#ThinkCognition

Am I cognitively impaired?

Barts-MS rose-tinted-odometer: ★★

Last Wednesday I chaired a debate about the following case scenario, who many of you may identify as being very close to home. Professor Dawn Langdon, a neuropsychologist, made the case for testing cognition against Professor Nikos Evangelou, a neurologist, who said no we should not assess this patient’s cognition.

What would you want if this patient was you?

A 48-year commercial solicitor with early secondary progressive MS is having increasing problems coping at work due to cognitive issues. He is worried that he may have to stop working. He has had MS for 16 years and was originally treated with interferon-beta and was subsequently switched to DMF 5 years ago because of local tolerance issues around injection site reactions and severe lipoatrophy. Although his last MS relapse was more than 10 years ago, his neurological functioning has deteriorated over the last three to four years with reduced mobility, bladder and bowel problems and sexual dysfunction. He has also been depressed. He is currently on oxybutynin, sildenafil and citalopram in addition to DMF. His most recent MRI showed three new T2 lesions and increased brain volume loss compared to his last MRI done 18 months ago.

Would it help in the management of this patient if you knew he was cognitively impaired; i.e. would you refer this patient for a formal neuropsychological assessment?

Although Professor Evangelou won the debate, i.e. he swung the vote from 13% to 28% in his favour, the majority of attendees wanted this patient to have a formal cognitive assessment. Do you agree?

The cognitive assessment should simply be an extension of the neurological examination, i.e. another functional system. In other words just as we like to know if our patients have weakness in a limb we need to know if they have cognitive impairment in one of their cognitive domains. This can help in so many ways.

Prognostically, poor cognition predicts a poorer outcome. Knowing someone has a poor prognosis may nudge both the neurologist and/or patient to a higher efficacy therapy, i.e. to flip the pyramid.
Assessing disease activity, i.e. worsening disability or cognitive relapse. This could trigger a treatment switch, for example in the patient above Prof. Evangelou suggested switching this patient onto siponimod.
Helping in diagnosis, i.e. dissemination in space. Cognition is another anatomical space and it may provide the neurologist with additional information.
Diagnosing MS in patients with RIS (radiologically isolated syndrome); cognitive impairment demonstrates they have involvement of at least one functional system and if the MRI shows dissemination in time diagnosis could change from RIS to MS and the patient could be then started on treatment.
Risk assessment; patients with cognitive impairment are at higher risk of having accidents, in particular, motor vehicle accidents, poor adherence to medication, missing medical and other appointments and not being able to cope with their own self-care. It is well known that MS patients with cognitive impairment often need help with their financial affairs.
Targeted treatment; for example, referral for cognitive rehabilitation and the use of cognition aids.
Review of medication; i.e. stopping or switching medications that may exacerbate cognitive impairment. For example, this patient needed his oxybutynin stopped or changed to a non-CNS penetrant anticholinergic (trospium) or to a new class of treatment (mirabegron). Many of the symptomatic medications we use exacerbates or worsen cognition.
Screening for depression and anxiety; patients with MS who are cognitively impaired may have comorbid depression and anxiety that may be exacerbating their poor cognition.
Medical retirement; knowing someone with MS has cognitive impairment may help make the case for medical retirement. Prof Langdon pointed out that cognitive impairment is a common cause for pwMS for underperforming at work. Instead of them being let go, or fired, knowing they have cognitive impairment may protect them under employment law.
Social services; knowing someone with MS is cognitive impaired can help make the case for extra or specific social services and support.

These are just a few examples of why it is important to assess cognitive impairment in routine MS practice. If you can come up with any more reasons please let me know.

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.

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

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

What is advanced MS?

Barts-MS rose-tinted-odometer – zero stars

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CoI: multiple

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

Barts-MS rose-tinted-odometer – zero stars

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CoI: multiple

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