The 7^th Annual Meeting of the European Academy of Neurology (EAN) - the largest neurology congress in Europe - was held virtually between the 19^th and 22^nd June 2021 and drew over 11,000 participants. The overarching theme of this year’s congress was ‘Towards Precision Neurology’, reflecting a focus on current and future use of precise tools such as genetics, imaging and omics for the diagnosis and personalised treatment of neurological disorders.

EAN President Claudio Bassetti, Bern, Switzerland, began the opening plenary session by reviewing key activities and future initiatives across the EAN’s four main pillars - science, education, membership and advocacy/communication. The vision of EAN is to be the home and voice of neurology in Europe, with a mission to reduce the overall burden of brain diseases. The ‘Big 6’ is a new EAN theme focused on key steps for the promotion/preservation of brain health and prevention of neurological diseases.

The 'Big 6' is a new EAN theme

“The spread of COVID-19 has not only profoundly changed our lives and habits but has also pushed us to discover innovative ways of working and interacting, while also stimulating a great amount of scientific activity.”

Raphaela Goldbach-Mansky, Bethesda, MD, USA

The opening lecture of EAN 2021 was delivered by Juergen Knoblich, Vienna, Austria, and explored insights from the laboratory that may profoundly influence how neurology research is conducted in the future. To combat the difficulties of murine modelling, cerebral organoids have been developed which can be used to model human brain development and recapitulate neurodevelopmental disorders in stem cell derived 3D cultures.

“The human brain is the most complex and most fascinating organ that mother nature has created - but this complexity comes at a price as the brain is also home to some of the most devastating disorders.”

Juergen Knoblich, Vienna, Austria

Thomas Berger, Vienna, Austria, explained that there is a co-occurrence of fatigue, depression and pain in multiple sclerosis (MS) which may indicate a symptom complex involving the same morphological and pathological pathways. Inflammation also plays a key role, causing structural neuroaxonal damage and interfering with the synthesis of relevant neurotransmitters. Dysfunctional reward processing might therefore represent a common, probably pathophysiological cause, for this symptom complex which is dominated by fatigue, concluded Dr Berger. Treatment options for fatigue in MS include drugs that enhance monoamine neurotransmission and dopamine synthesis, and inhibitors of glutaminergic neurotransmission. Anti-inflammatory drugs may also be of therapeutic benefit as evidenced by the reduction in fatigue seen in the ENER-G (NCT00464074) and TYNERGY (NCT00884481) trials of natalizumab.

Functional correlates and diagnostics for fatigue in relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) were reviewed by Iris-Katharina Penner, Düsseldorf, Germany. Objective assessment of fatigue in MS remains challenging and confounding symptoms and factors must be considered. Neuropsychological tests which include speed components and basic attention provide the best correlation with fatigue, but assessments must span several hours in order to reliably capture performance decrease over time. Motivational aspects and disease-coping mechanisms are individualised variables that can impact on fatigue.

Stine Knudsen-Heier, Oslo, Norway, explored fatigue in MS from a somnologist’s perspective, explaining that sleep disorders, which occur commonly in MS, are important negative contributors to both fatigue and quality of life. Methods for assessing disordered sleep in the clinic include screening tools, clinical interviews, questionnaires and polysomnography. Treatment is vital as sleep disorders and MS can have additive effects creating a vicious cycle of fatigue. Options include changing the disease-modifying therapy (DMT) if this is affecting sleep/fatigue or undertaking treatment targeted at the underlying sleep disorder which may be insomnia, sleep apnoea, restless leg syndrome (RLS) or circadian rhythm disorder.

Magnetic resonance imaging (MRI) represents the most powerful paraclinical tool to predict and monitor individual disease course in MS, said Christian Enzinger, Graz, Austria, with number and accrual of T2-hyperintense lesions, presence of gadolinium-enhancing (Gd+) lesions, infratentorial and spinal cord lesions all having prognostic value. Automated lesion assessment is on the horizon and technical advances will soon make it possible to measure whole brain and grey matter atrophy. Recent international MAGNIMS-CMSC-NAIMS consensus guidelines on the use of MRI in MS offer valuable guidance in specific situations and propose standardised protocols.

Body fluid biomarkers in MS were discussed by Charlotte Teunissen, Amsterdam, the Netherlands, who highlighted neurofilament light (NfL) as the major marker for monitoring treatment effects in MS, both in relapsing and progressing forms. Additional disease progression and prognostic biomarkers are still needed, with the novel protein contractin-1 (CNTN1) having emerged recently as a promising candidate. Potential biomarkers can also be identified by novel screening methods such as Olink. Efforts to optimise the implementation of body fluid biomarkers in MS remain ongoing.

“Current experience with NfL monitoring on a monthly or 3-monthly basis for every MS patient will give us a lot of insight into how best to use this biomarker in daily clinical practice.”

Charlotte Teunissen, Amsterdam, the Netherlands

Yvonne Naegelin, Basil, Switzerland, examined lessons learnt from the COVID-19 pandemic for the virtual monitoring of patients with MS using digital biomarkers. Sensors in smartphones - such as accelerometers, gyroscopes and magnetometers - can facilitate reliable continuous monitoring. However, ‘smart’ architecture for digital solutions and biomarkers are still needed to improve real-world monitoring in clinical studies and practice. Our future will be increasingly digital and we need to accelerate this progress, Dr Naegelin concluded. The ultimate aim is to improve the lives of patients with MS through development of innovative tools that can comprehensively characterise the disease process, facilitate the development of better treatments and enable personalised disease management.

How to individualise DMT treatment decisions in daily routine practice were discussed by Mar Tintore, Barcelona, Spain. Although the natural history of MS is changing in today’s era of effective treatments, it remains a disabling condition, with both axonal damage and progression starting at disease onset. MRI is a high impact prognostic factor and clinical features/biomarkers at presentation can also help identify patients at risk for early disability. Dr Tintore stressed that early treatment of MS is crucial and that patients’ lifestyles and preferences, together with geographic specificities, should help to inform individual treatment strategies.

Four key prognostic factors in MS

“The broader use of high efficacy treatments in MS is very important - remember that time is brain and spinal cord.”

Mar Tintore, Barcelona, Spain

This teaching course explored the mode of action of the ~20 DMTs now available to modulate or suppress the immune processes underlying disease pathogenesis in MS.

Injectables for MS - namely interferon-β (IFN-β) and glatiramer acetate (GA) - were reviewed by Ron Milo, Ashkelon, Isreal. These drugs marked the first DMTs to be approved for the treatment of MS and act as immunomodulators.

Much of the neuroprotective effect of IFN-β is likely due to downregulation of myelin and axonal destruction due to inhibition of microglia activation and gliosis. Both IFN-β and GA show moderate but sustained long-term efficacy, said Dr Milo, and benefit from a robust safety profile. However, long-term tolerability and non-compliance issues can lead to reduced patient adherence.

Oral therapies for MS were covered by Celia Oreja-Guevara, Madrid, Spain. Teriflunomide blocks dihydroorate dehydrogenase (DHODH) to inhibit proliferation of autoreactive lymphocytes and demonstrated a reduction in annualised relapse rate (ARR) in the TEMSO (NCT00134563) and TOWER (NCT00751881) clinical studies. Similarly, dimethyl fumarate, which activates Nrf2 inducing a shift towards a naïve/anti-inflammatory cell repertoire, reduced both ARR and disability progression in clinical trials. Sphingosine-1-phosphate (S1P) modulators work by sequestering lymphocytes to lymphoid organs, therefore reducing migration into the central nervous system (CNS), and may also exert direct CNS receptor effects. The efficacy of fingolimod was confirmed in the FREEDOMS (NCT00289978) and TRANSFORMS (NCT00340834) clinical studies. Ozanimod showed a significant reduction in ARR in the SUNBEAM (NCT02294058) and RADIANCE (NCT02047734) trials, but statistical significance in disability progression outcomes was not reached. Ponesimod is approved for active relapsing MS based on the OPTIMUM study (NCT02425644), while siponimod is the only S1P agent indicated for active SPMS based on significant reduction in confirmed disability progression (CDP) seen in the EXPAND (NCT01665144) trial.

Paul Friedemann, Berlin, Germany, examined monoclonal antibody (mAb) therapies for MS, which include natalizumab and the anti-CD20 mAbs ocrelizumab and ofatumumab. Natalizumab binds specifically to alpha-4-β-1 integrin preventing transmigration of lymphocytes from the circulation to the CNS; clinical efficacy was confirmed in the pivotal AFFIRM trial (NCT00027300). Anti-CD20 mAbs that work via B-cell depletion have also shown substantial efficacy in relapsing MS, with both ocrelizumab and ofatumumab achieving significant reductions in ARR in the OPERA I (NCT01247324) and II (NCT01412333) and ASCLEPIOS I (NCT02792218) and II (NCT02792231) trials, respectively. Ocrelizumab was also the first therapy to show a benefit on disability progression and MRI measures in PPMS, achieving a significant reduction in 12-week CDP in the ORATORIO trial (NCT01194570).

Therapeutic concept, application, efficacy, risk of AEs and rebound activity

Tjalf Ziemssen, Dresden, Germany, discussed immune reconstitution therapy (IRT) for MS which includes alemtuzumab, cladribine and haematopoietic stem cell transplant (HSCT). The IRT approach works by depleting key immunopathogenic immune cell components and ‘resetting’ to a new functional phenotype. IRT involves intensive short-term immunosuppression with the result that treatment-related risks are heavily front-loaded. Benefits include a low risk of progressive multifocal leukoencephalopathy (PML), opportunistic infection and secondary malignancy. Pregnancy is also safe post-immune reconstitution and the overall pharmacovigilance burden is reduced.

In this engaging ‘controversy’ session, Joachim Burman, Lisbon, Portugal, argued that autologous HSCT (aHSCT) represents the most effective therapy for patients with aggressive MS. He described aHSCT as a one-time treatment that offers the ‘unique advantages’ of achieving functional improvement in ~50% of treated patients. The majority of patients are stabilised with aHSCT and maintain durable no evidence of disease activity (NEDA) for very long periods of time - sometimes for life.

Ludwig Kappos, Basil, Switzerland, countered that aHSCT is not the only option for severe MS and other approved treatments, such has B-cell depleting mAbs, have proved very effective with a more favourable safety and tolerability profile. He conceded that, although evidence from uncontrolled studies and registries supports higher efficacy of aHSCT in suppressing inflammatory disease activity, the advantage over B-cell mAbs is difficult to quantify and questionable in progressive MS.

“As long as further studies do not provide more evidence about the optimal candidate for aHSCT, this procedure should only be offered patients with aggressive MS after a course of B-cell depletion has failed to control the disease.”

Ludwig Kappos, Basil, Switzerland

Selected congress highlights in MS

In closing, Programme Committee Chair, Tony Marson, Liverpool, UK, explained that plans are already well developed for the 8^th Annual EAN congress which will take place in Vienna, Austria under the overarching theme ‘Getting Evidence into Practice’. We very much hope this will be an in-person event, stressed Dr Marson but contingency plans are in place for a hybrid congress or reversion to a virtual congress if required.

“The aim for 2022 is to have a congress that represents the whole of Europe with a pan-European flavour. It will be a celebration that we can finally come together again after this really challenging time with the COVID-19 pandemic.”

Tony Marson, Liverpool, UK