to delayed disability worsening in pwMS.

It is clear that ageing impacts one’s ability to recover from CNS damage. It has been known for some time from clinical and animal studies that remyelination and neuronal plasticity are less efficient as you get older, which is why older pwMS recover from relapses less well than younger people. The animal studies below show that there is real biology behind these observations. Oligodendrocyte (myelin-producing) progenitor cells (OPCs) isolated from the brains of neonate, young and aged female rats show an approximately 50% difference in the levels of proteins they make. Differences were noted in both myelin-associated proteins and proteins that control several metabolic pathways. This study has clinical implications and can act as a read-out for finding drugs that could be used as anti-ageing agents.

There are several interesting biological targets and drugs that already exist for targeting ageing. Metformin, a drug for treating diabetes, is one of the lead compounds going in an MS clinical trial at the moment. It is believed that its antiageing effects of performing are mediated via the so-called NRF2 or programmed cell survival pathway. Interestingly, fumarates (e.g. dimethyl fumarate) and ketogenesis also activate this pathway. Could DMF, and the other fumarates, be the panacea antiageing drug we need for tackling progressive or more advanced MS? Yes, I think so but to convince Biogen to follow the money is proving more difficult than we anticipated. We approached them recently to do a combination DMF-plus trial with another class of drug to augment DMF’s response and they said no. Pity because I think they are missing a trick and an opportunity to create new intellectual property.

Physiological ketosis from caloric restriction, intermittent fasting or low-carbohydrate diets is another way of activating the NRF2 pathway. The biology behind this is probably via β-hydroxybutyrate, a ketone body, which works via the hydroxycarboxylic acid receptor 2 (HCA2). Interestingly, this is the same receptor DMF activates.

Other anti-ageing treatments and strategies include exercise and avoiding getting comorbidities, which accelerate ageing, in particular, the metabolic syndrome (obesity, hypertension, glucose intolerance or diabetes) and smoking. The driver of the metabolic syndrome seems to be hyperinsulinaemia and the diets referred to above are all very effective in suppressing or reducing circulating insulin levels.

So in 2021 if you have MS you need to think seriously about what you can do to tackle early and accelerated ageing. Most of the things you can do now involve lifestyle changes, which are often hard to implement. My advice would be to implement the changes slowly and you may find over time that the behavioural changes you make will stick. There is a lot of evidence for this from the field of behavioural psychology.

The above advice is part of the holistic approach to the management of MS I have been pushing for several years and my adoption of the ‘marginal gains philosophy’ for managing MS.

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

“Ask not what your neurologist and HCP can do for you, but what you can do yourself to optimise your own MS management and long-term MS outcome.”

de la Fuente et al. Changes in the Oligodendrocyte Progenitor Cell Proteome with Ageing. Mol Cell Proteomics. 2020 Aug;19(8):1281-1302.

Following central nervous system (CNS) demyelination, adult oligodendrocyte progenitor cells (OPCs) can differentiate into new myelin-forming oligodendrocytes in a regenerative process called remyelination. Although remyelination is very efficient in young adults, its efficiency declines progressively with ageing. Here we performed proteomic analysis of OPCs freshly isolated from the brains of neonate, young and aged female rats. Approximately 50% of the proteins are expressed at different levels in OPCs from neonates compared with their adult counterparts. The amount of myelin-associated proteins, and proteins associated with oxidative phosphorylation, inflammatory responses and actin cytoskeletal organization increased with age, whereas cholesterol-biosynthesis, transcription factors and cell cycle proteins decreased. Our experiments provide the first ageing OPC proteome, revealing the distinct features of OPCs at different ages. These studies provide new insights into why remyelination efficiency declines with ageing and potential roles for aged OPCs in other neurodegenerative diseases.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

How is your end-organ functioning?

Barts-MS rose-tinted-odometer: ★

My prediction or dream for 2021 is that smouldering MS will be accepted by the wider MS community as being the ‘real MS’ and that simply suppressing the immune response to what is causing MS, i.e. relapses and/or focal MRI activity, will be accepted as folly. What matters most to pwMS will be their end-organ, i.e. the size, reserve capacity and function of their brains and spinal cords.

In the same way as patients with a chronic heart or kidney disease ask their cardiologists or nephrologists what is my cardiac ejection fraction or creatinine clearance, markers of end-organ function of the heart and kidneys, respectively, I suspect pwMS will be asking what is the current state of their brains and spinal cords and how has the measures changed from last year. To answer our patients’ questions we are going to have much better functional and structural outcome measures or just maybe patients will be telling us how they are doing via their own self-monitoring initiatives.

The two studies below one looking at the thickness of retinal layers in the eye and the other the size of the thalamus, or deep grey matter structures, in the brain, show that loss of neurons or atrophy predicts future disability. The problem I have with anatomical studies is that by the time you measure and show loss of neurons or atrophy it is too late, i.e. the damage is done and is irreversible. There is data out there that shows loss of function precedes the loss of neurons and that some of the early loss of function may in fact be reversible. Therefore we are going to need to measure function as well as structure.

It is clear that our current clinical outcome measures are too insensitive to change, which is why we are going to need more sensitive and frequent monitoring of function to get on top of smouldering MS. The question is ‘so what if you detect subclinical worsening of function in MS what are you going to do about it?’. In the future, we will be adding-on new therapies to existing anti-inflammatory DMTs that will allow us to go beyond NEIDA (no evident inflammatory disease activity) to tackle smouldering MS. I am acutely aware that we are not there yet when it comes to combination therapies, but that is clearly the direction of travel the MS community is heading. Let’s hope the regulators agree and support the emerging development framework for combination therapies and allow us to start as many trials as soon as possible.

So if you are an MSologist and are reading this post don’t be too surprised if your patients start demanding more detailed functional and structural monitoring of their brains and spinal cords. Wouldn’t you if you had MS?

Maria Cellerino et al. Relationship Between Retinal Layers Thickness and Disability Worsening in Relapsing-Remitting and Progressive Multiple Sclerosis. J Neuroophthalmol. 2020 Dec 29.

Background: Data regarding the predictive value of optical coherence tomography (OCT)-derived measures are lacking, especially in progressive multiple sclerosis (PMS). Accordingly, we aimed at investigating whether a single OCT assessment can predict a disability risk in both relapsing-remitting MS (RRMS) and PMS.

Methods: One hundred one patients with RRMS and 79 patients with PMS underwent Spectral-Domain OCT, including intraretinal layer segmentation. All patients had at least 1 Expanded Disability Status Scale (EDSS) measurement during the subsequent follow-up (FU). Differences in terms of OCT metrics and their association with FU disability were assessed by analysis of covariance and linear regression models, respectively.

Results: The median FU was 2 years (range 1-5.5 years). The baseline peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell + inner plexiform layer (GCIPL) were thinner in PMS compared with RRMS (P = 0.02 and P = 0.003, respectively). In the RRMS population, multivariable models showed that the GCIPL significantly correlated with FU disability (0.04 increase in the EDSS for each 1-μm decrease in the baseline GCIPL, 95% confidence interval: 0.006-0.08; P = 0.02). The baseline GCIPL was thinner in patients with RRMS with FU-EDSS >4 compared with those with FU-EDSS ≤4, and individuals in the highest baseline GCIPL tertile had a significantly lower FU-EDSS score than those in the middle and lowest tertile (P = 0.01 and P = 0.001, respectively). These findings were not confirmed in analyses restricted to patients with PMS.

Conclusions: Among OCT-derived metrics, GCIPL thickness had the strongest association with short-medium term disability in patients with RRMS. The predictive value of OCT metrics in the longer term will have to be further investigated, especially in PMS.

Burggraaff et al. Manual and automated tissue segmentation confirm the impact of thalamus atrophy on cognition in multiple sclerosis: A multicenter study. Neuroimage Clin. 2020 Dec 25;29:102549.

Background and rationale: Thalamus atrophy has been linked to cognitive decline in multiple sclerosis (MS) using various segmentation methods. We investigated the consistency of the association between thalamus volume and cognition in MS for two common automated segmentation approaches, as well as fully manual outlining.

Methods: Standardized neuropsychological assessment and 3-Tesla 3D-T1-weighted brain MRI were collected (multi-center) from 57 MS patients and 17 healthy controls. Thalamus segmentations were generated manually and using five automated methods. Agreement between the algorithms and manual outlines was assessed with Bland-Altman plots; linear regression assessed the presence of proportional bias. The effect of segmentation method on the separation of cognitively impaired (CI) and preserved (CP) patients was investigated through Generalized Estimating Equations; associations with cognitive measures were investigated using linear mixed models, for each method and vendor.

Results: In smaller thalami, automated methods systematically overestimated volumes compared to manual segmentations [ρ=(-0.42)-(-0.76); p-values < 0.001). All methods significantly distinguished CI from CP MS patients, except manual outlines of the left thalamus (p = 0.23). Poorer global neuropsychological test performance was significantly associated with smaller thalamus volumes bilaterally using all methods. Vendor significantly affected the findings.

Conclusion: Automated and manual thalamus segmentation consistently demonstrated an association between thalamus atrophy and cognitive impairment in MS. However, a proportional bias in smaller thalami and choice of MRI acquisition system might impact the effect size of these findings.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

What is your ACB?

ACB = anticholinergic burden

Barts-MS rose-tinted-odometer: ★

“I had no idea oxybutynin and other anticholinergics affected cognition to such an extent” is the standard response I get when I discuss the impact of the most commonly prescribed drugs for MS-related bladder problems (urgency and frequency). 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 approximately 7 points on the standardised IQ scale. Although I stopped prescribing oxybutynin decades ago it is often still prescribed.

And it is not only common bladder medications that have anticholinergic effects the list, which is long, also includes tricyclic antidepressants and over the counter anti-histamines. Tricyclic antidepressants are often prescribed to help pwMS with pain and are used as sedatives. It is remarkable how often neurologists and pain doctors reach from the prescription pad to prescribe amitriptyline to their patients. I think it is time for us to step back from this practice as we now have other options or better medication with less off-target anticholinergic effects.

It is also worth noting that exposure to anticholinergics increases your risk of developing dementia. There have been several population case-control studies showing this. As MS affects cognition 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 reevaluate how we manage bladder dysfunction and other symptomatic problems in MS and avoid prescribing drugs with anticholinergic effects.

The study below compared a relatively new class of drug represented by mirabegron that works on the so-called beta-3 adrenergic receptor and showed it was as effective as anticholinergic drugs in controlling bladder symptoms in MS. However, as it is a newer drug it is more expensive than the commonly prescribed anticholinergics and GPs, therefore, are often reluctant to prescribe mirabegron. The question I ask is if they had MS and bladder dysfunction, which agent would they like to be on. I bet mirabegron would be their choice. ‘Prescribe for your patients what you would want to be prescribed to you’ is a maxim that should be commonly used by doctors.

Anticholinergics also make MS-related constipation worse and cause dryness of the mouth that is often the most common adverse effect that causes patients to stop taking their medication.

Another trend has been the off-label prescribing of anticholinergic agents to promote remyelination, in particular, the drug clemastine. The clinical data on clemastine is at present rather weak and we need to wait for further trials to try and confirm preliminary results in pwMS. In addition, you may not need to take clemastine for prolonged periods of time to promote remyelination as once the demyelinated areas are remyelinated the drug could theoretically be stopped. So I don’t advocate the off-label use of clemastine or benztropine, another remyelinating anticholinergic, in pwMS because of the downside of cognitive impairment for questionable benefits in relation to remyelination.

Can I suggest you review your symptomatic medications and ask yourself what your anticholinergic burden (ABC) is and if it is high you should review your medication with your MS team to see if anything can be done to reduce the burden on your brain? There is an online ACB (anticholinergic burden calculator) that makes this task relatively easy and provides you with a risk score. Although this calculator was created for confusion, falls and death in the elderly it is still useful to give you an idea of your anticholinergic burden. Any score of 3 or higher is undesirable.

I would be interested to know if any of you have stopped taking and anticholinergic and noticed an improvement in your cognition?

Glykas et al. B3 agonists or anticholinergics in the treatment of the lower urinary tract dysfunction in patients with multiple sclerosis?-A randomized study. World J Urol. 2021 Jan 2. doi: 10.1007/s00345-020-03555-8.

Introduction and objective: Multiple sclerosis (MS) is the most frequent autoimmune demyelinating disease of the central nervous system. MS patients usually present with lower urinary tract dysfunction (LUTD). Objective of this study is to evaluate and compare the efficacy and safety of treating MS patients with LUTD with either a b3 agonist (mirabegron) or anticholinergics. The study’s primary outcome is the LUTD symptom improvement.

Material and methods: This is a multi-center, single-blinded, comparative study including 91 MS patients with LUTD. At baseline, patients underwent thorough clinical examination, urine cultivation and abdominal ultrasound and completed urination diaries and specific, validated questionnaires (NBSS, MusiQoL). At second visit, patients were administered either mirabegron or anticholinergics. Treatment was always carried out alongside with MS treatment. Reevaluation was performed 3 months after first visit. Patients underwent the same clinical and imaging tests that were carried out at first visit.

Results: We compared several clinical and imaging parameters between the two groups at first visit and month 3 after treatment. Νo statistical difference was noted between the mirabegron group and the anticholinergic group in terms of LUTD improvement. In both groups, improvement from baseline regarding LUTD was recorded. Statistical analysis was performed using the paired and unpaired t test method. No patient discontinued either medication due to side effects.

Conclusions: MS patients receiving either mirabegron or anticholinergic therapy for LUTD showed improvement. Nevertheless, no statistical difference was noted between the two cohorts at 3 months in terms of drug efficacy in all the statistically significant parameters.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Unsteadiness

Barts-MS rose-tinted-odometer: ★★★★★

How many of you people who have MS (pwMS) have balance problems; i.e. when you stand and close your eyes or try and stand on one leg you tend to fall?

Since my accident, I have been having problems with balance. I first noticed it when I tried to stand on one leg and I would feel unsteady. When walking to and from the bathroom at night I tend to veer to one side. I suspect my balance problems are due to vestibular problems as a result of my head injury and possibly due to my neck injuries. I say possibly due to my neck injury as the concept of cervical vertigo or cervicogenic unsteadiness is very controversial in neurology. But as there are specialised receptors in the neck that pick-up neck rotation it is possible that these have been affected by the injury and surgery.

Despite my balance problems not affecting most things I do, it makes it difficult to complete what I call routine or standard daytime tasks. For example, getting dressed in the morning; when I put on underpants or trousers I have often have to sit down. Leaning forward to pick-up things off the floor is now very difficult I as I tend to tip forwards. I can’t stand on my tiptoes to get things off a high-shelf; I now have to use a chair. These things add up and are a sign that things are not right.

I have never specifically focused on subtle balance issues in my MS clinic, which must be very common in pwMS. I would be interested to know if any of you suffer from balance problems? Have you been referred for a physical assessment? Have you has specific rehabilitation exercises to address the issue? Has the rehab helped?

It is clear that since I became aware of my balance issues and I have started doing specific exercises to address the issue, things have improved. I can now stand on either leg unsupported for over a minute when just a few weeks ago I could only manage to do this for a few seconds. Whether this will translate in better functioning remains to be seen.

There are a number of well-established rehabilitation programmes that have been shown to help with balance problems. So my advice to you is rather than suffering in silence ask for an assessment and a referral for vestibular or balance rehabilitation. If you don’t try and correct the problem it is likely to get worse. And don’t accept no for an answer. There are also a lot of online tools available to help you with self-assessments and self-rehabilitation if you are that way inclined.

Kalron et al. The effect of balance training on postural control in people with multiple sclerosis using the CAREN virtual reality system: a pilot randomized controlled trial. J Neuroeng Rehabil. 2016 Mar 1;13:13. doi: 10.1186/s12984-016-0124-y.

Background: Multiple sclerosis (MS) is a multi-focal progressive disorder of the central nervous system often resulting in diverse clinical manifestations. Imbalance appears in most people with multiple sclerosis (PwMS). A popular balance training tool is virtual reality (VR) with several advantages including increased compliance and user satisfaction. Therefore, the aim of this pilot RCT (Trial registration number, date: ISRCTN14425615, 21/01/2016) was to examine the efficacy of a 6-week VR balance training program using the computer assisted rehabilitation environment (CAREN) system (Motek Medical BV, Amsterdam, Netherlands) on balance measures in PwMS. Results were compared with those of a conventional balance exercise group. Secondary aims included the impact of this program on the fear of falling.

Methods: Thirty-two PwMS were equally randomized into the VR intervention group or the control group. Each group received balance training sessions for 6 consecutive weeks, two sessions per week, 30 min sessions. Clinical balance tests and instrumented posturography outcome measures were collected upon initiation of the intervention programs and at termination.

Results: Final analysis included 30 patients (19 females, 11 males; mean age, (S.D.) = 45.2 (11.6) years; mean EDSS (S.D.) = 4.1 (1.3), mean disease duration (S.D.) = 11.0 (8.9) years). Both groups showed a main effect of time on the center of pressure (CoP) path length with eyes open (F = 5.278, P = .024), sway rate with eyes open (F = 5.852, P = .035), Functional Reach Test (F = 20.841, P = .001), Four Square Step Test (F = 9.011, P = .031) and the Fear of Falls self-reported questionnaire (F = 17.815, P = .023). In addition, significant differences in favor of the VR program were observed for the group x time interactions of the Functional Reach Test (F = 10.173, P = .009) and fear of falling (F = 6.710, P = .021).

Conclusions: We demonstrated that balance training based on the CAREN device is an effective method of balance training for PwMS.

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

Epidemic

Barts-MS rose-tinted-odometer: ★

Do you live in Scotland? Thes latest MS incidence (new cases) and prevalence (all cases) figures from the Scottish Highlands should make Scottish public health officials shiver.

In the Scottish Highlands, there are now over 18 people diagnosed with MS every year per 100,000 population with a total of 376 people with MS per 100,000 population. These figures may be artificially low as a lot of people born in the highlands may move away, for example to University or to work, and don’t get counted or included in these figures.

This is one of the highest, if not the highest, MS incidence rates in the world and about 30% higher than the figure from about a decade ago. This would indicate that we are still living through an MS epidemic and something needs to be done about it as urgently as possible.

What can be done? If MS is preventable the Scots should be setting-up and testing various MS prevention strategies to see if they can lower the incidence or at least stop its continual rise. This may be an opportune time to look into vitamin D prevention trials and campaigns to get first and second degree relatives to sign-up for more targeted MS prevention studies.

Francisco Javier Carod-Artal. The epidemiology of multiple sclerosis in the Scottish Highlands: Prevalence, incidence and time to confirmed diagnosis and treatment initiation. Mult Scler Relat Disord. 2020 Nov 28;47:102657.

Introduction: Although multiple sclerosis (MS) is frequent in the northern hemisphere, there have not been recent epidemiological studies in the Scottish Highlands about MS.

Objectives: To get updated data regarding MS prevalence, incidence and mortality in the Highlands. Time between symptom onset and MS diagnosis was also evaluated in incident MS cases and the pattern of use of disease-modifying therapies (DMTs) was analysed.

Methods: Study population was people with MS under the care of the Highland Health and Social Care Partnership. The catchment area included North area (Wick, Thurso, Brora, Invergordon), Center (Inverness, Aviemore, Nairn, Fort William), and West coast (Ullapool, Skye). Data were obtained from the MS database at Raigmore hospital (prevalence, midyear 2017) and the prospective hospital-register based study (diagnosis) that was carried out over a 12-month period, in 2016. The 2010 McDonald criteria for diagnosis of new MS cases were used. Crude prevalence and incidence and 95% confidence interval (CI) were calculated for the MS adult onset population, and data was standardised to the European standard population 2013; cause-specific mortality rate was analysed. Pattern of use of DMTs during the first year of diagnosis was also registered.

Results: 745 patients were registered in the MS database. 75.4% (562 cases) were females, and female/male ratio was 3:1. Mean age of population was 54.1 ± 14.1 years (range: 15-95 years). Mean number of years since diagnosis was 8.5 ± 4.6 years. Estimated prevalence for the population aged 15 and older was 376 cases per 100,000 inhabitants (95% CI: 354-399). 36 incident MS cases were registered in 2016 (88.8% females; mean age 40.4 ± 12.1 years). Annual incidence in Highlands was 18.2 per 100,000 inhabitants (95% CI: 14-24). The mean period of time from symptom onset to diagnosis was 38.8 ± 43.2 months. 47.2% (17/36) did not take any DMT during the first year after the diagnosis.

Conclusion: Prevalence and incidence of MS in the Scottish Highlands is high. Although the gap period between symptom onset and diagnosis is moderate, a significant proportion of recently diagnosed MS patients were not keen to start a DMT the first year after the diagnosis.

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

Bring back the experts

Barts-MS rose-tinted-odometer: ★★

“I think the people of this country have had enough of experts”, Michael Gove, June 2016.

Of the many positive things to come out of the COVID-19 pandemic and our response to it is the end of the era of denigrating the expert. Yes, expertise and in particular deep expertise really matters and that applies to the diagnosis and management of multiple sclerosis.

What is the difference between expertise and deep expertise? For example, I am registered by the General Medical Council in the UK as a neurologist and hence a medical expert in the practice of neurology. This means I can see, diagnose and manage anybody with a neurological problem. However, my sub-speciality is multiple sclerosis and related diseases (deep expertise). If you had a myopathy or a disease of muscles would really want me to be your treating neurologist. I suspect not; you would probably want to see a neurologist who specializes in muscle diseases. Although, I can quite easily read about the latest evidence and research into myopathies and give you an expert opinion, as I don’t have the day-to-day experience (deep expertise) in managing patients with myopathy you would not be given the best advice. Who knows if my self-directed rapid myopathy update would be good enough? Would I have enough insight and experience to only read the best most up-to-date evidence or would I be influenced by some whacky off-the-wall myologist (muscle expert)?

We need, more than ever, a serious pushback on ‘fake news sites’, ‘lobby groups with vested interests’, ‘social media groups without expert input’ and ‘anti-science movements with unsubstantiated conspiracy theories’ to name the most obvious.

We also need to understand and learn to live with and be comfortable with uncertainty. Yes, that means accepting that experts may disagree with each other. Science is not black-and-white and is usually grey and as more evidence emerges and innovations or ideas become adopted or accepted the colour or advice becomes closer to being black or white. Science and the acceptance of science take time.

This is where inspired leadership comes into play. In any field, there are leaders who have the necessary reputations and trust that people will follow their advice. These leaders are often good communicators and have the uncanny ability to provide a balanced view of the state of play when the evidence is not black-and-white and they can communicate uncertainty in a way that makes sense and is understandable to the general public. Dr Anthony Fauci, from the NIH, comes to mind with his level headed approach to the COVID-19 epidemic in the US. On the other hand, there are many examples of bad or poor leadership during this pandemic, which has resulted in squandering of political capital, confusion and lack of trust. I don’t think I need to give specific examples of poor leadership there are many obvious ones.

In the MS space, there is different advice being peddled by various groups about what to do about vaccinating people with MS on anti-CD20 therapies with the newly licensed or soon to be licensed coronavirus vaccines. I think there is broad consensus that a live replicating viral vaccine is a no-no in people on anti-CD20 therapies. However, this advice is irrelevant as the three coronavirus vaccines at the head of the queue are not live replicating virus vaccines. The Oxford-AstraZeneca vaccine uses a viral vector (chimpanzee adenovirus) to deliver the construct (nucleotide message) to express the immunogen, but it is a replication-deficient virus so is highly likely to be safe in people with MS on anti-CD20 therapies.

Another bit of misinformation that is doing the rounds is that these vaccines will trigger MS relapses. This is based on extrapolating data on two non-peer-reviewed cases of CNS demyelination in the Oxford-AstraZenca (Ox-AZ) trial and several cases of transverse myelitis in patients who have had COVID-19. One case on in the Ox-AZ trial, who received the vaccine, had an initial attack or relapse and was subsequently diagnosed as having MS; i.e. assume because they had pre-existing lesions and were now shown to have a second attack or new lesions consistent with dissemination in time. The other case had an episode of vaccine-related transverse myelitis (TM), which is relatively common with vaccines in general. Please note that vaccine-related TM is not MS. The only vaccine that has been reported to potentially trigger MS relapse is the live yellow-fever vaccine and this is based on one report that has subsequently not been replicated. Therefore, there is no current evidence that coronavirus infection or coronavirus vaccines trigger MS relapse. This in my opinion is not a reason to avoid having the coronavirus vaccine at present. This opinion may change if new data emerges to the contrary.

Another bit of grey advice that is being peddled as black or white is that people with MS (pwMS) on anti-CD20 therapy should delay their next infusion or miss one or two infusions to allow B-cell reconstitution before they have a coronavirus vaccine. What is the evidence for this? There is no definitive evidence. Yes, I agree that in general people on anti-CD20 therapies have blunted antibody responses to wild-type SARS-CoV-2 infection and to other vaccines including vaccines with so-called neoantigens or new antigens that the immune system has not seen before. However, this doesn’t mean these people haven’t developed immunity to the infection of vaccine that is long-lasting. For one the vast majority of pwMS on an anti-CD20 therapy who get COVID-19 make an uneventful recovery. Why? Almost certainly this recovery is due to cellular and not humoral (antibody) immunity. Do you then think this cellular immunity simply vanishes? Highly unlikely. Normal people who have COVID-19 and who lose their antibody responses still have cellular immunity. My interpretation of this data is that pwMS who are on an anti-CD20 therapy should simply go ahead and have the coronavirus vaccine when it is offered to them and not to worry about whether or not they mount an antibody response. Whilst this is happening companies like Roche-Genentech (ocrelizumab & rituximab) and Novartis (ofatumumab) or the wider MS community should be funding studies to look at both antibody and cellular immunity to the coronavirus vaccines in pwMS on these therapies so that we can develop an evidence base. The data collected as part of these studies will not only be relevant to SARS-CoV-2 infections and vaccines but other infections and future vaccines.

In my opinion, it is more important for pwMS to be vaccinated than to not be vaccinated. This is because vaccination policy is really about population, or subpopulation, health and stopping the spread of the virus and protecting the individual is a secondary aim. If you have MS and would rather wait for data to emerge on the safety and efficacy of the vaccine in the MS population it will take another 6 to 12 months, and maybe longer, and then the evidence if not collected prospectively as part of a well-controlled trial may not answer the questions you have. Also in 6-12 months, the pandemic is likely to be over and hence these questions may never get answered.

So my gut feeling based on scientific principles is that all pwMS should be vaccinated. If the initial roll-out of vaccines means the vaccines may be rationed I would argue we prioritise pwMS (1) over the age of 50, (2) those with significant comorbidities, (3) those on immunosuppressive therapies, in particular, those on anti-CD20 therapies and natalizumab and (4) those pwMS doing essential jobs with significant face-to-face contact with the general public (healthcare workers, care workers, teachers, etc.) to get the vaccine first.

Disclaimer: As I am not a public health or vaccine expert you need to interpret my advice with care.

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Do you smell like someone who has MS?

Barts-MS rose-tinted-odometer: ★★★★★

Did you know that because you have MS you are likely to have different odours on your breath compared to someone who doesn’t have MS? In other words, you have a characteristic MS smell.

Multiple sclerosis is usually referred to as a complex disease, i.e. it is caused by an interaction between genetic factors and the environment and bad luck. Some people have difficulty getting their heads around this relatively simple concept.

Now I want to take it one step further. MS must be a metabolic disease, i.e. MS must have a characteristic metabolic signature that differentiates it from other diseases and from ‘normality’. The reason I say this that metabolism is the great integrator of your genome and how your genes interact with the environment (microbiome, diet, season, stress, medications, etc.). If MS is a complex disease it must manifest metabolically with a unique profile.

If the MS metabolome has a characteristic metabolic signature and some of the metabolites are likely to be volatile and released in your breath, it may be possible to train a nose, either a dog’s nose or an electronic nose to detect the presence of this metabolic signature in your breath that can then be used to diagnose MS. Science fiction or not?

This may sound like science fiction but this approach is being evaluated in neurodegenerative diseases such as Parkinson’s disease and the data looks very compelling. I even know a few Parkinson’s disease experts who say they can smell if someone has Parkinson’s disease or not.

The MS study below, although a pilot, shows promising results. Using an eNose or electronic nose the investigators first taught an AI engine to what people with MS smell like. The taught AI engine, using a new cohort of study subjects, was then able to identify who has MS from healthy controls with a sensitivity of 0.75 or 75%, which to me is very good as a starting point. Imagine how this will improve as eNose technology improves and the AI engine is given more people with MS to smell and learn from.

I see a future when we use devices such as the eNose or metabolic profiling and artificial intelligence to identify people at risk of MS or with asymptomatic MS for MS prevention studies. Smell or eNose technology will become more sophisticated with time. I see a future when it will become mainstream and be part of the new healthcare environment we work in. Patients attending their GPs or an emergency department with a diagnostic problem will be sent for an eNose evaluation as part of the diagnostic work-up. This routine screening may open a window into the early detection of MS and other diseases. Watch this space!

Ettema et al. Detecting Multiple Sclerosis via breath analysis using an eNose, a pilot study. J Breath Res. 2020 Dec 3. doi: 10.1088/1752-7163/abd080. Online ahead of print.

Objective: In the present study we investigated whether Multiple Sclerosis (MS) can be detected via exhaled breath analysis using an electronic nose. The AeonoseTM (an electronic nose, The eNose Company, Zutphen, The Netherlands) is a diagnostic test device to detect patterns of volatile organic compounds in exhaled breath. We evaluated whether the AeonoseTM can make a distinction between the breath patterns of patients with MS and healthy control subjects.

Methods: In this mono-center, prospective, non-invasive study, 124 subjects with a confirmed diagnosis of MS and 129 control subjects each breathed into the AeonoseTM for 5 minutes. Exhaled breath data was used to train an artificial neural network (ANN) predictive model. To investigate the influence of medication intake we created a second predictive model with a subgroup of MS patients without medication prescribed for MS.

Results: The ANN model based on the entire dataset was able to distinguish MS patients from healthy controls with a sensitivity of 0.75 [95% CI: 0.66-0.82] and specificity of 0.60 [0.51-0.69]. The model created with the subgroup of MS patients not using medication and the healthy control subjects had a sensitivity of 0.93 [0.82-0.98] and a specificity of 0.74 [0.65-0.81].

Conclusion: The study showed that the AeonoseTM is able to make a distinction between MS patients and healthy control subjects, and could potentially provide a quick screening test to assist in diagnosing MS. Further research is needed to determine whether the AeonoseTM is able to differentiate new MS patients from subjects who will not get the diagnosis.

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CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#ThinkCognition: how precious is my brain?

Barts-MS rose-tinted-odometer: ★

As someone with MS do you worry about how you are going to cope with ageing and old age?

As MS shreds both your brain and cognitive reserve will MS bring forward and accelerate the ageing process and the time when you may develop neurodegenerative diseases such as Alzheimer’s disease? These are all hypotheses but are very relevant to people with MS (pwMS) and their families.

I recall how much stick I got from the MS community, including some very close colleagues when I tried to rebrand MS as a ‘preventable dementia’. The objective of the #ThinkCognition campaign was to make the MS community look beyond the blinkers of the EDSS and realise that MS was not only physical disabling but it was affecting cognition much earlier than people realised. For example, 40% of people already have significant cognitive impairment in at least two cognitive domains at the CIS (clinically-isolated syndrome) stage of their disease. If you go earlier to RIS (radiologically-isolated syndrome) or asymptomatic stage of the disease about a quarter of subjects have cognitive impairment. People with RIS and CIS are not aware of having cognitive impairment because the brain is able to compensate for the damage at an early stage.

In early MS cognitive impairment is more likely to cause cognitive fatigue and be associated with anxiety and depression than overt cognitive problems. The brain compensates for the damage by doing extra work, consuming more energy and getting tired more easily. Most people with MS realise they attention spans are often markedly reduced because of this phenomenon.

The reason why 50% of pwMS living in Europe are unemployed at an EDSS of 3.0 to 3.5 is not physical but cognitive disabilities. The #ThinkCognition campaign highlights the early hit the MS brain takes and makes the argument for effective early treatment to prevent dementia.

The problem with society’s view of dementia, i.e. of a little old lady with poor memory in a care home, is that it doesn’t easily translate to MS. What you have to remember is that dementia is a syndrome and MS is a well-known cause of dementia. The definition of dementia is that it is an acquired (not born with it), chronic (greater than 6 months), progressive condition (gets worse over time) that affects cognition in multiple domains (for example, problem-solving, processing speed, memory, speech, calculations, etc.) and impacts on the individuals occupational and social functioning. I would challenge anyone to say that worsening MS-related cognitive impairment fulfil this definition of dementia. The good news is that dementia associated with MS is preventable, i.e. if you treat MS early and effectively you will stop the end-organ damage and prevent the consequences of MS on longterm cognitive functioning.

Now the question about bringing forward ageing and the presentation of other neurodegenerative diseases is an open question. Below is a case report of an elderly woman with MS who presents with memory loss and a workup showed a pattern of cognitive decline that was more in keeping with Alzheimer’s disease than MS. She then goes onto to have diagnostic amyloid and is diagnosed as having Alzheimer’s disease. One could argue if she didn’t have MS this may have protected her from getting Alzheimer’s disease or at least delayed its onset by several years.

It is important to stress that the type of cognitive impairment associated with MS is very different to that of classic or amnestic Alzheimer’s disease and well-done neuropsychological tests should be able to differentiate the two conditions (see pilot study below). Saying that I have a handful of patients with ‘cognitive MS’ who have taken a massive hit on their ability to store and process short term memory because in their case MS has affected the temporal lobes and their connecting structures that are critical for memory.

Other issues that the #ThinkCognition campaign addresses are (1) the need to be able to identify relapses as being purely cognitive, (2) using cognitive impairment to say that patients with RIS have CIS or MS so they can be treated, (3) using a change in cognition to define worsening MS or progressive disease, (4) incorporating cognition into our treatment target in MS, (5) including cognitive screening or testing as part of the annual MS assessment and (6) including cognition in our longterm treatment goal of maximising brain health for the life of the pwMS.

I want to point out that none of the points I make in this post is necessarily accepted by the wider MS community and many of the points remain controversial, which is why I would encourage a debate around these issues. What I can tell you, however, if I had MS I would want my neurologist and MS team to treat me as if my brain was the most precious thing on planet earth; I would want them to protect my cognition and make it their number one objective. I suspect this is easier said than done.

Progressive brain volume loss or atrophy in a pwMS over 18 months

Jakimovski et al. Differential Diagnosis of Cognitive Decline in Elderly Individuals With Multiple Sclerosis. Cogn Behav Neurol. 2020 Dec;33(4):294-300.

Due to increasingly improved disability outcomes, and the resultant significantly improved life span, of the multiple sclerosis (MS) population, questions regarding cognitive aging and the prevalence of comorbid Alzheimer disease (AD) have emerged. We describe neuropsychological and MRI-based changes that occurred in an 84-year-old MS patient with comorbid amnestic mild cognitive impairment (a precursor to AD) and cerebrovascular pathology. The neuropsychological examination demonstrated impairment in cognitive processing speed as well as in verbal and visual memory-domains that are potentially affected by any, or all, of the three co-existing diseases. Amyloid-based PET imaging showed increased focal uptake within the gray matter of the occipital lobe. We highlight how these clinical and radiologic observations can inform future research that could elucidate interactions between MS, a probable AD diagnosis, and cerebrovascular pathology in elderly individuals with MS. A comprehensive neuropsychological examination of multiple cognitive domains of individuals with MS may aid in the differential diagnosis of late-in-life cognitive decline.

Roy et al. Preliminary investigation of cognitive function in aged multiple sclerosis patients: Challenges in detecting comorbid Alzheimer’s disease. Mult Scler Relat Disord. 2018 May;22:52-56.

Background: Cognitive impairment can be seen in patients of all ages with multiple sclerosis (MS). However, there is limited research on neurocognitive disorder in older adults with MS and how to detect Alzheimer’s disease (AD) or its prodromal stage, amnestic mild cognitive impairment (aMCI). Thus, the MS clinician is challenged to discriminate between signs of MS-related cognitive decline versus a secondary neurodegenerative process.

Objective: Compare cognition in older MS patients to patients with AD and aMCI.

Methods: We evaluated cognitively impaired and unimpaired MS patients, AD patients, aMCI patients, and healthy controls (HCs), all elderly (n = 20 per group). AD and aMCI diagnoses were derived by consensus conference independent of the MS research project. Neuropsychological measures assessed domains commonly affected in AD, including verbal memory and expressive language.

Results: Cognitively impaired and unimpaired MS groups did not differ on any measures sensitive to AD. Unimpaired MS patients were comparable to HCs. Impaired MS patients showed decreased semantic fluency, similar to aMCI patients. Lastly, while both AD and aMCI groups had deficient memory retention, there was no evidence of a retention deficit in either MS group.

Conclusion: Our findings suggest that the cognitive profiles of MS and AD are distinct. In contrast to AD, MS is not associated with impairment of memory consolidation. However, there may be overlap between cognitive deficits related to MS and aMCI. Thus, evidence of poor memory retention, in an older MS patient may merit comprehensive dementia evaluation. The study is preliminary and includes no AD biomarkers (e.g., amyloid imaging) to confirm or rule out AD pathology.

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Twitter: @gavinGiovannoni Medium: @gavin_24211

December blues

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

How are you feeling today? Are you depressed? Do you know what symptoms of depression to look for?

When my first patient with MS committed suicide it came as a real shock to me. He was a very likeable 32-year old man with secondary progressive MS. I used to see him at least once a year. I would go out into the waiting area of outpatients and call his name, he would insist on pushing himself into my consulting room in his wheelchair. He was angry and always very impatient when I insisted on going through the usual list of questions about his bladder, bowel and sexual dysfunction, falls, sleep, spasms, mood etc. When I go to the question about his mood he would always answer me with a question; how would I feel if I was in his position? It was his way of saying, yes, I am depressed what do you expect. He was impatient and was always pushing to get to the stage in the consultation when he could ask me questions about all the things he had been researching on the web.

Can I try this treatment? Is there anything I would recommend to help remyelinate his damage nerves, What do I think of turmeric? Why can’t I have a stem cell transplant? What did I think of very high-dose vitamin D therapy? What about rejuvenation therapy? Why am I not eligible for natalizumab? Are there any trials I can participate in? The questions would come at me like a machine gun firing bullets. What I didn’t realise at the time is that this was his way of trying to find some glimmer of hope in the MS research pipeline; something to give him hope for the future. He was well-read and intelligent enough to know that progressive MS at the time was a one-way street and MS had cost him all of the things he cherished; i.e. his ability to play sport and work, his girlfriend, his friends and more recently his ability to live independently. He had had to move back into his childhood home with his ageing parents for financial reasons. As his life contracted around him he had become increasingly isolated; he had stopped seeing his friends and would rarely go out.

In retrospect, I should not have been surprised to receive an email from his father to say that their son had been found dead in bed with a suicide note. Cause of death suffocation. In the suicide note, he had specifically asked for his remaining savings, just over £9,000, to be donated towards MS research. I suggested to his father that it would be best to donate the money to the MS Society. Unlike Professor Tom Bothwell*, one of my early mentors, who would often attend the funeral of his patients I didn’t go to his funeral despite being invited. One of my regrets; I had let him down both in life and now in death.

This patient taught me that it doesn’t matter how disabled a patient with MS is it is important to be positive and to spread hope. I am not talking about creating false expectations but giving them realistic examples of things that can be done to improve their quality of life and outcome. The latter may be in relation to the latest or future MS research or simple advice about what can be done to improve their day-to-day functioning. Involving patients like this in helping others, in doing research, provides them with a purpose. Don’t underestimate the power of being respected and being wanted. Having self-worth makes life worth living. This is one of the reasons I have become so interested in social capital, the social determinants of health and marginal gains; there is always something you can do to improve the quality of life of someone with MS. Do you agree? This is why we at Barts-MS want to expand our service to provide so much more than neurological support for the patients under our care.

It is clear that mood is a spectrum and it can be quite normal to feel low compared to other times. However, when low mood starts to impact on your ability to function in the home environment (relationships, domestic chores, self-care, etc.), at work (underperforming, missing work, etc.), or socially (avoiding going out or not interacting with family and friends) or you start to have negative and intrusive thoughts about your self-worth and possibly suicidal thoughts, low-mood becomes pathological and you need help.

Depression also impacts how your body functions and causes the so-called vegetative symptoms of depression that could also indicate that you are depressed; these include weight loss and loss of appetite or the opposite of weight gain and increased appetite, insomnia or excessive sleepiness, fatigue, low energy levels, poor concentration and inattention. So if you have noticed a change in any of these ask yourself whether or not you are depressed.

It is important to realise that depression is very common in people with MS (pwMS); the lifetime prevalence of major depression in pwMS is 40-50%. There are many reasons why pwMS get depressed. Depression can be a reactive depression in relation to the emotional response to the diagnosis of MS, losing your job, getting divorced or been told you have progressive disease. However, it can be due to the effects the disease has on the brain. It is important to know that pwMS who are depressed have a much worse outcome in terms of disability progression. I suspect it is not necessarily depression that causes MS to progress or worsen more quickly, but the damage to the brain that causes a worse MS outcome also causes depression. I suspect MS damages the circuits and neuronal networks that lead to depression.

**Kaplan-Meier estimates of age at EDSS score milestones**: Kaplan-Meier estimates of age at Expanded Disability Status Scale (EDSS) score milestones 3.0 (A and B), 4.0 (C and D), and 6.0 (E and F) stratified by depression diagnosis (A, C, and E) and exposure to antidepressants (B, D, and F). Image from Neurology.

There are many effective ways to treat MS-related depression so don’t suffer in silence. If you are depressed please speak-up contact your HCP and ask for help.

Please note that depression and the definition of depression are cultural. Some societies don’t even have a word to describe depression and hence depression in these cultures usually manifest with other systemic complaints such as fatigue, tiredness, poor concentration, insomnia, pain and reduced cognition. So if you are not sure about being depressed you can always complete one of the many online depression screening tools. I would recommend the HAD (hospital anxiety and depression) scale, which has been well validated in pwMS.

I would be interested to know if you are asked about mood when you have your annual MS follow-up appointment and if you have any advice to give your peers who may be depressed.

* To read about Prof Tom Bothwell please read my Medium post ‘Emulating your Mentor‘.

Binzer et al. Disability worsening among persons with multiple sclerosis and depression: A Swedish cohort study. Neurology. 2019 Dec 10;93(24):e2216-e2223. doi: 10.1212/WNL.0000000000008617. Epub 2019 Nov 8.

Objective: Depression is common in multiple sclerosis (MS), but its impact on disability worsening has not yet been determined. We explored the risk of disability worsening associated with depression in a nationwide longitudinal cohort.

Methods: This retrospective cohort study used linked data from 3 Swedish nationwide registries: the MS Register, National Patient Register, and Prescribed Drug Register. Two incident cohorts were developed: cohort 1 included all registered cases of MS in the MS Registry (2001-2014) with depression defined as ≥1 ICD-10 code for depression; and cohort 2 comprised all cases of MS in the MS Registry (2005-2014) with depression defined as ≥1 prescription filled for an antidepressant. Cox regression models were used to compare the risk of reaching sustained disability milestone scores of 3.0, 4.0, and 6.0 on the Expanded Disability Status Scale (EDSS) between persons with MS with and without depression.

Results: Cohort 1 included 5,875 cases; 502 (8.5%) had depression. Cohort 2 had 3,817 cases; 1,289 (33.8%) were prescribed an antidepressant. Persons with depression were at a significantly higher risk of reaching sustained EDSS scores of 3.0, 4.0, and 6.0, with hazard ratios of 1.50 (95% confidence interval [CI] 1.20-1.87), 1.79 (95% CI 1.40-2.29), and 1.89 (95% CI 1.38-2.57), respectively. A similar increased risk among persons exposed to antidepressants was observed, with hazard ratios of 1.37 (95% CI 1.18-1.60), 1.93 (95% CI 1.61-2.31), and 1.86 (95% CI 1.45-2.40) for sustained EDSS scores of 3.0, 4.0, and 6.0, respectively.

Conclusion: Persons with MS and comorbid depression had a significantly increased risk of disability worsening. This finding highlights the need for early recognition and appropriate treatment of depression in persons with MS.

CoI: multiple

Twitter: @gavinGiovannoni

Medium: @gavin_24211