Does MS cause dementia?
I would be interested to know if any of you think you have severe cognitive impairment or dementia. Have you raised this with your MS team? Have they sent you for a cognitive assessment?
One of my readers has just asked me to comment on a recent meta-analysis showing that the incidence of comorbid dementia in people with multiple sclerosis (MS) is very high (see paper below). Approximately 38,000 pwMS were assessed across 10 published studies, and about 5% had a diagnosis of dementia. Dementia was particularly high in studies in the USA, where 16% of pwMS had dementia. Older pwMS were particularly at risk. This is an old story, but it deserves further discussion.
In 2013, the European Medicines Agency invited me to give a talk on the treatment of MS. This was at a multistakeholder meeting aimed at improving MS treatment and clinical trials for MS. To shift the debate, what I call reframing, I decided to define MS as a preventable dementia. My talk triggered several altercations with different members of the audience. One very senior Italian academic accused me of being irresponsible and that MS was not a dementia. Another Canadian academic said to me after the meeting that I was being reckless. He had looked after many patients with MS who were blissfully ignorant of their cognitive impairment and were fine without the knowledge of having dementia. A senior pharmaceutical medic congratulated me on being brave enough to highlight the elephant in the room.
My EMA talk predated the ‘MS Brain Health: Time Matters’ policy initiative. However, I think defining MS as a preventable dementia is at the core of what we have tried to do with the report.
MS is the commonest non-traumatic disabling condition to afflict young adults, and given sufficient time, it causes physical disability in the majority of pwMS. However, MS has a relatively modest impact on life expectancy, reducing it by an average of between 3 and 8 years. As a result, MS has a high socioeconomic impact because pwMS live a long time with disability.
Evidence is now overwhelming that early effective treatment can prevent irreversible damage from accruing, which is linked to poor outcomes and long-term disability. Despite this, many countries and neurologists still delay access to highly effective disease-modifying therapies (DMTs) for people with multiple sclerosis (pwMS). Neurologists are well aware that patients with MS may present with cognitive impairment as the dominant feature. Most textbooks of neurology include MS in tables listing causes of dementia. Therefore, the concept of MS being a dementing illness is not novel.
How do we define dementia? The Diagnostic and Statistical Manual of Mental Disorders (DSM) defines dementia as a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness. Based on this definition, I argue that a significant proportion of pwMS would fulfil these contemporary diagnostic criteria for having dementia, i.e. loss of cognition severe enough to interfere with normal activities of daily living, being present for more than six months, not present at birth, and finally in the vast majority of cases not being associated with a loss or alteration of consciousness.
In the DSM, activities of daily living are categorised into four domains: physical, mental, social, and occupational. MS is well established as a physically disabling condition; in natural history studies (pre-DMT era), the median time to reach the irreversible disability levels of EDSS 4, 6, and 7 is 8, 20, and 30 years, respectively.
The mental or cognitive domain is often overlooked, with most pwMS developing significant cognitive impairment over time. Cognitive impairment is typically present early in the disease course, deteriorates over time, and is strongly associated with brain volume loss, T1 hypointense lesion volume (referred to as "black holes") on MRI, paramagnetic rim lesions (PRLs), and slowly expanding lesions (SELs). In cross-sectional studies, cognitive impairment is found in 30-57% of patients presenting with CIS (clinically isolated syndrome) and in approximately 25% of patients with radiologically isolated syndromes (RIS) or asymptomatic MS. In an Argentinian study of subjects who developed CIS after leaving school, it was found that their school performance in the last three years of school was poorer than that of age and sex-matched controls, implying that asymptomatic MS had affected their cognition years before clinical onset. Similarly, approximately 25% of subjects identified as having radiologically isolated syndromes (RIS), or asymptomatic MS, have significant cognitive impairment on formal testing.
The social impact of MS is rarely discussed. PwMS are more likely to be socially isolated, split from their partners and commit suicide. Compared to patients with other chronic diseases, such as cancer, patients with MS are twice as likely to be abandoned by their partners. Anxiety and depression are common in pwMS, and personality changes are well described. These psychiatric manifestations of the disease may explain why MS has a more significant impact on interpersonal relationships than other disabling diseases that don’t primarily involve the brain, for example, rheumatoid arthritis and cancer.
The final domain is occupation; approximately 50% of pwMS are unemployed ten years after the onset of the disease, at a stage of the disease characterised by mild physical disability, i.e., approximately 3.0-3.5 on the Expanded Disability Status Scale (EDSS). The early impact of MS on employment at low levels of physical disability is almost certainly due to ‘hidden symptoms’, in particular, cognitive impairment, depression, anxiety and fatigue.
Brain volume loss, considered a biomarker or integrator of neuroaxonal loss in many neurodegenerative dementing diseases, occurs early in MS. The rate of brain volume loss is relatively constant at all stages of the disease, including CIS, relapsing-remitting and both secondary and primary progressive MS. Brain atrophy is also noted in subjects with RIS and probably explains the associated cognitive impairment that occurs in a proportion of subjects very early in the asymptomatic phase of the disease.
As part of the “rebranding MS as a dementia” campaign, I did two short online surveys to explore whether or not people with MS are aware of MS being a potential dementia and being associated with progressive and accelerated brain atrophy. After the online campaign using social media, 67% of respondents agreed that MS is a dementing disease, with only 15% of respondents disagreeing, and the remainder being unsure. Their neurologist or other healthcare professionals had never informed eighty per cent of respondents about brain volume loss or brain atrophy. Eighty-five per cent and 88% of respondents would want to know if they had brain atrophy and progressive brain atrophy, respectively. Notably, 77% of subjects stated that this knowledge would affect their choice of DMT.
Since running this campaign and speaking about it at numerous MS meetings, I have been chastised that the message is too negative and potentially stigmatising for pwMS. In a subsequent survey, 62% of respondents agreed that rebranding MS as a dementia would be stigmatising, with 18% disagreeing with this and the remainder being undecided. However, in the same survey, 98% of respondents stated that we should not ignore early cognitive impairment as an important issue for people with MS (pwMS). 76% felt that early MS-related cognitive impairment justified the use of an early, highly effective treatment paradigm or what I call flipping the pyramid.
In summary, MS is associated with early cognitive impairment and progressive brain volume loss that markedly reduces the quality of life, daily functioning and employability of pwMS. Despite the message that MS is a dementing illness being a negative one unless pwMS and their families are made aware of this issue, how can they weigh up the risks and benefits of DMTs, in particular the more effective DMTs, which generally come with more risks, but have been shown to have the most significant impact in reducing the rate of brain atrophy? Yes, alemtuzumab and AHSCT, arguably the most risky DMTs used to treat MS, have the most extraordinary effect in slowing down brain volume loss. This is why if I had MS, I would want to be treated with alemtuzumab or AHSCT.
I have tempered my message and now refer to MS as a ‘preventable cause of dementia’. I have never hidden these facts from my patients. If pwMS are expected to make informed decisions about therapies with potentially life-threatening adverse effects, they need to know about the consequences of untreated or undertreated MS. The days of the paternalistic healthcare professional are long gone; we need open and honest partnerships with our patients. This does not mean that one size fits all, and where necessary, a paternalistic approach to the management of specific patients with MS may be needed; in my experience, this is the minority of patients and requires a judgment call, which is why the practice of medicine remains an art rather than a science.
I would be interested to know if any of you think you have severe cognitive impairment or dementia. Have you raised this with your MS team? Have they sent you for a cognitive assessment? Are you aware of the results? Have you been referred for cognitive rehabilitation?
Paper
Introduction: Multiple sclerosis (MS), as an autoimmune demyelinating disorder, is associated with cognitive dysfunction. Dementia can result from severe cognitive dysfunction or other pathways in MS, but the exact mechanisms and prevalence are unknown.
Objective: This review aimed to determine the pooled prevalence and risk of dementia in people with MS (PwMS).
Design: This meta-analysis was performed in accordance with the guidelines established by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA).
Methods: Embase, PubMed, Web of Science, and Scopus were comprehensively searched up to August 29, 2024, to identify observational studies that examined the prevalence or hazard ratio (HR) of dementia among PwMS. This meta-analysis used a random-effects model to calculate the pooled prevalence and risk of dementia among PwMS, where the prevalence rate and HR were the main metrics for effect size.
Results: Ten studies, including a total of 37,831 PwMS, estimated the prevalence of dementia in PwMS to be 5.31% (I2 = 99.2%, 95% CI: 2.25%-11.98%). In addition, a meta-analysis of four studies assessed the HR of dementia among PwMS, revealing a pooled HR of 1.67 (p < 0.01, I2 = 73.5%, 95% CI: 1.31-2.13).
Conclusion: While dementia is not a common feature of MS, PwMS still have a significantly higher risk of developing it, compared to healthy indiviuals. However, the considerable variability across studies indicates that these estimates should be interpreted with caution, as inconsistencies in research approaches may have influenced the results. These findings warrant further validation.
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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.
“In summary, MS is associated with early cognitive impairment and progressive brain volume loss that markedly reduces the quality of life, daily functioning and employability of pwMS.”
Did you get out of the wrong side of bed? Depressing post. It’s bad enough to tell a 20 year old that they have MS, adding dementia to the list of problems they can likely expect in the future will really push them over the edge.
MS research / treatment advances have been treading water for the last 10-15 years. Apart from the anti-CD20 therapies, there have been no therapies to stop the underlying smouldering inflammation, no remyelination therapies, no neuro-restorative therapies…. Rebadging the disease doesn’t really help patients - it may nudge them towards Alemtuzumab (if it’s available).
I’m going to rewatch England’s victory against Spain to cheer me up. Any chance of a positive post in August?
I'm a bit unsure about this - and of course very alarmed - I'm aware of significant cognitive impairment from my MS, but dementia is a very dramatic raising of the stakes, isn't it? Is cognitive impairment understood to be the beginning of dementia? I can see statistics suggest we're vulnerable to later dementia - but is cognitive impairment mild dementia - or is the latter something different in kind?
I am slightly reassured to note that some research suggests MS patients are LESS vulnerable to Alzheimer's