cognitive impairment – Prof G's MS Blog Archive

Swiss-cheese

Barts-MS rose-tinted-odometer: zero-stars

What do you say when I colleague chastises you for stating the fact that MS is potentially a ‘preventable dementia’? This particular colleague was clear that there is no need to draw any parallels between MS and other neurodegenerative diseases because of the negative connations that the term dementia has. I had to remind him that MS ticks all the boxes for being classified as a dementia; i.e. (1) MS is an acquired and not a congenital disorder; (2) MS is a chronic progressive disease; (3) MS impacts on multiple cognitive domains and (4) MS impacts on social and occupational functioning. Have I missed something?

I also had to remind this colleague that almost every neurology or psychiatry textbook included MS on its list of causes of dementia. I am not prepared to peddle alternative facts because pwMS may find it distressing to find out that if MS is left to its own devices it will shred their brains and cause dementia. Please note the rose-tinted-odometer is set to zero for this post.

The small study below reiterates what we already know that both relapsing and progressive patients have cognitive problems that correlate with physical disability. This study also confirms that T1 hypodensities or blackholes on MRI, particular in the thalamus (a deep grey matter structure in the brain) predicts cognition problems. T1 hypodense MS lesions or black holes, or at least a proportion of them, have been shown to be very destructive and include lesions with so-called phase-rims (iron around them) and a subset we call SELs (slowly expanding lesions). Some neuroradiologists often describe an MS brain with a high volume of black holes as being similar to Swiss cheese in reference to Emmental cheese.

Now for the good news is that these studies below are on patients with significant end-organ damage and if we can diagnose and treat MS effectively early on we can prevent or at least delay the end-organ damage and the progressive loss of cognition. This is why we have spent years promoting the concepts of ‘Time-is-Brain’, ‘Treat-2-Target of NEDA’, ‘Rapid escalation’, ‘Flipping-the-Pyramid’, ‘Brain Health’, ‘Beyond-NEDA preventing end-organ damage’, ‘Holistic Management’, ‘Marginal Gains’, etc. Buried in all of these concepts is the use of effective DMTs to prevent end-organ damage and to prevent dementia.

I am very pleased that my pwMS in Australia have taken this one step further and launched their own awareness campaign, albeit sponsored by Biogen, to raise awareness about early effective treatment (www.msmotion.com.au). The campaign is been run by a group of MS social media influencers. I met them all virtually last year and spoke to them about the concepts that underpin our ‘Brain Health: Time Matters’ policy document. It would be great if pwMS across the world could do a similar thing.

Do you agree with my colleague above that we should try and protect pwMS from the harsh realities of MS and what can happen to their brains if we don’t manage their MS appropriately? Or should we peddle false facts and a rose-tinted view of the world?

de Paula Gois et al. Associations between cognitive and clinical disability across MS subtypes: The role of the underlying brain damage. Mult Scler Relat Disord. 2020 Dec 19;48:102701.

Background: Cognitive impairment (CI) is present in all stages and subtypes of multiple sclerosis (MS). However, the majority of studies examined relapsing-remitting (RRMS) patients, and did not address cognitive phenotyping. Is still not clear whether patients with progressive MS (PMS) have a distinct pattern of CI compared to RRMS. In addition, there is conflicting data regarding the correlation between clinical and cognitive disability.

Objective: To investigate the differences of CI between PMS and RRMS patients, evaluating cognitive phenotypes. We also aimed to analyze the association between physical and cognitive disability with MRI measures of grey-matter atrophy and lesion burden.

Methods: Thirty patients with PMS and twenty-four with RRMS underwent neurological, neuropsychological (BRB-N, Boston Naming, and Tower of London), and MRI assessments (3T). Brain volume evaluations were performed using FreeSurfer. Principal Components Analysis on neuropsychological yielded six principal cognitive domains. Cognitive deficits were classified according to three categories: no CI, impairment in isolated cognitive domain, or impairment in combined domains.

Results: In the overall sample, the most frequently impaired cognitive domains were information processing speed (IPS) and visual memory. PMS patients had a higher prevalence of verbal memory and verbal fluency deficits, and more frequent impairment in combined cognitive domains compared to RRMS individuals. After multivariable regression analysis with clinical variables, EDSS was associated with most cognitive domains. Nevertheless, after including T1-lesion volume in the model, it was the most consistent predictor of cognitive performance. To further analyze the interaction between EDSS and T1-lesions, we performed GLM analysis with EDSS and T1-hypointense lesion volume as covariates, and T1-lesion volume adjusted better the model for verbal memory (p = 0.013), IPS (p = 0.021) and total number of impaired cognitive domains (p = 0.021).

Conclusions: RRMS and PMS patients tend to have a similar neuropsychological profile in general, but the extent of CI was greater in PMS patients. Worse cognitive performance was associated with increased physical disability, but this correlation was no longer significant after controlling for T1-lesion volume, suggesting that the underlying MS pathology might be involved in this relationship. Thalamic and T1-lesion volumes were the most consistent MRI predictors associated with cognitive disability.

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

Grey matter, matters

How big is your grey matter iceberg?

As you are aware, MS is an iceberg, with most of the MS disease activity and resultant damage being hidden. The study below expands the concept of the MS iceberg to the cerebral cortex or grey matter. Most lesions (~80%) found at post-mortem in the grey matter are not detected using specialised MR imaging. Please note that post-mortem MRI imaging in more standardised than that which happens in clinical practice and I suspect even more lesions will be missed in real-life.

Is this study important? You bet. We know that these grey matter lesions are associated with cognitive impairment, loss of brain volume and in particular progressive grey matter atrophy and are associated with poor longterm outcome and reduced quality of life.

Do you want to know what your true MS disease burden is? Based on this data and other studies it looks as if MRI is not the best way of doing this. I suspect a better marker will be ‘deep phenotyping’, i.e. interrogating the function of your nervous system using stress tests to see how you perform. Knowing you have cognitive impairments, for example, slow cognitive reaction times, difficulty with concentration and attention, poor memory or other specific deficits may be more meaningful to you. Or not? I say ‘or not’ as not all pwMS want to know that have cognitive impairment; they argue if nothing can be done about it is best to ignore it. This is called the ‘ostrich syndrome’.

Knowing you have cognitive deficits will allow you to take specific actions to address the problem and to potentially make important real-life decisions about your future. It also allows your HCP to take action to address some medical issues that are linked to cognitive impairment, i.e. poor adherence to treatments, physical accidents and comorbid depression and anxiety to name a few. One could argue that pwMS who have cognitive impairment should be put on a high-risk register for more proactive management and care.

It is clear that the burden of MS is not only physical but cognitive as well. This is another reason to diagnose, treat and manage MS effectively and as early as possible to prevent end-organ damage and preserve your grey matter. Can I please remind you that no all DMTs are made equal when it comes to preserving brain volume or grey matter.

This post reminds me of an infographic I put together about 5 years ago called ‘Grey Matter, Matters’, which I used to support a campaign I started to redefine MS as a ‘preventable dementia’.

Do you agree with me?

Piet M Bouman et al. Histopathology-validated recommendations for cortical lesion imaging in multiple sclerosis. Brain. 2020 Aug 21;awaa233. doi: 10.1093/brain/awaa233.

Cortical demyelinating lesions are clinically important in multiple sclerosis, but notoriously difficult to visualize with MRI. At clinical field strengths, double inversion recovery MRI is most sensitive, but still only detects 18% of all histopathologically validated cortical lesions. More recently, phase-sensitive inversion recovery was suggested to have a higher sensitivity than double inversion recovery, although this claim was not histopathologically validated. Therefore, this retrospective study aimed to provide clarity on this matter by identifying which MRI sequence best detects histopathologically-validated cortical lesions at clinical field strength, by comparing sensitivity and specificity of the thus far most commonly used MRI sequences, which are T2, fluid-attenuated inversion recovery (FLAIR), double inversion recovery and phase-sensitive inversion recovery. Post-mortem MRI was performed on non-fixed coronal hemispheric brain slices of 23 patients with progressive multiple sclerosis directly after autopsy, at 3 T, using T1 and proton-density/T2-weighted, as well as FLAIR, double inversion recovery and phase-sensitive inversion recovery sequences. A total of 93 cortical tissue blocks were sampled from these slices. Blinded to histopathology, all MRI sequences were consensus scored for cortical lesions. Subsequently, tissue samples were stained for proteolipid protein (myelin) and scored for cortical lesion types I-IV (mixed grey matter/white matter, intracortical, subpial and cortex-spanning lesions, respectively). MRI scores were compared to histopathological scores to calculate sensitivity and specificity per sequence. Next, a retrospective (unblinded) scoring was performed to explore maximum scoring potential per sequence. Histopathologically, 224 cortical lesions were detected, of which the majority were subpial. In a mixed model, sensitivity of T1, proton-density/T2, FLAIR, double inversion recovery and phase-sensitive inversion recovery was 8.9%, 5.4%, 5.4%, 22.8% and 23.7%, respectively (20, 12, 12, 51 and 53 cortical lesions). Specificity of the prospective scoring was 80.0%, 75.0%, 80.0%, 91.1% and 88.3%. Sensitivity and specificity did not significantly differ between double inversion recovery and phase-sensitive inversion recovery, while phase-sensitive inversion recovery identified more lesions than double inversion recovery upon retrospective analysis (126 versus 95; P < 0.001). We conclude that, at 3 T, double inversion recovery and phase-sensitive inversion recovery sequences outperform conventional sequences T1, proton-density/T2 and FLAIR. While their overall sensitivity does not exceed 25%, double inversion recovery and phase-sensitive inversion recovery are highly pathologically specific when using existing scoring criteria and their use is recommended for optimal cortical lesion assessment in multiple sclerosis.

Keywords: cortical lesions; double inversion recovery; multiple sclerosis; phase-sensitive inversion recovery; post-mortem imaging.

CoI: multiple

You don’t have to lose your marbles by taking a statin

Barts-MS rose-tinted-odometer ★★★★★

As you know high-dose simvastatin 80-mg per day is being tested in a phase 3 trial in the UK (MS-STAT2). I have referred several patients to participate in this study. Despite this, there has always been a worry about this treatment strategy because statins have been associated with changes in cognition, which is why I have always said that if I needed a statin I would take one that was non-CNS penetrant, for example, pravastatin.

The publication below is reassuring in that it shows that statin therapy in a population of elderly Australians was not associated with any greater decline in memory or cognition over 6 years compared to non-statin users. In fact, statin usage actually attenuated the decline in specific memory test performance in participants with heart disease and the genetic dementia risk factor apolipoprotein Eε4.

You may ask what has this got to do with MS? I think a lot. One of the theories of delayed or late worsening in MS is related to early ageing mechanisms. This is why it will become important in the future to tackle ageing as a potential add-on treatment for MS (please see my previous blog post, ageing, on this topic).

Samaras et al. Effects of Statins on Memory, Cognition, and Brain Volume in the Elderly. Journal of the American College of Cardiology, Volume 74, Issue 21, November 2019 DOI: 10.1016/j.jacc.2019.09.041

Background: There is widespread consumer concern that statin use may be associated with impaired memory and cognitive decline.

Objectives: This study sought to examine the association between statin use and changes in memory and global cognition in the elderly population over 6 years and brain volumes over 2 years. Interactions between statin use and known dementia risk factors were examined.

Methods: Prospective observational study of community-dwelling elderly Australians age 70 to 90 years (the MAS [Sydney Memory and Ageing Study], n = 1,037). Outcome measures were memory and global cognition (by neuropsychological testing every 2 years) and total brain, hippocampal and parahippocampal volumes (by magnetic resonance) in a subgroup (n = 526). Analyses applied linear mixed modeling, including the covariates of age, sex, education, body mass index, heart disease, diabetes, hypertension, stroke, smoking, and apolipoprotein Eε4 carriage. Interactions were sought between statin use and dementia risk factors.

Results: Over 6 years there was no difference in the rate of decline in memory or global cognition between statin users and never users. Statin initiation during the observation period was associated with blunting the rate of memory decline. Exploratory analyses found statin use was associated with attenuated decline in specific memory test performance in participants with heart disease and apolipoprotein Eε4 carriage. There was no difference in brain volume changes between statin users and never users.

Conclusions: In community-dwelling elderly Australians, statin therapy was not associated with any greater decline in memory or cognition over 6 years. These data are reassuring for consumers concerned about statin use and risk of memory decline.

CoI: multiple

Chicken or Egg?

Rose-tinted-odometer = ★

Brain Health is a major theme of this blog. Why?

We think that to ‘maximise brain health for the life of a person with MS (pwMS)’ we need to manage MS actively and holistically and promote brain-healthy behaviours. The ‘we’ here is not only HCPs but you and society, which includes regulators, politicians, educationalists, pharma, etc.

Another thing that people don’t get is that ‘life is a sexually-transmitted age-dependent neurodegenerative disease’ and that if we live long enough our nervous system fails. As MS reduces our reserve, by shredding axons, synapses and causing neuronal loss it brings age-dependent neurodegeneration forward.

Early ageing and MS worsening overlap and we face a big challenge separating progressive MS from premature ageing. This is why when people state that treatment X, for example, HSCT, halts progression they are exposing their naivety and lack of understanding of MS. HSCT is not anti-ageing and hence that component of MS worsening can’t be altered. In the case of HSCT, it may hasten the ageing process as some of the chemotherapy agents used as part of HSCT are neurotoxic.

HSCT supporters will typically point to the amazing EDSS data showing disease stabilisation and in some cases improvement. But MS is more than lower limb function and walking. What needs to be presented are multi-domain outcomes across multiple functional systems, in particular, cognition. MS is first and foremost a ‘preventable dementia’ and hence we need to monitor cognition over time and see what our treatments are doing to cognition.

The study below relates to ‘normal ageing’ but may be relevant to pwMS. It shows that playing analogue or board games reduces age-related cognitive decline. I suspect, based on the cognitive reserve hypothesis, these findings will apply to pwMS as well. Do you play board games? If you do you it may delay or slow down MS-related cognitive decline. Who would have thought of playing Monopoly as a potential DMT in MS?

Altschul & Deary. Playing Analog Games Is Associated With Reduced Declines in Cognitive Function: A 68-Year Longitudinal Cohort Study. The Journals of Gerontology: Series B, gbz149. Published 18-Nov-2019.

Objectives: Playing analog games may be associated with better cognitive function but, to date, these studies have not had extensive longitudinal follow-up. Our goal was to examine the association between playing games and change in cognitive function from age 11 to age 70, and from age 70 to 79.

Method: Participants were 1,091 non-clinical, independent, community-dwelling individuals all born in 1936 and residing in Scotland. General cognitive function was assessed at ages 11 and 70, and hierarchical domains were assessed at ages 70, 73, 76, and 79 using a comprehensive cognitive battery of 14 tests. Games playing behaviors were assessed at ages 70 and 76. All models controlled for early life cognitive function, education, social class, sex, activity levels, and health issues. All analyses were preregistered.

Results: Higher frequency of playing games was associated with higher cognitive function at age 70, controlling for age 11 cognitive function, and the majority of this association could not be explained by control variables. Playing more games was also associated with less general cognitive decline from age 70 to age 79, and in particularly, less decline in memory ability. Increased games playing between 70 and 76 was associated with less decline in cognitive speed.

Discussion: Playing games were associated with less relative cognitive decline from age 11 to age 70, and less cognitive decline from age 70 to 79. Controlling for age 11 cognitive function and other confounders, these findings suggest that playing more games is linked to reduced lifetime decline in cognitive function.

CoI: none

My prevention hat

About three years ago I started wearing another hat; a preventive medicine hat.

We started the Preventive Neurology Unit within our medical school focusing on MS, Parkison’s Disease and all-cause dementia. The unit is growing rapidly and gaining momentum. It was with great pride that I was able to attend and speak at first symposium. I have uploaded my slides for anyone who wants to download them for personal use.

It is clear that we have an obligation to the next generation of pwMS. The study below shows that young people with MS take a massive cognitive hit. The study shows that at a presentation about a quarter of young people with MS have cognitive impairment at baseline and ~15% had a measurable decline over the next 2 years. In a world where our self-worth is largely defined by our cognition, these figures are scary. The observation that MS is a dementing disease is not new and goes back many decades.

The willingness of the MS community to accept this is worrying; they say calling MS a dementing disease is stigmatising. Yes and no. Yes, if you want to put your head in the sand and no if you want the MS community to do something about it. It is clear that the dementia is preventable; i.e. the less brain damage that you allow to accumulate the less cognitively impaired the pwMS will become. This is the message behind our treat-early treat-effectively campaign and why we need to flip the pyramid. Access to the most effective treatments early on is the only way to really prevent end-organ damage.

More importantly, is the observation that MS is preventable. We estimate that by tackling childhood and adolescent obesity and smoking may reduce the incidence of my MS by ~25%. Vitamin D supplementation may reduce the incidence by a further 40%. Preventing EBV infection with a vaccine strategy may prevent the majority of people developing MS. May be admitting how bad MS is at a personal and population-level will get funders to put more money and resources into prevention.

I think we should call a spade a spade and forget the rose-tinted world most people like to live in. We need to take MS prevention seriously; we owe it the next generation of people who are destined to develop MS. Wouldn’t it be nice if they didn’t get MS?

Wallach et al. Cognitive processing speed in pediatric-onset multiple sclerosis: Baseline characteristics of impairment and prediction of decline. Mult Scler. 2019 Nov 28:1352458519891984.

BACKGROUND: Cognitive impairment occurs in approximately one-third of pediatric-onset multiple sclerosis (POMS) patients. The Symbol Digit Modalities Test (SDMT), a widely used cognitive screen in adults, has yet to be incorporated early into the standard care of POMS.

OBJECTIVE: To screen for cognitive impairment early in the course of POMS and analyze predictive factors.

METHODS: Of the 955 POMS or clinically isolated syndrome (CIS) patients prospectively assessed from March 2014 to July 2018, 500 POMS and 116 CIS patients met inclusion criteria (disease onset before the age of 18, one or more SDMTs, and 8 years or older at the time of testing). Those with relapse were analyzed separately from those who were relapse-free.

RESULTS: At initial assessment, the mean (interquartile range (IQR)) age at symptom onset was 13.5 years (12.0, 15.9) and the mean (±SD) disease duration was 3.0 ± 2.9 years. Impaired processing speed occurred in 23.4% of POMS and in 16.4% of CIS. On serial testing (n = 383, mean follow-up: 1.8 years), 14.1% had clinically meaningful decline predicted by older age of multiple sclerosis (MS) onset and male gender. Disease relapse or steroid use led to transient worsening on the SDMT.

CONCLUSION: Early in the disease, some POMS and CIS patients are at risk for cognitive impairment and subsequent decline.

CoI: multiple

#ThinkCognition

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

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

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

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

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

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

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

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

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

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

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

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

CoI: multiple

Old age; how is it going to affect me?

Is ageing a disease? It is if you have MS.

We have been making the argument for moving our treatment target in MS to focus on old age; i.e. how do we your HCPs get you to old age with enough brain to deal with the ravages of age-related cognitive impairment?

It is clear that your brain and cognitive reserves are what protects you from the ‘normal age-related neuronal drop-out’, which occurs as part of normal life. We know that MS shreds both brain (size) and cognitive (synapses) reserve and hence it should bring forward age-related cognitive impairment in MSers. The latter was a hypothesis, but the study below shows it is not necessarily a hypothesis anymore. In summary, older MSers are more likely to be cognitively impaired (77%) compared to younger MSers (43%). The challenge is to prevent this. How? Early effective treatment to stop the shredder and to make sure we tackle smouldering MS.

Do you need any more evidence? Please ask your neurologist if you have NEDA is there any evidence of smouldering MS? He/She may want to know what smouldering MS is. You can then tell them it is what is happening at the bottom of the treatment pyramid that is out of sight of our routine monitoring. This is the reason why you need to self-monitor and if you are getting worse you need to ask what can be done about it.

Branco et al. Aging with multiple sclerosis: prevalence and profile of cognitive impairment. Neurol Sci. 2019 Apr 23. doi: 10.1007/s10072-019-03875-7.

BACKGROUND: The increase in life expectancy of patients with multiple sclerosis (MS) requires a better knowledge of disease features in the older patients group.

OBJECTIVE: To describe the prevalence and profile of cognitive impairment (CI) in older patients with MS and perform a comparison with younger patients.

METHODS: Patients were consecutively recruited for 6 months. Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop Test. CI was defined as impairment in ≥ 2 cognitive domains.

RESULTS: We identified 111 patients older than 55 years (mean age 59.7 years). The prevalence of CI was 77.4%, which was significantly higher than in younger patients (42.8%; p < 0.01). Information processing speed was the most impaired domain (68.8%), followed by verbal learning (49.5%), executive function (47.7%), and visuospatial learning (26.6%). We found no significant differences in the prevalence of impairment in the distinct cognitive domains between older and younger patients with CI. Depression and fatigue were not associated with increased CI among patients in the older age group (p > 0.70).

CONCLUSION: There is a remarkably high frequency of CI in older patients with MS. The similar profile of CI between older and younger patients suggests that CI is mostly directly related to MS itself and not to comorbid age-related disorders.

CoI: multiple

The Learner

Do we need to include cognition as a treatment target in multiple sclerosis?

In every clinic, I do patients with MS complain of cognitive symptoms. Either it is increasing forgetfulness, difficult multi-tasking, the inability to learn and use a new technology or cognitive fatigue.

Case study: One of my high functioning patients, who worked in a large City law firm, simply could not keep up and was recently 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; please remember this was 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 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 just 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.

In the analysis below, of the pivotal phase 3 fingolimod trials, we showed that not being able to improve on the Paced Auditory Serial Addition Test (PASAT) at baseline predicted a worse outcome. The PASAT is a very sensitive cognitive test that used to part of the battery we called the MS Functional Composite (MSFC). The PASAT is not very nice to do and has now been replaced by the SDMT (symbol digital modality test).

When you start doing cognitive screening tests such as the PASAT and SDMT you tend to improve the scores due to a learning effect. We hypothesised that pwMS who couldn’t learn i.e. were unable to improve their PASAT scores at baseline would do worse. This is exactly what we found and we noted it regardless of treatment allocation; i.e. whether you were on fingolimod or placebo. 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. 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. Active MS in the past had primed their brains to continue deteriorating; previous damage or a new type of MS lesion, possibly SELs (slowly expanding lesions) was driving their worsening.

The message here is that it is very important to prevent the ravages of MS by treating as early and effectively as possible. In some pwMS, this is easy because you present early before too much damage has accrued. In others, you may have longer asymptomatic periods during which you have already acquired a lot of damage. Regardless of what group you are in, you need to seriously consider getting on top of your MS disease activity as soon as possible to prevent further damage.

It is clear from the Sormani meta-analysis (article 2 below) that you do best on DMTs that have the greatest impact on inflammatory activity (new MRI lesions) and those that reduce brain volume loss the most. This is why flipping the pyramid and going for the most effective DMTs first-line is a very appealing treatment strategy; particularly those that ‘normalise’ brain volume loss.

This study also raises the question about whether or not we should be monitoring cognition in routine clinical practice? This topic is a hot potato and gets discussed and debated all the time. At the moment I think 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, may change when siponimod gets licensed. It is clear in the siponimod trial that siponimod delayed cognitive worsening compared to placebo. The following is the siponimod data that was presented at the AAN and EAN last year.

I believe that everyone with MS should have the option of monitoring their own cognition. If your cognition is improving and/or is stable that is good news. If, however, cognition is worsening then a frank discussion needs to be had about why it is getting worse and can anything be done about it. There are many reasons why pwMS may have worsening cognition and some of these are treatable. This is why we have developed an online cognitive test, which we are currently validating, to allow self-monitoring of cognition. If you had access to the test would you use it?

Article 1

Sormani et al. Learning ability correlates with brain atrophy and disability progression in RRMS. J Neurol Neurosurg Psychiatry. 2019 Jan;90(1):38-43.

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.

Article 2

Sormani et al. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann Neurol. 2014 Jan;75(1):43-9.

OBJECTIVE: To evaluate the extent to which treatment effect on brain atrophy is able to mediate, at the trial level, the treatment effect on disability progression in relapsing-remitting multiple sclerosis (RRMS).

METHODS: We collected all published randomized clinical trials in RRMS lasting at least 2 years and including as endpoints disability progression (defined as 6 or 3 months confirmed 1-point increase on the Expanded Disability Status Scale), active magnetic resonance imaging (MRI) lesions (defined as new/enlarging T2 lesions), and brain atrophy (defined as change in brain volume between month 24 and month 6-12). Treatment effects were expressed as relative reductions. A linear regression, weighted for trial size and duration, was used to assess the relationship between the treatment effects on MRI markers and on disability progression.

RESULTS: Thirteen trials including >13,500 RRMS patients were included in the meta-analysis. Treatment effects on disability progression were correlated with treatment effects both on brain atrophy (R(2) = 0.48, p = 0.001) and on active MRI lesions (R(2) = 0.61, p < 0.001). When the effects on both MRI endpoints were included in a multivariate model, the correlation was higher (R(2) = 0.75, p < 0.001), and both variables were retained as independently related to the treatment effect on disability progression.

INTERPRETATION: In RRMS, the treatment effect on brain atrophy is correlated with the effect on disability progression over 2 years. This effect is independent of the effect of active MRI lesions on disability; the 2 MRI measures predict the treatment effect on disability more closely when used in combination.

CoI: multiple

What is happening to my cortex?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CoI: multiple

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