When your neurologist looks in your eyes with an ophthalmoscope he/she is looking for the telltale signs of previous damage to the optic nerve. The sign we look for is optic disc pallor. The optic disc is made up of nerve fibres from the retina, which then pass out of the back of the eye to form the optic nerve. If you have had optic neuritis in the past and have lost nerve fibres this can be detected with an ophthalmoscope, OCT (optical coherence tomography) or with retinal photography. Nerve fibre loss from optic neuritis makes the optic disc look pale (see figure below).
The optic disc receives its blood supply from small arteries from the back of the eye; the amount of blood is proportional to the number of nerve fibres in the optic disc. The lower the number of nerve fibres the fewer blood vessels there are the paler the disc looks. Please remember red blood cells are red and give a health optic disc a pinkish colour (see top images above).
Did you know that with a typical attack of optic neuritis you lose about 20% of the nerve fibres in the eye? If you lose so many nerve fibres why isn’t your vision so badly affected in that eye? That is simply because your visual system is able to compensate for the damage; it has spare capacity. Despite this most pwMS who have optic neuritis will know that although their visual acuity, or gross vision, may have recovered they have subtle deficits that we don’t routinely test for. For example, colour vision is often abnormal; colours appear washed out. Contrast sensitivity is abnormal; you may have difficulty distinguishing between shades of grey. Depth perception is all over the place; you need binocular (both eyes) vision for accurate depth perception. If you have poor depth perception you may see things in 3D when they should be in 2D and you may have difficulty judging distances. You may also find that you are hypersensitive to bright lights or lights with certain wavelengths; I find a lot of pwMS become intolerant of fluorescent lights after an attack of optic neuritis.
The problem with the COVID-19 induced changes in our MS service is that with remote consultations I can do this aspect of the neurological examination. Is it important? Yes, firstly it allows one to determine what neuronal systems have been affected by MS, which is required for diagnosis, i.e. dissemination of disease in space, and secondly for assessing your EDSS or Expanded Disability Status Scale.
I am telling you all this as we developed a web-EDSS that requires you to know if your neurological examination is normal or abnormal. Having optic disc pallor is one clinical sign that may affect the EDSS. If you can’t get this information from your neurologist you can get a reasonable idea if your optic nerve has been affected by MS by downloading and using one of the many colour vision applications on your smartphone; we recommend using ‘eye handbook’ as it is free. So before completing your webEDSS you will need to know if you have abnormal colour vision in your left or right eye; this could be used as a proxy for optic nerve involvement. Please note if you have congenital colour blindness, which is more common in males, you can’t use this sign as a proxy for optic nerve involvement.
I have been a big proponent of self-monitoring and using data and its interpretation to change my own and hopefully my patients’ behaviour. However, since reading Shoshana Zuboff’s book on surveillance capitalism over the Christmas break I am having second thoughts.
Surveillance capitalism is how tech companies are using the surplus data they collect on us to create detailed individualised digital profiles and to then use the profiles to target us with adverts or to repackage the data and to sell it on for third parties to use. This is a big business and is getting bigger.
In parallel to this happening in the commercial sector, it is beginning to happen in medicine, i.e. we are developing health and wellness, and disease-specific self-monitor, apps for our patients. A lot of these apps are being developed and controlled by the pharmaceutical companies and there is no transparency about how the data will be potentially used in the future. Combine data from these health apps with general data collected from other sources and we have a big brother scenario, where third parties can start to target you subliminally. For example, the data could be used to suggest you change your treatment.
To avoid the misuse of self-monitoring data we are going to have to develop an ethical code of practice that is transparent to all concerned. I personally think we should own our own data and if it is harvested, either overtly or covertly, we should know how it is being used. We should also have the right to delete our harvested data and hence prevent third parties exploiting it.
The following is my presentation from ECTRIMS two years ago when I make the argument for self-monitoring. I am now going to have to include a disclaimer saying yes self-monitoring has the potential to transform the way we manage MS, but it is important that the data collected as part of self-monitoring is owned by the person being monitored and that the data cannot be used for other reasons without informed consent. Do you agree?
BACKGROUND: Digital self-monitoring, such as through smartphone applications (apps) or activity trackers, could be applied to monitor the health of people with multiple sclerosis (MS). This self-monitoring could facilitate personalized therapies and self-management of MS. The acceptance of digital self-monitoring tools by patients depends on them being able and willing to use these tools in their daily lives.
METHODS: In-depth interviews were conducted with seven adults with MS before and after participation in a study in which they used an activity tracker and an MS-specific smartphone app for 4 weeks. We inquired about experiences with the tools in daily life and needs and wishes regarding further development and implementation of digital self-monitoring for people with MS.
RESULTS: The smartphone app and the activity tracker increased respondents’ awareness of their physical status and stimulated them to act on the data. Challenges, such as confrontation with their MS and difficulties with data interpretation, were discussed. The respondents desired 1) adaptation of digital self-monitoring tools to a patient’s personal situation, 2) guidance to increase the value of the data, and 3) integration of digital self-monitoring into treatment plans.
CONCLUSIONS: These findings show that patients can provide detailed descriptions of their daily life experiences with new technologies. Mapping these experiences could help in better aligning the development and implementation of digital self-monitoring tools, in this case smartphones and activity trackers, with the needs and wishes of people with MS.
You see me once a year for 15 minutes, you look at my MRI report and blood results, you ask me a lot of questions, you examine me and then you tell me that everything is fine. At my last visit, you said my MS was stable, you mentioned to me that I was NEDA, because I had had no relapses, no new lesions on my MRI and my EDSS was static at 3.0.
I have now looked up and read about NEDA (no evident disease activity) and I disagree with your assessment. I am clearly getting worse. The Christmas before last I remember going for a 5-mile walk with my family after lunch and managed it fine. When I tried the same walk last Christmas I had to turn back after a mile because my right leg was dragging.
I also have other problems that you didn’t pick up on during the consultation. I now have to get up 2 or 3 times at night to pass urine. My memory is much worse than it was last year. My head feels foggy all the time as if I have a permanent mild hangover. I now avoid any social occasions with colleagues after work. The truth is I am too tired to at the end of the day to do anything else than get home. I feel exhausted most of the time. I have stopped gardening.
I think I have developed secondary progressive MS. Do you agree? Would it be possible to see you sooner to discuss this? Is there anything you can do about my deterioration in functioning?
Yours sincerely
Patient Y
Does this story sound familiar?
At first glance, it is easy to say this person has SPMS. But do they?
Based on the definition of SPMS it seems likely, i.e. objective worsening of function for at least 6-12 months independent of relapse activity. Based on the latter it seems Patient Y is not having relapses. As for the objective worsening of function the interpretation is in the eye of the beholder. As far as the neurologist is concerned the patient is not deteriorating because the EDSS is stable. In comparison, the patient has documented, albeit rather crudely, a drop if in functioning. Who do you believe?
The scenario illustrates what will happen when MSers begin to self-monitor and prepare for clinic appointments in advance, i.e. they will potentially be self-diagnosing secondary progressive or worsening MS.
However, I want you to take a step back and ask could the deterioration be due to something else, something reversible? If it is due to something else it may be treatable and potentially reversible.
Does this patient have any reversible comorbidities that could be responsible for the deterioration? Smoking, hypertension, diabetes, metabolic syndrome, obesity, underactive or overactive thyroid function, renal, liver, heart or lung disease? If a woman, is she menopausal? What about mental health issues; depression and anxiety? Is this patient drinking too much alcohol? Is the patient malnourished? They may be eating a diet of toast and tea.
Is this patient sleeping well? Getting-up 2 or 3 times a night to pass urine means their sleep hygiene is very poor. Just improving this patient’s bladder problems will have a major impact on their daytime fatigue and work performance.
What about a chronic infection? Could this patient have a low-grade urinary tract infection? What about their oral health; could they have gingivitis or periodontitis? Sinusitis?
Is this patient exercising enough? I suspect not. The drop off in the walking distance could be deconditioning, i.e. losing fitness because of lack of exercise. In this particular patient, I suspect this, however, is unlikely because deconditioning is unlikely to result in a dragging leg on walking a mile.
What medication is this patient on? Are they are on an anti-spastic medication or anticholinergics for their bladder problems? Both these class of drugs affect cognition and may explain the memory loss and brain fog. I have commented on baclofen being particularly problematic in the past.
How well is patient Y? Patient Y seems to have become socially isolated and withdrawing from having social interactions with their work colleagues. The patient has stopped gardening, which helps improve mental health. What about the home environment? Is patient Y’s relationship with the family stable, etc? What are this patient’s finances like? Are they in debt? Are they struggling economically?
Could this patient have smouldering MS? Does this patient need an MRI of the spine and a lumbar puncture to measure CSF neurofilament levels? We know that brain MRI will not pick-up all disease activity. Does this patient need to start a DMT or have a DMT switched and escalated? I would be very interested to know how this patient’s cognitive function is and whether or not they have a swiss cheese brain (lots of black holes) and brain volume loss. Having this information makes a diagnosis of SPMS and/or smouldering MS more likely.
How old is patient Y? If they are over the age of 50 we may be seeing early ageing.
Making a diagnosis of SPMS is not simple and most neurologists would prefer not to do it. However, if we are to improve the lives of our patients we need to take a holistic approach to the management of MS. Clinical practice must not be a box-ticking exercise. We need to provide our patients with the tools to self-monitor, self-diagnose and self-manage. We need them to become partners on a life-long MS journey that will result in better outcomes and happier and more content MSers and HCPs.
To reiterate the philosophy of marginal gains “if you break down everything we can think of that goes into improving MS outcomes, and then improving it by 1%, we will get a significant increase when we put them all together”. This case vignette illustrates this very well.
I hope this post motivates you to start self-monitoring and to start preparing for your consultations with your HCP. You need to have a list of questions to ask. Don’t let your neurologist or HCP fob you off. You know yourself better than they do; please don’t forget this.
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?
Mechanisms of neuronal loss in MS
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.
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.
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?
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.
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.
