AAN2019 – Prof G's MS Blog Archive

Just arrived back from the AAN 2019 in Philadelphia. Jetlagged, which is why I am writing this at 2 am in the morning.

As always the AAN is more a meeting of meetings or networking in academic lingo. These meetings have allowed us to progress several of our ideas including (1) DrK’s #MSAttack study with natalizumab, (2) to think more deeply about our proposed ADIOS Trial (adaptive dosing ocrelizumab study), (3) support for our plasma cell and (4) social capital hypotheses and to (5) to gain a deeper understanding of the emerging new ’safety’ issues surrounding alemtuzumab.

Alemtuzumab is getting an unnecessarily rough ride. I had an opportunity to review all of the vascular events and AEs that led to the EMA triggering article 20. These are all rare events. The intracranial haemorrhages appear to be related to transient hypertension and may relate to the amount of hydration the US infusion centres use when administering alemtuzumab. It is clear that MSers develop a transient rise in blood pressure when receiving alemtuzumab, which means this rare complication can be derisked with anti-hypertensives.

When it comes to the cases of arterial dissections and arterial thromboses on alemtuzumab I was not convinced alemtuzumab is to blame. The majority of the cases had comorbidities or had had procedures that are a more likely explanation for the ischaemic events. In many of the cases, the events were poorly characterised and it was not clear if they had occurred at all; this is particularly in relation to the so-called myocardial infarctions.

It is clear that most if not all of the ‘vascular cases’ have arisen in the USA. Why? I suspect it is because alemtuzumab is being used in a much riskier and older population compared to the other parts of the world. Herein lies the problem. The fact that the EMA has now copied the FDA and made alemtuzumab a 3rd-line DMT will shift the use of alemtuzumab into a riskier older population and thereby increase the likelihood of us seeing these vascular AEs in Europe.

To be honest I am not convinced that the risk-benefit profile of alemtuzumab has changed at all. I would, therefore, appeal to the EMA to include the new AEs in the SmPC, but not to change alemtuzumab’s label. We need to be able to offer alemtuzumab to MSer with early MS when they have the most to gain from the treatment. I am sure MSers are in the best position to weigh up the risks and benefits of alemtuzumab. My big fear is that restricting access to alemtuzumab will simply increase HSCT tourism abroad.

If I needed proof that our blog is read it was in abundance at the AAN. Several people were interested in our ADIOS trial and were thinking of doing versions of their own. The one caveat was new data that Stephen Hauser presented showing that the efficacy of ocrelizumab may be linked to the level of B-cell depletion, i.e. the greater the peripheral B-cell depletion the greater the treatment effect of ocrelizumab on disability progression. There was no dose-related signal on MRI or relapses because these have a floor effect, i.e. virtually all patients are NEDA 1&2 and hence it is impossible to use these outcomes to assess a dose-effect. The one caveat is the dose effect on disability was confounded by body weight; i.e. the larger the patients the less B-cell depletion. As you know MSers with an increased BMI (body mass index) are at increased risk of comorbidities, which may explain why they do less well on ocrelizumab and the observation has nothing to do with the level of peripheral blood B-cell depletion.

The peripheral B-cell depletion data, however, needs to be taken further and tissue and CNS B-cell depletion kinetics need to be studied further. I am convinced the ADIOS trial will be a good place to start with some of these studies. Clearly, it is time to get our grant writing hats on. We need to do this study in the UK.

DrK and I had several meetings with key stakeholders in Biogen about our #MSAttack study. There is little doubt about the efficacy of natalizumab in MS, its safety even in JCV-positive MSers when used for short periods, its rapid onset of action (weeks) and it reversibility (washout) that make it the only suitable DMT for this study. We have changed our trial design slightly, but hopefully, we will be able to get this study funded in the near future. If the #MSAttack study is successful it will change the way we treat and think about active MS and may help natalizumab obtain a first-line indication, which many MSers and CISers deserve; particularly if you want to save brain and spinal cord.

NeuroDoc Gnanapavan got very excited when she saw some posters supporting the use of proteasome inhibitors as a treatment for autoimmune disease. This supports our new SIZOMUS trial (Safety of IxaZOmib targeting plasma cells in Multiple Sclerosis) to try and scrub the brain clean of plasma cells. We will be letting you know much more about this trial in the next few weeks now that we have ethics and MHRA approvals. We will be needing volunteers for this study.

Saul, or Dr Reyes to some, is now one of the pioneers in studying social capital and MS outcomes. His poster on the topic was well received. It is clear that the social determinants of health outcome are very important and have not been systematically studied in MS. Dr Reyes will be changing all that and has many activities planned as part of his ECTRIMS fellowship The poster he presented at the AAN is self-explanatory, but if you have any queries please don’t hesitate to ask.

I have a new hero or heroine; Dr Riley Bove, from UCSF. Riley has developed a telemedicine service to help people with neurological problems in resource-poor areas. The service is provided for free by the USCF residents and staff and is linked to an educational course to train the staff in these countries. The whole service is run using Zoom an online teleconferencing service. Well done Riley; if you lived in the UK I would be putting your name forward for an honours award from our Queen. And if I had more bandwidth I would join and contribute to your service; maybe something for my retirement? Could this platform be expanded to help diagnose and manage MS in resource-poor settings?

It is now 4:10 am and I am beginning to feel a bit groggy. So I will signoff now but will come back with some more AAN highlights in the week.

CoI: multiple

I arrived in Philadelphia on Thursday to attend the 2019 AAN annual meeting. The programme of this year continues much of what was started in 2017 and 2018 around burnout and its opposite wellness.

The AAN states: “Neurology is the only medical speciality that has both one of the highest rates of burnout and the lowest rates of work-life balance. AAN leadership is well aware of your daily challenges and how emotional exhaustion can lead to the loss of interest and enthusiasm for practising medicine. It’s important to remember that it is possible to prevent burnout as well as restore well-being. Your health matters to the AAN and we’re here to help. Each day AAN staff and member volunteers are working on your behalf to decrease regulatory hassles to make it easier to be a successful neurologist. Additionally, we’ve compiled the following resources to provide you with tips, tools, and strategies for cultivating well-being and resiliency in your life.”

After last years meeting, I penned the following which I posted on Medium. Little has changed but is clear that neurologists and clinicians, in general, are facing an existential crisis.

Is the art of medicine, and by inference neurology, in terminal decline? Reflections on attending the 2018 American Academy of Neurology meeting in Los Angeles.

The most important part of attending large International conferences is the time for thought, reflection and importantly introspection. The AAN 2018 was no exception. The programme was informative, in a disturbing sort of way, in that a lot of the teaching sessions were dedicated to survival in the workplace; i.e. dealing with burnout, mentorship, work-life balance, mindfulness and meditation, giving and receiving feedback and many issues related to private practice.

When I was a trainee I was expected to be resilient; I simply had to get on with the job at hand. I was too busy to think about or identify these sorts of issues. I am not even sure if ‘burnout’ was an identified problem back in the late ’80s when I started my clinical training. For me, and most of my colleagues, internal medicine and neurology was a calling; ‘our vocation’. Being a doctor was more than simply doing a job. What has changed? My wife tells me the millennials have changed things; they are not as accepting as we were of the status quo and want something different out of life. Play and leisure define the millennials and not their work. Is this true? If yes, maybe I need to play more and work less hard?

The millennials demanding something different from life doesn’t explain it all. Something more seismic is happening to society and medicine. In the current era, often referred to as the post-industrial era, technology has democratised knowledge and the medical profession’s power base of asymmetric knowledge has been eroded. This is leading to an existential crisis for the profession. Unless you have a technical skill that you have honed over years with practice, for example, a surgical skill, our knowledge-based skills are being challenged by the crowd and algorithms. This is leaving the average neurologist frightened and bewildered; like a rabbit caught in the headlights. In the past, my colleagues used to get excited about major advances in medicine. Now what seems to excite them most are reminiscences from the past, from the era when our seniors seemed to be the masters of the universe.

Gone are the days of the clinical anecdote. Big data is now king. I heard a talk at the AAN2018 on pathogen discovery using deep nucleic acid sequencing of clinical samples (blood, spinal fluid, biopsies, etc.) and clever bioinformatics; unsurprisingly, it outperformed the clinicians. Gone are the days when an astute well-trained clinician would have the edge over their colleagues. In the current era technology and big data trump clinical skills and human knowledge.

Another example of a threat to neurology is the revolution that is happening in relation to gene therapy and RNA interference. Both are creating an unprecedented need for presymptomatic genetic diagnosis. Why waste time screening for single genes? Why not simply do whole genome sequencing on everyone at birth so that we can identify treatable genetic diseases, risk profile everyone for common diseases and then let algorithms analyse and reanalyse the genomes of the world’s populations as new information becomes available? It won’t be doctors that will be making diagnoses or treatment decisions it will be algorithms.

Neurologists still cling to the neurological examination claiming it is too complex for a machine to do and interpret. This is clearly not true. Data is emerging that the way we use our smartphones and how we interact with the web tells tech giants, such as Google and Facebook if we are depressed or have signs of early Parkinsonism. Image analysis using artificial intelligence of pictures taken of suspicious skin lesions and the retinae of diabetics are outperforming dermatologists and ophthalmologists at diagnosing skin malignancies and diabetic retinopathy. The same goes for image analysis in radiology and pathology. Why wouldn’t machines get better than us at interpreting physical function?

As we enter a world of smart wearables and other smart technologies it is only a matter of time before a robot will be able to perform and interpret a neurological examination better than we can. I have little doubt that the neurological examination will be deconstructed, improved on and ultimately performed by machines.

So how are we physicians and neurologists going to ensure our survival? Dare I suggest we redefine our role? Clearly, the part we play as diagnosticians will become less important as the algorithms take over this role. Treatment of disease will increasingly be delivered by assistants using care pathways and standardised protocols. IT systems linked to the electronic record will analyse variance. Any variance from the protocol will trigger an investigation into our practices. I am already aware of this happening in multiple sclerosis in relation to possible over- and under-prescribing of highly-effective disease-modifying therapies or DMTs.

To survive in the brave new world neurologists will need new skills, particularly in relation to sifting, curating and communicating information. We will increasingly be called upon to fight fake news and anti-science movements so as to protect our patients from harm. To be effective in this role will need to actively engage with the new media and acquire new digital skills. Neurologists will need to become better listeners and better communicators. We will need to shift the focus from a disease-centric worldview to a preventative and holistic worldview. Treating disease will become a smaller part of our work. We will need to train and support teams of assistants and nurse practitioners who will do the majority of the hands-on work. We will need to become knowledgeable and skilled in lifestyle and wellness counselling. More importantly, we are going to have to walk the talk; we are going to have to live our lives the way we want our patients to live theirs. Neurologists who lead by example will become the pioneers of a new type of neurological practice. Based on my experience at the AAN2018 I would call this Wellness Neurology.

Are you prepared to retrain as a wellness neurologist?

I am still haunted by the concluding lines from The Great Gatsby that are as relevant to me today as they were when I read them as a 16-year old: “So we beat on, boats against the current, borne back ceaselessly into the past.”

Tag: AAN2019

AAN 2019 Living Well