It is 25 years to the day that I arrived in London to start my PhD on body fluid biomarkers in MS.
What has changed in the last 25 years?
I am still into MS body fluid biomarkers and I am fortunate to have been one of the innovators, and early adopters, of using neurofilament light chain levels in MS clinical practice. NFL is making a big difference and will almost certainly change the way we practice. I predict peripheral blood NFL levels will become the MSologist’s equivalent to CRP in rheumatology.
In the last 25 years, I have witnessed a transformation in MS care from one in which we had no DMTs to one in which we have so many options. Even HSCT is back on the table. When I did due diligence on setting up an HSCT treatment programme at the Royal Free back in 1999 I decided it was too risky; back then the mortality rate was close to 5%. Now the mortality is below 1% and closer to 0.3%-0.5% in low-risk subjects. Many of my colleagues now put HSCT on the table as a treatment option, with many UK centres beginning to use it in everyday practice. I anticipate us getting the necessary funding to run our head-2-head study of HSCT vs. Alemtuzumab so that we will be able to present the risk and benefits of these two treatment options to pwMS.
Other important innovations have been the adoption of the early effective treatment paradigm, treat-2-target of NEDA, rapid escalation and flipping the pyramid. I have also seen the ushering in of the immune reconstitution therapies and have started to participate in the debate of what an MS cure may look like. We are now looking beyond NEDA to the ambitious target of treating MS to maximise lifelong brain health.
I have seen the concept of combination therapy strategies begin to gain traction with several trials underway to target neuroprotection, remyelination and neuro-restoration. The holistic management of MS movement is now the norm, which not only focuses on MS-specific disease mechanisms but also addresses comorbidities and lifestyle factors.
We are looking beyond the relapsing phase of MS and have a licensed treatment for primary progressive MS and potentially another for secondary progressive MS. We are starting a new PPMS trial that aims to protect hand and arm function in pwMS who are already using wheelchairs. A lot of us are pushing for MS to go back to being one and not two or three diseases.
But what has revolutionised the field of MS the most in the last 25 years has been the democratization of knowledge and the emergence of social media as a forum to empower people with MS. No longer do neurologists control knowledge. People with MS are now true partners. The inevitable downside of social media has been the spread of anti-science movements. At least the latter has nudged neurologists and other healthcare professionals to join the debate and to start using social media to communicate with their patients.
My big disappointment is the fact that we haven’t started MS prevention trials. This is despite us have good evidence that EBV is likely to be the cause of the disease. However, this is a challenge I look forward to tackling in the next 25 years. What I am very proud of is our patient and public engagement programmes to raise awareness about the issue of MS prevention.
I feel privileged to be part of such a golden era in the history of both London and the field of MS and to have worked with such dedicated people at the Institute of Neurology and now at Barts and The London.
From a personal perspective, I am obviously older and I think a little wiser. I have two grown-up daughters and I am still happily married to my wife of 32 years. I am still running, albeit shorter distances and less often, and I have taken up gardening. I am also trying to walk-the-talk and to live a brain healthy lifestyle; in particular, eating real food. I admit I feel better for it and would recommend it to everyone.
I now identify myself primarily as a Londoner with a waning South African identity, which saddens me a bit. I often cry for my beloved country and miss my mother and siblings and many other things about my homeland. Maybe one day I will become a swallow and return more regularly. As for British politics, I feel European and doubt I will lose this identity any day soon. I have too many continental friends and colleagues who shape my worldview.
Here’s to wishing myself happy anniversary and to the next 25 years as a Londoner!
Yesterday there was a press release from Roche announcing ORATORIO-HAND a new phase 3 trial in people with PPMS, but only this time recruitment will extend beyond EDSS 6.0 up to EDSS 8.0, i.e. wheelchair users. The primary outcome will be the 9-hole peg test.
For people in the field of MS, the announcement of the ORATORIO-HAND trial represents a milestone in the history of MS. It challenges the dogma that once you have more advanced MS (progressive disease) that you are ‘irredeemable’ and sends a message of hope to all people with MS in wheelchairs that we haven’t forgotten you.
I hope that our long-running #ThinkHand campaign will play a part to play in getting the wider MS community and other relevant stakeholders behind this study.
Alison Thomson presenting our #ThinkHand campaign at the 2016 MS Trust Conference
Please note that I have a new disclosure in that I will be the principal investigator on this study.
As promised the following is my slide deck from my presentation at the NIH grand round on Tuesday morning (12-June-2018). I was surprised to find out that none of the MSologists at the NIH prescribe DMTs; they leave the decision up to the treating neurologist. The NIH MSologists only see patients as part of research protocols. However, the resources at their disposal for research is quite extraordinary. They are a very privileged group of researchers.
After the meeting, someone asked me what excites me most about MS research at the moment? Can you guess what I said?
The following is a list of my top priorities in relation to MS-related research:
MS prevention: EBV vaccination study.
MS prevention: Treating infectious mononucleosis to see if we can reduce the risk of MS.
MS prevention: a very large big-data population-based vD supplementation trial (The ‘Gary Cutter’ Trial).
MS prevention: getting high-risk children to not get obese, to remain vD replete and not to smoke to hopefully lower their risk of getting MS.
MS prevention: to create a trial ready cohort of people at high-risk of getting MS for future interventions (I have some ideas about what these should be).
#ThinkPlasmaCell: to test treatment strategies to scrub the CNS clean of OCBs.
#ClinicSpeak: to equip pwMS with tools to self-monitor and self-manage their MS and to get them to change the way they are managed by the healthcare system.
#ThinkHand: treating more advanced MS to protect upper-limb function (ocrelizumab in PPMS and cladribine in progressive MS)
#ThinkCure: deep phenotyping of patients in long-term remission post an IRT to see if we can define an MS cure.
#BrainHealth: getting HCPs in the field of MS to think beyond NEDA and to treat-2-target of maximised brain health over the lifetime of their patients
Neuroprotection: combination therapy trials to slow down or halt worsening of MS disability. It is folly to expect neuroprotection to work as a monotherapy; it needs to be on top of a high-efficacy DMT.
Remyelination and Neurorestoration: to test novel treatments to try to promote recovery of function in pwMS with disability.
You know you are getting old when you start getting invited to give named lectures.
2018 Multiple Sclerosis Charcot Lecture
Made possible by the patronage of Jackie Havener and the Anne Lee Sahm Memorial
Monday, June 11, 2018 | 6:30 PM
THE NATIONAL PRESS CLUB, 529 14TH Street, NW – 13th floor, Washington, DC 20045
What can the convergence of the epidemiology and biology of multiple sclerosis tell us about its cause? How soon can we start MS prevention trials?
Presented by: Gavin Giovannoni, MBBCh, PhD
Professor of Neurology, Barts & The London School of Medicine and Dentistry, Queen Mary University London
This particular lecture is a daunting one, particularly in view of the previous speakers. However, I am very passionate about the topic and have a renewed sense of purpose. #PreventingMS is what I am planning to spend most of the latter part of my career working on. Some of you may, or may not, know that I have taken on a new role as co-director of the Preventive Neurology Unit within the Wolfson Institute of Preventive Medicine. Our lead diseases are MS, Parkinson’s disease and all-cause dementia.
Preparing this lecture is making me think very hard about what we can realistically achieve within a 5-10 year timeline in relation to MS. One thing I am sure of is that I will have to leave it up to my colleagues to find out if our prevention strategies work; it is a 20+ year experiment. However, we owe it to the next generation of MSers to try and prevent them getting MS in the first place.
The latest review by Alfredsson & Olsson summarises what is currently know about MS from the environmental perspective and highlights several modifiable factors.
Lifestyle and environmental factors potently influence the risk of multiple sclerosis (MS), because genetic predisposition only explains a fraction of the risk increase. There is strong evidence for associations of Epstein-Barr virus (EBV) infection, smoking, sun exposure/vitamin D, and adolescent obesity to risk of MS. There is also circumstantial evidence on organic solvents and shift work, all associate with greater risk, although certain factors like nicotine, alcohol, and a high coffee consumption associate with a reduced risk. Certain factors, smoking, EBV infection, and obesity interact with human leukocyte antigen (HLA) risk genes, arguing for a pathogenic pathway involving adaptive immunity. There is a potential for prevention, in particular for people at greater risk such as relatives of individuals with MS. All of the described factors for MS may influence adaptive and/or innate immunity, as has been argued for MS risk gene variants.
Do you believe MS is a preventable disease? To add a little extra to the lecture I would appreciate it if you could complete the following survey. I plan to present the results as part of the lecture. Thank you.
This week’s BMJ has a rapid recommendation piece on the advantages of using atraumatic needles in routine clinical practice. Let’s hope this will now drive the necessary changes we have been arguing for, for several years. Our aim is to get neurologists and MSers to rethink CSF analysis for monitoring MS.
Post-dural-puncture headache is a common complication after lumbar puncture, affecting up to 35% of patients
This headache results from sustained leakage of cerebrospinal fluid from a dural tear; it can be debilitating and require return to hospital for narcotics or invasive therapy
We issue a strong recommendation for use of atraumatic needles in all patients (adults and children) undergoing lumbar puncture because they decrease complications and are no less likely to work than conventional needles
Atraumatic needles are more expensive, but evidence suggests that they reduce costs overall compared with conventional needles
Why is this paper so important? We have known about post-LP headaches being much more common with traumatic or cutting LP needles, but despite this many NHS hospitals continue to purchase these needles because they are cheaper. The people in charge of procurement have to stay in budget this year and hence don’t really care about the downstream costs of treating the complications of LPs nor the misery caused to thousands of patients every year suffering from the complications of LPs. We started our #AtraumaticNeedle campaign several years ago as part of our public engagement programme in the run-up to our PROXIMUS trial. The following are our three papers on the subject and our #ClinicSpeak LP Web App. What have your LP experiences being like; good, bad or indifferent? Barts-MS paper 1 Davis et al. Atraumatic needles for lumbar puncture: why haven’t neurologists changed? Pract Neurol. 2016 Feb;16(1):18-22.
Diagnostic lumbar puncture is a key procedure in neurology; however, it is commonly complicated by post-lumbar puncture headache. Atraumatic needle systems can dramatically reduce the incidence of this iatrogenic complication. However, only a minority of neurologists use such needles. In this paper, we discuss possible reasons why neurologists have not switched to new technology, looking more at diffusion of innovation rather than lack of evidence. We suggest ways to overcome this failure to adopt change, ranging from local interventions to patient empowerment.
BACKGROUND AND PURPOSE: Lumbar puncture (LP) is a key diagnostic procedure in medicine. Post-lumbar puncture headache (PLPHA) is a well-recognized complication of LP. Evidence suggests that using atraumatic needles for diagnostic LP (ATNLP) reduces the risk of PLPHA. However, clinicians in Europe and the USA routinely use traumatic needles for diagnostic LP (TNLP). The occurrence of PLPHA following ATNLP and TNLP was compared in a clinical setting. Further, a survey was performed exploring use of ATNLP amongst UK neurologists.
METHODS: Service development study. Patients were followed up 2 and 7 days after LP using blinded telephone assessment. A questionnaire was developed to assess the use of ATNLP amongst UK neurologists. Frequency, onset, duration and severity of PLPHA were recorded as were use of analgesia, general practitioner consultations, hospital readmissions, days off work due to PLPHA and cost. Neurologists were asked about their familiarity with, and use of, ATNLP.
RESULTS: One hundred and nine participants attending the Royal London Hospital were included, and 74 attendees of the Association of British Neurologists 2012 conference completed an on-site questionnaire. ATNLP reduced the rate of PLPHA (27.1% vs. 60.4%; P < 0.01). In those participants who developed PLPHA symptoms were short-lived (mean 50 h vs. 94 h, P = 0.02) and less severe after ATNLP. Use of ATNLP led to significant cost savings. Only one in five UK neurologists regularly use ATNLP stating lack of training and availability of atraumatic needles as main reasons.
CONCLUSIONS: ATNLP significantly reduces the risk of PLPHA. Training is required 3 to facilitate a change from TNLP to ATNLP amongst clinicians.
When I was at the ANZAN meeting in Darwin I was shown the results of a recent survey of Australian people with MS regarding their research priorities. The number one unmet need was for researchers ‘to find a cure for MS via repair and regeneration of cells’. This is easier said than done. I also have problems linking ‘an MS cure’ with the concepts of ‘repair and regeneration’. In this post, I try and explain why.
Although a large part of this post is repetitive from past posts, sometimes it is helpful to repeat oneself. How will we know if we have cured MS? The current thinking is that MS is an autoimmune disease of the central nervous system that is driven by MS lesions. We think the MS lesion is responsible for both acute (now) and delayed (in the future) neuronal loss. The permanent loss of neurological function (impairment or disability) is due to neuronal loss, which can be measured clinically (neurological examination and cognitive testing), electrically with evoked potentials, using MRI (brain atrophy or loss of brain volume) and/or biochemically using spinal fluid neurofilament levels. Acute Neuronal Loss (the Shredder or Scissors): Inflammation in the active MS lesion transects neuronal processes, or axons, acutely that results in loss of function. If the lesion is an eloquent site it causes a relapse. Loss of function is then restored by the surviving axons taking over the function of the lost axons, or other areas of the brain taking on new functions, we call this axonal and cortical plasticity, respectively. Recovery can only occur if there is sufficient reserve capacity. The accumulation of damage and ageing reduces reserve capacity, which explains why recovery from relapses tends to fail with more advanced disease and with advancing age. This is why it is important to treat MS early so as to protect reserve capacity.
Delayed Neuronal Loss (Slow Burn): Neuronal processes (axons) that survive being transected are compromised and never recover fully. They may remain demyelinated, or if they are remyelinated the myelin sheath never gets back to what it was in health. In addition, the so-called microenvironment within the chronic MS lesion is stressful to the axon. All these processes program the previously damaged axons to die off over time. This is why anti-inflammatory therapies that switch off the development of new focal MS lesions may not prevent the delayed neuronal loss that characterises progressive MS. Even if we were able to cure MS as an autoimmune disease we may not be able to stop, or prevent, progressive disease from occurring in the future as it may already be programmed to occur from previous damage that has accumulated in the past. In other words, progressive MS is like a ticking ‘time bomb’ in people who have acquire d a lot of damage from MS in the past.
Premature ageing: We also seem to forget that as we get older we lose brain; this is what we call age-related cognitive, or neuronal, decline. From the age of 35 our brains start to shrink and our neuronal systems start to fail. The manifestations of this are not that subtle; how often do you battle to find the right word, or remember an important fact, only to find that your memory has failed you. Similarly, your balance is just not as good as it once was; you realise that you can’t put on your trousers standing-up unsupported and you have to resort to sitting down, or holding onto to a piece of furniture, for balance. If we all lived long enough we would all dement from natural ageing. Evolution never designed our brains to function for as long as we are living today. What protects us from the ageing process is brain reserve; the more brain reserve we have the later we will present with our dementia. As MS reduces brain reserve we hypothesise that people with MS (pwMS) will notice age-related cognitive decline earlier than their peers in the general population. So even if we cure you of your MS you may still get a drop off in neuronal function earlier than expected that is simply due to ageing. This early drop-off in your neuronal function will probably be interpreted as MS-related, and not age-related decline.
The insights above highlight some of the reasons why we started the ‘Brain Health: Time is Brain’ campaign and why it is going to be so hard to prove that we have cured MS. However, if we don’t define what a cure looks like we won’t find it.
Defining a cure in MS: Based on what I have said above you may be cured of our MS, but still, have progressive disease. The difference between progressive disease, which is due to previous MS damage and that which is due to premature ageing is that the former should burn-out, i.e. after a period of time, your worsening disability should stop (flat-lining). In comparison, premature ageing is unlikely to stop. In comparison defining a cure in people who are young, with reserve capacity, who have been treated earlier would be easier. I hope you can see that this definition of a cure is incompatible with the terms ‘repair’ and ‘regeneration’. The latter are separate processes that are independent of a cure. We clearly need repair and regeneration agents to treat pwMS who have accumulated a significant amount of damage to their nervous systems. In comparison, in pwMS who have been cured of their MS and have not had any significant damage will not need to undergo treatments to repair and/or regenerate their nervous systems. Importantly, a cure can only really occur in relation to IRTs (immune reconstitution therapies; e.g. alemtuzumab, cladribine & HSCT), i.e. treatments that are given as short courses that address the underlying ‘cause’ of MS. Maintenance treatments that need to be given continuously can’t cure MS, because when you stop the treatment MS disease activity tends to return. Let’s say we have treated a group of pwMS early in the course of their disease with an IRT and they have gone into long-term remission with no evident disease activity (NEDA). How long should we wait before declaring a victory over their MS; 15, 20 or 25 years? In the past, I have proposed defining a cure as NEDA at 15 years post-treatment as a starting point. Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a standard end-point that should be accepted by the wider community; this may be wishful thinking many in the field are saying that we can’t cure MS, therefore, we should not be having this discussion. In addition, the average time to the onset of secondary progressive MS is ~14-15 years so one would expect to see a significant proportion of people manifesting with SPMS in this timeframe. If we had got the autoimmune hypothesis wrong and the IRTs don’t work then I would estimate at least a third should have SPMS if our hypothesis is wrong. The problem with 15 years is that it is too long to wait; some pwMS want to know ‘now’ if an IRT offers a cure, therefore we need data to convince the naysayers to support the ‘cure hypothesis’. Hopefully, convincing data will change their minds and get them to at least offer IRTs to more of their patients.
Deep phenotyping: We are therefore proposing a deep phenotyping project to look at pwMS who are NEDA-2 post-IRT to see if we can find any evidence of ongoing inflammatory, or neurodegenerative, MS disease activity. We propose interrogating them in detail and comparing them to a similar cohort of pwMS who are being treated with maintenance DMTs. Deep phenotyping is simply a term to interrogate brain and spinal cord integrity in a lot of anatomical and functional detail to see if an IRT has stopped ongoing damage and protected reserve capacity. At the same time, we plan to look for evidence of ongoing inflammation in the spinal fluid. One of the problems I am finding with pwMS who have had an IRT and are now in long-term remission is that they forget that they have MS and simply get on with their lives. They disengage from the MS community; they stop reading MS blogs and stop coming to MS research meetings. In short, these people act as if their MS has gone away. They act differently and start to believe they have been cured of MS. Therefore, I see the biggest problem of doing this study will be difficult recruiting subjects; who will want to take a day off work and come into a research unit to be interrogated in detail? Deep phenotyping will include quantitative neurological examinations, multiple questionnaires (PROMS), multidimensional MRI scans, a full set of sensory evoked potentials and central motor conduction times, detailed neuropsychological testing, a large number of blood tests and a lumbar puncture. The latter is to make sure spinal neurofilament levels are normal and to see if the oligoclonal bands (antibodies) have disappeared. I am hoping they will have disappeared. If we can show that the majority of the subjects in an IRT cohort has stabilised with no evidence of progressive disease compared to the maintenance DMT group we may convince the field of the value of IRTs. What do you think? Will you be convinced?
I have just had a very enjoyable meeting in Darwin and want to thank the Australian and New Zealand Association of Neurologists (ANZAN) for being so hospitable and for inviting me to give several talks, in particular, the Ian McDonald memorial lecture. The following is my presentation that you can view as a slideshow or you can download from SlideShare. I have also provided the links for you to read about Ian McDonald.
W. Ian McDonald (1933-2006)
The primary objectives of my talk were (1) to celebrate W. Ian McDonald, (2) to make the case that MS is one disease and not two, or three, diseases and (3) that more advanced MS (formerly called progressive MS) is responsive to anti-inflammatory treatments. However, the latter response is relatively small and depends on reserve capacity, which is responsible for the recovery of function. This is why I stressed to the audience that they need to manage expectations about what to expect from DMTs in this population of people with more advanced MS. To read about Prof. W. Ian McDonald I suggest you read the following articles, which provides some context to the initial part of my talk/slides. 1. Prof Giovannoni’s Medium Post – 4-minute read 2. Prof. Compston’s obituary in the Independent – 15-minute read 3. Prof. Compston’s Brain article – 60-minute read Google Slide Show:
The following two presentations are from last week’s ABN meeting in Birmingham on the topic of the need for combination therapies. It is clear that based on the current efficacy profile of DMTs if we are going to make a difference to people with MS we are going to need to build a sandwich of treatments targeting different pathogenic, including premature ageing.
I gave these presentations as back-to-back talks on the silent symposium platform. A silent symposium is when you speak softly into a microphone and your audience listens to you wearing headsets. The idea is to allow the symposium to occur in the same venue as the posters and exhibitions and make too much noise; not too dissimilar to a silent disco.
At the ABN last week we have a masterful presentation from Prof. Bas Bloem, a neurologist from the Nijmegen in the Netherlands. He is really pushing the bubble in terms of service development in the Parkinson’s Disease (PD) space. He is a big proponent of so-called ‘Participatory Medicine’. The latter is something we at Barts-MS are trying to do with our MS Service. If you have the time could you please watch the TEDx talk below and let us know your thoughts. We are interested in hearing about your experiences, good or bad, about participating in your own healthcare.
Our self-monitoring initiative and patient-activation programmes could be view as Participatory Medicine. Are you already your own neurologist?
