Our team of writers are reporting live from Athens and have picked key notes from Day 5 - use the links to skip to the sections below, or scroll to view the full summary.
Kumaran Deiva gave a great overview of the immune system and the current thinking on how it causes the clinical presentations of autoimmune neurological diseases. It is still unclear how exactly auto-active cells against brain antigens arise. The ‘inside-out’ theory proposes that when brain cells die due to trauma, infection or other reasons, it may release brain antigens that activate T cells, which then enter the brain and cause auto-immune encephalitis. Antibodies against autoantigens can cause pathology either via directly blocking the target protein (by cross-linking and subsequent internalisation resulting in loss of function), or by initiating complement-dependent lysis. Autoantigens named several times during the session were myelin oligodendrocyte glycoprotein (MOG), Anti-N-methyl-D-aspartate receptor (NMDAR) and Aquaporin-4 (AQP4). However, antibodies against voltage-gated potassium channel-complex (VGKC) are no longer thought to be pathogenic. Some newer research suggests that the gut-brain axis may play an important role as it has been reported that the intestinal microbiota composition influences the balance of T cell subtypes and their activation state.
Dr Yael Hacohen then presented on ‘Encephalitis: infectious vs. autoimmune aetiologies’. Prevalence of autoimmune encephalitis is similar to infectious encephalitis (13.7 cases versus 11.6 per 100,000 people), so one of the take-home messages from this session was to consider the possibility of an autoimmune response when faced with encephalitis. However, a separation of viral and autoimmune causes is not always easy or possible. For example, 26% of children with Herpes simplex virus encephalitis will relapse with anti-NMDAR encephalitis, days, months or even years later.
Other important points made were that MOG-antibody associated autoimmune response is associated with an increasing number of syndromes such as recurrent, isolated and bilateral optic neuritis, acute disseminated encephalomyelitis (ADEM), neuromyelitis optica spectrum disorders (NMOSD) and multiphasic disseminated encephalomyelitis (MDEM). Diagnosing these neuroinflammatory conditions still relies heavily on the physician as laboratory tests have limited utility and may take too long to perform. Analogous to ‘Time is motor neuron’ in spinal muscular atrophy (SMA), in neuro-inflammatory diseases ‘Time is brain’. Outcomes are significantly better with early treatment and there is a limited therapeutic window before damage becomes permanent, so immediate treatment with acyclovir and steroids may be helpful even before a definitive diagnosis is reached. More detailed diagnostic algorithms are available.
This session featured short summaries of the various central themes of the meeting. For neuromuscular disease, Professor Thomas Sejersen recapitulated how next generation sequencing (NGS) has revolutionised diagnosis. In the last two years, the number of neuromuscular disease-causing genes has increased by 70, from 465 to 535. Genetic diagnosis can now differentiate between limb‐girdle (LGMD) and milder forms of Duchenne (DMD) or Becker (BMD) muscular dystrophy. Definitive genetic diagnosis can guide treatment and may offer the opportunity to participate in clinical trials. Check the ‘Gene Table of Neuromuscular Disorders’ to keep track of the identified genes.
Professor Sejersen also highlighted the impressive disease modifying treatments for SMA and the new consensus care guidelines for both SMA (Mercuri et al., 2018; Finkel et al., 2018) and DMD (Birnkrant et al., 2018 parts 1, 2 and 3). Duchenne and SMA care guidelines aimed at families and healthcare providers can be found on the TREAT-NMD website.
The excitement in the field about new treatment options such as antisense oligonucleotides, gene and cell therapy and oral splicing modulators is undeniable. Industry representation with exhibition booths and sponsorship leaned heavily towards these new modalities with Biogen, Avexis (now owned by Novartis) and Roche presenting on their exciting spinal muscular atrophy programmes. Other companies advertising their neuromuscular gene (and cell) therapies were Audentes, Sarepta and bluebird bio. Audentes will be presenting new data on their X-linked myotubular myopathy program AT132 in two weeks at the World Muscle Society meeting, so watch out for their press release. They plan to expand the ongoing phase 2 trial with eight more patients and hope to file for approval within the next two years. Bluebird bio is also planning on filing for approval of its haematopoietic stem cell therapy (transduced with a lentiviral vector) for cerebral adrenoleukodystrophy (CALD) in the next year or so.
This was a very stimulating meeting, with participants and presenters from all over the world. We learned a lot about the current and upcoming treatment options for neuromuscular disease, much more than we could cover in these blogs. In all the enthusiasm about these new therapies, we should not forget the real reason behind the excitement. The new disease-modifying therapies have unprecedented therapeutic benefits which could make a huge difference to the quality of life for patients. Walking around Athens on uneven sidewalks sometimes challenging for an able-bodied person, we can’t help but think on the boulders Edward Ndopu in his wheelchair had to push up the mountain just to get to the Congress to talk to us about his experiences with SMA (see here). Let us hope for a future where fewer and fewer children must toil like Sisyphus.
We hope that we managed to convey how these new treatment options will change future clinical practice and whet your appetite for more. If so, the 14th EPNS Congress will take place from 1-5 June 2021 in Glasgow, United Kingdom. Much can happen in two years and with the current pace of therapeutic development, we are sure to see more approved or about to be therapies in that time.
Even more on gene therapy today – see the new data from the SPR1NT and STR1VE-EU studies in spinal muscular atrophy and a thought-provoking discussion of the ethical dilemmas associated with gene therapy trials. What are the adverse events seen with gene therapy and how will next generation sequencing change your medical practice?
The EPNS Congress 2019 is the place to be this week for all that is happening in paediatric neurology. We look ahead to the highlights in neuromuscular disorder research that the epgonline.org team will be reporting on.
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