I once proposed the question, “ask not what your healthcare professional (HCP) or MS research community can do for you, but what you can do for yourself?” and had quite a lot of pushback from some readers. Why?
I started developing this diagram more than a decade ago summarising the holistic management of MS. What I mean by this is that if we, or more importantly you in partnership with your HCP, address every item on this diagram you should be able to optimise the management of your MS and maximise your brain health.
Surely the therapeutic aim in MS must be to get every person with MS to old age with as healthy a central nervous system as possible so that you can age normally. I find it difficult to communicate such a long term target to my patients and their families because most people, including the healthcare community, have relatively short or intermediate-term goals.
Please note the diagram on the holistic management of MS is not all black-and-white but has some shades of grey. The reason for the grey boxes is that we are not there yet in terms of having licensed treatments, but we are working on them. You may realise that this diagram covers the management of not only active MS, but smouldering disease as well.
Please note there is some overlap between MS-specific targets and non-MS or brain health targets, for example, exercise is neuroprotective and promotes remyelination and recovery. Every item on the diagram above has been covered before on this blog so nothing should come as a surprise to you unless you are new to the blog.
Are you up for taking on the ‘Holistic Management Challenge’ yourself? Do you have enough information? Do you have enough support from your HCP to do so?
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.
As 2021 rapidly speeds up and COVID-19 leaves its trail of destruction it is clear to see how important general and brain health is for resilience against disease and its broader impact. These lessons go beyond COVID-19 and apply to any disease. This is why our #BrainHealth #TimeMatters campaign is so important for people with MS (pwMS) and the general public and why prehabilitation needs to become a way of life. I know this is easier said than done, but start small and gradually expand your horizons.
It is often said to make good habits stick start doing one thing at a time and try and do it for 2-3 weeks and then the behaviour becomes sticky and you are more likely to persist with it longterm.
I am so pleased that the messages from our ‘Brain Health: Time Matters in MS’ policy document are finally getting traction and buy-in from the wider MS community. Shortly before my accident, I spoke to a group of Australian MS social media influencers about the principles of Brain Health and they went away and produced some online materials that will help spread the philosophy and nudge other pwMS and the wider MS community to take MS Brain Health more seriously.
It was quite clear that when we developed the MS policy document that the message of maximising Brain Health was as relevant to the general population as to pwMS, which is why we went on to write a new and separate policy document ‘Time matters A call to prioritize Brain Health’ and launched the ‘Think Brain Health’ campaign, which targets the general population. Although this focuses on preventing age-related cognitive impairment and neurodegeneration the messages are very similar to one we promote to pwMS.
I was, therefore, thrilled to see that Alzheimer’s Research UK have copied our slogan and have launched their own Think Brain Health campaign. May be Oscar Wilde was correct when he said: “Imitation is the sincerest form of flattery”. For me, the important take-home message is that Brain Health is becoming a treatment target and putting preventive neurology centre stage.
If you have MS you should know your blood pressure, your BMI (body mass index), your lipid status and whether or not you have impaired glucose tolerance or diabetes. In other words, all pwMS should have an annual health check outside of their MS clinic appointment to be screened for comorbidities. We know that pwMS have a higher chance of developing comorbidities that speed up worsening disability. This is why the holistic management of MS is so important. Preventing the development of comorbidities is part of our treatment strategy to maximise the lifelong brain health of someone with MS. Even if we can’t prevent you developing a comorbid disease then aggressively managing comorbidities will help improve MS outcomes.
The substudy of the SPRINT hypertension trial (see below) shows that targeting a systolic BP of less than 120 mm Hg, compared with less than 140 mm Hg, was associated with a smaller increase in cerebral white matter lesion volume. This raises the question that if you have MS and are hypertensive should you be lowering your systolic blood pressure to less than 120 mm Hg or less than 140 mm Hg? I would suggest the former. Preventing new hypertension-related white matter lesions must be part of the treatment target for people with MS. It also makes it easier to interpret the annual monitoring MRI; we don’t want to escalate your DMT based on new vascular lesions.
Please note that pwMS who have one of four comorbidities (smoking, hypertension, diabetes or dyslipidaemia) do much worse than pwMS with no comorbidities. On average, pwMS with comorbidities need to use a walking stick 6 years earlier than pwMS who don’t have comorbidities. This 6-year difference in disability outcomes is bigger than the treatment effect of interferon-beta.
If you don’t know what your blood pressure it please make a point to see your family doctor or pharmacist or you can purchase or borrow a self-administered BP machine to check your own BP on a regular basis. This should be part of your MS self-management.
IMPORTANCE: The effect of intensive blood pressure lowering on brain health remains uncertain.
OBJECTIVE: To evaluate the association of intensive blood pressure treatment with cerebral white matter lesion and brain volumes.
DESIGN, SETTING, AND PARTICIPANTS: A substudy of a multicenter randomized clinical trial of hypertensive adults 50 years or older without a history of diabetes or stroke at 27 sites in the United States. Randomization began on November 8, 2010. The overall trial was stopped early because of benefit for its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. Brain magnetic resonance imaging (MRI) was performed on a subset of participants at baseline (n = 670) and at 4 years of follow-up (n = 449); final follow-up date was July 1, 2016.
INTERVENTIONS: Participants were randomized to a systolic blood pressure (SBP) goal of either less than 120 mm Hg (intensive treatment, n = 355) or less than 140 mm Hg (standard treatment, n = 315).
MAIN OUTCOMES AND MEASURES: The primary outcome was change in total white matter lesion volume from baseline. Change in total brain volume was a secondary outcome.
RESULTS: Among 670 recruited patients who had baseline MRI (mean age, 67.3 [SD, 8.2] years; 40.4% women), 449 (67.0%) completed the follow-up MRI at a median of 3.97 years after randomization, after a median intervention period of 3.40 years. In the intensive treatment group, based on a robust linear mixed model, mean white matter lesion volume increased from 4.57 to 5.49 cm3 (difference, 0.92 cm3 [95% CI, 0.69 to 1.14]) vs an increase from 4.40 to 5.85 cm3 (difference, 1.45 cm3 [95% CI, 1.21 to 1.70]) in the standard treatment group (between-group difference in change, -0.54 cm3 [95% CI, -0.87 to -0.20]). Mean total brain volume decreased from 1134.5 to 1104.0 cm3 (difference, -30.6 cm3 [95% CI, -32.3 to -28.8]) in the intensive treatment group vs a decrease from 1134.0 to 1107.1 cm3 (difference, -26.9 cm3 [95% CI, 24.8 to 28.8]) in the standard treatment group (between-group difference in change, -3.7 cm3 [95% CI, -6.3 to -1.1]).
CONCLUSIONS AND RELEVANCE: Among hypertensive adults, targeting an SBP of less than 120 mm Hg, compared with less than 140 mm Hg, was significantly associated with a smaller increase in cerebral white matter lesion volume and a greater decrease in total brain volume, although the differences were small.
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?
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.
Help! How do I manage progressive brain atrophy in a patient who is NEDA-3?
End-organ damage is a catch-all phrase for the degeneration of the brain; it occurs as part of the ageing process that some consider pathological and others as a normal fact of life. I have hinted that I consider it both because end-organ damage is potentially modifiable via lifestyle modifications and pharmacological interventions. If it was a normal process it should not be modifiable. How can you be more normal than normal? Making ageing a disease also has political ramifications, for example, it will almost certainly incentivise Pharma to develop treatments for ageing.
In MS end-organ damage is massively accelerated by the MS disease process itself, i.e. inflammation and demyelination, and from delayed downstream processes triggered by inflammation, for example, energy failure, microglial activation, ongoing inflammation driven by antibodies, possible slow viral infection and its consequences and comorbidities. It is clear that all people with MS will have end-organ damage, but what can we do about it? To be honest, apart from early treatment to prevent damage, we haven’t got an evidence base about how to manage this problem in MS.
As an example, I saw a patient earlier this week. He has relapsing-remitting MS diagnosed in the mid-2000s and started on interferon-beta (Avonex). He also has type 1 diabetes which he developed when he was 14 years of age, 8 years before he was diagnosed with MS. His diabetes was poorly controlled initially but is now well controlled on an insulin pump. He has renal (proteinuria), eye (retinopathy) and hypertension as complications of his diabetes. His hypertension is controlled on medication. He has been relapse-free and his MRI has not shown any obvious new lesions over the last 6 years; i.e. he is NEDA-3. He does not smoke, but he drinks between 3 and 4 units of alcohol per day. He was referred to me because he is sick and tired of injecting himself with interferon and he has heard of a new drug called ocrelizumab. He wants to be switched to it because is more efficacious and only give every 6 months. His treating neurologist said no, hence his referral to me for a second opinion.
When I went through his history it is clear he has had no relapses in the last 6 years and is fully functional and working full-time. I reviewed his MRIs and I agree he has no new lesions over the last 6 years, but he has developed quite profound and progressive brain atrophy over this timeframe; he is definitely not NEDA-4. What do I do?
Do I switch him from interferon-beta to ocrelizumab? Or do I leave him on Avonex, which is doing its job and rendering him NEDA-3?
If I do switch him to ocrelizumab, will it normalise his brain volume loss? Will he become NEDA-4?
What is causing his brain volume loss? MS, hypertension, diabetes, alcohol or something else?
Do I tell him about his gross brain atrophy, which he is blissfully unaware of?
Do I offer him a formal cognitive assessment to see if he has cognitive impairments? If he has a cognitive assessment and they come back abnormal, which they are likely to, how do I tell him? Will knowing he cognitively impaired affect his management?
Do I offer him a lumbar puncture to measure his spinal fluid neurofilament levels?
Do I recommend any add-on off-label treatments that may help?
Or do I just take the easy option and send him back to his neurologist with a recommendation to leave things as is?
Can I suggest we debate these issues over the next few days and I can then potentially do a live webinar on the issue of end-organ damage and how to handle the problem of progressive brain volume loss on DMTs when you are NEDA-3.
