Case study: smouldering MS on dimethyl fumarate
To switch to alemtuzumab or cladribine you would need to have had a relapse and new lesions on your MRI. You would not be eligible for AHSCT as DMF is not classified as a high-efficacy DMT.
I am a 48-year-old female (1.71m, 71kg) who has probably had MS since 2002. My initial presentation was optic neuritis but was only diagnosed in 2016 after having had episodes of facial numbness and tingling (opposite sides). Prior to being diagnosed, I had fatigue, which was put down to my work.
I was diagnosed with RRMS based on the above, findings on MRI (more than 10 lesions) and a visual evoked potential. I did not have a lumbar puncture. I was started on DMF (Tecfidera) and have been relapse-free with no new lesions on the annual brain MRIs. I have ongoing symptoms that have been put down as an exacerbation of existing symptoms.
I am reasonably active but struggle with cognitive fatigue, poor cognition and brain fog. Multi-tasking is a challenge, walking and talking seems more draining and difficult than for example running for longer distances by myself. The more fatigued I get, the harder I find it to string a sentence together.
I used to be a very high achieving professional, used to multi-tasking, but my verbal intake capacity has suffered as shown in a recent neuropsychology assessment. I am now no longer able to work in my profession due to my cognition and fatigue issues.
I am about to switch to ocrelizumab, mainly as I am still getting side effects from DMF, such as hot flushes with associated fatigue. I am hoping ocrelizumab might improve my fatigue and brain fog.
Rather than switching to ocrelizumab, should I instead look at immune reconstitution therapies like alemtuzumab (Lemtrada), cladribine (Mavenclad) or HSCT - or will it be too late? I am aware that alemtuzumab is being discouraged as it would mean that I have to self isolate for 3 months and that the current pandemic situation makes this DMT switch even riskier.
Prof’ G Opinion
Unfortunately, under the NHS England guideline if your MS is inactive (no relapses or MRI activity) you can only switch horizontally to another DMT that is licensed for active MS. This would include interferon beta, glatiramer acetate, teriflunomide, ocrelizumab and ofatumumab. To be treated with alemtuzumab or cladribine you would need to have had a relapse and new lesions on your MRI. Under the London AHSCT guidelines, you would not be eligible for AHSCT as you have not failed a high-efficacy DMT.
I am not sure it is too late for an IRT, but I would need to see your investigations and exam you. Responses to most anti-inflammatory DMTs including IRTs depends on whether or not you have active disease.
I am not sure that you do have to self-isolate for three months after alemtuzumab treatment. As we now have vaccines and treatments for COVID-19 the risk of COVID-19 is much lower. I now only recommend 4 weeks of self-isolation post-alemtuzumab, to cover the at-risk period before innate immunity has recovered. However, saying this alemtuzumab-treated patients need to be sensible about trying to avoid high-risk COVID-19 environments.
However, as you are having ongoing symptoms it suggests your MS may be active. In our centre, we would offer you a lumbar puncture and CSF analysis and if you had raised neurofilament levels would classify you as having active disease and offer you a switch. It would be very helpful to know what has been happening to your brain volume over the last few years and also to know if you have acquired any lesions in your spinal cord. Has your neurological examination and EDSS changed over the last few years? Have you been self-monitoring and documented worsening of physical functioning? All this information adds to the picture to help decide if you have worsening or stable and active or inactive MS.
Yes, you may have what we call smouldering MS or progression independent of relapses (PIRA), based on what you have told me about your worsening cognition. Whether this is due to MS, another disease process or superimposed ageing is a moot point.
Your story is very typical and I spend a lot of time discussing smouldering MS with my own patients. I don’t know if there are any other systemic factors that need addressing to try and optimise your general health.
Many neurologists would label you as having secondary progressive MS and offer you the option of switching to siponimod. However, on the NHS you still need to have had a relapse or new lesions on MRI to be eligible for siponimod. The label of secondary progressive MS would not be appropriate for you as it would make you ineligible to a switch to one of the other agents referred to above and under NHSE guidelines your current DMT would need to be stopped.
You illustrate the big unmet need in MS and are the reason why we need add-on therapies to address smouldering MS. Have you discussed clinical trials with your MS team?
You may be interested in our SIZOMUS trial where we are adding on a CNS-penetrant drug to target B-cells and plasma cells within the CNS. The hypothesis we are testing is whether or not the intrathecal antibodies from these cells are driving smouldering MS.
The issues raised in your case are reminiscent of many of the issues I have discussed in the recent case study of someone switching from natalizumab to alemtuzumab based on progressive brain volume loss (23-Aug-2021).
Your multitasking difficulties
The fact that you have noticed that you battle with multitasking tells me that you have reduced reserve. As a result, you have to concentrate on doing one task at a time. This is why pwMS have problems in the knowledge economy that requires cognitive multitasking and why so many pwMS have difficulty at work and often have to stop working relatively early in the course of their disease. You illustrate this.
A recent study showed that this phenomenon is not limited to cognition but physical activities as well. In the so-called walking-while-talking task they show how doing a mental task whilst walking causes your walking to deteriorate (Henning et al. Validating the walking while talking test to measure motor, cognitive, and dual-task performance in ambulatory individuals with multiple sclerosis. Mult Scler Relat Disord. 2021 Jun 30;54:103123.)
I actually know several patients who have had falls when taking on a mental task whilst walking.
I hope I have answered all of your questions adequately. Are there any people out there in a similar position to this patient? If yes, what have you done to manage your MS?
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.
I also have identical features, except I have managed to reduce my working hours rather than stop altogether. I was taken off Tecfidera at the start of the pandemic, as my Lymphocyte count was very low (0.4). I am still waiting for the count to raise enough to move to Aubagio.
I am fortunate to have two very supportive MS nurses and was referred to the Neuro OT service. His advice has been brilliant, making me consider the Boom/Bust effect and the three Ds - Delay, Delegate or Dump. He has recommended planning in periods of 'rest' throughout my week but this isn't always practical. Having said that, just being mindful of this need has forced me to stop every now and again, before I reach Bust! The OT also recommended that after an illness or infection, I do not push myself to be better too quickly. Rest, be kind and pace yourself! Probably sounds obvious advice for many, but as a working Mum of two children with an ageing mother.... I've not had the brain space or time to consider my own needs.
I tripped while walking and thinking about something else the other day which means a bill for a veneer on one of my front teeth.