Thomas Berger and Kailash Bhatia discuss new horizons for the EAN
Feature:
Diagnosing
Synucleinopathies: Will Parkinson's Disease or Dementia with Lewy Bodies Become ‘Biologically’ Defined?
Editorial Board 07 Welcome
Foreword
Congress Review
10 Review of the 10th European Academy of Neurology (EAN) Congress, 29th June–2nd July 2024
Congress Features
24 Advancements in the Early Identification and Treatment of Alzheimer’s Disease
Katie Wright
29 Invasive Neuromodulation: Present and Future
Ada Enesco
Symposium Reviews
33 Reimagining Myasthenia Gravis Care: Current Strategies and New Developments
42 Updated Insomnia Guidelines and Latest Real-World Evidence Data on Daridorexant
Poster Review
51 Efficacy and Safety of Nipocalimab in Patients with Generalised Myasthenia Gravis: Top Line Results from the Double-Blind, Placebo-Controlled, Randomised Phase III Vivacity-MG3 Study
Abstract Reviews
56 EpilepsyPOWER: A Project to Favour the Inclusion of People with Epilepsy in Workplaces
Narducci et al.
58 Automatic Method for Jitter Estimation in Electromyographic Signals
Malanda et al.
60 Idebenone Treatment for Leber Hereditary Optic Neuropathy: Time to Clinically Relevant Recovery in the LEROS Study
La Morgia et al.
Congress Interviews
71 Thomas Berger
77 Nils Erik Gilhus
Interviews
81 Olivier Rascol and Wassilios Meissner
87 Kailash Bhatia
Infographic
92 Myotonia: Are We Underestimating the Burden in Myotonic Disorders?
Feature
94 Diagnosing Synucleinopathies: Will Parkinson's Disease or Dementia with Lewy Bodies Become ‘Biologically’ Defined?
Poewe
Articles
99 Patterns of Laryngeal Changes on Clinical Application of Mechanical Insufflation-Exsufflation Seen with Transnasal Laryngoscopy for Patients with Varied Neurological Conditions and Bulbar Impairment
Boggiano et al.
109 A Rare Case of Cervical Intramedullary Spinal Cord Abscess
Chow et al.
119 Bromocriptine in the Management of Central Hyperthermia
Narayanankutty et al.
"Boon stressed the burden of neurological diseases, which constitute 43% of the global disease burden and cost Europe approximately 1.7 trillion EUR."
Editorial Board
Editor-in-Chief
Prof Lászlo Vécsei
University of Szeged, Hungary
Contemporary Head of the Neuroscience Research Group and President of the Doctoral Council, Department of Neurology, University of Szeged, Hungary. Professor Lászlo Vécsei has published over 600 peer-reviewed articles, primarily focusing on the pathomechanism of neurodegenerative disorders and multiple sclerosis.
Prof Ranko Raicevic
Military Medical Academy, Serbia
Dr Natan Bornstein
Shaare-Zedek Medical Center, Israel
Prof Giancarlo Comi
Scientific Institute San Raffaele, Italy
Dr Rita Krishnamurthi
Auckland University of Technology, New Zealand
Dr Giuseppe Lanza
University of Catania, Italy
Prof Amos Korczyn
Tel-Aviv University, Israel
Prof Nils Erik Gilhus University of Bergen, Norway
Prof Hans-Peter Hartung University of Düsseldorf, Germany
Prof Stefan Schwab University of ErlangenNuremberg, Germany
Dr Nitin Butala Baptist Health, Florida, USA
Prof Antonio Federico University of Siena, Italy
Prof Alberto Dubrovsky Favaloro University, Argentina
Dr Inna Lutsenko I.K. Akhunbaev Kyrgyz State Medical Academy, Kyrgyzstan
Dr Marco Feligioni
European Brain Research Institute ‘Rita Levi Montalcini’ Foundation, Italy
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EMJ Neurology is a free, open-access, peer-reviewed eJournal aiming to elevate the quality of neurology care globally by informing experts on the function and disease of the nervous system to help advance the development of this field.
The journal is published annually, six weeks after the European Academy of Neurology (EAN) Congress, and features highlights from this congress, alongside interviews with experts in the field, reviews of abstracts presented at the congress, as well as in-depth features on congress sessions. Additionally, it covers advances within the clinical and pharmaceutical arenas by publishing sponsored content from congress symposia, which is of high educational value for healthcare professionals. This undergoes rigorous quality control checks by independent experts and the in-house editorial team.
EMJ Neurology also publishes peer-reviewed research papers, review articles, and case reports in the field. In addition, the journal welcomes the submission of features and opinion pieces intended to create a discussion around key topics in the field and broaden readers’ professional interests. The journal is managed by a dedicated editorial team that adheres to a rigorous double-blind peer-review process, maintains high standards of copy editing, and ensures timely publication.
EMJ Neurology endeavours to enhance knowledge, stimulate discussion, and contribute to a better understanding of disorders of the nervous system. Our focus is on research that is relevant to healthcare professionals in this field. We do not publish veterinary science papers or laboratory studies not linked to patient outcomes. We have a particular interest in topical studies that advance research and inform of coming trends affecting clinical practice in neurology.
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Dear Readers,
Welcome to the 2024 issue of EMJ Neurology, bringing you all the latest from the 10th Congress of the European Academy of Neurology (EAN), which this year took place in Helsinki, Finland.
Neuromodulation was the prevailing theme in this year’s Congress, so be sure not to miss our feature covering a session on invasive neuromodulation, including deep brain stimulation and high-intensity focused ultrasound ablation. With therapies for Alzheimer’s disease showing a promising future, you might be interested in reading our feature covering advancements in the early identification and treatment of this disease.
Among the selected abstract summaries from the event, you will also find a range of topics covered, such as a compelling summary of a project for helping the inclusion of people with epilepsy in the workplace, as well as a study for an automatic method for jitter estimation in electromyographic signals. Be sure not to miss an article providing a perspective on diagnosing synucleinopathies and discussing the potential of a biological definition for Parkinson’s disease.
I would like to close by thanking all our authors, peer reviewers, Editorial Board, and other contributors for making this issue so special with such great content. Until next year’s issue, be sure to rate our content on our page, and we look forward to receiving your submitted articles!
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Evgenia Koutsouki
Foreword
I am proud to present the 12th edition of EMJ Neurology, featuring a selection of in-depth interviews from leading experts, late-breaking original abstracts, peer-reviewed articles, and visually captivating infographics. This edition includes a comprehensive coverage of the 10th European Academy of Neurology (EAN) Congress, hosted in Helsinki, Finland, from the 29th June–2nd July 2024. The Congress represented a pan-European focal point for neurologists and neuroscientists to collaborate, discuss challenges, and share breaking news in treatment strategies for various neurological disorders.
This year, the Congress explored ‘Neuromodulation: advances and opportunities in neurological diseases’, through workshops, special sessions, and plenary symposia. Our coverage contains a feature article on the plenary symposium ‘Invasive neuromodulation: Hot topics and future directions’, including a presentation by EAN President Paul Boon and President-Elect Elena Moro.
EMJ spoke with award-winning neurologists and scientific committee members at the EAN. Notably, an interview with the Chair of the Scientific Committee, Thomas Berger, laid out the vision and mission of the EAN beyond 2024. Additionally, a roundtable interview with Olivier Rascol, Toulouse University Hospital, France, and Wassilios Meissner, University of Hospital Bordeaux, France, discussed mounting evidence demonstrating the potential of glucagon-like peptide-1 receptor agonists as a diseasemodifying therapy for Parkinson’s disease.
The articles in this issue cover a diversity of topics. This includes studies demonstrating the safety and feasibility of transnasal laryngoscopy during mechanical insufflation–exsufflation, and a call for clinicians to consider central hyperthermia as a differential diagnosis in patients with central neurological disease.
May it not only captivate their interest but also enrich their understanding of the ever-evolving field of neurology
Finally, I thank all the authors, peer reviewers, interviewees, and Editorial Board members who have made the publication of this issue of EMJ Neurology possible. Their dedication and expertise have elevated this issue, supporting EMJ’s goal to elevate healthcare globally. I hope that our readers enjoy delving into the available content; may it not only captivate their interest but also enrich their understanding of the everevolving field of neurology.
Lászlo Vécsei University of Szeged, Hungary
EAN 2024
Since the EAN's inception in 2009 and inauguration in 2014, more than 110,000 participants have attended, 21,846 abstracts have been submitted, and over 21,500 annual individual memberships have been renewed
Review of the 10th
European Academy of Neurology (EAN) Congress Congress Review
THE 10th anniversary Congress of the European Academy of Neurology (EAN) in Helsinki, Finland, marked a significant milestone in European neurology collaboration.
The historic coastal city of Helsinki, regarded for its seamless integration of nature and urban culture, was more than an idyllic location for the EAN 2024 Congress. Innovative research on weak magnetic fields in human brains, leading to the development of advanced imaging techniques, and recent discoveries by Finnish investigators on the molecular genetic causes and risk factors of numerous nervous system disorders demonstrate Finland as a neurology research hub. These breakthroughs made Helsinki the optimal stage for the EAN 2024 Congress.
Paul Boon, EAN President, and Alice Accorroni, Chair of the Resident and Research Fellows Section (RRFS), commenced the Welcome Ceremony, celebrating a decade of remarkable achievements and reflecting on the future of EAN. Notably, since EAN's inception in 2009 and inauguration in 2014, more than 110,000 participants have attended the Congress, 21,846 abstracts have been submitted, and over 21,500 annual individual memberships have been renewed. Expressly, 2024 set new records with over 7,000 in-person and 2,000 virtual participants from 112 countries, 370 invited speakers, and 2,777 submitted abstracts.
Moreover, the EAN has expanded its network, now comprising 48 national neurological society members, with Malta being the latest addition. The EAN's mission to foster community is evident in its board members' visits to 14 countries in 2024, participating in national neurological society meetings, such as the American Academy of Neurology Congress and the Swiss Brain Plan.
One of the significant accomplishments of the EAN board and scientific team was the drafting and publishing of 'Strategic Neurological Research Agenda for Europe: Towards Clinically Relevant and PatientCentred Neurological Research Priorities'. Boon highlighted how, prior to this publication, there was a complete absence of a unifying document providing an up-to-date research agenda for European neurology research, but at the same time, patient-centred and clinically relevant for
Gilhus called the EAN the 'best instrument through international cooperation to improve treatment for brain disorders and to promote brain health'
neurologists. The EAN has attempted to fill the gap with the publication of this paper, which is just one step to enhancing the phase of clinical neurology in the European space.
Discussing the future of patient care, Boon stressed the burden of neurological diseases, which constitute 43% of the global disease burden and cost Europe approximately 1.7 trillion EUR. The forthcoming COIN-EU study led by the EAN aims to provide comprehensive cost data for neurological diseases across Europe. Additionally, the EAN established new task forces on environmental influences in neurology and AI in clinical neurology, reflecting the EAN's commitment to addressing the global burden of neurological diseases and emerging challenges.
This year's Congress focused significantly on the EAN's Brain Health Mission, which promotes brain health awareness. Boon noted that brain health is essential to the general public and neurologists, as very few parts of the medical curriculum are devoted to prevention. The dream, as introduced by Boon, would be for "young kids throughout Europe to think or have an idea about brain health, just as they have the proper idea about dental hygiene." Accordingly, the RRFS launched the NeuroArt contest to celebrate 10 years of EAN and RRFS, and to present European neurologists' creativity. Accorroni stated that creativity and art boost wellbeing and promote brain health, a concept at the heart of the EAN agenda.
Revolutionary chocolatier Dominique Persoone, creator of the Chocolate Line lab in Brussels, delivered a talk exploring the myriad ways to experience chocolate. Notable creations presented during the opening ceremony included the 'chocolate shooter', which involved snorting chocolate powder through the nose, enabling aromas to be absorbed swiftly by the brain. The entire welcome ceremony auditorium participated in a taste of three of Persoone's creations, where he combined sound, scents, and chocolate to create an interactive and sensational experience.
Boon discussed the established evidencebased benefits of having a healthy relationship with chocolate. Multiple studies demonstrated the association of high levels of flavonoids and polyphenols in dark chocolate with neuroprotection and increased neuronal and vascular cell growth in memory networks. While the mechanisms are not fully understood and may be linked to the antioxidant effect of flavonoids on inflammation, underlying mechanisms of brain ageing, the positive effect of dark chocolate on human cognition and happiness is clear.
After the audiences’ chocolate tasting session, Boon invited President-Elect Elena Morrow to the stage where together they awarded Elinor Ben-Menachem, University of Gothenburg, Sweden, and Nils Erik Gilhus, University of Bergen, Norway, with EAN Honorary Memberships for their significant contributions to neurology. Ben-Menachem thanked the EAN board, award committee, and one of her early career mentors, Wallace Tourtellotte, stating that the award was final evidence of her acceptance into European society and evidence of her impact on patient lives. Gilhus called the EAN the "best instrument through international cooperation to improve treatment for brain disorders and to promote brain health", calling on neurologists to take what they learn at EAN to improve patient care.
Following the award presentations and an address by Reetta K. Kälviäinen, President of the Finnish Neurological Society, the welcome ceremony concluded with a musical performance and birthday song for EAN's 10th anniversary, showcasing the Kantele, a traditional Finnish instrument.
EMJ was thrilled to be part of the EAN 2024 Congress and looks forward to attending the 2025 Congress, which will take place in Seville, Spain. Until then, enjoy the highlights presented at this year's Congress.
Ethnic Differences in Access to Stroke Care in Europe
LATEST research presented at the EAN 2024 Congress has brought to light ethnic and racial disparities in access to stroke treatments in Europe.
Researchers from the Agostino Gemelli University Polyclinic Foundation IRCCS in Rome, Italy, conducted a retrospective cohort study which aimed to evaluate the effect of geographic origin and race on access to acute stroke care and treatment. The study utilised data collected between 2015–2022 at the institution’s emergency department. The participants were divided into two groups: Western Europeans and non-Western Europeans.
Results showed that the non-Western European group had a lower likelihood of receiving intravenous thrombolysis, which is the standard reperfusion treatment for patients with acute ischaemic stroke. Additionally, emergency department access for stroke mimics was less frequent among racial minority groups, and Black
While racial inequalities in stroke management have been extensively documented in the USA, this study is the first of its kind in Europe
and Asian individuals had a higher incidence of brain haemorrhages compared to White individuals.
Intravenous thrombolysis is crucial for treating acute ischaemic stroke, it must be administered within 9 hours of stroke onset. Early recognition of symptoms and timely intervention are critical. However, the study noted that language and cultural differences could have an impact on prompt administration of treatment in non-Western European patients in Western hospitals.
While racial inequalities in stroke management have been extensively documented in the USA, this study is the first of its kind in Europe. The findings of which demonstrate that these disparities exist even within universal healthcare systems and are not solely due to the presence or absence of universal insurance.
The researchers call for immediate measures to address these disparities by employing educational campaigns for healthcare personnel and 24-hour availability of interpreters at healthcare facilities to ensure adequate care is provided across all racial groups.
Parental Smoking Linked to Higher Multiple Sclerosis Risk
RESULTS from a new study presented at the EAN 2024 Congress showed that maternal smoking during pregnancy, and exposure to parental smoking during early years of life, can significantly increase the risk of developing multiple sclerosis (MS) later in adulthood.
The study was part of the Environmental Risk Factors in Multiple Sclerosis (EnIMS) project, which is a large multinational casecontrolled, population-based study. The researchers analysed data from Canadian, Italian, and Norwegian populations to investigate the link between MS and maternal and parental smoking habits. Active smoking is a known risk factor for MS and poor prognosis; however, the impact of past exposure to parental smoking, particularly maternal smoking during pregnancy, had not yet been clearly defined. The researchers aimed to study if parental smoking could be associated with MS status.
The results revealed a strong association between MS and maternal smoking during pregnancy among Norwegians
The results revealed a strong association between MS and maternal smoking during pregnancy among Norwegians, while paternal smoking showed a tendency to be associated with MS among Canadians. However, no significant association with parental smoking was found in the Italian population. The absence of consistent associations across all populations may indicate that parental smoking’s impact on MS risk is smaller compared to other factors. MS is a complex disease influenced by a combination of genetic and environmental factors. With the timing of exposure, these environmental factors such as breastfeeding and mononucleosis, play an important role.
The researchers stressed that parental smoking needs to be investigated further, as exposure to parental behaviour can affect the child’s risk of developing noncommunicable diseases, such as diabetes and cardiovascular diseases. Future research should focus on exploring MS risk factors in more depth, along with patient prognosis. Especially since parental smoking habits are a new concept in MS.
The Link Between Nightmares and Dementia
ADULTS who frequently have distressing dreams are significantly more likely to experience cognitive decline and develop dementia, according to research carried out at Imperial College London, UK.
Numerous psychological factors can cause nightmares, including stress, anxiety, and depression. Additionally, research has revealed genetic factors that may underpin the likelihood of an individual experiencing distressing dreams. The impact of nightmares on neurological conditions is a growing field of interest, and previous research has established a relationship between nightmares and Parkinson’s disease. A study recently presented at the EAN 2024 Congress is the first to investigate the effect of distressing dreams on cognitive decline and the development of dementia.
The research team analysed data from middle-aged adults from the Midlife in the United States (MIDUS) study, and from 2,600 older adults from the Osteoporotic Fractures in Men Study (MrOS) and the Study of Osteoporotic Fractures (SOF). The results demonstrated that middleaged adults who reported having weekly distressing dreams were four times more likely to experience cognitive decline than those who reported having no distressing
dreams. Similarly, older adults experiencing distressin dreams were 2.2 times as likely to develop dementia.
This pioneering study highlights the importance of dreams in neurological research, particularly the impact of nightmares on neurodegeneration. The results may enhance awareness among physicians regarding the significance of understanding the impact of dreams on patients' neurological health. Possible strategies to reduce the frequency of distressing dreams include neuropsychiatric medication to treat the psychological basis and image rehearsal therapy, a cognitive behavioural therapy specifically designed to treat nightmares.
Previous research has established a relationship between nightmares and Parkinson’s disease
Auricular Vagal Nerve Stimulation in Patients with Mild Cognitive Impairment due to Alzheimer’s Disease
ADAM Broncel, on behalf of his team at Neuromedical, Lodz, Poland, presented a study in a late-breaking news session at the EAN 2024 Congress on the use of auricular vagal nerve stimulation in patients with mild cognitive impairment due to Alzheimer’s disease.
Previous studies have shown that vagal nerve stimulation activates limb structures involved in memory processing and has a proven cognitive-enhancing effect on patients with Alzheimer's disease.
For this trial, auricular transcutaneous vagal nerve stimulation was applied to the study subjects during sleep, for a period of 3 and 6 months. This was a randomised, double-blind, placebo-controlled study with the patient’s compliance controlled via a dedicated software with continuous cloud data collection. The inclusion criteria comprised females and males aged ≥49 and ≤85 years who met the diagnostic criteria for mild cognitive impairment due to Alzheimer’s disease, confirmed by psychological tests. For this study, Broncel and colleagues excluded individuals who presented neurological or psychiatric disorders, clinically relevant medical comorbid medical conditions, or implantable medical devices.
From this criteria, 60 randomised patients were selected, with 51 of those successfully completing the study. Of this cohort, 35 were in the active group, expressing mild cognitive impairment due to Alzheimer’s, and 16 comprised the placebo group.
The ADAS-COG score, the primary outcome in this study, is a cognitive rating scale, designed to assess the cognitive and behavioural domains affected by Alzheimer’s disease. Broncel showed that the ADAS-COG score changed from baseline in sham and treatment patients at Weeks 4, 8, and 12. Compared to the sham group, those receiving treatment exhibited a significant decline in ADAS-COG. As ADASCOG is a measure of the patient’s mistakes, this decline suggests cognitive improvement from those treated with auricular transcutaneous vagal nerve stimulation.
The team continued the follow-up to Week 26, with cognitive improvement persisting in the treatment group only. Patients from Weeks 26–60 were then not treated and assessed again at Week 60, showing a decline in cognitive function. These findings show statistically significant cognitive improvement between placebo and active treatment in the ADAS-COG score, as well as improvements in other tests, such as the verbal memory probing tests. Broncel concluded that auricular vagal nerve stimulation could be an effective therapeutic treatment for mild cognitive impairment and patients with early Alzheimer's disease.
Patients from Weeks 26–60 were then not treated and assessed again at Week 60, showing a decline in cognitive function
Opioids and the Risk of Dementia
“AS THE world population continues to increase and humans live longer and longer, the prevalence of dementia is rising,” began Nelson Pourhadi, Danish Dementia Research Centre, Copenhagen, Denmark, in his presentation at the EAN 2024 Congress.
1,872,854 individuals from the Danish National Registries, aged between 60–75 years.
Within this group, 93,638 patients developed dementia between 2000–2020.
He added that it is estimated that by the year 2050, there will be around 140 million people living with dementia. Pourhadi wished to analyse the association between dementia and opioid use, which is also increasing rapidly worldwide.
Previous research has shown the potential links between neuroinflammation and opioid use, and the temporary, reversible effects of opioids on the brain, which are well-documented; however, their effect on cognition and dementia is still unknown. In order to analyse this connection, Pourhadi conducted research involving 1,872,854 individuals from the Danish National Registries, aged between 60–75 years. Within this group, 93,638 patients developed dementia between 2000–2020. The team monitored opioid use amongst the cohort within 5 years of the diagnosis.
They found that the use of opioids was associated with a slightly increased risk of all-cause dementia before 90 years old, in the general population. Opioid exposure below 90 total standardised dose (TSD; 1 TSD is equivalent to 30 mg oral morphine) was not consistently associated with dementia. Exposure to more than 90 TSDs was significantly associated with an increased risk of dementia. The team found that this was the case even with weak opioid use and that there was an increased risk of dementia with over 90 TSDs of opioids, regardless of when the patients stopped treatments with regards to dementia diagnosis.
The full study analysed various other contributing factors such as the role of chronic pain; however, this research provided important evidence that opioid use above 90 TSDs increases the risk of developing dementia. Increasing opioid use additionally increased the risk of dementia. Pourhadi emphasised the importance of this research and the need for further studies analysing the causality between this association, as well as investigating the various subtypes of dementia.
Anticoagulant Versus Antiplatelet Treatment for Secondary Stroke Prevention in Patients with Active Cancer
RESEARCH presented at the EAN 2024 Congress explored the association between cancer and strokes; with approximately one-to-two out of 10 patients with stroke having a co-diagnosis of cancer. Furthermore, up to 10% of patients with cryptogenic stroke also have occult cancer, defined as a new diagnosis of cancer within a year after stroke.
To explain the aetiology of this association, Kielkopf noted several biological factors, such as hypercoagulability, adverse effects of treatments, and stress. Both cancer and stroke also share common risk factors, including atrial fibrillation, obesity, and tobacco use. Clinical characteristics of cancer-related strokes include multiterritory infarction and certain laboratory findings, namely elevated d-dimer, white blood cell count, thrombocytes, fibrinogen, c-reactive protein, lactate dehydrogenase, and reduced haemoglobin. Furthermore, patients also typically show absence of susceptibility vessel signs.
Up to 10% of patients with cryptogenic stroke also have occult cancer
The study in question aimed to investigate the outcomes of acute ischaemic stroke in patients with active cancer based on the type of antithrombotic therapy for secondary prevention in a real-world population: anticoagulation versus antiplatelet therapy. The inclusion criteria comprised individuals with active cancer, defined by the International Society on Thrombosis and Haemostasis (ISTH) as "new or recurrent cancer diagnosed or treated within 6 months prior to the index stroke, or a metastatic cancer." The researchers excluded individuals with a cancer diagnosis after hospital discharge, no secondary prevention documented at discharge, cardioembolic stroke, and death during index hospitalisation.
The types of anticoagulation treatments included vitamin K antagonists, low molecular weight heparins, and direct oral anticoagulants, whilst the antiplatelet drugs included aspirin and clopidogrel. As noted by Kielkopf, the primary outcome was the overall mortality within a year after index arterial ischemic stroke. One hundred and thirty five patients were included in the final study, 58 of which treated with anticoagulation and 77 treated with antiplatelet therapy at time of discharge.
Summarising the key findings, Kielkopf noted that patients suspected of having highly active paraneoplastic coagulopathy are often treated with anticoagulation and show poorer outcomes after stroke. Additionally, results showed no clear superiority of anticoagulation over antiplatelet drugs as secondary prevention in cancer-related strokes.
New Advances in Predicting Outcomes in Autoimmune Encephalitis
RECENT findings highlight significant advancements in predicting the outcomes of anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis (anti-NMDARE), a treatable condition often leading to long-term disability.
Anti-NMDARE is characterised by antibodies against the NMDAR in the brain, causing severe neurological symptoms. While treatable, the condition often results in prolonged recovery periods. The existing anti-NMDARE One-Year Functional Status (NEOS) scores the likelihood of a patient's independence 1-year post-diagnosis, factoring in the effects of the first-line treatment after 4 weeks. Researchers have developed a new predictive model, NEOS2, which forecasts patient outcomes before treatment initiation and identifies those likely to benefit from first-line treatment. The new NEOS2 model offers predictions during diagnosis, potentially guiding early treatment decisions more effectively. These findings were presented as late-breaking research at the EAN 2024 Congress.
This study was international and multicentric, combining data from cohorts in France, Germany, the Netherlands, Spain, and Japan, involving 712 patients (79% female, average age 23 years). Researchers developed and validated multivariable models to predict three outcomes: improvement after first-line treatment (NEOS2-T), 1-year functional status (NEOS2), and return to school or work (NEOS2-W). The predictive accuracy of these models was assessed through logistic regression analyses and simplified for clinical application.
The NEOS2 model demonstrated a predictive accuracy of 80%, comparable to the original NEOS score. The NEOS2-T model showed a predictive accuracy of 81–83% for predicting improvement following
NEOS2-T and NEOS2 scores accurately distinguished between patients with a high likelihood of improvement and those at risk of first-line treatment failure
first-line immunotherapy, effectively identifying patients who might benefit from early intensified treatment, and potentially enhancing patient outcomes through the development of tailored treatment strategies.
Notably, high accuracy of the NEOS2 score in predicting long-term outcomes was observed. Approximately 80% of patients were independent 1-year after diagnosis, and 74% had resumed school or work. The NEOS2-T and NEOS2 scores accurately distinguished between patients with a high likelihood of improvement and those at risk of first-line treatment failure, with corresponding predictions for acceptable and poor outcomes. Furthermore, the ability to predict return-to-school or work outcomes, which is a very longterm measure (3 years), using the same variables underscores the robustness of the NEOS2 model.
The authors concluded that the NEOS2 model represents a significant advancement in the management of anti-NMDARE. It offers clinicians a powerful tool to predict patient outcomes and tailor treatments effectively from the point of diagnosis, leading to proactive management. Future research should further validate these models and explore their integration into clinical practice to improve patient care and outcomes.
The NEOS2 model demonstrated a predictive accuracy of
This is comparable to the original NEOS score
%
Transcranial Ultrasound Shows Promise in Parkinson’s Disease Diagnosis
NEW findings have highlighted the potential of transcranial ultrasound (TU) as a diagnostic tool for Parkinson's disease (PD) in a Swedish population.
There is significant diagnostic uncertainty in PD, with an estimated 10–25% misdiagnosis. Moreover, the current gold standard approach is post-mortem histology. Therefore, there is a need for complementary, cost-effective tools to diagnose PD and distinguish between atypical parkinsonism and essential tremor. Despite the established use of TU to detect hyperechogenic substantia nigra (SN+) as a biomarker for PD, its clinical relevance in Sweden has remained unclear until now. This study evaluated the diagnostic value of TU, and the results were presented at the EAN 2024 Congress.
Despite the established use of TU to detect hyperechogenic substantia nigra (SN+) as a biomarker for PD, its clinical relevance in Sweden has remained unclear until now
From 2013–2017, a cohort of 75 patients with Parkinsonism was examined using TU to investigate the SN+ status concerning PD, atypical Parkinsonian disorders, and essential tremors. The study aimed for an extended follow-up period to ensure accurate final diagnoses. By 2024, the mean follow-up time reached 95 months, during which the initial diagnosis was revised in 36 cases, amounting to a significant 47% of the patients. Three patients were excluded from the study due to inadequate transcranial bone windows for TU.
The findings revealed that 41 out of 56 true patients with PD exhibited the SN+ finding, while only two of the 16 patients without Parkinson's did so, highlighting a statistically significant association (p<0.001). The study reported a sensitivity of 73% and an accuracy of 76%, indicating some limitations in TU's standalone diagnostic efficacy. However, the specificity and positive predictive value were notably higher at 87.5% and 95.3%, respectively.
There is significant diagnostic uncertainty in PD, with an estimated 10–25 % misdiagnosis
Researchers concluded that TU could be a valuable supplementary tool in PD diagnostics within the studied population, particularly due to the high probability of SN+ supporting an early diagnosis. However, they cautioned against using TU as a primary diagnostic method due to its unsatisfactory sensitivity and accuracy. The researchers emphasised the need for further studies, mainly focusing on TU reproducibility and comparative studies between TU and PET/single-photon emission computed tomography imaging.
Chimeric Antigen Receptor T Cell Therapy:
A New Treatment for a Demyelinating Central Nervous System Disease
FEMALE and Asian populations are the most often diagnosed populations with neuromyelitis optica spectrum disorder (NMOSD), a central nervous system (CNS) demyelination disease. A recent clinical trial from Wuhan, China used resident CNS B cells as a target for a novel chimeric antigen receptor (CAR) T cell therapy.
NMOSD is characterised by the presence of the anti-AQP4 antibody, leading to severe neurological impairment and high relapse rates. Ninety percentage of positive serum tests for NMOSD are female patients, and Asian populations are three times more likely to have the condition compared to non-Asian groups. At the 2024 EAN Congress, Chuan Qin of Tongji Hospital, Wuhan, China, presented a recent study that conducted a single cell analysis of an anti-B cell maturation antigen (BCMA) CAR-T cell therapy in patients with CNS autoimmunity, namely NMOSD.
The research indicated a significant expansion of plasmablasts and plasma cells in cerebrospinal fluid (CSF) samples from patients with NMOSD. Unlike circulating B cells, these CNS-resident B cells showed enrichment in complement, IL-6, suggesting that CSF and blood B cells have different origins. Current treatment options for NMOSD are monoclonal antibody therapies, of which there are three; however, mAb treatments face limitations due to poor blood–brain barrier penetration.
Anti-BCMA CAR-T cells effectively crossed the blood-CSF barrier, targeted pathogenic plasma cells, and mitigated neuroinflammation in patients with NMOSD
In their study, Qin and colleagues investigated solutions to overcome this shortfall, designing BCMA CAR-T cell therapy to target an antigen predominantly expressed in plasma cells and mature B cells, BCMA. CAR-T cells have much better permeability through the blood–brain barrier. The clinical trial followed a '3+3' doseescalating design with patients with NMOSD who had recurrent attacks despite standard treatments.
had enhanced bowel and bladder function showed better ambulation of patients had improved visual acuity achieved drug-free remission 75 67 50 92 % % % %
Results showed significant improvements, with 92% achieving drug-free remission at a median follow-up of 5.5 months. Notably, 50% of patients had improved visual acuity, 67% showed better ambulation, and 75% had enhanced bowel and bladder function. Single-cell analysis revealed that CAR-T cells displayed increased gene expression related to immune response and chemotaxis, aiding their entry into the CNS and resulting in neuroinflammation suppression.
Although promising, limitations should be considered when evaluating the significance of results including the small sample size of 12 patients. However, there is a strong basis for further research on the subject given the anti-BCMA CAR-T cells effectively crossed the blood-CSF barrier, targeted pathogenic plasma cells, and mitigated neuroinflammation in patients with NMOSD, demonstrating a therapeutic potential.
Advancements in the Early Identification and Treatment of Alzheimer’s Disease
THIS YEAR marked the 10th Congress of the European Academy of Neurology (EAN), hosted in Helsinki, Finland, from 29th June–2nd July 2024. The penultimate afternoon saw an insightful symposium that delved into the current advances in early identification of, and current anti-amyloid antibody therapies for, Alzheimer’s disease (AD). With talks from Sebastiaan Engleborghs, University Hospital Belgium, Ghent, Belgium; Milica Kramberger, University of Ljubljana, Slovenia; and Youssuf Saleh, University of Oxford, UK, this session identified the pillars of AD diagnosis and how the advent of novel disease-modifying therapies could revolutionise the field of AD treatment research.
EARLY DIAGNOSIS: AN ETHICAL CONUNDRUM
Engleborghs explained that the current approach to AD identification focuses on the concept of timely diagnosis; however, the ability to screen for AD before symptom onset raises an ethical debate. Should screening protocols be introduced for early disease identification while AD remains an incurable disease? All three speakers discussed the importance of patients reserving the right to choose to remain unaware of whether they have AD. However, with the emergence of disease-modifying therapies (DMT), particularly those targeting the earliest symptomatic phases of AD, there is an increasingly strong argument in favour of early diagnosis.
Whilst some patients would prefer not to receive a diagnosis, others, such as those with a family history of AD, are more likely to seek out screening opportunities to pursue early identification. Screening is usually carried out with apolipoprotein E (APOE) genotyping, as APOE is a significant genetic biomarker; however, clinical judgment remains crucial in determining cognitive decline and ultimately providing a diagnosis of AD. Differential diagnoses
of other neurodegenerative diseases with similar initial presentations, such as vascular cognitive impairment, dementia with Lewy bodies, and frontotemporal dementia, should also be considered. Before widespread screening could be rolled out, there is still a need for advancements in diagnosis protocol, specifically concerning biomarker-based approaches that, when partnered with APOE genotyping, could provide an even higher disease prediction rate.
BIOMARKERS: WHAT ARE THE OPTIONS?
The three core biomarkers used in the identification of AD are fluid, imaging, and blood biomarkers, the presence of which indicates the onset of neurodegeneration. Other signs of neurodegeneration include the levels of neurofilament light chain in cerebrospinal fluid (CSF), a nonspecific marker for neuronal injury or neurodegeneration, a decrease in hippocampal volume, and a decline in cognitive function as measured by subjective questionnaires.
Should screening protocols be introduced for early disease identification while AD remains an incurable disease?
FLUID BIOMARKERS
Kramberger discussed how fluid biomarkers, measured in plasma or CSF, are initially used to determine the presence of AD. The primary detectable fluid biomarker, found up to 18 years before symptom onset, is the amyloid beta peptide (Aβ). The secondary fluid biomarker is phosphorylated tau (P-tau), which is detectable 11 years before cognitive decline and has numerous isoforms that present at varying points along the AD continuum. The increased levels of these P-tau in CSF are in response to Aβ deposition in early AD, and as Aβ accumulates, the more widespread deposition of P-tau can be seen on tau-PET scans. However, in their 2020 study, Mattsson-Carlgren et al.1 discovered that two isoforms, P-tau217 and P-tau181, preceded a positive AD Tau-PET scan. Furthermore, elevated plasma phosphotau concentrations correlate with greater cognitive decline over time, validating its utility in assessing disease progression.
IMAGING TECHNIQUES
Neuroimaging biomarkers are detected using MRI or PET scans and are used to assess the stage and severity of the
disease. CT scans are also utilised to observe atrophy and vascular changes, while MRI offers more detailed insights that have proved a useful tool for decisions regarding patient suitability for DMTs. Other, more specific, neuroimaging biomarkers can be used collectively to create a detailed picture of a patient’s disease status. These include fluorodeoxyglucose-PET, which shows levels of neurodegeneration; amyloid-PET, which provides visualisation of amyloid plaques; and tau-PET, which detects the density and distribution of aggregated tau neurofibrillary tangles.
A recent study suggests that plasma P-tau, which surpasses amyloid-PET and structural MRI in sensitivity for forecasting cognitive decline, could rival tau-PET in predicting cognitive impairment over 6 years.2 Additionally, tau-PET scans are highcost, and given the predictive accuracy of P-tau serum, the fluid biomarker test could overtake tau-PET as the go-to method for tau protein identification.
BLOOD-BASED BIOMARKERS
Blood-based testing is also used, and, although currently less established, these tests offer a promising first step in a multi-
stage diagnostic process. Krambereger discussed a recent study that has underscored the growing significance of blood biomarkers given their high sensitivity and specificity in AD identification.3 These biomarkers demonstrate high sensitivity and specificity, making them a point of interest. However, real-life cohorts differ significantly from controlled research cohorts, introducing complexities such as comorbidities that can influence biomarker outcomes. To integrate blood-based biomarkers into routine clinical practice, substantial advancements are necessary. This includes standardising populations, establishing reference standards, and leveraging real-world datasets to comprehensively evaluate various factors that may impact diagnostic accuracy for AD.
The introduction of anti-amyloid treatments as DMTs for AD changes the field drastically
In the new revised criteria, these biomarker types are further subcategorised into three groups: core biomarkers, nonspecific biomarkers, and biomarkers of common non-AD co-pathologies.4 Kramberger explained: “The two latter markers are relevant to AD diagnosis and staging because AD most often occurs with co-pathologies in older adults.” Therefore, testing for these specific types of biomarkers could significantly impact clinical outcomes in older adults.
WHAT ARE THE CURRENT TREATMENT OPTIONS?
Engleborghs started his talk by explaining that addressing behavioural and psychological symptoms of dementia involves both non-pharmacological approaches, such as behavioural therapies, and pharmacological interventions, such as cholinesterase inhibitors and memantine, tailored to manage specific symptoms. Additionally, controlling cardiovascular risk factors, promoting cognitive and physical activities, and moderating alcohol intake have been shown to positively influence
disease progression in individuals with AD. These multifaceted approaches underscore the comprehensive nature of current treatment strategies in managing AD symptoms and improving the overall quality of life (QoL) for patients. Engleborghs stated that the introduction of anti-amyloid treatments as DMTs for AD changes the field drastically. From there, the operational, societal, and ethical considerations of DMTs were outlined.
DISEASE-MODIFYING THERAPIES: A BRIEF HISTORY
Although there are currently two DMTs available in the USA, neither of these options were available in Europe at the time of the EAN 2024 Congress. The first DMT was granted approval by the FDA in 2021, with a 2016 study demonstrating the drug’s ability to clear amyloid plaques in patients with AD.5 As explained by Engleborghs, the effects of the drug on cognitive decline were initially inconclusive; subsequent posthoc analyses indicated potential cognitive benefits at higher doses, although further rigorous evidence is needed to confirm these findings. Despite these uncertainties, the conditional approval from the FDA marked a significant step forward in the treatment landscape for AD.
The second DMT showed a significant slowdown in cognitive decline among patients receiving the drug compared to those on a placebo. A 2022 study demonstrated that the drug exhibited promising results in preserving QoL with less decline observed in treated individuals compared to those in the placebo group.6 These clinical findings were considered meaningful, leading to its approval by the FDA. The third and final DMT demonstrated a slowing in cognitive decline by approximately 30%, offering a clinically relevant effect.7 However, only a small proportion of patients with AD will be eligible for these DMTs. There is an indication, though not yet conclusive evidence, that the earlier these treatments are introduced, the more significant the impact on delaying disease progression.
In his closing remarks, Engleborghs emphasised that several clinical and ethical questions remain unanswered, including the necessity for clinical trials in preclinical AD, the requirement for postmarketing monitoring and research, and the need for ongoing research into new therapeutic targets. In the near future, DMTs are anticipated to include antiamyloid monoclonal antibodies that activate microglia, facilitate phagocytosis of fibrillar amyloid, and promote degradation in the endosomal/lysosomal system.
WHAT CAN WE DO NOW?
The final speaker of the session, Saleh, reflected on what researchers and healthcare professionals could be doing going forward. This included selecting the right patients for DMTs, assessing the efficacy of these treatments, and monitoring disease progression. One
method of measuring disease progression between these stages involves using neurofilament light chain as a biomarker of neuronal injury, which sensitively detects neurodegeneration and can predict progression to an AD diagnosis. While it serves as a primary endpoint in clinical trials for amyotrophic lateral sclerosis, neurofilament light chain has not yet been fully validated for use in AD. Unlike serum biomarkers, PET imaging provides a spatial view of pathology, offering insights into disease staging and progression monitoring. It has been effectively utilised to assess treatment efficacy, employing a PET-based staging system.
CONCLUSION
Considerations regarding diagnostic procedures and their ethical implications are multifaceted as the psychological burden of a patient being diagnosed with
The primary detectable fluid biomarker, found up to 18 years before symptom onset, is the amyloid beta peptide (Aβ)
Neuroimaging biomarkers are detected using MRI or PET scans and are used to assess the stage and severity of the disease
an incurable disease must be taken into account. There is ongoing debate regarding the implementation of population-level screening versus targeted case-finding strategies. The potential benefits of such approaches include the ability to detect AD early, which could lead to earlier interventions and better patient QoL. Proposed methods include initial evaluation by general practitioners, followed by confirmatory biomarker tests. Another ethical dilemma surrounds the routine use of APOE genotyping in AD diagnosis, given its strong association with increased risk but not a definitive diagnosis, necessitating careful genetic counselling. The overarching
References
1. Mattsson-Carlgren N et al. Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer's disease. Sci Adv. 2020;6(16):eaaz2387.
3. Coulthard E, Hosseini AA. Blood biomarkers: ready for clinical practice?
goal is to promote early diagnosis of AD to facilitate timely treatment with DMTs, underscoring the importance of ethical sensitivity in navigating these diagnostic pathways.
Finally, while biomarkers are the primary tool for AD identification, it is pertinent to remember that approximately 30% of cognitively intact elderly people are amyloid positive, and the eventual development of symptoms cannot be predicted.8 Therefore, it is when neuropsychological assessments, neuroimaging techniques, and biomarkers are used collectively that a definitive diagnosis can be made.
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J Neurol Neurosurg Psychiatry. 2023;94(6):409-10.
4. Jack CR Jr et al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimers Dement. 2024. [Epub ahead of print].
5. Sevigny J et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. 2016;537(7618):50-6.
6. van Dyck CH et al. Lecanemab in early Alzheimer's disease. N Engl J Med.
2023;388(1):9-21.
7. Sims JR et al. TRAILBLAZER-ALZ 2 Investigators. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):51227.
8. Petersen KK et al. Predicting amyloid positivity in cognitively unimpaired older adults: a machine learning approach using A4 data. Neurology. 2022;98(24):e2425-35.
NEUROMODULATION was the overarching theme of the European Academy of Neurology (EAN) Congress 2024, held from 29th June–2nd July in Helsinki, Finland. Hot topics and future directions in invasive neuromodulation were discussed in an exciting session chaired by Elena Moro, CHU Grenoble, France, and Jukka Peltola, Tampere University, Finland, addressing new techniques such as deep brain stimulation (DBS) and focused ultrasound for the treatment of a range of neurological disorders.
DEEP BRAIN STIMULATION FOR MOVEMENT DISORDERS
Publications in the field of DBS have been increasing exponentially since 2000, explained Moro, and movement disorders are the area in which DBS has the most success. DBS of the subthalamic nucleus (STN) is now a recognised surgical treatment option in advanced Parkinson’s disease (PD), and continues to be effective beyond 15 years from the time of intervention.1 The EAN and Movement Disorder Society (MDS) have published guidelines for invasive treatment in PD, with strong evidence that DBS is effective in relieving motor symptoms not only in advanced PD, but also in early PD with motor fluctuations.2
The landscape of DBS device development has undergone huge advances; for instance, in the field of electrodes, the use of directional leads can now allow for a more targeted therapeutic effect, avoiding potential adverse events. Moro also highlighted the emerging role of subthalamic beta-band activity as a feedback signal for DBS, and a realtime ‘biomarker’ of PD motor symptom severity. Beta-band activity is particularly concentrated in the motor area of the STN in patients with PD, where the electrode is placed for stimulation.
The higher the energy supplied to the STN, the stronger the suppression of Parkinsonian beta oscillations, leading to better patient outcomes in terms of rigidity and bradykinesia. Moro explained that this neurostimulation is able to ‘normalise’ the pathological brain patterns associated with PD. A similar phenomenon has also been observed in theta activity of patients with dystonia, with recent data suggesting a selective modulation of the cortico-basal ganglia network activity during globus pallidus internus DBS.3
Based on this exciting data, Moro introduced the concept of adaptive stimulation, which could enable the reading of patient-specific electrical signals with electrodes, and react accordingly to fine-tune the voltage current sent to the brain. “How could adaptive/closedloop stimulation improve the current DBS outcome in movement disorders?” he asked. Permanent electrodes can now record beta activity in patients with PD, both at home and in the clinic, and modulate this activity in real-time. Moro explained that future focus should lie in improving stimulation programming, with faster programming and more effective paradigms; helping to better understand pathophysiologic biomarkers for gait and balance issues, as well as neuropsychological issues; and reducing unnecessary stimulation with less DBS-
induced dyskinesia, dysarthria, and ataxia, and potentially less maladaptive stimulation effects. Moro added that the new era of digital health, AI, and neuroimaging will also revolutionise the DBS field in the near future.
HIGH-INTENSITY FOCUSED ULTRASOUND ABLATION
Raul Martinez-Fernandez, Centro Integral de Neurociencias HM Cinac, Madrid, Spain, explained that focused ultrasound (FUS) lies in the range of non-invasive to mildly invasive neuromodulation. He opened his session discussing ablation, the only FUS approach currently approved for clinical use. High-intensity FUS thermoablation uses a temperature increase to perform lesions on patients with PD, and carries the key advantage of not requiring any surgical incisions, as opposed to craniectomy or brain penetration, and producing the lesion progressively and in a controlled manner.
A lot of the evidence underlying the performance of a lesion is based on neuromodulation of abnormal brain networks. Recent findings from thalamotomy for essential tremor and PD showed that it led to the reversal of neural networks or metabolic patterns related to these conditions. In a milestone study in 2016, patients who underwent FUS thalamotomy showed significantly higher improvement in tremor compared to the sham procedure group.4 Furthermore, across various studies of FUS thalamotomy, FUS subthalamotomy, and globus pallidus FUS for PD, treated patients underwent a significant 62% reduction in tremor, 52% reduction in Parkinsonism, and 69% treatment response (≥3 point increase in dyskinesia or motor scale) compared to the sham arm, respectively.
Martinez stressed that long-term follow-up of patients is crucial, as PD is a progressive, neurodegenerative condition. In a recent study, Martinez et al.5 found that, after 3 years, the effect of a well-located lesion is sustained, with patient symptoms remaining more controlled than at baseline.
Although side effects, such as gait and speech impairment, tingling, and motor weakness, are frequent after FUS ablation, they usually resolve over the weeks or months following FUS.
Long-term follow-up of patients is crucial, as PD is a progressive, neurodegenerative condition
Beyond unilateral ablation, Martinez also touched on bilateral ablation. The bilateral approach, historically associated with more complications, has been revisited in recent studies with the less invasive FUS technique. However, these studies are still preliminary, and Martinez emphasised that selecting the right patients is crucial in order to maximise therapeutic effects and minimise side effects.
Summarising the indications for FUS ablation, Martinez listed focal motor impairment (e.g., tremor, asymmetrical Parkinsonism, dystonia), medically refractory patients, and patients who are disabled. FUS ablation has been refined over the past few years, and will continue to improve in future years. Critical learning points for clinicians will include patient selection, improvement in treatment performances through technological advances, and patient management and follow-up. He stressed the importance of selecting the right approach, such as DBS or FUS, for the right patient. “These are not competitive, but complementary tools,” he said.
Across various studies of FUS thalamotomy, FUS subthalamotomy, and globus pallidus FUS for PD, treated patients underwent a significant reduction in tremor, and reduction in Parkinsonism
% %
Different to thermoablation, BBB opening produces a mechanical effect, opening the tight junctions of the BBB
BLOOD-BRAIN-BARRIER OPENING
Martinez moved on to another application of FUS, moving away from ablation, to low intensity blood-brain-barrier (BBB) opening. This approach does not aim to treat conditions symptomatically, but to slow down the neurodegenerative process. It consists of the injection of a contrast agent in the bloodstream, and delivery of low intensity energy on focal areas of the brain. Different to thermoablation, BBB opening produces a mechanical effect, opening the tight junctions of the BBB. Phase I studies for AD, amyotrophic lateral sclerosis, and PD have now been conducted, including a pilot exploratory study of striatal BBB opening in PD,6 as the striatum is one of the key structures of neurodegeneration in PD. In another preliminary 2024 study for AD, ultrasound BBB opening was performed in the frontal lobe of one hemisphere, using the non-treated hemisphere as a control, and coupled with aducanumab monthly for 6 months, which led to a significant reduction in amyloid burden in the treated hemisphere, increasing the therapeutic effect of aducanumab.7
This approach is also receiving a lot of attention in neuro-oncology, with several ongoing studies assessing the effect of BBB opening in the borders of operated brain glial tumours to increase the effect of chemotherapy. Martinez added that BBB also holds promise as a diagnostic tool, as a form of liquid biopsy to detect molecules for glial tumours or neurodegeneration(e.g., α-synuclein, tau) travelling into the bloodstream.
LOW-INTENSITY FOCUSED ULTRASOUND NEUROMODULATION
The last FUS approach discussed by Martinez was low-intensity FUS neuromodulation, which is also not a thermal, but mechanical, type of modulation. The main advantage of this novel approach, compared to transcranial magnetic stimulation or electrical stimulation, is that it enables clinicians to reach deep brain areas, such as the globus pallidus internus or STN. Studies have suggested that this approach works via
modulation of calcium mechanosensitive ion channels, and pathology data from animal models have shown that it is a ‘harmless’ technique. Preliminary studies have applied low-intensity FUS neuromodulation to patients with drug-resistant epilepsy, PD, and essential tremor, with promising results.
References
1. Bove F et al. Long-term outcomes (15 years) after subthalamic nucleus deep brain stimulation in patients with Parkinson disease. Neurology. 2021;97(3):e254-62.
2. Deuschl G et al. European Academy of Neurology/Movement Disorder Society - European Section guideline on the treatment of Parkinson’s disease: I. Invasive therapies. Eur J Neurol. 2022;29(9):2580-95.
Martinez summarised that FUS can be used in different modalities, with different objectives. While FUS ablation is clinically approved and effective in treating essential tremor and PD, FUS with BBB opening is now a potential technique for disease modification in neurodegeneration, and FUS neuromodulation has emerged as a new, non-invasive tool.
3. Averna A et al. Pallidal and cortical oscillations in freely moving patients with dystonia. neuromodulation. 2023;26(8):1661-7.
4. Elias WJ et al. A randomized trial of focused ultrasound thalamotomy for essential tremor. N Engl J Med. 2016;375(8):730-9.
5. Fundación de investigación HM. Subthalamotomy by ExAblate transcranial system to treat motor features of Parkinson’s disease.
6. InSightec. A study to evaluate temporary blood brain barrier disruption in patients with parkinson’s disease dementia. NCT03608553. https://clinicaltrials.gov/study/ NCT03608553
7. Rezai AR et al. Ultrasound blood-brain barrier opening and aducanumab in Alzheimer’s disease. N Engl J Med. 2024;390(1):55-62.
Reimagining Myasthenia Gravis Care: Current Strategies and
New Developments
This symposium took place at the European Academy of Neurology (EAN) Annual Congress, held from 29th June–2nd July 2024 in Helsinki, Finland
Speakers: John Vissing,1,2 Heinz Wiendl,3 Kristl Claeys4
1. Copenhagen Neuromuscular Centre, Rigshospitalet, Denmark
2. University of Copenhagen, Denmark
3. Department of Neurology with the Institute for Translational Neurology, University Hospital of Münster, University of Münster, Germany
4. Department of Neurology and Neuromuscular Reference Centre (NMRC), University Hospital Leuven, Belgium
Disclosure: The symposium was sponsored by Janssen Pharmaceutica N.V., a Johnson and Johnson company. Vissing has participated in advisory boards, or received honoraria or research support from Alexion Pharmaceuticals, argenx BVBA, Dianthus Therapeutics, Horizon Therapeutics, Johnson & Johnson, NMD Pharma, Regeneron, Roche, Toleranzia AB, and UCB Biopharma SPRL; and has been a principal investigator in myasthenia gravis clinical trials sponsored by Alexion Pharmaceuticals, argenx BVBA, Dianthus Therapeutics, Horizon Therapeutics, Janssen Pharmaceuticals, Novartis Pharma AG, Regeneron, Roche, and UCB Biopharma SPRL. Wiendl has participated in scientific advisory boards, or received speaker honoraria, from Alexion, Argenx, AstraZeneca, Argo Biopharma, BioCryst Pharmaceuticals, Bristol Myers Squibb, Dianthus Therapeutics, Immunovant, Inc., Johnson and Johnson, Muna Therapeutics, Myrobalan Therapeutics, and Novartis; and has also received myasthenia gravis research support from Alexion, Argenx, and Deutsche Myasthenie Gesellschaft e.V. Claeys has received speaker and advisory board honoraria from Alexion, Alnylam, Amicus Therapeutics, ArgenX, Biogen, CSL Behring, Ipsen, Johnson & Johnson, Lupin, Pfizer, Roche, Sanofi-Genzyme, and UCB; and research funding from CSL Behring and Roche.
Acknowledgements: Medical writing assistance was provided by freelance medical writer Amanda Barrell, Brighton, UK.
Disclaimer The opinions expressed in this article belong solely to the named speakers.
Keywords: Acetylcholine receptor, activities of daily living (ADL), batoclimab, C5 complement inhibitor, efgartigimod, generalised myasthenia gravis (gMG), myasthenia gravis (MG), neonatal Fc receptor (FcRn), neuromuscular junction, nipocalimab, patient care, standard of care (SOC), therapeutic strategies.
Support: The support for the publication of this article was provided by Janssen Pharmaceutica N.V., a Johnson and Johnson company. The symposium content and views expressed herein are those of the speakers. The content is intended solely for EMEA healthcare professionals. Medical writing was provided by EMJ. Johnson & Johnson reviewed for accuracy and compliance.
PHARMA PARTNERSHIP
Meeting Summary
Myasthenia gravis (MG) is an autoimmune disease caused by autoantibodies targeting proteins on the neuromuscular junction. Around 85% of patients have antibodies against the muscle acetylcholine receptor (AChR), while up to 10% have antibodies against the muscle-specific kinase (MuSK). Rarer forms of the condition are low-density lipoprotein receptor-related protein 4 (LRP4) positive MG, and seronegative MG, in which no AChR, MuSK, or LRP4 autoantibodies are detected. MG, which can be ocular or generalised, is characterised by muscle weakness, which can be severe and debilitating.
Despite advances in treatment, a significant proportion of patients living with generalised MG (gMG) continue to experience symptoms and poor quality of life (QoL). During this symposium, John Vissing, Professor of Neurology at the University of Copenhagen, and Director of the Copenhagen Neuromuscular Centre, Denmark; Heinz Wiendl, Professor of Neurology at the University of Münster, Germany; and Kristl Claeys, Professor of Neurology at the University of Leuven, Belgium, discussed the current challenges and future potential of MG treatments. They emphasised the need for patient-centred evaluations, discussed the pathophysiology, and highlighted the challenges of current immune therapies. They also explained how new generations of targeted immune therapies, such as neonatal Fc receptor (FcRn) inhibitors, could help tackle this area of unmet need by potentially ameliorating disease manifestations.
Introduction
MG is a rare immunoglobulin G (IgG) autoantibody-mediated disease, characterised by fluctuating weakness of the voluntary muscles.1 The weakness, which tends to worsen with activity as the day progresses,1 is caused by the pathogenic IgG-mediated disruption of cholinergic transmission at the neuromuscular junction.1,2 The majority of people with MG, around 85%, are AChR+, and up to 10% have antibodies against MuSK.3 Rarer forms of the condition are seronegative MG, in which no AChR, MuSK, or LRP4 autoantibodies are detected, and LRP4+.3
In ocular MG, the weakness affects the extraocular muscles, manifesting as diplopia and palpebral ptosis.1 gMG can also affect the bulbar muscles (causing difficulties with speaking, swallowing,
and chewing), the extremities (impeding gait and everyday activities), or axial muscles (causing weakness in the back and neck, and leading to painful spasms).1 gMG treatments include cholinesterase inhibitors, immunosuppressants, and targeted immunotherapies; yet, symptom persistence, exacerbations, and side effects are common with current therapies.2
Optimising Patient Outcomes and Satisfaction
While the past few decades may have seen a drastic reduction in gMG mortality,4 many patients still experience symptoms and poor QoL.5,6 “We have come a long way,” said Vissing, explaining that in the decade following diagnosis, many patients become asymptomatic, “but we still have
quite a big group of patients, 15–20%, who have significant symptoms at two years.”7 Illustrating the impact this can have on people’s lives, Vissing shared a video of a 41-year-old female talking about living with gMG. Her disease manifestations, the patient said, included difficulty breathing, chewing, swallowing, and speaking, as well as cognitive challenges, which can vary from “day to day, week to week, and month to month.” “I might have reasonably wellcontrolled symptoms in the morning, but by the evening I may not be able to get up and down the stairs,” she said, adding that when her symptoms were under control, she lived “what looks like a normal life on the outside.” “But I miss out on a lot of things because I am very aware of not overextending or asking too much of my body and causing an exacerbation. […] It can be a very lonely disease […] because you have to continually cancel plans […] and miss out on the things that give life texture and colour,” the patient said.
Patient-Centred Evaluation
Currently, there are limited data on the time it takes to reach an acceptable state, or remission, in MG, and most studies assessing long-term outcomes are rated by clinicians rather than patients, said Vissing. Minimal symptom expression (MSE), defined as an MG Activities of Daily Living (MG-ADL) total score of 0–1,8 could be a patient-centred way to measure disease impact. In a study of 85 patients with AChR+ refractory gMG treated with immunotherapy, 55.8% had reached MSE by Year 1, and 60.3% at Year 2.9 “The amount of time to achieve MSE in patients undergoing immunotherapy was very long, and not all patients managed to achieve it,” said Vissing, adding that another study had shown patients with a high disease burden (MG‐ADL score ≥6) “rarely achieved” MSE after 1 year of treatment.10
The Patient Acceptable Symptom State (PASS), which defines a threshold of the individual’s satisfaction with their MG status, is another patient-centred method of assessing symptom burden.11 It consists of a single, dichotomous question, i.e.: "Considering all the ways you are affected
by myasthenia gravis, if you had to stay in your current state for the next months, would you say that your current disease status is satisfactory?"11 Response options are "yes" or "no".11 Studies using PASS have shown that patient dissatisfaction with disease state is common. In one study of 100 patients living with gMG, one-third reported a negative PASS status, meaning they were dissatisfied with their current symptom state.12 Increasing MG symptoms, fatigue, depression, low MG-related QoL, and shorter disease duration were all associated with a negative PASS status.12 In another study of 86 patients with MG, the median time to reach a positive PASS status after a post-diagnosis negative PASS status was 15 months (95% CI: 11–18).11 Of the 67 patients with MG who achieved PASS ("yes"), 61 (91%) achieved it by 25 months post-diagnosis (Figure 1).11
In addition, the estimated thresholds for commonly used MG health scales, including the MG-ADL, the Quantitative MG Scale (QMGS), MG Composite (MGC), Myasthenia Quality of Life (MG-QoL15), and EuroQol 5-Dimension (EQ5D), all reflected patientacceptable states, as per the PASS status.13
Time for Change
Vissing explained that the gMG field is “turning towards the potential of patientcentred assessment.” The MG-ADL, for example, is now a common primary outcome of MG clinical trials,14 and a recent consensus paper recommended the use of PASS following MG-ADL.15 “PASS is a wonderful key to the toolbox, if the patient answers 'no', we open the toolbox and start investigating, whether they are depressed, whether they have symptoms, and so on. It’s a really good question, it takes no time at all, and it complements the MG-ADL,” Vissing said.
ABC of Current gMG Treatments
The fact that many patients still report poor QoL, despite the wide range of therapies available, shows there is a need for “better, quicker acting, more efficacious medicines”, Vissing said.
Figure 1: Time to Patient Acceptable Symptom State (PASS) “Yes” with Kaplan-Meier (n=67).11
Median time to PASS “Yes”: 15 months (95% Cl: 11–18)
Outlining the current gMG treatment landscape, Wiendl explained that cholinesterase inhibitors, such as pyridostigmine, are usually prescribed as a first-line therapy and, in mild MG, can produce rapid relief of symptoms.16 However, most people living with the condition will also require immunosuppressive treatment to suppress autoantibody production. 16 Wiendl explained that autoantibodies drive gMG pathophysiology by altering the neuromuscular junction, resulting in weakened signal transduction and impaired muscle contraction.17,18 Depending on the type of gMG, the autoantibodies target key molecules at the neuromuscular junction, i.e., AChR, LRP4, or MuSK,18 and pathological changes in the thymus are believed to play a pivotal role in the pathogenesis of AChR+ MG.16 It is worth noting, however, that the pathophysiology of the disease is not yet fully understood in seronegative patients.18 Wiendl said: “We do not know if that is a sensitivity of detection issue, or whether there are other targets we have not yet recognised.”
Immune Therapy: Current Challenges and Future Potential
Immune therapy suppresses the overactivation of cellular elements of the specific and non-specific immune system. Current standard of care includes nonselective immunosuppressants, designed to inhibit or alter the immune response in the peripheral immune system.19 New treatment strategies, however, aim to selectively restore the body’s tolerance towards autoantigens, keeping the healthy immune system intact.20 “The Holy Grail of the new therapies is to alter the pathological process, and while not harming the rest of the immune system. To put it another way, if you eliminate the immune system, you would ‘cure’ MG, but the person couldn’t live,” Wiendl explained.
A number of immunosuppressive agents are currently available for the treatment of gMG. These include corticosteroids, azathioprine, mycophenolate mofetil, cyclosporin, cyclophosphamide, tacrolimus, and rituximab.21 Yet, such agents have
highly variable latency of action, with azathioprine, for example, taking between 6–18 months, and corticosteroids 2 weeks, to elicit a response.21 Furthermore, they can present substantial risks of severe adverse side effects, Wiendl said, adding: “MG is one of the diseases that is very treatable, in principle, with just corticosteroids. But they are nasty in their mid- and long-term side effects.” Potential corticosteroid-related adverse events include Cushing’s syndrome, hyperglycaemia, hypertension, stomach ulcers, and myopathy, as well as skin atrophy/thinning, cataracts and glaucoma, osteoporosis, and osteonecrosis.22 Steroids are not the only MG treatment that carries side effect risk. Azathioprine, for example, can cause hepatoxicity, leukopenia, and nausea, and mycophenolate mofetil may lead to nausea, vomiting, diarrhoea, leukopenia, and opportunistic infection. Cyclosporine A’s potential side effects include hypertension, paraesthesia, and nephrotoxicity.23 Rituximab, an anti-CD20 antibody, works by depleting B cells, an effect that persists even after treatment discontinuation, and elicits a lasting change to the immune repertoire.23,24
New, targeted agents, such as C5 complement inhibitors and FcRn blockers, are emerging for more selective treatment of gMG. “These two groups of molecular compounds are changing the picture of neurological immunotherapy dramatically,” explained Wiendl. Complement inhibitors, which have been developed in the AChR+ population only, prevent C5a-induced chemotaxis of the proinflammatory cells, thereby preventing the formation of C5b9-induced membrane attack complexes.25 This may prevent complement-mediated membrane damage at the post-synaptic membrane of the neuromuscular junction.25 FcRn blockers selectively target FcRn IgG recycling, lowering circulating IgG, including the pathogenetic autoantibodies.26 This, Wiendl said, may improve gMG manifestations. To date, the European Medicines Agency (EMA) has approved efgartigimod and rozanolixizumab,27,28 while two more FcRn blockers, nipocalimab and batoclimab, are currently in late-stage development.2,29 “These two groups of compounds [C5 complement inhibitors
and FcRn blockers] have considerable advantages over almost all the other immunotherapies we are currently using,” said Wiendl.
Evolving Treatment Pathways
Evolving from immunosuppressive to immune-targeted therapy will require collaboration with the medical community, and a focus on how to optimise the evolving gMG treatment landscape. Ending the talk, Wiendl highlighted a proposed treatment pathway, published in last year’s German Guideline for the Management of Myasthenic Syndromes (Table 1), to help guide individual treatment decisions.30
Current and Future FcRn Blockers
In the last presentation, Claeys provided a more in-depth overview of FcRn blockers. FcRn, she explained, is a receptor that binds to IgG and protects it from degradation, prolonging its half-life.26 This can result in decreased circulating IgG levels, including the pathogenic autoantibodies that are responsible for gMG symptoms.26
Four FcRn have been developed for gMG. Efgartigimod, which is delivered via intravenous (IV) or subcutaneous (SC) infusion, is indicated as an addon to standard therapy in adults with AChR+ gMG.27 Rozanolixizumab, which is delivered as a SC infusion, is indicated as an add-on to standard therapy for those with AChR+ or MuSK+ gMG.28 A Phase III trial of nipoclimab (NCT04951622), now completed, evaluated the agent, which is delivered via IV in AChR+, MuSK+, and LRP4+ patients with gMG. The trial was positive, meeting its primary endpoint (change of MG-ADL score from baseline to Weeks 22, 23, and 24).31,32 A Phase III trial of batoclimab (NCT05403541) is still ongoing in AChR+ patients, with a primary endpoint of change in MG-ADL score at Week 12.33 Each of these four FcRn inhibitors fall into one of two dosing pattern categories, namely cyclic, where patients undergo an initial cycle of treatment with any additional treatment cycle being based on clinical
Glucocorticoids and/or:
Azathioprine; Mycophenolate mofetil;*
Cyclosporine A;* Methotrexate*
Mild/moderate disease activity/ severity
Glucocorticoids and/or:
Azathioprine; Thymectomy
Surgery High disease activity/severity, including refractory to therapy
Complement inhibitors
FcRn modulators
CD20-antibodies*
Glucocorticoids and/or
Mycophenolate mofetil;*
Cyclosporine A;* Methotrexate;* Tacrolimus*
1
Glucocorticoids and/or
Azathioprine
Choice 2
Glucocorticoids and/or
Mycophenolate mofetil;*
Cyclosporine A;* Methotrexate;* Tacrolimus*
±Glucocorticoids and/or an additional treatment option for mild/moderate disease activity
evaluation, or predictable (fixed dosing), where treatment cycles are administered weekly or every 2 weeks.
• Cyclic dosing:
• efgartigimod: once weekly for 4 weeks, with re-treatment being based on upon symptom resurgence and clinical evaluation27
• rozanolixizumab: once weekly for 6 weeks, with re-treatment being based on upon symptom resurgence and clinical evaluation28
• Predictable dosing:
• nipocalimab: once every 2 weeks32
• batoclimab: once every 1 or 2 weeks33
FcRn Inhibitors: The Latest Data
Claeys gave an overview of the currently available data on FcRn efficacy and safety, starting with the ADAPT Phase III study of efgartigimod, in which the primary endpoint was percentage of AChR+ patients who were MG-ADL responders in the first treatment cycle (8 weeks).34 A total of 84 patients received 10 mg/kg IV
Table 1: Scheme for the disease-modifying therapy of myasthenia gravis.30
once weekly plus standard of care (SOC), while 83 received placebo plus SOC. Key inclusion criteria were gMG Myasthenia Gravis Foundation of America (MGFA) Class II–IV, with or without AChR antibodies; an MG-ADL score of ≥5; and receiving stable gMG treatment. Key exclusion criteria were rituximab or eculizumab in the previous 6 months, IV immunoglobulin (IVIg) or plasma exchange (PLEX) in the previous month, thymectomy in the previous 3 months, and pregnancy. At 8 weeks, 68% (44/65) of the AChR+ patients in the efgartigimod treatment group were MG-ADL responders, compared with 30% (19/64) in the placebo group (odds ratio: 4.95; 95% CI: 2.21–11.53; p<0.0001).34 The most common adverse events in the efgartigimod group were headache (29%), nasopharyngitis (12%), nausea (8%), diarrhoea (7%), upper respiratory tract infection (11%), and urinary tract infection (10%). These figures were broadly similar in the placebo plus SOC group. Rates of severe infection were low, at 1.2% (n=1) in the placebo plus SOC group, and 2.3% (n=2) in the treatment plus SOC group.34
The primary endpoint of the MycarinG Phase III study of rozanolixizumab was change in MG-ADL score from baseline to Day 43.35 Key inclusion criteria were MGFA Class II–IV, AChR+ or MuSK+, MG-ADL score ≥3, QMG score ≥11, and being considered for additional therapy, such as IVIg or PLEX. Key exclusion criteria were recent active/ serious infection, severe oropharyngeal or respiratory weakness, and myasthenic crisis, defined as total IgG ≤5.5 g/L. Over 6 weeks, 66 patients were randomised to weekly rozanolixizumab at 7 mg/kg plus SOC, 67 to weekly rozanolixizumab at 10 mg/kg, and 67 to placebo plus SOC. Greater reductions from baseline in MGADL score were observed at Day 43 for both rozanolixizumab groups than in the placebo with SOC group, with leastsquares mean differences from placebo of -2.59 (95% CI: -4.09 to -1.25; p<0.0001) for rozanolixizumab 7 mg/kg, and -2.62 (95% CI: -3.99 to -1.16; p<0.0001) for rozanolixizumab 10 mg/kg.35 There was one case (2%) of severe infection of COVID-19 pneumonia in the placebo plus SOC group,
and no severe or serious infections in either of the rozanolixizumab groups. Headache was the most common adverse event, affecting 29 (45%) of patients in the rozanolixizumab 7 mg/kg plus SOC group, and 26 (38%) in the rozanolixizumab 10 mg/ kg plus SOC group. In most cases, it was mild or moderate, with the more severe headaches being mainly recorded in the higher dose group.35
In the Vivacity-MG Phase III trial, 98 patients received nipocalimab plus SOC, and 98 received placebo plus SOC for 24 weeks.32 Key inclusion criteria were MGFA IIa-IVb, AChR+, MuSK+, LRP4+, or seronegative, and an MG-ADL score ≥6. Confirmed or suspected clinical immunodeficiency syndrome not related to gMG treatment and family history of congenital or hereditary immunodeficiency were the key exclusion criteria.31 Greater mean change in MG-ADL was seen with nipocalimab in seropositive patients with gMG over Weeks 22–24 (-4.7 points [standard error: 0.329]), with the difference of least-squares means compared with placebo plus SOC being -1.45 points (standard error: 0.470; p=0.002).32 The most common adverse events reported by the nipocalimab group were headache (14.3%), muscle spasms (12.2%), and peripheral oedema (11.2%), said Claeys. The rates of severe infection in this 24-week trial was 3.1% for the nipocalimab-treated patients, compared to 4.1% for the placebo group.”32
“Even though the FcRn inhibitors are lowering the IgG levels in the blood, it is clear that the rates of severe infection are very low,” Claeys said.
FcRn Inhibitors in Practice
In routine practice, there are potential benefits and advantages associated with both the cyclic and the predictable dosing patterns, Claeys noted. Sharing her personal opinion, she said: “In cyclic dosing, the benefit could be that the treatment cycles are administered based on the patient’s needs. For the predictable or fixed dosing, the benefits could be that this may provide a more sustained
disease control. Potential drawbacks in cyclic dosing could be that you have to wait for a clinical deterioration before you can start a new cycle of treatment, and the treatment-free periods could be short. The potential drawback for predictable dosing could be logistical challenges, such as patients having to come into the clinic every 2 weeks.” More real-world evidence and clinical experience, she added, is needed to help physicians understand which FcRn blockers will be most useful in which patient groups going forward.
References
1. Garzón-Orjuela N et al. Quality of life in refractory generalized myasthenia gravis: a rapid review of the literature. Intractable Rare Dis Res. 2019;8(4):231-8.
2. Antozzi C et al. Safety and efficacy of nipocalimab in patients with generalized myasthenia gravis: results from the randomized Phase 2 vivacity-MG study. Neurology. 2024;102(2):e207937.
3. Lazaridis K, Tzartos SJ. Autoantibody specificities in myasthenia gravis; implications for improved diag-nostics and therapeutics. Front Immunol. 2020;11:212.
4. Jordan A, Freimer M. Recent advances in understanding and managing myasthenia gravis. F1000Res. 2018;7:F1000.
5. Sobierajski T et al. Diagnosis and therapy of myasthenia gravis-the patients’ perspective: a cross-sectional study. Front Neurol. 2023;14:1214041.
6. Petersson M et al. Patient-reported symptom severity in a nationwide myasthenia gravis cohort: cross-sectional analysis of the Swedish GEMG study. Neurology. 2021;97(14):e1382-91.
7. Tomschik M et al. Subgroup stratification and outcome in recently diagnosed generalized myasthenia gravis. Neurology. 2020;95(10):e142636.
8. Vissing J et al. ‘Minimal symptom expression’ in patients with acetylcholine receptor antibodypositive refractory generalized myasthenia gravis treated with eculizumab. J Neurol. 2020;267(7):1991-2001.
9. Uzawa A et al. Minimal symptom expression achievement over time in generalized myasthenia gravis. Acta
Summing up, Claeys said: “FcRn blockers are targeted, biological drugs that could be effective, well tolerated, and used in a broad population of patients with gMG. The different dosing strategies offer benefits and drawbacks for different patients, and this may allow for a more personalised approach to treatment.”
Neurol Belg. 2023;123(3):979-82.
10. Lee I et al. One‐year follow‐up of disease burden and medication changes in patients with myasthenia gravis: from the MG Patient Registry. Muscle Nerve. 2022;66(4):411-20.
11. Martinez-Harms R et al. Time to achieve a patient acceptable symptom state in myasthenia gravis. Front Neurol. 2023;14:1187189.
12. Andersen LK et al. Causes of symptom dissatisfaction in patients with generalized myasthenia gravis. J Neurol. 2022;269(6):3086-93.
13. Mendoza M et al. Patient-acceptable symptom states in myasthenia gravis. Neurology. 2020;95(12):e1617-28.
14. Guptill JT et al. Addressing outcome measure variability in myasthenia gravis clinical trials. Neurology. 2023;101(10):442-51.
15. Meisel A et al. Expert consensus recommendations for improving and standardising the assessment of patients with generalised myasthenia gravis. Eur J Neurol. 2024;31(7):e16280.
16. Nair SS, Jacob S. Novel immunotherapies for myasthenia gravis. ImmunoTargets Ther. 2023;12:25-45.
17. Gilhus NE et al. Myasthenia gravisautoantibody characteristics and their implications for therapy. Nat Rev Neurol. 2016;12(5):259-68.
18. Koneczny I, Herbst R. Myasthenia gravis: pathogenic effects of autoantibodies on neuromuscular architecture. Cells. 2019;8(7):671.
19. Selter RC, Hemmer B. Update on immunopathogenesis and immunotherapy in multiple sclerosis. Immu-noTargets Ther. 2013;2:21-30.
21. Farmakidis C et al. Treatment of myasthenia gravis. Neurol Clin. 2018;36(2):311-37.
22. Liu D et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013;9:1-25.
23. Alhaidar MK et al. Current treatment of myasthenia gravis. J Clin Med. 2022;11(6):1597.
24. Pollastro S et al. Sensitive B-cell receptor repertoire analysis shows repopulation correlates with clinical response to rituximab in rheumatoid arthritis. Arthritis Res Ther. 2024;26(1):70.
25. Mantegazza R et al. Complement inhibition for the treatment of myasthenia gravis. Immunotargets Ther. 2020;9:317-31.
26. Zhu LN et al. FcRn inhibitors: a novel option for the treatment of myasthenia gravis. Neural Regen Res. 2023;18(8):1637-44.
27. European Medicines Agency (EMA). Vyvgart Summary of Product Characteristics. 2022. Available at: https://www.ema.europa.eu/en/ documents/product-information/ vyvgart-epar-product-information_ en.pdf. Last accessed: 2 July 2024.
28. European Medicines Agency (EMA). Rystiggo Summary of Product Characteristics. 2024. Available at: https://www.ema.europa.eu/en/ documents/product-information/ rystiggo-epar-product-information_ en.pdf. Last accessed: 2 July 2024.
20. Fissolo N et al. Treatment with MOGDNA vaccines induces CD4+ CD25+ FoxP3+ regulatory T cells and upregulates genes with neuroprotective functions in experimental autoimmune encephalomyelitis. J Neu-roinflamm. 2012;9:1-3.
29. Benatar M et al. Batoclimab as induction and maintenance therapy in patients with myasthenia gravis:
rationale and study design of a Phase 3 clinical trial. BMJ Neurol Open. 2024;6(1):e000536.
30. Wiendl H et al. Guideline for the management of myasthenic syndromes. Ther Adv Neurol Disord. 2023;16:17562864231213240.
31. Janssen Research & Development, LLC. A study of nipocalimab administered to adults with generalized myasthenia gravis. NCT04951622. https:// clinicaltrials.gov/study/NCT04951622.
32. Antozzi C et al. Efficacy and safety
of nipocalimab in patients with generalized myasthenia gravis- top line results from the double-blind, placebo-controlled, randomized Phase 3 vivacity-MG3 study. Poster EPR116. European Academy of Neurology Congress, 29 June–2 July, 2024.
33. Immunovant Sciences GmbH. Phase 3 study to assess the efficacy and safety of batoclimab as induction and maintenance therapy in adult participants with generalized myasthenia gravis. NCT05403541. https://clinicaltrials.gov/study/
NCT05403541.
34. Howard JF et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, Phase 3 trial. Lancet Neurol. 2021;20(7):526-36.
35. Bril V et al. Safety and efficacy of rozanolixizumab in patients with generalised myasthenia gravis (MycarinG): a randomised, double-blind, placebo-controlled, adaptive Phase 3 study. Lancet Neurol. 2023;22(5):38394.
Updated Insomnia Guidelines and Latest Real-World Evidence Data on Daridorexant
This symposium took place on the 30th June 2024, as part of the 10th Congress of the European Academy of Neurology (EAN) held in Helsinki, Finland, between the 29th June–2nd July 2024
Chairperson: Anna Heidbreder1
Speakers: Yves Dauvilliers,2 Diego García-Borreguero,3 Claudio Liguori4,5
1. Kepler University Hospital, Linz, Austria
2. Université de Montpellier, France
3. Sleep Research Institute, Madrid, Spain
4. Sleep Medicine Center and Epilepsy Center, Neurology Unit, University Hospital of Tor Vergata, Rome, Italy
5. Department of Systems Medicine, University of Rome Tor Vergata, Italy
Disclosure: Heidbreder has received honoraria for lectures and/or advisory boards from Bioprojet, Idorsia, Inspire, and Vanda. Dauvilliers has received fees for seminars, board engagement, and travel to and from conferences from Avadel Pharmaceuticals, Bioprojet, Idorsia, Jazz Pharmaceuticals, Orexia Therapeutics, and Takeda. García-Borreguero has received research support from MSD and Roche; and has acted as a consultant for American Regent, Emalex Biosciences, Ferrer International SA, Idorsia, Liu Pharma, Roche, and Synendos Pharma. Liguori has served on speaker boards, as a consultant, advisory board member, or author, or received research funding from Altis Pharma, Angelini Bioprojet, Bruno Farmaceutici, Cristalfarma, Ecupharma, Energy Health, Eisai, Idorsia, Italfarmaco, Jazz Pharmaceuticals, Kolfarma, Lundbeck, Medicair, Takeda, UCB, and Zambon.
Acknowledgements: Medical writing assistance was provided by Samantha Coates, Reading, UK. Thanks are given to the presenters of the sessions summarised in this article.
Support: The publication of this article was funded by Idorsia, who reviewed the content for medical accuracy. The views and opinions expressed are exclusively those of the speakers.
Meeting Summary
During this symposium, held at the 10th Congress of the European Academy of Neurology (EAN), speakers highlighted that chronic insomnia disorder (CID) is under-recognised and under-treated. Comorbid disorders associated with CID include
PHARMA
psychiatric conditions, neurological disorders, and cardiovascular disease. Untreated, CID can negatively impact mental, physical, and occupational health. Consequently, the presence of CID should be evaluated and actively treated independent of comorbidities.
The concept of CID is characterised by a perpetuating cycle of hyperarousal. It is proposed that dual orexin receptor antagonists (DORAs) reduce hyperarousal and restore sleep–wake balance via antagonism of orexin 1 and orexin 2 receptors.
The European Insomnia Guidelines 2023 recommend cognitive behavioural therapy for insomnia (CBTi) as first-line treatment in adults. CBTi can be administered inperson or digitally. However, CBTi is not always available, can be costly in terms of time and resources, and not all individuals respond to therapy. Where CBTi is not effective or practical, the guidelines recommend short-term therapy (≤4 weeks) with benzodiazepines, benzodiazepine receptor agonists, the DORA daridorexant, or lowdose sedating antidepressants. DORAs can be used for >3 months in some cases, and prolonged-release melatonin for up to 3 months in individuals aged ≥55 years.
In Phase III trials, daridorexant reduced electroencephalography (EEG) features associated with hyperarousal in individuals with CID, reduced cumulative night-time waking, particularly time spent in long wake bouts, and improved daytime functioning. Real-world evidence showed that daridorexant improved sleep parameters in individuals with CID, including those with and without neurologic and psychiatric comorbidities.
Introduction
Chronic insomnia disorder is defined as difficulty falling asleep, staying asleep, and/ or early-morning awakening experienced at least three times per week for at least 3 months, with impairment in daily functioning.1 Chronic insomnia disorder is the most prevalent sleep disorder worldwide, with 6–15% of adults globally meeting diagnostic criteria.1,2
Anna Heidbreder, Kepler University Hospital, Linz, Austria, explained that insomnia prevalence is not equal across the population: it increases with age,3 and is increased in specific population groups, including females and those with comorbid neurological conditions (e.g., Parkinson’s disease, multiple sclerosis, Alzheimer’s disease, and restless legs syndrome).4-7 Furthermore, there is an association between chronic insomnia disorder and other major comorbidities, including cardiovascular disease, Type 2 diabetes, and mental health disorders (e.g., depression, anxiety, post-traumatic stress disorder).6,8,9
Disease Burden of Chronic Insomnia Disorder
Heidbreder emphasised that insomnia is a “24-hour disease,” as in addition to nighttime symptoms (difficulty initiating or maintaining sleep and/or early-morning awakening despite adequate opportunity for sleep), chronic insomnia disorder also impacts daily living. Indeed, insomnia can lead to difficulties with social, occupational, cognitive, academic, and behavioural functioning.3,10 Chronic insomnia can lead to difficulties with social, occupational, cognitive, academic and behavioural functioning, negatively impacting mental, physical and occupational health, and decreasing health-related quality of life (HRQoL).1,11 Additionally, there are implications for public safety, with an increased risk of road- and work-related accidents in individuals who have insomnia versus those without.1,12
Claudio Liguori, University Hospital of Tor Vergata, and Department of Systems Medicine, University of Rome Tor Vergata, Italy, highlighted that chronic insomnia
disorder can exacerbate, or contribute to, comorbid conditions. For example, sleep alteration may be considered as a marker of early-stage Alzheimer’s disease.13 Furthermore, insomnia is highly prevalent in individuals with neurological disease (7.3% overall prevalence for any neurological condition), with particularly high prevalence in vascular dementia (67%), headache (53–61%), Parkinson’s disease (54–60%), epilepsy (34–58%), obstructive sleep apnoea (39–58%), mild cognitive impairment (44%), Alzheimer’s disease (25–35%), restless legs syndrome (17–26%), and multiple sclerosis (23%).6,7,14,15
Liguori stressed that, regardless of comorbidities, chronic insomnia disorder is recognised as a distinct condition, requiring specific and adequate management.16 As discussed later, recent real-world studies have investigated the impact of pharmacological treatment for chronic insomnia disorder in individuals with comorbid conditions, including obstructive sleep apnoea and psychiatric disorders.
Sleep Architecture in Chronic Insomnia Disorder
Yves Dauvilliers, Université de Montpellier, France, explained that sleep architecture varies across individuals with chronic insomnia disorder.16 Compared with a ‘good sleeper’, people with chronic insomnia disorder may show a high number of arousals and fragmented rapid eye movement (REM) sleep, or overall shortened sleep duration on EEG.16 Common to both of these profiles is a perpetuating cycle of hyperarousal.17,18
The Role Played by Orexin in Sleep–Wake Balance and Hyperarousal
Dauvilliers explained that, in the absence of insomnia, sleep–wake balance is mutually inhibitory and anchored by the neuropeptide, orexin.19,20 On the contrary, in individuals with chronic insomnia disorder, it is thought that a
dysregulation of orexin activity occurs. Therefore, antagonism of orexin 1 and orexin 2 receptors by DORAs is needed to reduce orexin activity and effectively ‘switch off’ hyperarousal, restoring the sleep–wake balance (Figure 1).17,18
Evidence for Hyperarousal as an Underlying Cause of Insomnia
Hyperarousal has been investigated as an underlying cause of insomnia using multiple methodologies. Dauvilliers presented results from a post hoc analysis including pooled data from clinical trials and polysomnography (PSG) studies. EEG features associated with hyperarousal were increased in people with chronic insomnia disorder versus those without. Specifically, during wake and sleep Stage 1 (N1), individuals with insomnia had increased relative alpha and theta power, but reduced relative delta power, compared with those without insomnia. In addition, during N2, relative delta power decreased in those with insomnia versus those without insomnia.21
Data from PET further support a role for hyperarousal in chronic insomnia disorder. In a study assessing regional cerebral glucose metabolism, higher metabolic activity in wake-promoting brain regions, including the anterior cingulate cortex, hypothalamus, and ascending reticular activating system were detected during wake-to-non-REM (NREM) sleep transition in those with insomnia versus controls.22,23 This failure of arousal mechanisms to decline during wake-to-sleep transition may translate into an inability to fall asleep. Additionally, individuals with insomnia had reduced metabolic activity in wake-promoting brain regions while awake compared with controls, potentially explaining the fatigue experienced during the day by individuals with chronic insomnia disorder.22 It is postulated that this daytime impairment may reflect decreased activity in the prefrontal cortex resulting from inefficient sleep.
DORAs
work on the orexin system to “switch off” hyperarousal in insomnia1
Figure 1: Dual orexin receptor antagonists act on the orexin system to ‘switch off’ hyperarousal in insomnia.17,18
Orexin2
Precipitating event/stressor
Genetic vulnerability
Abnormalities in neurobiological processes
Moderators (eg, age, sex, medical comorbidities, medications)
Hyperarousal
Psychological and behavioral processes
DORAs1 Antagonism of orexin receptors restores the sleep–wake balance in chronic insomnia disorder1
Chronic insomnia disorder Adverse health outcomes
The European Insomnia Guidelines 2023
Diego García-Borreguero, Sleep Research Institute, Madrid, Spain, presented an overview of the recently updated European Insomnia Guidelines 2023.24 Within the guidelines, recommendations for diagnosis and treatment are graded according to an alphabetical system, where (A) represents a ‘Very Strong’ recommendation, and (B) represents a ‘Strong’ recommendation.
Diagnostic Management Guideline Recommendations
Diagnosis of insomnia, with or without comorbidities, involves several stages, including:24
• general clinical history and examination (A), which can include consideration of former and present disorders; personality factors, work, and partnership situation; substance use; physical examination and laboratory testing; and information from a bed partner/caregiver;
• sleep history (A), which can include sleep complaints and daytime functioning; work/time circadian factors; sleep–wake patterns, including use of a sleep diary; information from a bed partner/caregiver;
• actigraphy, if suspicion of irregular sleep–wake schedules or circadian rhythm sleep–wake disorders, or leg movement during sleep (A), or to quantify rest activity (A); and
• PSG, if suspicion of other sleep disorders or comorbid sleep disorders (A), treatment-resistant insomnia (A), or suspicion of large discrepancy between subjective versus objective measures of sleep (B).
García-Borreguero stressed that quantitative criteria related to sleep-onset latency, sleep duration, or the frequency of nocturnal awakenings do not have to be fulfilled in order to diagnose chronic insomnia disorder, which mainly relies upon symptoms described by the patient.
Figure adapted from Levenson JC et al.17
DORAs: dual orexin receptor antagonists.
Figure adapted from Levenson JC, et al. Chest 2015.2 DORA, dual orexin receptor antagonist. 1. Palagini L, et al. J Sleep Res 2023;32:e13825; 2. Levenson JC, et al. Chest 2015;147:1179–92.
Treatment Guideline Recommendations
García-Borreguero reiterated that the European Insomnia Guidelines 2023 state that insomnia disorders should always be actively treated (A).24 Additionally, in the presence of comorbid conditions, clinical judgement should be used to decide whether insomnia or the comorbid condition should be treated first, or whether both should be treated at the same time (A).24
CBTi is recommended as first-line therapy for chronic insomnia disorder, administered either in person or digitally (A).24 CBTi can be effective in adults of all ages, with or without comorbidities, when programmes are completed and recommendations are followed. However, CBTi may not be available or adequate for all people with insomnia. For example, there may be instances where insufficient numbers of CBTi providers lead to unacceptable delays in treatment initiation.16,25 When CBTi is not sufficiently effective or available, a pharmacological intervention can be offered or combined with CBTi.24
Pharmacological treatments for insomnia differ in their mechanisms of action (MoA), efficacy, and tolerability,26 and include:
• DORAs
• MoA: blockade of orexin 1 and orexin 2 receptors27
• benzodiazepines and benzodiazepine receptor agonists
• MoA: antihistaminergic effect, inhibition of serotonin, and norepinephrine reuptake29
• prolonged-release melatonin
• MoA: agonist of melatonin type 1 and type 2 receptors, mimicking the normal period of nocturnal melatonin secretion.30
The clinical treatment algorithm classifies treatments according to the recommended duration of therapy (Table 1).24 Benzodiazepines (A), benzodiazepine receptor agonists (A), and low-dose sedating antidepressants (B) can be used for the short-term treatment of insomnia (≤4 weeks).24 Longer-term treatment with these substances may be initiated in some cases, considering advantages and disadvantages (B).24 DORAs can be used for short-term treatment (≤12 weeks) (A) and periods of up to 3 months or longer in some cases (A), whereas prolonged-release melatonin is recommended for up to 3 months only in individuals aged >55 years (B).24
Long-term (up to 3 months) (A) or longer (>3 months) on an individual basis (A)
Receptor Agonists
(≤4 weeks) (A)
Long-term (>4 weeks) in certain cases (B)*
Long-term (≤3 months) in individuals aged >55 years (B)
*Off-label use (A): ‘Very Strong’ recommendation; (B): ‘Strong’ recommendation. N/A: not applicable.
(≤4 weeks) (B)
Long-term (>4 weeks) without comorbidities in certain cases (B)
Table 1: European Insomnia Guidelines 2023: recommended pharmacological treatments (available in Europe) if cognitive behavioural therapy for insomnia is not effective.24
Light therapy and exercise interventions may be used as adjunct therapies to CBTi (B).24 Antihistaminergic drugs, antipsychotics, fast-release melatonin, ramelteon, and phytotherapeutics are not recommended for insomnia treatment (A).24
The Dual Orexin Receptor Antagonist, Daridorexant, in the Treatment of Chronic Insomnia Disorder
Daridorexant is approved for the treatment of insomnia in adults in the USA, Europe, the UK, Switzerland, and Canada.31-35 Clinical trials showed that daridorexant improved subjective and objective sleep measures, as well as daytime functioning f or up to 12 months.36-38
Dauvilliers presented results for daridorexant 50 mg (Study 301), which is the recommended dose approved by the European Medicines Agency (EMA).
In Study 301, daridorexant 50 mg significantly improved both sleep and daytime functioning.36 The WASO change from baseline to Month 3 with daridorexant 50 mg was -29.4 minutes (95% CI: -33.4, -25.4), which was significant versus placebo (p<0.0001).36 Daridorexant 50 mg also improved LPS at Month 3 (change from baseline to Month 3 was -34.8 minutes [95% CI: -38.1, -31.5]; p<0.0001 versus placebo).36
Several post hoc analyses have been reported for Study 301. The finding from one post hoc analysis showed that daridorexant reduced EEG features associated with hyperarousal and did not significantly change sleep spindle properties in individuals with chronic insomnia disorder.39 Additionally, daridorexant 50 mg significantly reduced cumulative wake time versus placebo along the entire night, after both 1 and 3 months of treatment.40 In a post hoc analysis investigating the impact of daridorexant on wake bouts, wake bouts were defined as either short (≤6 minutes) or long (>6 minutes). When mean cumulative time spent in long or short wake bouts across the 8-hour PSG night were determined, it was shown that the increase in sTST observed with daridorexant versus placebo in Study 301 was underpinned by a reduction in time spent in long wake bouts.40 This decrease from baseline in time spent in long wake bouts was associated
with an improvement in IDSIQ sleepiness domain scores.40
Participants who completed the 12-week Phase III studies were invited to enrol in a 40-week double-blind extension study.37 Participants originally randomised to daridorexant (10 mg, 25 mg, or 50 mg) remained on their respective treatments, while participants originally randomised to placebo were re-randomised to daridorexant 25 mg or placebo. In participants who originally entered Study 301, daridorexant 50 mg demonstrated persistent efficacy up to 1 year of treatment (exploratory analyses), as measured by mean change from baseline in sTST and improved daytime functioning (measured by mean change from baseline in IDSIQ total score).37
Safety analyses over the extension study showed a safety and tolerability profile similar to the initial Phase III studies.37 The overall incidence of treatment-emergent adverse events (TEAE) was similar across groups (35–40% for all daridorexant groups and placebo groups in the extension study). The incidence of serious TEAEs was <5.5% in all groups, and TEAEs leading to treatment discontinuation were generally similar between daridorexant groups (1.4–6.6%) versus placebo (4.7%), respectively.37
The most commonly reported TEAEs that started or worsened during the doubleblind period with daridorexant 50 mg versus placebo were nasopharyngitis (8.0% versus 4.7%), accidental overdose (2.9% versus 0%), and somnolence (2.9% versus 0%), respectively.37 There was no evidence of excess next-morning sleepiness or rebound insomnia in participants who received daridorexant.37
Dauvilliers summarised that, during the clinical trial programme, daridorexant 50 mg was well tolerated, with no signs of dependency, improved sleep throughout the night, and improved daytime functioning with up to 1 year of treatment.36,37
Real-World Experience with Daridorexant Treatment in Chronic Insomnia Disorder
The European Insomnia Guidelines 2023 state that, while “the introduction of DORAs has probably been the most significant recent development in the pharmacological treatment of insomnia […] data remain to be validated through practical experience in everyday practice.”24 Liguori presented outcomes from four real-world studies with daridorexant that included patient populations with comorbid conditions or individuals who were already receiving alternative pharmacotherapy for insomnia and were switched to daridorexant.
Daridorexant Impact on Sleep and Quality of Life in Real-World Practice
In Germany, analysis of the Mainz Sleep Registry showed statistically significant improved sleep parameters (WASO, LPS, sTST, and TST) and HRQoL (measured using the European Quality of Life Visual Analogue Scale and European Quality 5 domain index) in individuals with insomnia disorder (n=32) treated with daridorexant 50 mg for up to 6 months.41,42
Daridorexant Treatment in Comorbid Insomnia and Sleep Apnoea
A study in the USA investigated daridorexant treatment in a cohort that included individuals with comorbid insomnia and sleep apnoea (COMISA).43 Liguori explained that COMISA is a highly prevalent and debilitating condition that is particularly challenging to diagnose and treat: 39–58% of individuals with obstructive sleep apnoea (OSA) experience insomnia symptoms, and 29–67% of individuals with insomnia meet diagnostic criteria for OSA.15
• Compared with those with insomnia or OSA alone, individuals with COMISA experience greater impairments in daytime functioning and HRQoL, and increased depressive and anxiety symptoms.15
• In this relatively small real-world study, treatment with daridorexant 25 mg or daridorexant 50 mg for ≥30 days reduced Insomnia Severity Index (ISI) for individuals with COMISA (n=15; change from baseline -6.9; p<0.01) and without COMISA (n=61; change from baseline -7.3; p<0.0001).43
• This study also reported results for individuals who switched to daridorexant from a prior insomnia pharmacotherapy (n=63/80, 78.8%). In this analysis, mean ISI score improved in the group of individuals who switched from any pharmacotherapy to daridorexant (n=63; 7.0±0.54 standard error of the mean [SEM]); p<0.0001) and in individuals who switched to daridorexant from zolpidem or eszopiclone (n=23; 7.6±0.86 [SEM], p<0.0001).43
Daridorexant Treatment in Individuals with Comorbid Insomnia and Psychiatric Disorders
A study from Pisa, Italy, reported outcomes with daridorexant 50 mg treatment for 3 months in a population that included individuals with comorbid unipolar/ bipolar depression, anxiety disorders, or sedative hypnotic use or misuse (n=66).44
In this observational, uncontrolled study, insomnia, mood and anxiety symptoms were improved at Month 3 compared with baseline. Regression analysis showed that improvements in insomnia symptoms were associated with improvements in symptoms of comorbid conditions.44
A study from Rome, Italy, reported results from a population that included individuals with chronic insomnia disorder and comorbid depression, anxiety, or epilepsy (n=69).45 In this study, improvement in
References
1. Hafner M et al. The societal and economic burden of insomnia in adults: an international study. 2023. Available at: https://www.rand.org/ pubs/reseacrh_reports/RRA2166-1. html. Last accessed: 9 June 2024.
Clinical Global Impression (CGI-I) and Patient Global Impression (PGI-I) after 30 days of daridorexant 50 mg used as first drug chosen, add-on treatment, or switch from another drug was 58.0% for both outcomes. There was no difference between CGI-I and PGI-I according to the number of most common comorbidities, sex, number of previous medications, prior insomnia medication use, or insomnia duration.45 Of note, this study used a cross-tapering programme in patients under sedative hypnotics, in which these individuals reduced their sedative hypnotic dose by 25% each week over the course of 4 weeks whilst also receiving the full daridorexant 50 mg dose.45
On a related point, in a panel discussion following the presentations, GarcíaBorreguero emphasised that, when switching a patient from benzodiazepine treatment to daridorexant, it is very important to slowly reduce the dose of benzodiazepine as the daridorexant treatment is started. This is because benzodiazepines have a strong rebound effect, meaning that insomnia symptoms may transiently worsen beyond baseline levels once benzodiazepine treatment is withdrawn. The tapering of the benzodiazepine dose should be done as slowly as possible; this may take weeks or even months.
Liguori summarised that real-world experience with daridorexant was associated with significant improvements in sleep quality in people with chronic insomnia disorder, including those with and without neurologic and psychiatric comorbidities. Daridorexant was also associated with improvements in sleep quality whether used as a first-ever treatment, treatment switch, or add-on therapy.42-45
2. Dopheide JA. Insomnia overview: epidemiology, pathophysiology, diagnosis and monitoring, and nonpharmacologic therapy. Am J Manag Care. 2020;26(Suppl 4):S76-S84.
3. American Psychiatric Association, "Neurodevelopmental disorders," Diagnostic and statistical manual of mental disorders (2022) 5th edition, Arlington: American Psychiatric Publishing, pp.31-87.
4. Leger D et al. Prevalence of insomnia in a survey of 12,778 adults in France. J Sleep Res. 2000;9(1):35-42.
5. Mayer G et al. Insomnia in neurological diseases. Neurol Res Pract.
2021;3(1):15.
6. Mayer G et al. Insomnia in central neurologic diseases--occurrence and management. Sleep Med Rev. 2011;15(6):369-78.
7. Hening W et al. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med. 2004;5(3):237-46.
8. Remi J et al. Sleep-related disorders in neurology and psychiatry. Dtsch Arztebl Int. 2019;116(41):681-8.
9. Sawadogo W et al. Association between insomnia symptoms and trajectory with the risk of stroke in the health and retirement study. Neurology. 2023;101(5):e475-88.
10. Sateia MJ. International classification of sleep disorders-third edition: highlights and modifications. Chest. 2014;146(5):1387-94.
11. Kyle SD et al. Insomnia and healthrelated quality of life. Sleep Med Rev. 2010;14(1):69-82.
12. Leger D et al. Insomnia and accidents: cross-sectional study (EQUINOX) on sleep-related home, work and car accidents in 5293 subjects with insomnia from 10 countries. J Sleep Res. 2014;23(2):143-52.
13. Dauvilliers Y. Hypocretin/orexin, sleep and Alzheimer's disease. Front Neurol Neurosci. 2021;45:139-49.
14. Guarnieri B et al. Prevalence of sleep disturbances in mild cognitive impairment and dementing disorders: a multicenter Italian clinical crosssectional study on 431 patients. Dement Geriatr Cogn Disord. 2012;33(1):50-8.
15. Sweetman A et al. Co-morbid insomnia and sleep apnea (COMISA): prevalence, consequences, methodological considerations, and recent randomized controlled trials. Brain Sci. 2019;9(12):371.
16. Riemann Det al. Insomnia disorder: state of the science and challenges for the future. J Sleep Res. 2022;31(4):e13604.
17. Levenson JC et al. The pathophysiology of insomnia. Chest. 2015;147(4):1179-92.
18. Palagini L et al. Current models of insomnia disorder: a theoretical review on the potential role of the orexinergic pathway with implications for insomnia treatment. J Sleep Res. 2023;32(4):e13825.
19. Saper CB et al. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437(7063):1257-63.
20. Tsujino N, Sakurai T. Role of orexin in modulating arousal, feeding, and motivation. Front Behav Neurosci.
2013;7:28.
21. Di Marco T et al. Hyperarousal features in the sleep architecture of individuals with and without insomnia. J Sleep Res. 2024;DOI:10.1111/jsr.14256.
22. Nofzinger EA et al. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry. 2004;161(11):2126-8.
23. Buysse DJ et al. A neurobiological model of insomnia. Drug Discov Today Dis Models. 2011;8(4):129-37.
24. Riemann D et al. The European Insomnia Guideline: an update on the diagnosis and treatment of insomnia 2023. J Sleep Res. 2023;32(6):e14035.
25. Thomas A et al. Where are the behavioral sleep medicine providers and where are they needed? A geographic assessment. Behav Sleep Med. 2016;14(6):687-98.
26. Yue JL et al. Efficacy and tolerability of pharmacological treatments for insomnia in adults: a systematic review and network meta-analysis. Sleep Med Rev. 2023;68:101746.
27. Stahl SM. Mechanism of action of suvorexant. CNS Spectr. 2016;21(3):215-8.
28. Walsh JK, Roth T. “Pharmacologic treatment of insomnia: benzodiazepine receptor agonists,” Kryger M, Roth T, Dement WC (eds.), Principles and practice of sleep medicine (2015) 6th edition, Elsevier, pp.832-41.
29. Wichniak A et al. Effects of Antidepressants on Sleep. Curr Psychiatry Rep. 2017;19(9):63.
30. Buysse DJ, Tyagi S. “Clinical pharmacologfy of other drugs used as hypnotics,” Kryger M, Roth T, Dement WC (eds.), Principles and practice of sleep medicine (2015) 6th edition, Amsterdam, Netherlands: Elsevier, pp.432-45.
31. Idorsia Pharmaceuticals Ltd. QUVIVQ United States prescribing information. 2022. Available at: https://www. accessdata.fda.gov/drugsatfda_docs/ label/2022/214985s000lbl.pdf. Last accessed: 9 July 2024.
32. Idorsia Pharmaceuticals Ltd. QUVIVIQ summary of product characteristics European Union. Available at: https:// www.ema.europa.eu/en/documents/ product-information/quviviq-eparproduct-information_en.pdf. Last accessed: 9 July 2024.
33. Idorsia Pharmaceuticals Ltd. QUVIVIQ public assessment report Great Britain. Available at: https://mhraproducts4853.blob.core.windows.net/ docs/ed2aeb19a5f58327b069031bc07c8f3a3ad2dec2. Last accessed: 9 July 2024.
34. Idorsia Pharmaceuticals Ltd. QUVIVIQ Public Summary SwissPAR. Available at: https://www.swissmedic.ch/
swissmedic/en/home/about-us/ publications/public-summary-swisspar/public-summary-swiss-parquviviq.html. Last accessed: 9 July 2024.
35. Idorsia Pharmaceuticals Ltd. QUVIVIQ Canada Product Monograph. Available at: https://www.idorsia.com/dam/ jcr:049f93b6-4bac-47ef-ad4f01b28b6ffec9/quviviq-productmonograph.pdf. Last accessed: 9 July 2024.
36. Mignot E et al. Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebocontrolled, Phase 3 trials. Lancet Neurol. 2022;21(2):125-39.
37. Kunz D et al. Long-term safety and tolerability of daridorexant in patients with insomnia disorder. CNS Drugs. 2023;37(1):93-106.
38. Fietze I et al. Efficacy and safety of daridorexant in older and younger adults with insomnia disorder: a secondary analysis of a randomised placebo-controlled trial. Drugs Aging. 2022;39(10):795-810.
39. Di Marco T et al. Effect of daridorexant on sleep architecture in patients with chronic insomnia disorder - a pooled post hoc analysis of two randomized Phase 3 clinical studies. Sleep. 2024;DOI:10.1093/sleep/zsae098.
40. Di Marco T et al. Number, duration, and distribution of wake bouts in patients with insomnia disorder: effect of daridorexant and zolpidem. CNS Drugs. 2023;37(7):639-53.
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Efficacy
and
Safety of
Nipocalimab
in Patients with Generalised Myasthenia
Gravis: Top Line Results from the DoubleBlind, Placebo-Controlled, Randomised Phase III Vivacity-MG3 Study
This presentation took place at the 10th Congress of the European Academy of Neurology (EAN), held from 29th June–2nd July 2024 in Helsinki, Finland.
Presenter: Carlo Antozzi1
1. Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milan, Italy
Disclosure: Antozzi has received funding for travel, meeting attendance, and advisory board participation from Alexion, argenx, Momenta, Johnson & Johnson, and Sanofi. This study was supported by Janssen Research & Development, LLC.
Acknowledgements: Medical writing assistance was provided by Amanda Barrell, freelance medical writer, Brighton, UK.
Disclaimer The opinions expressed in this article are not necessarily those of Janssen Pharmaceutica N.V, a Johnson & Johnson company.
Support: The support for the publication of this article was provided by Janssen Pharmaceutica N.V., a Johnson and Johnson company. The content is intended solely for EMEA healthcare professionals. Medical Writing was provided by EMJ, based on data presented at EAN. Johnson & Johnson reviewed the article for accuracy and compliance.
Meeting Summary
Nipocalimab, a high-affinity, fully human, aglycosylated, effectorless, monoclonal antibody, has been developed as an add-on treatment for myasthenia gravis (MG). The agent, administered every 2 weeks, aims to selectively block neonatal Fc receptor (FcRn), in order to reduce levels of circulating immunoglobulin G (IgG) including autoantibodies and ameliorate disease manifestations, while preserving immune function.
In this poster presentation, Carlo Antozzi outlined top-line results from the 24week, double-blind, placebo-controlled, randomised Vivacity-MG3 Phase III study (NCT04951622).1 Nipocalimab, he explained, demonstrated efficacy and safety in a broad antibody-positive population, suggesting it could provide the first FcRn treatment option with a predictable dosing schedule in generalised MG (gMG).
PHARMA
Condition of Unmet Need
MG is a rare IgG autoantibody-mediated disease, characterised by fluctuating weakness of the voluntary muscles.2,3 The weakness, which tends to worsen with activity,3 is caused by the pathogenic IgG-mediated disruption of cholinergic transmission at the neuromuscular junction.2 In ocular MG, the weakness only affects the extraocular muscles, whereas gMG affects the bulbar muscle, extremities, or axial muscles.3
gMG is an area of unmet medical need. Although therapies, including cholinesterase inhibitors and immunosuppressants, are available, many people still experience symptoms, exacerbations, and reduced quality of life.2 In addition, such agents may be associated with side effects that can limit tolerability.2
Blocking FcRn: A New Approach
Nipocalimab is an investigational fully human monoclonal antibody designed to bind with high affinity and selectively block FcRn, reducing levels of circulating IgG antibodies, including autoantibodies, while also preserving immune function.4 As such, it is a targeted approach not resulting in broad immunosuppression.4 Developed as an
add-on treatment for MG to be administered every 2 weeks, nipocalimab could ameliorate disease manifestations, said Antozzi.
In a Phase II study, intravenous (IV) nipocalimab was shown to be generally well tolerated, and there was evidence of a dose-dependent reduction in MG Activities of Daily Living (MG-ADL) total score after 57 days.2 Vivacity-MG3, a Phase III, multicentre, randomised, double-blind, placebo-controlled study (NCT04951622),1 aimed to build on these findings. Topline results from the 24-week doubleblind phase were presented at the 10th Congress of the European Association of Neurology (EAN).5 In this study, nipocalimab demonstrated efficacy and safety in a broad antibody-positive population, including acetylcholine receptor (AChR+), muscle-specific tyrosine kinase (MuSK+), and low-density lipoprotein receptor 4 (LRP4+) positive patients.5
Vivacity-MG3 Phase III Study5
The study enrolled 153 adults with seropositive Myasthenia Gravis Foundation of America (MGFA) Class IIa–IVb gMG who had experienced an inadequate response (MG-ADL ≥6) to stable standard of care (SOC) treatment (see Table 1 for baseline characteristics). Of these, 77 patients
Table 1: Phase III Vivacity-MG3 study baseline characteristics.5
MG-ADL: Myasthenia Gravis Activities of Daily Living; QMG: Quantitative Myasthenia Gravis; SD: standard deviation; SOC: standard-of-care.
(63 AChR+; 12 MuSK+; 2 LRP4+) were randomised to IV nipocalimab plus SOC, and 76 patients (71 AChR+; 4 MuSK+; 1 LRP4+) to IV placebo plus SOC, for 24 weeks in the double-blind phase. A loading dose was administered at Week 0, after which patients were treated every 2 weeks. The primary endpoint was improvement in MG-ADL total score to Week 24, with improvement of Quantitative Myasthenia
Gravis (QMG) total score and MG-ADL responder rates being key secondary endpoints.
The double-blind phase was followed by an open-label phase of variable duration (ongoing), during which all participants will receive SOC plus nipocalimab every 2 weeks, and a safety follow-up of a further 2 weeks.
Figure 1: A) Mean (±standard error) change in Myasthenia Gravis Activities of Daily Living (MG-ADL) and B) Quantitative Myasthenia Gravis (QMG) over 24 weeks of treatment in the Vivacity-MG3 study.5
Nipocalimab + SOC (N=77) Placebo + SOC (N=76)
LS: least squares; MG-ADL: Myasthenia Gravis Activities of Daily Living; QMG: Quantitative Myasthenia Gravis; SE: standard error; SOC: standard-of-care; W: Week.
Results
The study recorded a statistically significant improvement from baseline in MG-ADL (Figure 1A, primary endpoint) and QMG (Figure 1B, first key secondary endpoint) in the nipocalimab arm, compared to the placebo arm.5 In the nipocalimab group, the mean (standard error [SE]) change in MG-ADL from baseline to the averaged total score across Weeks 22, 23, and 24 was -4.7 (0.33), compared to -3.25 (0.34) in the placebo group. The difference in least squares (LS) means (SE) was -1.45 (0.47), p=0.002. The mean (SE) QMG change from baseline over Weeks 22 and 24 was -4.86 (0.50), compared to -2.05 (0.50) in the placebo group. The difference in LS means (SE) was -2.81 (0.71), p<0.001. MG-ADL responder rate (percentage of patients with ≥2-point improvement on average change of MG-ADL, second key secondary endpoint) at Weeks 22–24 was 68.8% in the nipocalimab group, and 52.6% in the
placebo group (p=0.021). In addition, more patients achieved sustained response from Weeks 4–24 with nipocalimab compared to placebo. At Weeks 22–24, 46.8% of those in the nipocalimab group saw a ≥50% improvement in MG-ADL, compared to 25% in the placebo group (Figure 2).
During the double-blind phase, around onethird (31.2%; 24/77) of patients receiving nipocalimab achieved the pre-specified endpoint of minimal symptom expression, defined as an MG-ADL total score of 0 or 1, at any point. Overall, 13.2% (10/76) of those in the placebo arm achieved minimal symptom expression.
Nipocalimab was generally well tolerated in this 6-month study. In the treatment group, 81.6% (80/98) of patients experienced an adverse event (AE) and 9.2% (9/98) experienced a serious AE, compared to 82.7% (81/98) and 14.3% (14/98) in the placebo group, respectively. The most
*Responder rate: percentage of patients with ≥2-pt improvement on average change of MG-ADL over Weeks 22, 23, and 24. Early responder rate: percetnage of patients with ≥2-pt improvement on MG-ADL at Week 1 or Week 2. Sustained response: at least 2-pt improvement from Weeks 4–24 with no more than two non-consecutive excursions from Weeks 6–23. 50% symptom improvement: percetnage of patients with ≥50% improvement on average change of MG-ADL over Weeks 22, 23, and 24. P-values from CMH test controlling for baseline MG-ADL total score (<9, ≥9), autoantibody status, and region. N/A: Test not performed because a preceding comparison was not statistically significant at 2-sided alpha=0.05.
CMH: Cochran-Mantel-Haenszel; MG-ADL: MG Activities of Daily Living; N/A: not applicable; PBO: placebo; pt: point; SOC: standard-of-care.
common AEs were headache (14/98 [14.3%] in the treatment group; 17/98 [17%] in the placebo group), muscle spasms (12/98 [12.2%] in the treatment group; 3/98 [3.1%] in the placebo group), and COVID-19 (15/98 [15.3%] in the treatment group; 12/98 [12.2%] in the placebo group). Infusion reactions were also common, affecting 10 patients (10.2%) in the treatment group, and 11 (11.2%) in the placebo group.
References
1. Janssen Research & Development, LLC. A study of nipocalimab administered to adults with generalized myasthenia gravis. NCT04951622. https://clinicaltrials. gov/study/NCT04951622.
2. Antozzi C et al. Safety and efficacy of nipocalimab in patients with generalized myasthenia gravis: results from the randomized phase
Key Learnings
Summing up, Antozzi said Vivacity-MG3 was the first registrational study of an FcRn blocker to show sustained efficacy and a tolerable safety profile through 6 months of dosing.
3. Garzón-Orjuela N et al. Quality of life in refractory generalized myasthenia gravis: a rapid review of the literature. Intractable Rare Dis Res. 2019;8(4):231-8.
4. Ling LE et al. M281, an anti‐FcRn antibody: pharmacodynamics, pharmacokinetics, and safety across the full range of IgG reduction in a
5. Antozzi C et al. Efficacy and safety of nipocalimab in patients with generalized myasthenia gravis- top line results from the double-blind, placebo-controlled, randomized phase 3 Vivacity-MG3 study. Poster number: EPR-116. European Academy of Neurology (EAN) Congress, 29 June–2 July, 2024.
Abstract Reviews
Sharing insights presented at the 10th European Academy of Neurology (EAN) Congress, the following abstract reviews spotlight impactful developments in the field.
EpilepsyPOWER: A Project to Favour the Inclusion of People with Epilepsy in Workplaces
Authors: *F Narducci,1 G Baker,2 D Walsh,3 F Sofia,3 N Casalino,4 B Borin,4 F Pigni,5 S Louissi,5 M Kateva,6 S Duttenhöfer,7 M Tombini,1 V Di Lazzaro,1 G Assenza1
1. Department of Medicine and Surgery, Unit of Neurology, Neurophysiology, Neurobiology, and Psychiatry, Campus Bio-Medico University of Rome, Italy
2. Department of Molecular and Clinical Pharmacology, University of Liverpool, UK
3. International Bureau of Epilepsy, Dublin, Ireland
4. Luiss Business School, Rome, Italy
5. Grenoble Ecole de Management, France
6. Chamber of Commerce and Industry Vratsa, Bulgaria
7. emcra, Berlin, Germany
*Correspondence to f.narducci@unicampus.it
Disclosure: This project was financed by European Erasmus+ Funding (2021-1-IT02KA220-ADU-000028349). The authors declared no other conflicts of interest.
Despite good seizure control, unemployment and underemployment are more common among people with epilepsy (PwE) for several reasons, including stigma.1,2 The EpilepsyPOWER is a European project, involving five Countries (Italy, Bulgaria, France, Ireland, and Germany), aimed to improve PwE’s workplace inclusion. For this project, the authors made a systematic review of PwE’s employment conditions and legislation in
Europe, and developed surveys to explore work conditions among PwE and knowledge of epilepsy among higher education institutions (HEI).
MATERIALS AND METHODS
A systematic review on epilepsy and employment was performed, involving the selection of 55 articles from 1958–2023 and analysing employment rates and determinants of employment/ unemployment. The authors developed two anonymous surveys asking for PwE’s employment condition, stigma and disclosure, and HEI’s general knowledge and attitudes about epilepsy.
RESULTS
For all considered countries, no specific job legislation for PwE was found. Unemployment rates ranged from similar, to twice or three times the general population, and above all factors, seizure control and employers' attitudes contributed mostly to unemployment. Answers were collected from 567 PwE and 291 HEIs. Reported unemployment rates were 7.9% in Italy, 6.7% in Ireland, 8.5% in France, 15.0% in Germany, and 9.0% in Bulgaria. Rates of PwE who were fully employed were 42.9% in Italy, 53.0% in Ireland, 31.7% in France, 40.0% in Germany, and 47.9% in Bulgaria. As for disclosure, 24.2% of PwE did not disclose their condition in Italy, whereas 48.5% did not in Bulgaria (Figure 1). In most cases, HEI correctly defined epilepsy as a neurological
disorder and treatable in most cases. Although most respondents had seen a seizure, in some countries (Germany and Bulgaria), they did not know how to give first aid (Figure 2).
1: Rates of people with epilepsy disclosing their condition at work.
Figure
Figure 2: Rates of people among higher education institutions who know how to intervene in case of seizures.
CONCLUSION
Although rates of unemployment are not uniformly reported, a clear situation of disadvantage rises for PwE in Europe. Seizure control, good employers’ attitudes, training programmes, and job counselling were identified as key elements favouring employment among PwE. Exploring PwE work conditions and HEI perspectives may help to spread an inclusive culture of
integration and fight the marginalisation of PwE in workplaces, allowing them to get the right job position and better quality of life.
References
1. Wo MCM et al. Employability in people with epilepsy: a systematic review. Epilepsy Res. 2015;116:67-78.
2. Smeets VMJ et al. Epilepsy and employment: literature review. Epilepsy Behav. 2007;10(3):354-62.
Automatic Method for Jitter Estimation in Electromyographic Signals
Authors: *Armando Malanda,1 Daniel Stashuk,2 César Valle,1 Javier Rodríguez-Falces,1 Javier Navallas,1 Mamede de Carvalho,3,4 José Castro,3,4 Oscar Garnés-Camarena5
1. Public University of Navarra, Spain
2. University of Waterloo, Canada
3. University of Lisbon, Portugal
4. Santa María Hospital, Lisbon, Portugal
5. Jiménez Díaz Foundation University Hospital, Madrid, Spain
*Correspondence to malanda@unavarra.es
Disclosure: This work has been funded by the Department of Health of the Government of Navarra (project GN2022/29) and by the Spanish Ministry of Science and Innovation (project PID2022-136620OB-I00), with payments made to the Public University of Navarra. The authors have declared no other conflict of interest.
Keywords: Electromyographic, jitter, motor unit potential, neuromuscular junction disease, neuropathies.
Neurophysiological jitter measurement using concentric needle electrodes is a laborious and difficult task because potentials from several fibres may appear in the recordings due to the large recording areas of these electrodes.1 This work presents the use of an automatic method that estimates jitter from motor unit potential (MUP) trains recorded using concentric needle electrodes.2
METHODS
MUP intervals likely being formed by only one muscle fibre potential were detected from MUP trains. Then jitter measurements were performed between pairs of these intervals. One hundred and thirty-two electromyographic signals were recorded from eight patients with disorders of the neuromuscular junction or different neuropathies, using a Keypoint system and facial-concentric electrodes. These signals were decomposed into several MUP trains using decomposition-based quantitative electromyography software. Jitter measurements of mean absolute consecutive differences (MCD) were then estimated manually, using a home-made graphical interface (Figure 1A and B) and using the automatic method (Figure 1C and D).
RESULTS
From the 96 MUP trains valid for the analysis, 102 automatic and 84 manual jitter measurements were obtained. Comparative analysis yielded a mean of jitter differences of 1.74 µs; a mean of absolute differences of 2.73 µs; and values of -2.62, -0.35, 2.53, and 7.56 µs for the 5th, 25th, 75th, and 95th percentiles of the jitter differences distribution, respectively, which are nonsignificant clinically.
CONCLUSIONS
The proposed method can be a valuable tool in clinical practice for obtaining reliable automatic jitter measurements and also as a real-time guide for manual jitter measurements. Still, new tests should be carried out to broaden the scope of this study.
Figure 1: Examples of motor unit potential trains analysed by the manual method, with marked negative peaks (A and B); and by the automatic method, with highlighted valid intervals (C and D).
Obtained MCD values are shown.
MCD: mean absolute consecutive differences; ms: milliseconds.
References
1. Sanders DB, et. al. Single fiber electromyography and measuring jitter with concentric needle electrodes. Muscle Nerve. 2022;66(2):118-30.
2. Malanda A et al. Automatic jitter measurement in needle-detected motor unit potential trains. Comput Biol Med. 2022;149:105973.
Idebenone Treatment for Leber Hereditary Optic Neuropathy: Time to Clinically Relevant Recovery in the LEROS Study
Authors: *Chiara La Morgia,1,2 Thomas Klopstock,3 Patrick Yu-Wai-Man,4-8 Valerio Carelli,1,2 Xavier Llòria Llàcer,9 LEROS Study Group
1. IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy
2. Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
3. Friedrich Baur Institute at the Department of Neurology, University Hospital of LudwigMaximilians-Universität München, Munich, Germany
4. John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, UK
5. MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, UK
6. Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals, UK
7. Moorfields Eye Hospital NHS Foundation Trust, London, UK
8. Institute of Ophthalmology, University College London, UK
9. Chiesi Farmaceutici S.p.A, Parma, Italy
*Correspondence to chiara.lamorgia@unibo.it
Disclosure: The LEROS study was funded by Santhera Pharmaceuticals. Medical writing support was provided by nspm ltd, Switzerland, and funded by Chiesi Farmaceutici. La Morgia has acted as a consultant for Chiesi Farmaceutici, Regulatory PharmaNet, GenSight Biologics, and Thenewway srl; has received speaker honoraria for meetings from Chiesi Farmaceutici, Regulatory PharmaNet, GenSight Biologics, Thenewway, First Class srl, and Biologix; has received financial support for meetings and/ or travel from Chiesi Farmaceutici, Regulatory PharmaNet, GenSight Biologics, Thenewway, First Class, and Biologix; and has acted as a principal or study investigator for clinical trials sponsored by Santhera Pharmaceuticals, GenSight Biologics, Stoke Therapeutics, Stealth Biotherapeutics, and Reneo Pharmaceuticals. Yu-Wai-Man has received research support from Santhera Pharmaceuticals, Chiesi Farmaceutici, and GenSight Biologics; has received consultation fees from Santhera Pharmaceuticals, Chiesi Farmaceutici, and GenSight Biologics; has received consultation fees from Santhera Pharmaceuticals, Chiesi Farmaceutici, GenSight Biologics, Neurophth, and Stoke Therapeutics; has received speaker honoraria from Santhera Pharmaceuticals, Chiesi Farmaceutici, and GenSight Biologics; has received financial
support for meetings and/or travel from Santhera Pharmaceuticals, Chiesi Farmaceutici, GenSight Biologics, and First Class; has participated in an Advisory Board for Chiesi Farmaceutici and GenSight Biologics; and has acted as a principal or study investigator for clinical trials sponsored by Santhera Pharmaceuticals and GenSight Biologics. Klopstock has received research support from Santhera Pharmaceuticals, Chiesi Farmaceutici and GenSight Biologics; has received consultation fees from Santhera Pharmaceuticals, Chiesi Farmaceutici, and GenSight Biologics; has received speaker honoraria from Santhera Pharmaceuticals, Chiesi Farmaceutici, and GenSight Biologics; has received financial support for meetings and/ or travel from Chiesi Farmaceutici, GenSight Biologics, and First Class; has participated in an Advisory Board for Chiesi Farmaceutici and GenSight Biologics; and has acted as a principal or study investigator for clinical trials sponsored by Santhera Pharmaceuticals and GenSight Biologics. Carelli has received research support from Santhera Pharmaceuticals, Chiesi Farmaceutici, and GenSight Biologics; has received consultation fees from Santhera Pharmaceuticals, Chiesi Farmaceutici, and GenSight Biologics; has received speaker honoraria from Santhera Pharmaceuticals, Chiesi Farmaceutici, and GenSight Biologics; has received financial support for meetings and/ or travel from Chiesi Farmaceutici, GenSight Biologics, and First Class; has participated in an Advisory Board for Chiesi Farmaceutici and GenSight Biologics; and has acted as a principal or study investigator for clinical trials sponsored by Santhera Pharmaceuticals and GenSight Biologics. Llòria Llàcer is an employee of Chiesi Farmaceutici.
Acknowledgements: The authors would like to thank all patients and healthcare professionals participating in LEROS for their participation and contribution in collecting the data.
Leber hereditary optic neuropathy (LHON) is a mitochondrial disease resulting in bilateral central vision loss, primarily caused by one of three primary mitochondrial DNA (mtDNA) mutations (m.11778G>A, m.3460G>A, or m.14484T>C).1 Idebenone has shown a favourable safety and efficacy profile in the treatment of LHON.2,3 In LEROS, a Phase IV, open-label interventional study (NCT02774005), visual acuity (VA) outcomes following 24 months of idebenone treatment were compared to an external matched Natural History cohort.4 Here, the authors present the cumulative percentage of eyes with a clinically relevant recovery (CRR) from baseline (Kaplan Meier [KM] estimate) in idebenone-treated eyes by disease phase and primary mtDNA mutation, as a function of treatment duration.
MATERIALS AND METHODS
LEROS included patients with LHON aged ≥12 years and with a disease onset ≤5 years prior. Patients in the intention-to-treat cohort were treated with 900 mg/day idebenone and VA was measured over 24 months using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. CRR was defined as an improvement from ‘off-chart’ VA to at least 1.6 logMAR, or a ≥0.2 logMAR improvement if already ‘on-chart’. Eyes were stratified by time since symptom onset (subacute/ dynamic [≤1 year] and chronic [>1 year]).
RESULTS
The intention-to-treat population included 196 patients with a median age of 31.9 years. The overall KM estimate of a CRR from baseline increased progressively with idebenone in subacute/dynamic eyes
from 18.4% at Month 6 to 47.3% at Month 24. When assessing subacute/dynamic eyes, the KM estimate of a CRR increased progressively until the end of observation in those with a m.11778G>A mutation, from 13.0% at Month 6 to 37.7% at Month 24. The rate of CRR increased up to 12 months in eyes carrying a m.3460G>A mutation, from 14.4% at Month 6 to 33.4% at Month 12. The proportion of eyes with a m.14484T>C mutation and a CRR increased progressively from 30.7% at Month 6 to 80.0% at Month 24 (Figure 1A).5
The overall KM estimate of a CRR from baseline also increased in chronic eyes treated with idebenone, from 18.2% at Month 6 to 29.1% at Month 24. In the chronic phase, a progressive increase in CRR was observed in those with a m.11778G>A mutation, from 17.5% at Month 6 to 24.6% at Month 24. In eyes carrying a m.3460G>A mutation, the rate of CRR increased only up to 12 months from 13.2% at Month 6 to 26.0% at Month 12. In m.14484T>C eyes, an increase in CRR was observed up to Month 18, from 31.2% at Month 6 to 70.9% at Month 18 (Figure 1B).5
CONCLUSION
Overall, extended duration of idebenone treatment led to an increased rate of CRR, in both subacute/dynamic and chronic eyes. The proportion of m.11778G>A eyes with CRR increased progressively until the end of observation, irrespective of disease phase. In m.3460G>A eyes, an increasing rate of CRR was only observed up to 12 months of treatment. The observed improvement was most pronounced for eyes with the m.14484T>C mutation. Conclusions for m.3460G>A and m.14484T>C eyes are limited by the number of at-risk eyes available for analysis.
Figure 1: Kaplan-Meier estimate of a clinically relevant recovery from baseline in A) subacute/dynamic eyes and B) chronic eyes.
1. Carelli V et al. International consensus statement on the clinical and therapeutic management of Leber hereditary optic neuropathy. J. Neuroophthalmol. 2017;37(4)371-81.
2. Klopstock T et al. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain. 2011;134(9)2677-86.
3. Catarino CB et al. Real-world clinical experience with idebenone in the treatment of Leber hereditary optic neuropathy. J Neuroophthalmol. 2020;40(3)558-65.
4. Yu-Wai-Man P et al. Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial. Cell Rep Med. 2024;5(3)101437.
5. La Morgia C et al. Idebenone treatment for Leber hereditary optic neuropathy; time to clinically relevant recovery in the LEROS study. Eur J Neurol. 2024;31:e16337.
The following highlights showcase late breaking research presented at the 10th European Academy of Neurology (EAN) Congress. Topics ranged from the use of multimodal MRI to enhance Parkinson’s disease detection, to an identified link between alterations in brain-derived neurotrophic factor and plasmin-related proteins and regional brain atrophy in alphasynucleinopathies. Notably, we exhibit the EAN Tournament winner for neurologists in training for basic science, examining the abstract entitled ‘Widespread white matter axonal loss in narcolepsy Type 1’.
Narcolepsy Type 1 Linked to Brain White Matter Irregularities
A STUDY presented at the EAN 2024 Congress revealed significant white matter irregularities in the brains of individuals with narcolepsy Type 1 (NT1), a neurological disorder characterised by hypocretin deficiency, excessive daytime sleepiness, and cataplexy.
The study was conducted on postmortem brain tissue from four NT1 donors and 10 control subjects to assess axonal density, axonal injury, and myelin integrity. The regions of interest mainly included subregions of the midbrain, corpus callosum, cortical regions (anterior cingulate and occipital cortex), and the cerebellum, which served as a control region.
Results showed that patients with NT1 showed significantly lower axonal density in the reticular formation, pyramidal tract, corpus callosum, and anterior cingulate gyrus compared to control subjects. No significant differences were found in the cerebellum regarding axonal density, axonal injury, and myelin integrity measures, except for lower myelin density in the secondary visual cortex in patients with NT1.
The results underline the profound impact of NT1 on brain white matter, providing better understanding of the disease’s underlying mechanisms. As the results showed a significant reduction in the axonal density in various brain regions, this suggests that NT1 leads to widespread neuro-degradation, except in the cerebellum, which aligns with expected hypocretin projection patterns.
Patients with NT1 showed significantly lower axonal density in the reticular formation
In conclusion, this study marks a step forward in developing understanding of the neurological impact of NT1. The results align with prior published reports on in vivo brain imaging and typical hypocretin projection patterns. By bringing to light the specific areas of the brain affected by the disease, the research opens new avenues for targeted therapies and interventions aimed at mitigating the debilitating symptoms of NT1. However, further research is needed to fully understand the contributors of the pathophysiology of NT1, and to explore the extent of these findings and their implications for treatment and management strategies.
Long-Term Risks in Young Patients with Stroke
RESEARCH presented at the EAN 2024 Congress has revealed a longterm risk of recurrent vascular events and mortality in young patients with ischaemic stroke or transient ischaemic attack.
Between 2018–2020, the researchers conducted outpatient clinical follow-up assessments on 396 patients aged 18–55 years who had enrolled in one of three European centres with ischaemic stroke or transient ischaemic attack between 2007–2010. During a median follow-up of 11.8 years, 89 (22.5%) patients had experienced a recurrent vascular event, 62 (15.7%) had experienced a cerebrovascular event, and 34 (8.6%) had experienced other vascular events. Furthermore, 27 (6.8%) patients died during or before the follow-up assessment.
Atrial fibrillation present at baseline was significantly associated with a higher risk of recurrent vascular events
The analysis also revealed that over a 10year period, the incidence rates per 1,000 person-years for recurrent vascular events and cerebrovascular events were 21.6 (95% CI: 17.1–26.9) and 14.9 (95% CI: 11.3–19.3), respectively. Despite the increased occurrence of vascular events reported in the cohort, 22 (13.5%) patients were not receiving secondary preventive medication at the time of the follow-up assessment.
13.5 %
Despite the increased occurrence of vascular events reported in the cohort, 22 (13.5%) patients were not receiving secondary preventive medication at the time of the follow-up assessment
The researchers determined that atrial fibrillation present at baseline was significantly associated with a higher risk of recurrent vascular events. This association remained significant even after accounting for demographic factors and comorbidities. Additionally, it was found that cardiovascular risk factors became greater over time.
The results highlight the risk of recurrent vascular events, cerebrovascular events, and mortality in young patients with ischaemic stroke or transient ischaemic attack. Subsequently, future research should aim to develop personalised risk assessment and prevention strategies, and investigate if improved adherence to secondary preventive medications can reduce long-term risks in this patient group.
Alterations in BDNF and Plasmin-Related Proteins Associated with Regional Brain Atrophy in Alpha-Synucleinopathies
A NEW study from the Charles University and Motol University Hospital, Prague, Czechia, was presented this year at the EAN 2024 Congress, held in Helsinki, Finland.
On behalf of their colleagues, Zuzana
Nedelska presented the abstract ‘Alterations in BDNF and plasmin-related proteins are associated with regional brain atrophy in alpha-synucleinopathies’. As explained by Nedelska, plasmin is a serine protease that is regulated by activating tissue plasminogen activator, and inhibits plasminogen activator inhibitor-1 (PAI-1). Found in the blood serum, it acts to dissolve fibrin blood clots.
In this study, the team set out to better understand the associations of brainderived neurotrophic factor (BDNF) with regional brain atrophy in alphasynucleinopathies, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).
The study cohort comprised 34 patients with DLB, 12 patients with MSA, and 11 patients with PD, compared with 11 cognitively unimpaired controls, evaluated using brain MRI. Protein serum concentrations of tissue plasminogen activator PAI-1 and BDNF were quantified using ELISA and compared across the groups. An automated algorithm, called FreeSurfer v7.0 (Labratories for Computational Neuroimaging, Athinoula A. Martinos Center for Biomedical Imaging, Boston, Massachusetts, USA), measured regional brain atrophy.
Results revealed dysregulation in plasmin synthesis, notably across levels in PA-1
(p<0.001). For instance, patients with PD (p=0.027) and MSA (p<0.001) showed elevated levels of PA-1 compared to the control group. Moreover, BDNF levels were found to be elevated in DLB (p<0.001), PD (p<0.001), and MSA (p=0.012) compared to controls, and PAI-1/BDNF ratio differed in MSA versus DLB (p=0.008).
The authors concluded that alterations in BDNF and plasmin-related proteins are associated with regional brain atrophy in alpha-synucleinopathies. They theorised that the elevated BDNF levels additionally suggest a compensatory mechanism. These findings are highly significant, as the plasmin system and BDNF could be potential future therapeutic targets in PD, DLB, and MSA.
These findings are highly significant, as the plasmin system and BDNF could be potential future therapeutic targets in PD, DLB, and MSA
The Future of Rare Disease Treatment
NOVEL research presented at the EAN 2024 Congress has demonstrated the benefit of treatment of neurological signs and symptoms with N-acetyl-L-leucine (NALL) in patients with NiemannPark disease Type C (NPC).
Treatment with NALL after 1 year was associated with a significant reduction in disease progression
The research, helmed by Tatiana BremovaErtl, University Hospital Inselspital Bern, Germany, involved a Phase II, double-blind, randomised trial, followed by an open-label extension phase, to evaluate the long-term, neuroprotective effects of NALL for patients with NPC.
The patients were administered NALL orally two to three times per day, the study’s primary endpoint being the modified 5-domain NPC Clinical Severity Scale (CSS) (range 0–25 points; lower score representing better neurological status). Comparisons were made to the expected annual trajectory of disease decline established in published natural history studies. Exploratory endpoints included the 17-domain NPC-CSS (excluding hearing) and Scale for the Assessment and Rating of Ataxia (SARA).
In total, 54 patients (aged 6–57 years) were treated throughout the extension phase. The researchers found that, after 12 months, the mean (±standard deviation) change from baseline on the 5-domain NPC-CSS was -0.115 (±2.6) and 1.5±3.1 in the historical cohort (mean difference: 1.56; 95% CI: 0.31–2.92; p<0.017). This meant a 108% reduction in annual disease progression. The result of the 17-domain NPC-CSS was supportive of the primary analysis, and the improvements in neurological status demonstrated in the Parent Study’s primary SARA endpoint were sustained over the long-term follow up.
The team concluded that, for patients with NPC, treatment with NALL after 1 year was associated with a significant reduction in disease progression. These results were consistent with a neuroprotective, diseasemodifying effect.
Achieving Goal-Concordant Care After Severe Acute Brain Injury
LOSS of decisional capacity in patients with severe acute brain injury (SABI) often leaves families and clinicians in the intensive care unit (ICU) to navigate clinical decisions together.
New research presented at the EAN 2024 Congress evaluated the impact of prognostic scores on goal-concordant care from the perspective of clinicians, families, and patients.
The study, conducted at Lausanne University Hospital in Switzerland, enrolled 110 patients, 71 relatives, and 205 clinicians. At the time of enrollment, 65% of families reported having discussions about prognosis with clinicians, while 48% discussed the patient’s presumed wishes. Regarding goal-concordant care, 66% of families and clinicians agreed on their estimates of the patient's prognosis. Both groups felt that prognostic scores and their personal estimates significantly influenced their decisions in 46% and 55% of cases, respectively.
Results showed that the use of hypothetical prognostic scoring could markedly impact decision-making. For instance, when patients were given a 50% versus 90% risk of dependency, presumed decisions to withdraw life-sustaining treatment (LST) increased from 29% to 44%, respectively. Furthermore, 52% of participants expressed that they would strongly regret prolonging LST if the patient survived with severe, irreversible deficits, whereas 40% feared withdrawing LST even if the chances of recovery were extremely low.
Prognostic scores and personal assessments can have a substantial influence on decisions made by families. The authors concluded that early discussions about prognostic estimates and goals-of-care are crucial in making decisions that align with the patient's wishes.
Prognostic scores and personal assessments can have a substantial influence on decisions made by families
Enhancing Parkinson's Disease Detection with Multimodal MRI
A NEW study, presented at the EAN 2024 Congress, aimed to create a 3D convolutional neural network (CNN) utilising multimodal MRI to differentiate between control subjects and patients with Parkinson's disease (PD), as well as to use CNN to forecast the progression of PD.
By integrating MRI data with clinical and demographic information, CNN demonstrated promising results
Three cohorts were chosen for this study. The first cohort included 86 patients with mild PD, 62 patients with moderate-tosevere PD, and 60 controls; the second cohort included 56 patients with mild PD and 20 controls from the Parkinson’s progression markers initiative (PPMI) database; and the third cohort included 91 patients with mild PD and 38 controls. All participants underwent an MRI scan at baseline, as well as a clinical evaluation at baseline and at the 2-year follow-up. All patients with mild PD were classified as stable or worsening using k-means clustering based on baseline and follow-up Unified Parkinson's Disease Rating Scale III (UPDRS-III) values. CNNs were applied.
The CNN model demonstrated the ability to distinguish between patients with moderate-to-severe PD and controls, achieving a commendable level of performance. For patients with moderateto-severe PD compared to controls, the accuracy rate on the test dataset was nearly 75%, relying solely on MRI data for classification. However, when considering mild PD versus controls, the accuracy rate was approximately 65% on the test set, highlighting the challenges in extracting
discriminative features during the early stages of the disease. In differentiating between stable and worsening PD, the CNN achieved an accuracy rate of over 70% on the test set by combining raw MRI and clinical data.
By integrating MRI data with clinical and demographic information, CNN demonstrated promising results. CNN offers a valuable tool for early diagnosis and personalised treatment planning for patients with PD.
Congress Interviews
The following interviews from the EAN 2024 Congress showcase award-winning research and the vision for the EAN. We spoke with the Chair of the EAN Scientific Committee, Thomas Berger, Medical University of Vienna, Austria, who shared with us his commitment to making EAN “the Home of Neurology”. A discussion with the Moritz Romberg Lecturer Nils Erik Gilhus, University of Bergen, Norway, provided us insights into his exceptional career in myasthenia gravis research.
Q1Following the completion of your medical degree from the University of Vienna in 1991, what led you to pursue a career in neurology and later specialise in neuroimmunology?
EAN has to meet the slogan ‘home of neurology’, so we are all meeting in the dining room
Originally, I wanted to get into tropical medicine. However, Vienna is not a core site for tropical medicine. By chance, there was a call for three research fellow positions at Vienna at the Institute of Neurology. The Institute of Neurology is the oldest neuropathological institute in the world, founded in 1882, and there were three units: neuroimmunology, neuropathology, and neurochemistry. The Department of Neuroimmunology was for experimental neuroimmunology, led and headed by Hans Lassmann, a leading neuropathologist in the world dedicated to multiple sclerosis (MS) as well as neurodegenerative diseases, such as Alzheimer’s disease.
At the time, I applied for the research fellowship position at the Institute of Neurology and told myself I would see what happens. Unbelievable, but true, I got the position.
I can remember very well that the first time I came and introduced myself to Lassmann he said: “Do you want to do MS or Alzheimer’s research?” I said “I would prefer MS.” It was by chance, the flipping of a coin more or less. So, I started there with experimental neuroimmunology and neuropathology, also animal work. Following this, it was logical to continue in the clinical field of neuroimmunology. Once again, it was by chance, and I have no regrets. These were the crucial crossings in my career. Mainly, they happened by chance because one site offered more interesting possibilities or some advantages, or as I said, just by chance, because those research fellowship positions were not as readily available.
It was a good chance to get a foot into the door at the university, or at that time, the Faculty of Medicine. I believe a lot of things in this is a continuum; which also heralds true in research, because not all, even if it’s hypothesisdriven, is always the outcome of a rational thought, it happens often by chance. Nevertheless, you have to be alert to pick up the chances.
I think that’s the most important thing. This is nothing specific for research, but something that accounts for everything in life.
Q2As Chair of the Scientific Committee of the European Academy of Neurology (EAN), how have you shaped the 2024 scientific programme?
I have to be honest because the programme itself is not shaped or organised by the scientific committees but by the programme committee. However, indirectly, of course, the scientific committee has some influence on the programme. The scientific backbone of EAN are the scientific and coordinating panels, of which there are 32 at the moment that cover all fields of interest, including all disorders in neurology. They assemble more than 3,000 experts in their respective fields. What we usually do is release a call for those scientific and coordinating panels to propose programme items in terms of symposia, workshops, or any other EAN Congress sessions.
Because of the 32 panels, more than 200 proposals usually drop in, which are then rigorously evaluated. At the end of the day, the programme committee selects and puts together the programme for the next year’s Congress. The final step is, thus, not done by the scientific but by the programme committee, which is a big task. However, the scientific committee is responsible for the motivation and performance of the scientific and coordinating panels; therefore, it is the main body of the programme. In addition, every Congress has an overarching theme. The overarching theme is, again, proposed by the programme committee, and everybody, including the board, is either in appreciation or they have some adaptive comments. However, at the end of the day, the overarching theme also influences the suggestions in the proposals because, in a certain way, they should adhere to the overarching theme, not exclusively, but in a significant manner. The programme is linked to the overarching theme.
Q3Can you share your vision and key objectives for the 2024 EAN Congress in Helsinki?
My vision, apart from that it is a scientifically sound and highly interesting conference, regarding the participants coming from all over Europe and sometimes outside of Europe, they should have a good time not only because they learn new things and get the scientific context and education, but they also get to meet their colleagues. EAN has a slogan that is ‘we are the home of neurology’, so it is a kind of grand family party, where you meet once a year, see your colleagues from here and there, and you turn a corner and meet somebody that you have not seen for a long time. The atmosphere of this informal part is something that I think is for a family, for growth, and in the end, for wellbeing. This atmosphere should be met, and this is my vision because then people will make good memories, they will like it, and they will return with it. This is my vision, and of course, there are
The scientific backbone of EAN are the scientific and coordinating panels, of which there are 32 at the moment
objectives. The key objectives are to provide high-quality scientific content, the best education, good interactions, and collaborations, and have exchanges on various formal or business levels, because there are a large number of scientific panels, organisations, and committees assembling at the time of the annual EAN Congress. Additionally, partner organisations and liaison meetings are taking place here. It is a big, revolving, exchanging group of more than 7,000 people. I believe that is the main objective. EAN has to meet the slogan ‘home of neurology’, so we are all meeting in the dining room.
Q4
What are some of the most anticipated sessions or highlights featured in this year’s Congress?
I need to be honest again, that due to my duties on various board activities of EAN, my frequency of visiting scientific sessions is less than I would like. Nevertheless, there are those that are my personal highlights. My research topic is in MS and neuroimmunology, as we have talked about, and a lot of cutting-edge, new information
was presented. I like to go to sessions where you get the potpourri or kind of spectrum of various high-end lectures and presentations. The first one is linked to the overarching theme because there are plenary sessions, but also workshops focused on neuromodulation. Neuromodulation sounds a little dry and boring, but I think that it is an emerging field, and this is also the reason why it was chosen. There are a lot of developments going on, although it is in routine settings in certain disorders, like deep brain stimulation in movement disorders or noninvasive stimulation in patients with spinal cord trauma and pain, but there are permanent new advances; for example, non-invasive and non-lesional stimulation by MRI-guided high ultrasound techniques. These are technical developments that increase the efficacy of the intervention and lower potential side effects or unmanageable conditions. This is an extremely modern achievement for a segment of patients who do not represent the majority. Nevertheless, it is a high-end medicine in neurology, and it is
continuing to develop. I like these kinds of topics very much because it is future driven.
My second point, which is probably not that future-driven but is a review or retrospective historical view named lectures. The named lectures are for eminent colleagues, not only from Europe but from elsewhere. There is the Charles-Edouard Brown Sequard prize, the Camillo Golgi prize, the Moritz Romberg prize, and the brain prize. The awardees are chosen and are more or less elected, but this means that they are eminent researchers in their more mature professional lives, and they give lectures on their expertise, showcasing the historical developments in clinical research and what the future holds. These lectures cover heterogeneous topics, and it is inspiring to hear from those colleagues who really contributed to specific diseases, their mechanisms of understanding, and therapy. I believe that these lectures are motivating for the younger generation because they see how dedication, commitment, and curiosity towards a particular pathway can lead to great success.
Q5
You have previously said that you hope to see “the Home of Neurology growing to a mighty skyscraper of clinical neurology and neuroscience”. Looking beyond 2024, what future directions do you foresee for EAN?
It is always brave to make such a prognosis or expectation, but I believe this is more than true. I am totally convinced, and this is not only a gut feeling because I can prove in all aspects that the skyscraper of clinical neurology has reached the clouds. We are in the clouds, which does not mean that we have stopped growing and that there is no need for
We have to be the advocates for our patients because if they do not have us as advocates, we are doing the job wrong
further activities, improvements, optimisations, and developments, but the EAN has matured in its 10 years of existence. Since the birth of the EAN in 2014, it has developed into a neurological organisation in Europe, with some global impact. The impact of the EAN is on the level of education, research, science, and advocacy. We have to be the advocates for our patients because if they do not have us as advocates, we are doing the job wrong. Neurology is an extremely important field in medicine with an extremely high burden of disease, resulting in tremendous costs. However, this is not clear to the public. The public does not necessarily need to know all the details of neurology, but if the awareness is not there you cannot start, for example, prevention, because prevention requires a certain amount of knowledge and self-responsibility termed as health literacy. Only if people have awareness and know why, can they take on this responsibility. Going back to the skyscraper, I believe that we are now clearly in the cloud, but we need to get nearer to the sun still.
Q6Multiple sclerosis is regarded as a dramatically improving field of neurology, with many new therapeutics being developed or made available. As the National Multiple Sclerosis Coordinator of the Austrian Society of Neurology, and President of the Multiple Sclerosis Research Foundation in Austria, what are the remaining gaps in multiple sclerosis research and care?
There are always a lot of remaining gaps because we still are some way from being totally satisfied, where we understand everything and can handle the logical consequences, including therapy. However, there are two major gaps, which are also the pathways that are followed right now and are being heavily researched. The first one is prognostication and individualisation of therapy. Individualisation means that we move into a personalised approach, that any prognostic marker, be it a fluid body marker or a non-fluid body like imaging, needs to prove that it is individually working and not only on the group level. At the moment, we are at the group level, which is already a good development. Regardless, we now have to dissect this more and tailor it to the individual. This is a logical approach and if I can individually define the prognosis of a person with the diagnosis of MS or any other disorder, then I can also tailor my recommendations or activities, and introduce treatments. There is a plethora of treatments available and approved for MS and related disorders; however, not every patient needs a specific treatment or lifelong treatment. It would be a big advantage for patients if we could define individual risk for disease. It is not appendicitis, where you cut out the appendix and the problem is solved. We are dealing with a potentially chronic disease, so we have to prognosticate what might happen 30 years down the road, which is difficult, not only on a research activity or demand perspective, but also on
an intellectual perspective as it demands an intellectual vision.
Having said that, the logical consequence then is to tailor therapies. Now, as I said, the approved therapies are quite broad because when I started with MS clinically in 1994, which is now 30 years ago, we had different first treatments available. In the last 3 decades, treatments have expanded dramatically for the good of the patient. Nevertheless, the approach should be to stop the disease. Between using the terms stopping or turning down, the word is probably not important for the patient because they do not care what I term it as long as nothing happens anymore. However, cure is an emotionally different promise, and we cannot promise that we will cure MS. We can promise that we tried to stop it. So, the cure is the issue, and the cure will work via the immune system. There is progress in the immunological understanding of this autoimmune disorder, so there are thoughts of resetting autoimmunity, which means that we are truly not only stopping but curing the disease.
If you stop the autoimmune trigger or cascade, the problem is solved. We are not there yet, but we are far closer to this idea than 10 years ago.
Q7As Chair of the Task Force on Teleneurology, how has teleneurology developed in recent years, and how do you see its role evolving?
The Teleneurology Task Force was a response to the pandemic. We were immediately in this from one day to another, forced to establish ourselves in a more systematic way because the equipment and the possibilities were there before the pandemic, but our health system and technical systems were not ready. In a very short time, we, and this does not mean me, but those in my department and anybody in the medical field, tried to link with the patients who were not socially but physically distant. Therefore, teleneurology suddenly boomed. This was one of the good offsprings of the pandemic, because suddenly it
worked. We got diagnosis-related groups for that and we had no legal problems. We had consented, informed patients, so it worked suddenly and effectively. The next developmental step that occurred was AI and it can be argued that teleneurology is a part of this. In this way, the task force merged into a more overarching task force, which is AI in neurology. This is definitely the more important topic, rather than establishing remote conversation or even investigation tools here, because this is now a daily practice.
Teleneurology was a good reaction to a dramatic situation, as it enabled us to link with our patients, which was extremely good for both them and us. Nevertheless, the next step is digitalisation, AI, and deep cognitive algorithms. This is an important issue. We need to advance our performance, as digitalisation means we perform easier handling of data by merging, connecting, and also establishing data, which of course
If you stop the autoimmune trigger or cascade, the problem is solved. We are not there yet, but we are far closer to this idea than 10 years ago
causes a plethora of problems and questions. Regardless, I think it was good that the teleneurology Task Force transformed into the AI Task Force in neurology. As this is a demanding issue, it is essential to have a systematic approach. Otherwise, others will take over the field, and I am talking about for-profit organisations. I am not scared of the technologist because if you work long enough in any field you recognise that some little technical automatisation processes are always seen with scepticism because they are replacing humans. In labs, for diagnostic purposes, there was always scepticism because it not only optimises the process but removes the human element. This is true for many professions, probably not that much on the
level of physicians but definitely for nurses and technicians. Therefore, I believe that it is of the utmost importance that we create those things rather than any businessdriven models and enterprises that might use the data collected for other purposes.
Q8Looking back on your career, what has been your proudest achievement?
You can think about this question in various ways. However, I think the most important thing for me is if the things I have done in my professional career up to now and the future it will inspire, especially for younger colleagues, people, clinicians, researchers, and students, to dream a little bit more about the topic and to
be curious. If I can do this, I will believe I have fulfilled my mission. I have supervised more than 120 young medical students and also doctoral students writing their master thesis and PhD thesis, and for me, it was very reassuring that the majority of those got into the field of neurology, made it through residency, and are now neurologists. Mission accomplished. I think anything else can be temporarily important or scientifically important, but I think the most rewarding thing you can do is inspire other people to think and work and to expand themselves in the field, because then you care for sustainability in this specific field.
Professor in Neurology, Department of Clinical Medicine, University of Bergen; Senior Researcher at Department of Neurology, Haukeland University Hospital, Bergen, Norway
You have been a Professor of Neurology and Consultant Neurologist for over 30 years. What led you to pursue a career in neurology and later specialise in neuroimmunology?
Q2
We need to adapt guidelines to individual patients
The first and most important thing is that I wanted to be a doctor and see patients. I wanted to work in a discipline where I talk to patients and try to treat patients and improve their situation. Neurology is a very good example of such a discipline. In addition, when I started in neurology, I understood immediately that you become close to the patient when you treat a neurological disease. Neuroimmunology was a hot topic when I started, probably the hottest topic in medicine. It was new, it was emerging with exciting new data. It was like today’s AI or genetics some years ago, new and exciting. In Bergen, Norway where I worked, we had a very nice cooperation between basic immunologists and neurologists. We had a neuroimmunological laboratory interested in neurology. We were able to pursue new immunological questions from a clinical perspective. The lab adapted to our questions, so we did not need to go there to do pure immunology, but we could take with us our clinical interests and experience, it was a very good combination.
In the prestigious Moritz Romberg Lecture as part of the 2024 European Academy of Neurology (EAN) Presidential Symposium, you discussed individualised treatment for myasthenia gravis based on welldefined disease pathogenesis. Could you highlight the central thesis of your lecture?
A big challenge is the contradiction between individualised, personalised treatment, and general guidelines. We need general guidelines to lead our treatment in the correct direction and to be ambitious including new treatments. However, general guidelines do not fit every patient, doctors are required because we need to adapt guidelines to individual patients. What we do is that we try to find biomarkers able to subdivide patients in a way that means that patients with specific biomarkers will receive specific treatments known to work well for this subgroup. Improved specificity of biomarkers allows for multiple smaller groups of patients with their unique guidelines and treatments. This is a challenge, but we should try to combine the available factors discussed in my lecture and then produce guidelines that are useful for the defined subgroups. Adaptations must be made, but we also must accept that it is impossible to
Nils Erik Gilhus
make a guideline and follow it in detail for each patient.
Q3
What are the key innovations and takeaways regarding the individualised treatment of myasthenia gravis that you hope to impart to clinical scientists and healthcare professionals?
There are new drugs on the market like complement inhibitors, FcRn blockers, and B cell directed therapies. These drugs work quite well and have a rapid mode of action, working within 1–3 weeks. Additionally, very few long-term side effects are associated with these new drugs. However, they are much more expensive than the present treatment options.
What is the cost of these newer treatment options?
Doctors are unable to give precise figures, and they are different in different countries. The exact prices are often a secret. There are list prices and reduced prices after negotiations with health authorities. The initial price for some drugs were in my opinion unacceptable. Now the costs are lower, but still very high. Discussions are ongoing regarding which patient subgroups with myasthenia gravis qualify for these new treatments, and most importantly qualify for refunding of the costs. This discussion is on medical terms, but also with health administrators. If these drugs were free or cost the same as traditional treatment regimens, they would be useful for a large proportion of patients with myasthenia gravis.
However, these drugs are not readily available because of the high costs. An unsolved question so far is also when we should use complement inhibitors and
FcRn blockers, and which of the available preparations are to be preferred. We do not know because there are no comparative studies or trials. The patient characteristics in the various trials vary, and so real-world data will be important, as long as we do not have head-to-head comparisons.
Q4How have you seen the advent of new technologies and approaches significantly impact the field of myasthenia gravis in recent years?
For the brain, MRI is fantastic, we can gather a lot of imaging information, but myasthenia is a completely different story. For myasthenia gravis, I would have liked to have an image of the synapse, so that I could observe what is happening there. There are morphological changes at the synapse. Are they reversible? Probably yes. What do the postsynaptic membranes look like in patients with no symptoms but a lot of fatigue? We do not have techniques today to have an impression of the morphology at the post-synaptic membrane. I am not sure if it is possible and feasible, for example, using imaging MRI or microscopy to look at the cellular level. New assays to detect relevant muscle antibodies with high sensitivity and specificity is important. We need to try to find ways to subdivide acetylcholine receptor antibodies and see if we can identify subgroups that better reflect disease development, prognosis, and therapeutic response.
How have you seen the quality of life and outcomes in patients with myasthenia gravis change in the last 30 years?
I think there are data showing that patient outcomes are significantly better, but there are still many
challenges when it comes to treatment. We need new and better drugs, new knowledge, and better tests. However, an important element is to use what is available in the best way. Patients and neurologists are more aware of the available treatments and are more active in choosing optimal treatments today. We have looked at the number of consultations for myasthenia gravis in Norway. In specialist healthcare, we have seen an increasing number of consultations, with it near doubling during the last 10 years, while the number of patients is approximately the same. So, it seems that the patients are followed more frequently, and there is better follow-up from specialist healthcare. There is still a slight increase in mortality in myasthenia gravis, with a relative risk of 1.2–1.3 in the Nordic countries, but the overall mortality risk is lower now than 20 or 30 years ago and much lower than 40 or 50 years ago.
Q5With the 2024 EAN Congress theme focusing on ‘Neuromodulation: advances and opportunities in neurological diseases’, what are some of the most promising developments in both invasive and non-invasive neuromodulation techniques being presented?
Neuromodulation is a term that is relevant for many diseases mechanisms, it is an overarching term. However, what does it mean in myasthenia gravis? The disease pathogenesis is a dynamic process, the interaction between the nerve terminal and the muscle is dynamic all the time. The target for the antibodies is muscle tissue and not a nerve, and thus no neuromodulation. The muscle is continuously synthesising new acetylcholine receptor antibodies. When the antibodies find and destroy acetylcholine, the compensatory result is an increased production of new acetylcholine receptors. This is a very dynamic process. There will be an increased number of stem cells in the muscle, and the presynaptic terminals release more acetylcholine. The autoimmune
attack and receptor destruction has a lot of consequences at the neuromuscular junction, and some influence the pre-synaptic nerve.
Q6 How much of an impact do you believe the EAN Congress has both directly on neurologists globally and indirectly on patients?
I am a big fan of EAN, the Congress, and everything around the Congress. When 7,000 neurologists meet, I am sure that the clinical practice will be influenced when they return home. When I ended my talk and when I received honours, I ended by saying that I hope that patients will experience a difference when we neurologists come back from Helsinki. The improved treatment for myasthenia gravis throughout Europe is partly due to the education and information received at congresses like EAN. EAN is the largest neurology congress in Europe. It is not just a research congress, but one focused on clinical practice with teaching courses and information on disease. I think the EAN congress is one of the best ways
When
7,000 neurologists meet,
I
am sure that the clinical practice will be influenced when they return home
to influence at the European level and at clinical practices in all types of neurological institutions.
Q7
Mentorship has been a significant part of your career as a neurologist, with you having supervised over 30 accomplished PhDs. What challenges do you believe early career researchers and those pursuing PhDs in today’s world face, and what advice would you give them?
I think they should choose by heart; they should do what they would like to do at the moment. If you are active and have an ambition for your career as a doctor, you should be active both in clinic and research, but you should also do what you think is fun or optimal at that moment.
You never know what will be useful in 10, 20, or 30 years, or where you will be at that time. I think that if you pursue what you think is best for you today, that is a good thing. I have been very happy because I have been able to combine clinical work with research, teaching, and some administrative tasks, which I have enjoyed very much. For me, it has been perfect to combine them. I think I am first and foremost a doctor, and seeing patients has always been core element my professional life.
Among the 30–35 PhD candidates I have overseen, some have continued research and become leaders in research, some have been more interested in administration, and some have become leading clinicians. For all of them, their PhD and their
PhD-work has been useful and a good experience to improve their abilities. For me, this cooperation with young researchers has probably been the most rewarding of my activities. I have learned, I have exchanged ideas, I have had fun, and we have obtained excellent scientific results of clinical relevance. I attended a symposium on the EAN mentorship programme, and I have had a young mentee from Türkiye and one from Tunis in that program. I am an eager advocate for this programme. We have had very nice and interesting meetings, with clear aims for the mentorship. The combination of clinical work and research is great fun, and even more so if you are able to include international cooperation.
Interviews
A roundtable interview with Olivier Rascol, Toulouse University Hospital, France, and Wassilios Meissner, University of Hospital Bordeaux, France, discussed potential disease-modifying therapies for Parkinson’s disease. Kailash Bhatia, University College London, UK, highlighted how newly identified Parkinson’s disease biomarkers driven by AI are reshaping disease diagnosis.
Featuring: Olivier Rascol, Wassilios Meissner, and Kailash Bhatia
Olivier Rascol,1 Wassilios Meissner2
1. Professor of Clinical Pharmacology, Toulouse University Hospital, France
2. Professor of Neurology, University of Hospital Bordeaux, France
Professor Rascol and Professor Meissner, what would you consider the ‘turning points’ that inspired you to specialise in movement disorders, particularly Parkinson's disease?
Rascol: When I started as a neurologist and a clinical pharmacologist, there were a lot of interesting developments in movement disorders, particularly Parkinson's disease, based on the understanding of the dopamine hypothesis. That was the main reason for my curiosity in this area.
Meissner: For me, it was very simple. It was, in fact, not an active choice, which I never regret. At that time, I wanted to become a neurologist at the Charity Hospital in Berlin, and the only way was to accept a position in the movement disorder group. That was how I found myself on the topic of Parkinson’s disease and movement disorders.
Q2 In your opinion, what have been the most significant advancements in Parkinson's disease research over the past decade?
Meissner: The development of biological tests such as the alphasynuclein real-time quakinginduced conversion (RT-QuIC), which one day might help us make a more accurate diagnosis.
Rascol: I would add the importance of physical exercise in disease management and a multidisciplinary approach to the management of patients.
Q3 What motivated the initiation of the Lixipark trial?
Rascol: There was a background, particularly in logical data, suggesting a link between diabetes mellitus and an increased risk of Parkinson’s disease. Neuropathological studies also showed postmortem in the brain of patients with
Parkinson’s disease that there were abnormalities in insulin signalling biomarkers in the substantia nigra, which is affected in Parkinson's disease. We had a mature network of French clinical research centres, which put us in a position to run academic clinical trials. Furthermore, in 2012, there was the publication of an early pilot mono-centric clinical study run by a group at University College London, UK, showing that in randomised but non-blind conditions there was a possibility of some positive effects of exenatide, another GLP1 agonist close to lixisenatide, in parkinsonian patients. This initial result was confirmed in a subsequent double- blind study conducted by the same group and published in 2017, but these results were not yet available when we started our own project. Finally, we were fortunate to be provided with the lixisenatide medication for diabetic patients at no cost by Sanofi.
Meissner: Rascol nicely summarised that there were several developments that converged to allow us to conduct this clinical trial. I would add that there was data
from epidemiological studies and studies on patients with diabetes, showing, for example, that glucagon-like peptide 1 (GLP-1) receptor agonists as a whole group reduced the risk of patients with diabetes having an additional diagnosis of Parkinson’s disease. There was strong evidence from the bench and epidemiological studies.
Why was lixisenatide the chosen GLP-1 receptor agonist used in this study?
Rascol: When we commenced our clinical trial study, there were not as many GLP-1 receptor agonists available and we had direct links to Sanofi who provided the drug and the placebo for the study at no cost, accounting for a large part of the trial budget. Moreover, there are not many big differences between lixisenatide and exenatide. Retrospectively, these drugs have the advantage of being relatively small molecules, which can cross the blood–brain barrier, which might not be the case for some of the more recently developed drugs. It is an advantage for targeting Parkinson’s disease, a drug that is bioavailable for the brain.
Development of biological tests one day might help us make a more accurate diagnosis
Q4
Can you provide an overview of the Lixipark trial and its primary objectives?
Meissner: The overall objective was to assess the effect on the progression of motor symptoms as assessed by the MDS UPS Part III scores. It was a 1-year study, where patients were randomised equally to receive lixisenatide or a placebo for a year. Overall, 156 patients were enrolled and then followed up to 14 months because there was a 12-month treatment period where we hoped that the patients would be able to continue on their stable dopamine replacement regimen, and then after 12 months there was a washout of lixisenatide and the patients were seen 2 months later. The patients were then seen offstate to get an additional potential sign of the neuroprotective effect.
Rascol: The study should be seen as a proof of concept, which is robust because the methodology is clean, it is simple, the results are straightforward, and the study is multicentric. On the other hand, we only tested lixisenatide in certain types of patients (those at an early stage of the disease only), we only followed them for a year and tested only one dose. Therefore, there are still pending questions that should be assessed in a subsequent trial before one could recommend using this drug to treat Parkinson's disease, in spite of the fact that many patients are now anxious about getting treated with the drug. Moreover, from a practical perspective, lixisenatide is
not anymore available for the treatment of diabetes mellitus itself.
Q5What were the most significant findings from the Lixipark trial, and how do they contribute to the current understanding of Parkinson's disease?
Rascol: I would say the study represents a major breakthrough because it shows that we could, with this medication, block or significantly reduce the rate of progression or worsening in severity of the motor symptoms. Furthermore, 2 months after the lixisenatide washout, the difference was still significant between the placebo and lixisenatide-treated groups, which is strongly in favour of a longacting neuroprotective mechanism rather than a short-acting levodopa symptomatic effect. The study was well conducted, there were very few losses of follow-up and missing data. I believe that it is thanks to the quality of the centres, we train the French Network for good quality in clinical trials. Additionally, the results were consistent with what our colleagues at the University College of London, UK, reported previously in a smaller set of patients with exenatide. After 30–40 years of negative findings in the identification of neuroprotective intervention in Parkinson’s disease, this is the first robust finding. Some people might comment on the fact that it was only a three-unit treatment effect on the MDS-UPDRS scale we used
We need to further explore which is the best dose to improve and induce benefits in Parkinson’s disease
to assess disease progression, and we can discuss this aspect, but the data is the data and I believe it is unlikely to be biased. Therefore, in my view, this is an extremely important achievement after billions of dollars and decades of failures.
Meissner: You can very well imagine that based on these extremely encouraging data, we are interested in moving forward and confirming the data in a larger Phase III trial in Parkinson’s disease. We are also eager to learn about the results of the Phase III trial with exenatide, and the results should be available by the end of the year. Our results have also generated significant interest in colleagues focussed more on prodromal Parkinson’s disease, especially in REM sleep disorder cohorts. I had a lot of exchanges with people trying to understand how GLP-1 receptor agonists might be of interest in these early cohorts. Therefore,
there really is a lot of excitement currently in the field, and we would need more clinical trials to confirm this.
Q6Within medical research, there is significant attention being paid to the potential of GLP-1 receptor agonists to treat a variety of disorders, such as liver disease, chronic kidney disease, polycystic ovary syndrome, and disorders, such as from your research and reading. What are your thoughts on what appears to be the era of ‘GLP-1 receptor agonists’?
Rascol: I understand that in Denmark, the company that is developing these compounds makes billions in profit due to the expanding use of such medications. We should not forget, however, that GLP-1 agonists can also induce some side effects, such as rare but severe pancreatitis for example. It has been shown to benefit
weight loss, which is desirable for metabolic disorders, but this is sometimes ideal for patients with Parkinson’s disease, who we do not want to lose weight. The mechanism of GLP-1 receptor agonists appears extremely broad and with a lot of beneficial effects in a number of pathological conditions for the brain, the kidney, blood vessels, etc. It appears like there is a big future for these drugs in medicine. At the moment, we do not recommend yet using these drugs specifically for Parkinson’s disease, but this might be different for patients who have both diabetes mellitus and Parkinson’s disease.
Meissner: I think it would be really important to learn more about the biological mechanisms. In Parkinson's disease, we have some pre-clinical data and there has also been some exosomebased data published in 2017, but we do not know much about the effects. There could be
some brain-related effects, but there may also be some effects on inflammation, on peripheral inflammation, on the interplay between peripheral and central inflammation, and that may be a way it operates in a variety of disorders. However, we really need to learn more about that, and we had the chance to add a couple of ancillary studies to our trial. We are currently looking for potential biological mechanisms that lead to this effect in Parkinson’s disease.
Rascol: I would also like to add that it might not necessarily be appropriate to use the same dose to improve different disorders like diabetes and Parkinson's. We have been testing 20 mg/day, which is the recommended dose for diabetes mellitus, but some patients got nauseous and were allowed to reduce the dose by half to 10 mg and there was no strong evidence that the effect was less in this subgroup. Therefore, we need to further explore which is the best dose to improve and induce benefits in Parkinson’s disease.
Q7
What advice would you give to young researchers interested in pursuing a career in neurology and clinical pharmacology?
Meissner: Be persistent.
Rascol: Be curious and be motivated. One of the big issues at the moment is that many young neurologists are focused on their
own personal short-term quality of life, and it looks like they are less interested in making extraefforts to be involved in research activities. I think that one needs curiosity, motivation, patience, and perseverance to enjoy work and make it exciting and rewarding.
Q8
Professor Rascol, since you were appointed head of the Toulouse Clinical Research Centre in 1994, what has been your proudest achievement, and what do you hope to accomplish in the coming years?
Rascol: First, I hope to pass down the leadership in the best way possible. Second, I think that building the Toulouse Clinical Research Centre has been an exciting achievement that allowed us to improve our knowledge on different disorders and improve our management of patients. It was also the first step to build efficient clinical research networks like the NS-Park network, without which the Lixipark trial would have never happened. I believe that in clinical research, to be efficient and creative, you need to bring together different expertise, different profiles, enough access to patients, and education to patients to test new hypotheses. If we did not have strong clinical research centres and networks, we would not have been able to conceive such a programme, run it, and have enough credibility for industry partners.
The study represents a major breakthrough because it shows that we could, with this medication, block or significantly reduce the rate of progression or worsening in severity of the motor symptoms
Q9 Professor Meissner, since you were appointed head of the Department of Neurology for Neurodegenerative Diseases at the University Hospital Bordeaux, what has been your proudest achievement, and what do you hope to accomplish in the coming years?
Meissner: It has been only 4 years since I was appointed Head of the Neurodegeneration Department. I think we had the chance over the last 15 years to conduct the study because the evidence was pointing to what was going on. We have a very strong team with a lot of ideas in terms of improving patient care, so it is not only about research. From a research perspective, the Lixipark trial is my biggest achievement, and scientifically speaking it will be my greatest achievement. However, I think we need to go beyond drug development and develop a lot of complementary medicine strategies and have a holistic approach to patients and caregivers. I think this is something that we have led over the last couple of years and is something that we will continue pursuing.
Professor of Clinical Neurology, University College London, UK
Q1 What initially sparked your interest in Neurology, and what motivated you to pursue training in neurogenetics and movement disorders with the late Professor’s Anita Harding and David Marsden?
I completed my neurology training in Mumbai, India. At the end of my general medical degree, I was influenced by a toprate neurologist in Mumbai, Noshir Wadia. Wadia was studying a particular form of spinocerebellar ataxia in what turned out to be spinocerebellar ataxia Type 2. However, at that time, it was a mystery disease that afflicted young adults with cerebellar ataxia, who presented with the classic slow eye movements. I found that fascinating, so I decided to take up neurology training.
David Marsden, who could be considered as the founder of the new field of movement disorders within neurology. I would attend Marsden's famous book round and he took to me, and I became his research fellow. Eventually, I became a lecturer, then a senior lecturer, and finally a professor at Queen Square. I was very lucky to have incredible mentorship from Wadia to Harding, who really influenced me. Moreover, it was an exciting time in movement disorders. It was a relatively new field, and I was able to publish a lot with Masden even as a young fellow. I believe one has to be lucky and although many of my life decisions were by serendipity, one must take the opportunities that come their way and run with them.
Q2
One
must take the opportunities that come their way and run with them
After completing my neurology training, I worked with Wadia because I felt incomplete and unprepared to go into practice. My father wanted me to do so because we were middle class; he told me: “Why do you not start practising and earn some money?” But I wanted to explore research. With this in mind, I returned to Wadia and published a paper with him on multiple sclerosis in a top-rated journal, which was a rare feat, and usually there were only a few papers from India. However, my idea was to learn more about neurogenetics. Since he wanted clarification on ataxias and Anita Harding was the ataxia expert at Queen Square in London, UK, also working on genetics, I came to work with Harding. It was while working with her that I met
You currently have more than 600 peer-reviewed publications to your name for your research in neurology and movement disorders. What do you believe to be the current gaps in research in regard to dystonia and Parkinson’s disease?
One of the significant issues with dystonia is that it is like an orphan condition. If you mention dystonia to somebody, people are likely to wonder whether you are referring to a foreign country. It is not present in the public domain or even in the general practice domain, so most people do not know about dystonia. However, the most common form of dystonia is idiopathic cranial cervical dystonia, and many fundamental questions are unanswered. The disorder mainly afflicts women, particularly those aged 50–70 years. The cranio–cervical region is predominantly affected, it does
Kailash Bhatia
not spread and go anywhere else; and if you have torticollis, it is usually the head turn to the left. There are simple questions that need to be addressed. Why is it predominantly in women? Why at that age? Why to the left? We do not have answers, and though we have treatments like deep brain stimulation, we do not understand the basic pathophysiology of dystonia. This lack of understanding of the pathophysiology is why we do not have curative treatments. One of the problems, especially, is that it is challenging to get funding for research into dystonia. People do not recognise dystonia as an important neurological disorder which afflicts many people and affects their quality of life in a major way.
Parkinson’s disease is a fascinating area I have become increasingly interested in. There are numerous different aspects one would consider as being problematic. There is a considerable amount of genetic research for Parkinson’s disease that has helped us understand the pathophysiology of the disease. The discovery of alpha-synuclein was a monumental event, but if you look overall at the genetic causes of Parkinson’s, monogenic forms represent 2% or fewer cases. There are, of course, risk factor genes that might contribute an additional 7% in prevalence, but a large proportion of patients have idiopathic disease with no genetic cause.
That brings us to the question about the environment. There is a large gap in understanding the environmental causes of Parkinson’s disease. Although there are suggestions that pesticides, well water, and similar environmental factors contribute to Parkinson’s disease risk, we do
not have good studies looking at the environmental factors as the primary or maybe the adjunctive cause of Parkinson’s. How does the environment play a role? Furthermore, it is interesting that Parkinson’s is only seen in humans, and there is no natural model for it in animals. We share the vast majority of our genetic makeup with higher apes, but they do not develop Parkinson’s. It is a human disease. What is it with Parkinson’s disease that means it afflicts humans only?
The two important aspects for me are considering the contribution of ageing and the environment. We are spending considerable effort examining the genetics, and pathophysiological mechanisms from the genetics, but we need to pay more attention to these other factors. Additionally, another area that requires more attention is disease modification. We have been successful with symptomatic drugs and surgical options like deep brain stimulation, but
methods for disease modification, slowing down or changing the course of disease progression are still absent. There are some promising developments in disease modification, but we need to do better. Finally, researchers and clinicians primarily discuss Parkinson’s disease from the motor perspective, and available treatments target motor symptoms. Nevertheless, the quality of life and the non-motor problems later in life, including cognitive problems with apathy, anxiety, fatigue, and so on, are understudied. There needs to be more research to understand the non-motor side of Parkinson’s disease.
Q3
In the recently published article you co-authored entitled ‘Plasma proteomics identify biomarkers predicting Parkinson’s disease up to 7 years before symptom onset’, what were the key findings and what are their impact?
Before I discuss the key findings and the impact, I want to discuss the background of the study. Kevin Mills is an extremely bright academic at the University College of London Institute of Child Health in the UK, and we work together on several projects. One of the projects that we are collaborating on is funded by a European Union (EU) grant, called Propagageing, looking at ageing and Parkinson’s disease. While working together I told him that it would be of great interest if he could use his high-
performing liquid chromatography technology to identify a signature of Parkinson’s in the blood. There are several assays utilising cerebrospinal fluid and methods such as real-time quakinginduced conversion (RT-QuIC) for the blood that are becoming more accurate diagnostic tests. However, the question that we asked ourselves is, can we look at the difference in the protein makeup in the blood using a very detailed proteomic analysis to identify a signature for Parkinson’s disease that is different from healthy controls? If we could do that, would it be possible to look at patients with REM sleep behaviour disorder (RBD), which we know is a common prodromal symptom of several synucleinopathies, and ask who would go on to develop Parkinson’s?
The problem we faced was that we did not have samples from patients with RBD. This is where Brit Mollenhauer, University Medical Center Goettingen, Germany and her team came into the story because they had samples of people with well-defined RBD. We had the initial phase where we took a small number of patients with Parkinson’s disease compared to controls, and we had a very large number of proteins from that. Using machine learning, we were able to identify eight proteins from the dataset that could be used as a predictor signature of Parkinson’s disease in the blood. We applied this identified
A good mentor, identification of a niche, and patience are the three important aspects for an aspiring neurologist
signature to the RBD cohort provided to us by Mollenhauer, and we found an overlap, which allowed us to accurately predict those in the RBD cohort who went on to develop Parkinson’s disease. The reason why the findings may be useful is because RT-QuIC and seeding assays are difficult to apply globally, while most hospitals in the UK and worldwide have high-performance liquid chromatography and can use this discovery to validate our signature and use it as a Parkinson’s disease marker. This finding has been exciting, and though the results require validation, the study is robust and was extremely well done.
Q4
What are the implications of these findings for the use of machine learning in the identification of biomarkers and drug targets for Parkinson’s disease and other disorders?
The power of machine learning lies in large datasets. This study
is a good example of where you start with 1,280 proteins and then use an AI-driven methodology, looking at the functions of these proteins, for example, to be able to narrow down which may be important from a pathophysiological perspective. AI will drive our understanding of large datasets in a more meaningful way, whether that is applied in proteomics or genetics. At the moment, we are putting together very large datasets by combining clinical data, radiological or imaging data, and proteomics and metabolomics on a large dataset, we are then applying AI to see if there is a difference in patients that progress to Parkinson’s disease, multiple system atrophy, or progressive supranuclear palsy. Utilising AI for this type of analysis is going to be very powerful and will provide us with a lot of information.
Q5 You have recently been appointed as PresidentElect of the European Academy of Neurology (EAN), and have
stated that you plan to “support the core values of the EAN in promoting education, science, advocacy, and membership.” With this in mind, what is your vision for the future of EAN?
Firstly, I am delighted, honoured, privileged, and humbled to be resoundingly elected for this position. The European Academy of Neurology (EAN) is a growing organisation. At the EAN 2024 Congress, there were 7,000 in-person attendees and another 2,000 online, so we had an audience of nearly 10,000, which is a huge meeting and a momentous accomplishment. My view is that there should be a level playing field across all areas. For example, with the discoveries that we have discussed, there should not be a two-tier or threetier system coming in because some countries can have access to the latest investigations, while other countries in Eastern Europe, particularly, may not have the same access. The idea is that education and information should be available
equally to everybody and that is an important consideration for me. Everyone must have equal opportunities irrespective of gender, race, nationality, and other characteristics.
I want to foster and help young people come up, ensuring that they have a voice and are represented. These are not just words, and I mean what I say. As a professor, I have trained 86 fellows from 22 different countries, and many of them are leaders in their own right. You must give young people opportunities, whether that is being able to present at meetings or whether that is the question of education being available to everybody, so that everyone is aware of new findings happening in the world. I also want to bring advocacy to the political side and make government organisations aware of what is going on, particularly with rare orphan conditions. These rare neurological conditions tend to be ignored because they afflict very few people, but if you look at them collectively, the number of afflicted patients is huge. We must ensure that there are care pathways in place for patients with rare diseases, and through advocacy, we need to make governments and national bodies aware of this. These are just some of the goals I will pursue as President-Elect of EAN.
Q6Looking back at your career, what advice would you give to earlycareer neurologists?
It is important for young people to have a good mentor. If you have a mentor, the mentor can guide you and put you on the stage. A good mentor will recognise your talent and spirit and will help you achieve your goals. Your mentor should not be threatened by you, which can happen when you have young people coming up. The mentor should be secure, and if so, they can help you and make you secure. In addition to finding a good mentor, you need to recognise a particular niche for yourself, so look out for what is coming up and identify a niche for yourself. For example, you may say you want to be an expert in autoimmune movement disorders, so, rather than attempting to do everything, you should identify one or two places in which you can become a specialist in. As you write and publish, people will recognise you as the expert on the niche, which will ultimately lead to recognition. Finally, while it can be easy to get desperate, good things come to those who wait, so persevere. A good mentor, identification of a niche, and patience are the three important aspects for an aspiring neurologist.
Myotonia: Are We Underestimating the Burden in
Myotonic
Disorders?
Raising awareness of the burden of disease due to myotonia will enhance understanding of patients’ needs, and improve the management of myotonic disorders.
Myotonic Disorders Are Rare Inherited Neuromuscular Diseases1-4
Myotonic Dystrophy (DM)1,2
• Rare (AD inheritance; DM has a global prevalence of 1 per 10,0005)
• Impaired Cl- channel function
• Multisystemic: Myotonia is one of many possible symptoms
• DM2 symptoms can be non-specific and replicate other conditions
DM1 DM2
• Congenital, childhood, and adult onset
• More commonly adult onset
Non-Dystrophic Myotonia (NDM)3,4
• Ultra rare (prevalence AD forms: 1 in 250,000 to 1 in 400,000; AR forms: 1 in 25,000)
• Impaired CI- or Na+ channel function
• Myotonia is the main symtom6
• Variable age of onset, usually presents in first 2 decades of life
Cl- channelopathy
• Becker MC (AR inheritance)
• Thomsen myotonia congenita (MC)
Na+ channelopathy
• Paramyotonia congenita
• Sodium channel myotonia*
• Closely related SCNC4A myotonic disorders
*Includes myotonia fluctuans, myotonia permanens, and acetazolamide-sensitive myotonia.
DM1 Has Multisystemic Manifestations1,7-14
Multiple symptoms manifest at different ages and in all forms of DM1 onset.15,16
CNS EFFECTS /EDS
CARDIAC DEFECTS
SKELETAL MUSCLE MANIFESTATIONS (including myotonia and muscle weakness)
OCULAR EFFECTS
PULMONARY INSUFFICIENCY
GI DYSFUNCTION
Myotonia Symptoms Affect Many Different Areas of Patients with Myotonic
Location of Myotonia in DM1 and DM215,16
Myotonia precedes all other symptoms (including muscle weakness), and is present in all age groups, apart from at birth.15,16
DM1: Mainly (but not exclusively) distal muscles are affected with myotonia (hands, feet, but also face/jaw), however myotonia may present elsewhere, e.g. shoulders
DM2: Proximal muscles are more often affected with myotonia, however myotonia may also present in the hip and neck
The ENSA patient survey showed that 93% of patients had a current or previous history of myotonia; however, the burden of disease due to myotonia has not been fully addressed in these patients.21 Disease burden due to myotonia may include the following:
Unpredictable attacks
Attacks are life-long, unpredictable, and disabling. Feeling restricted, persistent tiredness, pain, and cramping.
Social anxiety
Unable to release handshake.
Difficulty eating. Problems speaking.
Issues with daily living Challenges with dressing. Difficulty with personal hygiene.
Reduced activity
Difficulty exercising or climbing stairs.
Work duties can be challenging.
Difficulty crossing streets.
Lack of independence
Occasional assistance if needing to drive.
Need help with some tasks.
This infographic presents highlights from a symposium held on 23rd April 2024 as part of the 8th International Myology Conference in Paris, France. The symposium and infographic were sponsored by Lupin Neurosciences.
Myotonia e.g. Grip Myotonia Is a Common, Overlapping Symptom in Myotonic Disorders that Impacts Quality of Life
• muscle stiffness/delayed muscle relaxation after forced contraction4,22
Grip Myotonia
Delayed Diagnosis of DM and NDM
• Diverse genetic and phenotypic manifestations make diagnosis of DM and NDM challenging8
• DM diagnosis is typically delayed by 3–12 years24
• NDM diagnosis is typically delayed by 15–17 years6,25
• The IMPACT patient survey showed that 65% of patients had NDM symptoms for >10 years before diagnosis6
• Myotonia intensity varies in NDM, depending on diagnosis
• impacts quality of life of individuals with myotonic disorders, including DM and NDM6,8,9,18,23
• is often perceived as lower priority versus other symptoms in individuals with multisystem myotonic disorders like DM9
Intensity of disability in NDM due to myotonia:
Becker MC
Thomsen MC Paramyotonia congentia
Myotonia Fluctuans Myotonia permanens
Objectives to Improve the Clinical Journey for Patients with Myotonia
Myotonia is one of the top five symptoms that patients with DM want to improve21
Improve understanding of myotonia symptoms and how they relate to disease pathophysiology
Recognise the impact of myotonia on patients’ health, wellbeing, and quality of life
Address the wellbeing of caregivers
Raise awareness of myotonia symptoms and burden across the medical community
Provide individualised care
References
1. Meola G. Acta Myol. 2020;39(4):222-34.
2. Vydra DG, Rayi A. 2024. Treasure Island (FL): StatPearls Publishing.
3. Lehmann-Horn F et al. Acta Myol. 2008;27(3):98-113.
4. Stunnenberg BC et al. Muscle Nerve. 2020;62(4):430-44.
5. Liao Q et al. Neuroepidemiology. 2022;56(3) :163-73.
6. Diaz-Manera J et al. EMJ. 2021;6(2):37-46.
7. MDF. 2018. Available at: https://www.myotonic.org/sites/default/files/pages/program/MDF_2018_CareConsider ationsChildhoodDM1.pdf. Last accessed: 01 July 2024.
8. Landfeldt E et al. J Neurol. 2019;266(4):998-1006.
9. Hagerman K et al. Muscle Nerve. 2019;59(4):457-64.
19. Nowak U et al. Poster 228 WMS Virtual Congress. 28 Sep-2 Oct 2020.
20. Philips L, Trivedi J. Neurotherapeutics. 2018;15(4):954-65. 20.
21. Díaz-Manera J et al. Poster 46. IDMC Meeting, 9-13 April 2024.
22. Morales F, Pusch M. Front Neurol. 2020;10:1404.
23. Suetterlin KJ et al. Exp Opin Orphan Drugs. 2020;8:43-9.
24. Dang U et al. Poster 65. IDMC Meeting, 9-13 April 2024.
25. Vereb N et al. J Neurol. 2021;268(5):1708-20.
Author:
Diagnosing Synucleinopathies: Will Parkinson's Disease or Dementia with Lewy Bodies Become
‘Biologically’ Defined?
*Werner Poewe1
1. Medical University Innsbruck, Austria *Correspondence to werner.poewe@i-med.ac.at
Disclosure: Poewe has received consultancy fees in relation to clinical drug development programs for Parkinson's disease, as well as lecture fees from Alterity, AbbVie, AC Immune, AstraZeneca, BIAL, Biogen, Britannia, Lilly, Lundbeck, Neuroderm, Neurocrine, Novartis, Orion Pharma, Roche, Takeda, Teva, UCB and Zambon. The author has declared no conflict of interest.
Parkinson’s disease (PD) is the second-most common neurodegenerative disease after Alzheimer’s disease (AD), with an estimated 6.1 million people affected worldwide.1 PD is also the fastest-growing neurodegenerative disorder, with an expected two-fold increase in prevalence over the next generation.1,2 The pathological hallmark of both PD and the overlapping condition of dementia with Lewy bodies (DLB) is the presence of intraneuronal and axonal inclusions, called Lewy bodies and Lewy neurites, in the substantia nigra and other brain areas that contain pathological aggregates of misfolded α-synuclein as their main constituents.3 Accordingly, both PD and DLB are classified among the synucleinopathies, which also include multiple system atrophy (MSA), where synuclein aggregates in glial cytoplasmic inclusions are a pathological hallmark.4
For decades, the mainstay of symptomatic therapy for motor symptoms of PD treatment has been dopamine substitution by administration of the dopamine precursor levodopa and other drugs that help maintain levels of dopamine and dopamine receptor activity in the striatum.5 While these therapies are able to provide long-term symptomatic control, they cannot slow or prevent the progression of the underlying pathology, thus increasing disability from a progressive combination of motor and non-motor symptoms over time. For this reason, there is a pressing need to identify disease-modifying treatment strategies; however, in the past, numerous clinical trials pursuing a multitude of different drug targets to slow disease progression have failed. The identification of novel targets and non-pharmacological strategies has led to a recent surge in disease-modification efforts, with 60 trials currently listed on ClinicalTrials.gov, including investigational therapies targeting pathological α-synuclein (McFarthing et al., unpublished data).
One of the major challenges, which may have contributed to the failure of past disease-modifying trials, is related to the timing of intervention. Current clinical diagnostic criteria for PD require the presence of cardinal motor features of the disease, but there is ample evidence to suggest that the underlying pathological events may start many years prior to the full expression of PD motor symptoms.6 There is justifiable concern that the start of disease-modifying interventions after PD motor symptoms are fully established may correspond to a relatively late time point on the trajectory of progressive PD pathology, and thus may have a reduced likelihood of success. Intervening at the earliest stages of the biological processes driving PD pathology would require diagnostic criteria that are anchored on reliable biomarkers of disease, potentially even enabling the identification of pre-clinical disease in asymptomatic subjects. The concept of a ‘biological’ definition of disease independent of the presence of defining clinical features has been pioneered by the Alzheimer’s field by developing a framework of biomarkers for Abeta- and tau-pathology, and imaging evidence for neurodegenerative brain changes.7 Similar efforts are now underway for Parkinson’s disease, and may have far-reaching implications not only for the planning of clinical trials but also for future implementation of PD risk screening programmes and ultimately efforts aimed at disease prevention.
LIMITATIONS OF CLINICAL DIAGNOSTIC CRITERIA
Current diagnostic criteria for PD are based on the clinical presentation of bradykinesia combined with limb rigidity and/or resting tremor, enforced by supportive criteria such as responsiveness to levodopa and the absence of exclusion criteria.8 When compared to diagnoses based on postmortem studies, however, the accuracy of the clinical criteria is suboptimal and error rates have been as high as 20%.9 The latter is mainly due to clinical overlap between PD and other neurodegenerative conditions such as MSA or progressive supranuclear palsy. Similarly, clinical criteria for MSA have
yielded accuracies of 94% in late disease stages, but this was only around 85% in early disease.10 In addition, current clinical criteria for PD are insensitive to the early appearance of non-motor symptoms prior to defining motor features like hyposmia, constipation, rapid eye movement sleep behaviour disorder, or autonomic dysfunction. Although these have been addressed in attempts to define diagnostic criteria for ‘prodromal’ PD,11,12 the predictive value for established PD is still limited.
DIAGNOSING PARKINSON’S DISEASE: THE ROLE OF BIOMARKERS
There are two biomarker categories that have already entered the arena of clinical routine: molecular testing for genetic PD subtypes and neuroimaging.
Genetic testing is particularly relevant in patients with a family history of Parkinsonism or early age at onset (defined as onset before the age of 50 years). Knowledge of the underlying gene defect within a family enables more effective counselling of patients, and increasingly, clinical trials are targeting specific genetic forms of PD, like GBA-PD or PD subjects with LRRK2 mutations.13
Molecular imaging using dopaminergic tracers has evolved into a routine diagnostic tool for PD, but has limited specificity since nigrostriatal dopaminergic denervation is also present in other types of degenerative Parkinsonism. Nonetheless, it is sensitive to early neurodegenerative change as shown by multiple longitudinal studies in subjects at risk for PD, like those with hyposmia or rapid eye movement sleep behaviour disorder. Recent advances in MRI techniques, including machine-learning algorithms to analyse volumetric, diffusion tensor, as well as multimodal magnetic resonance data, have improved differential diagnostic accuracy between different types of neurodegenerative Parkinsonism.14 In addition, novel magnetic resonance techniques have also enabled the detection of nigral pathology in PD by using ironsensitive sequences, diffusion tensor, or
neuromelanin imaging. Free water and neuromelanin MRI have also been studied as progression markers of nigral pathology in PD, producing promising results that may support their use as outcomes in diseasemodifying PD trials.15 The availability of PET tracers for amyloid beta and tau as key proteins driving disease pathology has been a major step forward in the ability to detect the effects of disease-modifying interventions in AD, and has also become a cornerstone of biological definitions of AD. Recent efforts to develop PET tracers for pathological brain depositions of α-synuclein have begun to bear fruit, and ACI-12589 has been shown to detect pathological α-synuclein and, so far, has been able to distinguish MSA from other synucleinopathies.16
Seed amplification assays (SAA) for detecting α-synuclein aggregates in cerebrospinal fluid (CSF) were first reported in 2016 and have since consistently demonstrated high diagnostic accuracy for PD and DLB versus controls.17 In addition, some studies have reported promising specificity in distinguishing between different synucleinopathies like PD and MSA by differences in the kinetics of SAA’s. These assays have also been reported to yield positive results in other biofluids like serum or blood, as well as in skin biopsies.18,19
TOWARDS A BIOLOGICAL DEFINITION
Two recent proposals for biological definitions of PD are intended to facilitate very early diagnosis of PD.20,21 One of them specifically also includes other Lewy-type synucleinopathies like DLB by putting different clinical expressions under the new umbrella term ‘neuronal synuclein disease’,21 a terminology that has somewhat blurred boundaries towards MSA, where synuclein pathology also occurs in neurons. The neuronal α-synuclein disease integrated staging system (NSD-ISS) is anchored on the presence of pathological α-synuclein in CSF, striatal dopaminergic denervation as assessed by dopamine transporter imaging with DAT-SECT, and the presence
of and degree of functional impairment from clinical symptoms. PD subtypes that lack synuclein pathology, like a proportion of cases with LRRK2-PD, would fall outside this biological classification system. Inherently, this system considers PD as one of several syndromatic expressions of the biological disease process. The ‘SynNeurGe’ framework, on the other hand, is designed to include the full spectrum of what is now recognised clinically as PD, combining the presence or absence of α-synuclein in CSF, evidence of underlying neurodegeneration assessed by dopaminergic imaging, and pathogenic genetic variants linked to PD. This framework also lists a broader spectrum of biomarkers and reviews the current evidence of their diagnostic performance, indicating that future refinements of the SynNeurGe classification will likely become possible by incorporating additional biomarkers.
Both frameworks have not yet been validated in prospective studies regarding their predictive value for symptomatic disease in biologically defined subjects without clinical symptoms, and thus are only appropriate for research purposes at present. Once validated, however, a framework based on a biological definition of PD or a broader spectrum of synucleinopathies that enables early diagnosis would be invaluable in supporting research and development, and improving the design of clinical trials in a number of ways, including pathogenic subtypespecific drug targeting and patient stratification. This approach is already underway in symptomatic patients with LRRK2 or GBA mutation, but the concept of biologically defined disease would open the door to a new type of disease-modification approach targeting asymptomatic individuals or those with subtle signs and symptoms that do not meet the threshold of current diagnostic criteria. Ultimately, this could pave the way towards populationbased risk screening and disease prevention strategies. However, there are still major issues that need to be addressed before such scenarios can be implemented. They include uncertainties regarding the validity and scalability of currently proposed biomarker anchors, specifically the alpha-
synuclein SAAs, as well as ethical concerns around the possibility of false positive or false negative biomarker results and their harmful effects. Above all, diagnosing a disease in people without symptoms at a time where there is very limited information on the risk of biomarker-positive individuals developing clinically relevant disease, and
References
1. Global Burden of Disease (GBD) 2016 Parkinson's Disease Collaborators. Global, regional, and national burden of Parkinson's disease, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol. 2018;17(11):939-53.
2. Dorsey R, Bloem B. The Parkinson pandemic—a call to action. JAMA Neurol. 2018;75(1):9-10.
3. Spillantini M et al. α-Synuclein in Lewy bodies. Nature. 1997;388:839-40.
4. Poewe W et al. Multiple system atrophy. Nat Rev Dis Primers. 2022;8(1):56.
5. Poewe W et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013.
6. Mahlknecht P, Poewe W. Pharmacotherapy for disease modification in early Parkinson's disease: how early should we be? J Parkinsons Dis. 2024;DOI:10.3233/ JPD-230354.
7. Jack C et al. NIA-AA Research framework: toward a biological definition of Alzheimer's disease. Alzheimer’s Dement. 2018;14(4):53562.
8. Postuma R et a. Validation of the
where there are no effective preventive interventions, is difficult to justify from an ethical perspective. This highlights the need for careful, long-term, prospective studies to understand the meaning of biological disease markers both at the population level and in specific risk groups.
MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord. 2018;33(10):1601-8.
9. Rizzo G et al. Accuracy of clinical diagnosis of Parkinson disease: a systematic review and meta-analysis. Neurology. 2016;86(6):566-76.
10. Virameteekul S et al. Pathological validation of the MDS criteria for the diagnosis of multiple system atrophy. Mov Disord. 2023;38(3):444-52.
11. Berg D et al. MDS research criteria for prodromal Parkinson's disease. Mov Disord. 2015;30(12):1600-11.
12. Heinzel S et al. Update of the MDS research criteria for prodromal Parkinson's disease. Mov Disord. 2019;34(10):1464-70.
13. Tolosa E et al. Challenges in the diagnosis of Parkinson's disease. Lancet Neurol. 2021;20(5):385-97.
14. Peralta C et al. International Parkinson Movement Disorders Society‐Neuroimaging Study Group. Pragmatic approach on neuroimaging techniques for the differential diagnosis of Parkinsonisms. Mov Disord Clin Pract. 2021;9(1):6-19.
15. Mitchell T et al. Emerging neuroimaging biomarkers across disease stage in Parkinson
disease: a review. JAMA Neurol. 2021;78(10):1262-72.
16. Smith R et al. The α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases. Nat Commun. 2023;14,6750.
17. Grossauer A et al. α-Synuclein seed amplification assays in the diagnosis of synucleinopathies using cerebrospinal fluid-a systematic review and meta-analysis. Mov Disord Clin Pratice. 2023;10(5):737-7.
18. Bellomo G et al. α-Synuclein seed amplification assays for diagnosing synucleinopathies: the way forward. Neurology. 2022;99(5):195-205.
19. Okuzumi A et al. Propagative α-synuclein seeds as serum biomarkers for synucleinopathies. Nat Med. 2023;29(6):1448-55.
20. Höglinger G et al. A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria. Lancet Neurol. 2024;(2):191204.
21. Simuni T et al. A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research. Lancet Neurol. 2024;23(2):178-90.
Patterns of Laryngeal Changes on Clinical Application of Mechanical
Insufflation-Exsufflation Seen with Transnasal Laryngoscopy
for Patients with Varied Neurological Conditions and Bulbar Impairment
Authors: *Sarah Boggiano,1,2 Shelley Holme,3 Sarah Wallace2,4
1. Speech Pathology Department, Royal North Shore Hospital, Sydney, Australia
2. Department of Speech, Voice and Swallowing, Wythenshawe Hospital, Manchester, UK
3. North West Ventilation Service, Wythenshawe Hospital, Manchester, UK
4. Division of Infection Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK
*Correspondence to shelley.holme@mft.nhs.uk
Disclosure: The authors have declared no conflicts of interest.
Mechanical insufflation-exsufflation (MI-E) is an intervention used for cough augmentation in patients with neurological conditions with bulbar impairment. This study aimed to explore implications for clinical practice in the use of transnasal laryngoscopy during MI-E.
Twenty-one patients underwent MI-E application with simultaneous transnasal laryngoscopy. Pressures were commenced at +15 cm H2O/-15 cm H2O and titrated according to an agreed algorithm. Outcomes collected included baseline bulbar function scores, optimal MI-E settings, and/or alternative secretion management strategies including medication recommendations.
Changes to pressure and/or modality were implemented in all but one patient. No adverse effects of laryngoscopy were seen. For patients with progressive bulbar palsy, limb onset amyotrophic lateral sclerosis, and other conditions with bulbar impairment, transnasal laryngoscopy resulted in discontinuation of MI-E in 54%, 0%, and 14%, respectively. Pressure changes were made for all patients remaining on MI-E and medication changes were made for 47% of patients across all conditions.
Transnasal laryngoscopy can be utilised to safely assess the impact of MI-E on laryngeal structures to optimise settings for patients with bulbar impairment. Cough augmentation strategies can be tailored accurately for patients with a variety of neurological conditions with bulbar impairment based on the results of transnasal laryngoscopy.
Key Points
1. Mechanical insufflation-exsufflation (MI-E) is a commonly used tool for cough augmentation and secretion clearance in patients with neurological conditions. However, methods for ongoing efficacy review are lacking in accuracy.
2. This is a retrospective observational study showing the safety and feasibility of carrying out transnasal laryngoscopy during the use of MI-E.
3. Individualisation of MI-E settings through the simultaneous use of transnasal laryngoscopy is a safe way of reviewing and in some cases extending, its effective use in patients with neurological disorders and bulbar impairment.
INTRODUCTION
Individuals with neuromuscular diseases (NMD), where deterioration in bulbar function coexists with respiratory muscle weakness, are at risk of dysarthria, dysphagia, and impaired cough. This contributes to difficulties in clearing oropharyngeal secretions, choking, laryngospasm, and aspiration.1,2 Bulbar impairment is caused by injury or degeneration of the corticobulbar tract and results in weakness or abnormalities in the control of hypopharyngeal and laryngeal structures.3 Pseudobulbar palsy can be a presenting symptom in a number of conditions, including bilateral cerebral infarction, demyelinating motor neuron diseases, tumours of the brain stem, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, multiple sclerosis, and trauma.4
For patients with dysphagia, with or without vocal fold motion impairment, alongside respiratory muscle weakness, the consequences are two-fold: the inability to protect the airway during swallowing, resulting in aspiration, and the inability to generate subglottic pressure for production of an effective cough.3 This combination gives rise to a significantly greater susceptibility to respiratory infection, hospitalisation, and in some conditions, long-term ventilation.5-10 In addition to the risk of infection, malnutrition secondary
to dysphagia has been shown to be a significant co-existing condition linked with poor survival rates and worsening respiratory function.11
Chest clearance techniques provide a proactive and preventive approach to the symptomatic relief and management of secretions for patients who have neurological conditions with bulbar impairment. Simple airway clearance techniques (ACT) require a level of respiratory muscle strength that renders them unfeasible as neurological status deteriorates. Mechanical insufflationexsufflation (MI-E) requires reduced physical input and offers several modes of delivery to allow for individualised patient care. Positive and negative pressure is sequentially applied to the airways to increase the expiratory flow rate and peak cough flow (PCF), facilitating the movement of pulmonary secretions. There have been a number of studies that have further examined the mode and benefits of action validating its use in neurological conditions.9,12-19 In addition to a reduced physical burden, MI-E has been shown to generate higher PCF values than other methods of cough augmentation in patients with NMD and other conditions, and as such,15,19-21 has been cited as the most effective treatment in patients with respiratory muscle weakness secondary to NMD.22,23
Despite compelling evidence for its use when simple ACTs are not effective, MI-E can also become challenging as neurology deteriorates further. This can in turn be attributed to advancing bulbar impairment, with potential for vocal fold abduction, motion impairment (inability to maintain open vocal folds), and an exaggerated response to stimuli.24
There are no standard guidelines for the set-up or progression of MI-E; however, high pressures have long been considered the most effective at secretion clearance, and the inclusion of an expiratory flow bias is proposed as a crucial component.16,25 More recently, MI-E during laryngoscopy has been shown to provoke varying levels of laryngeal response in healthy individuals using pressures ranging from +/-20 to +/50 cm H2O.26 A few studies in individuals with ALS showed treatment failure most likely during the insufflation phase, due to laryngeal adduction, with high pressures being most likely to provoke an adverse laryngeal response.27,28
This study considers further clinical findings and implications of using transnasal laryngoscopy when applying MI-E in patients who have neurological conditions with bulbar impairment, and whether direct visualisation can contribute heavily towards optimum efficacy and individualisation of therapy.
Objectives
The primary aim was to determine the most efficacious cough augmentation strategy whilst determining whether simultaneous MI-E and visualisation is a clinically viable, effective technique to achieve this.
MATERIALS AND METHODS
Design and Setting
The team conducted a retrospective observational study using analysis of routinely collected data from 21 patients referred to a joint physiotherapy/speech and language therapy (SLT) clinic within the Cough Augmentation Service.
At the tertiary care centre, patients with neurological conditions alongside bulbar impairment were routinely assessed for the provision of an MI-E device. Suitability was based upon bedside subjective and objective assessment with reference to contraindications and precautions discussed by Swingwood et al.29 and listed in the instructions for use of the Clearway 2 (Breas Medical, Mölnlycke, Sweden) and E70 (Philips Respironics, Murrysville, Pennsylvania, USA) cough assist devices.30,31
With a new awareness of laryngeal response to MI-E and an increasing number of patients with neurological conditions and bulbar impairment reporting a change in physical sensation whilst using MI-E or a feeling of reduced efficacy, a joint clinic was set up for visualisation of the larynx during MI-E. Visualisation via transnasal laryngoscopy was carried out based on the work of Andersen et al.26-28 The clinic was run jointly by a specialist SLT and a specialist respiratory physiotherapist. All referred individuals were triaged for suitability for the clinic, and consented prior to the visualisation and assessment procedure.
The Health Research Authority research ethics decision tool (National Health Service [NHS], London, UK) confirmed that this retrospective observational analysis of routinely collected clinical data in this patient cohort did not require formal research ethics committee approval.
Inclusion and Exclusion Criteria
Inclusion criteria included adults with neurological conditions alongside bulbar impairment within the service, who were already established onto MI-E or had been referred for set-up with concerns regarding tolerance of effective MI-E. As this group of patients had already been risk assessed for use of MI-E, there were no further criteria to screen against for exclusion, and no patient was excluded due to learning difficulties, severe bulbar impairment, or requirement of nasopharyngeal or oropharyngeal suction. Patients with suspected laryngospasm episodes were monitored closely with
adrenaline nebulisers, heliox, and medical support all readily available, if required, during the procedure.
Subjects
Assisted cough techniques were considered for patients with a PCF of 270 Lpm or less, and for patients with NMD with a PCF above 270 Lpm with a history of recurrent chest infection.32
Patients were referred into the joint SLT/ physiotherapy clinic if they reported or were observed to display the following changes in response to current MI-E regimes: reduced synchronicity with MI-E, incomplete chest expansion on insufflation (often with associated cheek/throat bulging), reports of being ‘unable to breathe’ during insufflation and/or exsufflation, reduced secretion clearance, and/or recurrent chest infection despite continued compliance with MI-E. Standard review methods were trialled at bedside in the first instance prior to referral into the clinic. These included alterations to timings, pressure, flow, and treatment regimes.
Severity of Bulbar Dysfunction
Bulbar impairment was recorded according to swallowing status using the International Dysphagia Diet Standardisation Initiative
Functional Diet Scale (IDDSI-FDS), as provided by their local SLT.33 The lower the score, the higher the degree of diet or fluid modifications required.
Speech functional status was scored by SLT using the ALS Severity Score (ALSSS) speech subscore during the clinic appointment.34 The higher the score, the higher the degree of impairment.
Video-Recorded Transnasal FibreOptic Laryngoscopy During MI-E
Using DiVAS software (DP Medical Systems, Chessington, UK), transnasal fibre-optic laryngoscopy (XION Medical EndoFLEX System, Berlin, Germany) with video nasopharyngoscope (EV-NC tube diameter 3.5 mm) was used to visualise hypopharyngeal and laryngeal structures
at baseline and response patterns during MI-E application using the E70 Cough Assist device set according to a standardised MI-E protocol. An appropriately sized Quadralite anaesthetic face mask (Intersurgical Complete Respiratory Systems, Berkshire, UK) was adapted with a hole punched in it to pass the scope. An attempt would be made to occlude the hole with the fingers once the scope was in position. The authors acknowledge this method does not fully negate air leak around the scope; however, subjective detection of air leak was considered insignificant.
Baseline assessment of hypopharyngeal and laryngeal structures commented on any changes in structure or movement. Observation of location, colour, and viscosity of secretions were made and were used in conjunction with a validated secretion scale (New Zealand Secretion Severity Score [NZSS]) by a flexible endoscopic evaluation trained SLT.35 Any concerns with high or tenacious secretion load were discussed with the team’s laryngology or respiratory physician colleagues.
No local anaesthetic was used during this procedure as per national guidelines, and because use of lidocaine may impact the laryngeal adductor reflex, which would interfere with the assessment of laryngopharyngeal sensory impact with MI-E.36,37 At times, flexible endoscopic evaluation with oral trials was clinically indicated for some patients as a part of standard dysphagia care, and was performed pre- or post-MI-E assessment during the same procedure.
MI-E Protocol and Target Outcome
Airway patency alongside patient feedback were the main outcome measures for pressure tolerance trials, with settings at this point considered to be optimal for the individual.
A standardised MI-E protocol was used: initial pressures started at +15/-15 cm H2O for a duration of 1.8/1.8 seconds each, low flow, no oscillations. Pressures were increased by increments of 2–5
cm H2O. Pressure increases were determined by patient feedback and real-time assessment of the impact on hypopharyngeal and laryngeal structures. Pressures were increased for as long as the airway remained patent (vocal folds and subglottis still visualised) and the patient was compliant. If airway patency was not visualised at the lowest pressure settings applied, alternative techniques such as breath stacking were taught using visual feedback via the monitor and biofeedback via placement of physiotherapist’s hand on the patient’s chest. Figure 1 illustrates the steps used to troubleshoot airway shutdown and pressure settings to determine optimal settings.
Images were captured, reported, and archived on the hospital electronic patient record, then interpreted and reported at the bedside utilising validated scoring systems evaluating hypopharyngeal and laryngeal anatomy for signs of secretions, physiology, and function.38 Each patient had an individualised report documenting structural changes, quantified secretion load, and the impact of any modifications to pressure, time, or flow rate on the laryngeal and pharyngeal structures. Any structural abnormalities seen were referred for review by the Ear, Nose, and Throat team.
Post-procedural Recommendations
Recommendations for medication changes were made based on observations of secretion load, viscosity, current medication regime, and likely origin of secretions based on colour and location of pooling (salivary, nasal, pulmonary). Suggestions followed national guidance for the management of hypersalivation and were reviewed by the medical team or general practicioner.39
Data Analysis
Retrospective tabulation of data was completed from clinician documentation. Data collection included participant demographics (age, medical diagnosis, sex), baseline swallowing and cough augmentation (IDDSI-FDS and ALSSS), baseline cough augmentation recommendations (MI-E settings if
applicable or other ACTs), reported frequency of chest infections in the preceding 12 months, and reason for referral into the clinic. Data were also collected on the optimal recommendations following the clinic (MI-E settings if applicable or other ACTs recommended) secretion ratings using the NZSS and any medication recommendations. Descriptive statistics were used to determine the patterns observed between groups.
RESULTS
Twenty-one patients were referred to the clinic over 24 months. Ages ranged from 18–87 years (mean: 59 years). Medical diagnoses included progressive bulbar palsy (PBP) as well as multiple sclerosis, spinal muscular atrophy, and cerebral infarcts (Table 1).
Severity of Bulbar Dysfunction
For patients with PBP, scores ranged from 0–8 (mean: 2.46; standard deviation: 2.90); however, the mode score was 0 (n=6), indicating the need for high levels of diet/ fluid modification, which itself indicates high bulbar dysfunction. For patients with all other conditions, their average IDDSIFDS ranged from 0–8 (mean: 2.28; standard deviation: 3.61), however; again with a mode of 0, this also indicates a need for diet modification, but to a lesser degree with some outlying patients improving this score.
ALSSS speech subscore results indicated a higher level of impairment in speech for those patients with PBP (n=13; median: 4.69) in comparison to the grouped ‘other neurological conditions’ (n=8; median: 5.5).34
Cough Augmentation Analysis
No adverse events were noted regarding laryngoscopy, and patients were considered overall to tolerate the procedure well. This procedure wielded clear guidance for individual patients and cough augmentation strategies based on visualisation at the laryngeal level. For patients with PBP
Table 1: Medical diagnosis of participants.
(n=13), transnasal laryngoscopy resulted in discontinuation of MI-E for seven patients (54%), and changes to settings for six (46%). These changes included reduced pressures for four (67%) and insufflation for only two patients (33%) to maintain airway patency. For those patients with MI-E discontinued, unsupported breath stacking was deemed the most suitable alternative for four (31%), and supported breath stacking with the use of a lung volume recruitment bag was commenced with three (23%).
For the singular patient with limb onset ALS, vocal fold adductor palsy was identified during this procedure (the patient had no previous exposure to transnasal laryngoscopy). Given the severity of this impairment, the patient was referred for urgent discussion with the managing medical team in relation to airway management consideration. Following this finding, cough assist use was restricted to insufflation only.
In the remaining other neurological conditions group (n=7), transnasal laryngoscopy resulted in discontinuation of MI-E for one patient (14%), who was subsequently taught unsupported breath stacking; changes to settings for five patients (71%) (pressures reduced to maintain airway patency for all five); and no changes to settings for one patient (14%).
Laryngeal Response Patterns
For patients with PBP, observed hypopharyngeal/laryngeal constriction was evident across all possible structures (Table 2), the most frequent region being the arytenoids. This also interferes with vocal fold abduction and would prevent airflow into the trachea. Patients with other neurological conditions exhibited similar obstruction frequency between tongue base, hypopharynx, and arytenoids, but these were seen at higher pressures than in patients with PBP. This is suspected to be due to a higher overall bulbar impairment in patients with PBP. When hypopharyngeal (base of tongue/pharyngeal wall) or laryngeal (arytenoid or vocal fold) obstruction/closure was observed and the airway was no longer visible (Table 2), changes were made according to the algorithm (Figure 1).
Secretion Medication
Recommendations
Fifty percent of patients (n=15) scored the most severe secretion rating (7 on the NZSS), indicating accumulated secretions and dysphagia. Signs of laryngopharyngeal reflux were observed, including erythema, oedema, and posterior commissure hypertrophy. Medication changes were recommended for 47% of patients (n=7) across all conditions based on signs of laryngeal mucosa changes related to
Table 2: Levels of hypopharyngeal/laryngeal changes.
true and false vocal fold adduction with obstruction to airway
reflux (proton pump inhibitors), and lower and upper airway secretion management deficit. For secretions originating from the trachea, mucolytics or regular nebulisers were recommended, and for salivary secretions, antimuscarinics or consideration of botulinum toxin injection to the salivary glands (as appropriate) were discussed with the MDT.
DISCUSSION
This study examines the findings and outcomes of using laryngoscopy to observe the laryngeal closure patterns induced by MI-E, and any potential clinical implications in patients with varied neurological conditions and bulbar impairment.
Unable to visualise airway (open vocal folds +/- subglottic space) on base settings due to hypopharyngeal or laryngeal closure
Trial Base Settings
Pressures +15/-15 cm H2O
Trial Times 1.8/1.8 seconds
Hypopharyngeal or laryngeal closure on exsufflation only. Airway visible on insufflation
Trial breath stacking technique under visualisation
Effective. Recommend breath stacking Ineffective. Recommend lung volume recruitment bag
Trial insufflation pressure only. Titrate pressures up by 2–5 cm H2O as tolerated/fatigue allows
Hypopharyngeal or laryngeal closure at end of insufflation or exsufflation
The sample size in this study was small, and patients were pre-selected for MIE; therefore, conclusions regarding the efficacy of MI-E are made cautiously. The team acknowledges the method of pressure increase used (2–5 cm H2O increments) could lead to patient fatigue should high pressures be reached; however, relatively low-pressure limits were observed, thus reducing the risk of procedural fatigue influencing observations. They also recognise that observations within the hypopharynx or larynx may not fully demonstrate clear patterns or trends.
Reduced insufflation or exsufflation time. Titrate pressures up by 2–5 cm H2O as tolerated/ fatigue allows
Hypopharynx not significantly impacted and laryngeal airway open
Increase pressures by +2 to 5 cm/ -2 to 5 cm H2O as tolerated/fatigue allows and assess impact
Titrate to maximum pressures ensuring visualisation of airway (open vocal folds +/subglottic space)
However, their understanding of the effects of MI-E on the larynx has been expanded and this visualisation tool has now become standard practice within the service. In addition, this work has improved the ability of the physiotherapists to understand issues patients may be experiencing based on subjective and objective bedside assessment.
Whilst visualisation resulted in changes in management for all patients, it is important to note that they could find no clear pattern in level of constriction or adduction,
Figure 1: Proposed flow chart to guide trials.
pressures, or choice of alternative cough augmentation strategies recommended following visualisation. Again, this is congruent with the work of other clinician researchers who reported the importance of individualised regimes for this cohort.27 One pattern that did emerge was that average pressures above +25/-25 cm H2O in the PBP group were shown to result in shutdown across all participants, which is important for clinicians to take into consideration with bedside set-up in this patient group.
Treatment efficacy was improved; however, the team are yet to confirm the functional impact of these changes on the medical status in relation to longer-term secretion management or chest infection rate. They would therefore recommend that future studies collect outcome data including chest infection rate, quality of life/patientrelated scales, and compliance with MI-E in relation to hospitalisations, to assess for trends or patterns concerning bulbar impairment and functional outcomes for this cohort.
Not all services have ready access to transnasal laryngoscopy for this purpose, but the authors hope that by building on previous evidence, this study further highlights the link between bulbar impairment and MI-E tolerance, and allows clinicians to consider that higher pressures may not be beneficial for this cohort and may, in fact, result in a more negative outcome.
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This study highlights the benefits of direct visualisation using transnasal laryngoscopy to optimise MI-E for patients with neurological conditions with bulbar impairment. This adds to the previous work by Anderson et al.,20 which looked at normal responses and patients with ALS and spinal onset.26-28 The work has proven safety in transnasal laryngoscopy for patients with bulbar onset and more severe bulbar impairment with an attempt to quantify the severity of their bulbar impairment. Differences in laryngeal changes between patient cohorts support the understanding of the appropriateness of MI-E for these patients. Characteristics such as hypopharyngeal and laryngeal closure help to inform and explain clinical observations. This will direct the team’s patient selection and assessment protocols moving forwards and contribute to the conclusion of previous researchers that individualised recommendations with visualisation are essential for optimisation of MI-E.40
CONCLUSION
Application of MI-E with direct visual feedback using transnasal laryngoscopy is a safe and effective method for determining the appropriateness of cough augmentation and most effective MI-E settings in patients with a range of neurological conditions with bulbar impairment. Cough augmentation strategies can be tailored accurately for patients with a variety of neurological conditions with bulbar impairment based on the results of transnasal laryngoscopy.
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A Rare Case of Cervical Intramedullary Spinal Cord Abscess
Authors: *Vanessa Jane Chow,1 Ali Al Shanta,1 Jawaria Qureshi,2 Shyam S Swarna1
1. National Spinal Injuries Centre, Stoke Mandeville Hospital, Aylesbury UK
2. Oxford University Hospital, UK
*Correspondence to vjchow@outlook.com
Disclosure: The authors have declared no conflicts of interest.
Acknowledgements The authors would like to thank the patient, who kindly agreed to have his case reported to create awareness of this rare condition. They also acknowledge the National Spinal Injuries Centre, Stoke Mandeville hospital, UK for letting us use the resources towards this manuscript.
Intramedullary spinal cord abscess (ISCA) is an exceptionally rare pathological condition with the potential to affect any segment of the spinal cord. The involvement of the cervical cord, however, is notably uncommon, with only 36% of the ISCA localised to this region. The authors present the case of a 67-year-old male who exhibited atypical clinical manifestations, including chronic neck and shoulder pain, and an acute onset of right sided weakness. Diagnostic imaging revealed a bi-loculated intramedullary ring enhanced lesion, suggestive of an ISCA. Initial intervention comprised of a cervical laminectomy and aspiration of the abscess. Despite this, the patient experienced progressive neurological decline involving all four limbs, necessitating a revision surgery with myelotomy. This was supplemented with an extended course of targeted antibiotic therapy guided by culture and sensitivity results. The patient subsequently demonstrated a gradual improvement in neurological function through comprehensive rehabilitation measures. In this instance, the ISCA was determined to be cryptogenic in origin. The patient's extensive comorbid conditions, coupled with the use of immunosuppressive medications, were likely contributory factors to the pathogenesis of the abscess. Importantly, a centrally located spinal cord abscess is less prone to cause irreversible vascular compromise compared to an epidural abscess. Thus, early detection and prompt treatment are essential to mitigating significant morbidity and mortality associated with this condition.
Key Points
1. Intramedullary spinal cord abscesses (ISCA) are exceptionally rare, with only 202 cases reported since 1830. Cervical ISCAs are even less common, accounting for just 36% of ISCA cases. Documenting these rare occurrences is crucial for expanding the limited knowledge base and providing valuable data for future research and clinical reference.
2. This case report details the clinical presentation, diagnostic process, treatment, and rehabilitation of a 67-yearold male with a rare cervical ISCA caused by Streptococcus intermedius. The patient had a complex medical history, including immunosuppressive therapy for granulomatosis with polyangiitis and colonisation with Mycobacterium avium.
3. Early recognition and intervention are of critical importance to prevent significant morbidity and mortality in cervical ISCA. The authors emphasise the need for comprehensive rehabilitative measures to enhance recovery and functional restoration, as well as heightened clinical vigilance and expertise in diagnosing such rare conditions, particularly in patients with atypical presentations and underlying immunosuppression. A multidisciplinary approach is essential for achieving optimal patient outcomes, and further research and documentation will be needed to improve the understanding and management of ISCA.
INTRODUCTION
The occurrence of intramedullary spinal cord abscesses (ISCA) is rare, a phenomenon attributable to a confluence of physiological and medical safeguards.1 A systematic review conducted in 2023 uncovered only 202 reported instances of this condition since its first documentation by Hart in 1830.2 These abscesses can involve any segment of the spinal cord; however, they predominantly manifest in the thoracolumbar region, with only 36% of ISCAs reported at the cervical level.2,3
The pathogenesis of these abscesses generally involves haematogenous dissemination of bacteria or pathogens from a distal infection site. This pathway is rarely associated with spinal cord involvement due to the body’s robust immune defences and the infrequency of pathogens that compromise these barriers. Factors such as immunosuppression or invasive medical procedures are critical in breaching these defences and facilitating the development of such abscesses. The integrity of the blood–brain barrier plays a pivotal role, meticulously regulating the ingress of infectious agents into the central nervous system, thereby substantially mitigating the risk of spinal cord infection.4
Complementing this, the spinal cord’s encasement within the vertebral column and protective meninges considerably diminishes its direct exposure to pathogens.
Moreover, the adept management of primary infections, such as antibiotics in contemporary clinical practice, further reduces the potential for bacterial dissemination to the spinal cord. The diagnostic complexity posed by the nonspecific symptomatology of intramedullary abscesses, which frequently mimics other neurological disorders, also likely contributes to their underdiagnosis and underscores their rarity. These factors collectively elucidate why ISCAs remain a rare clinical entity, emphasising the imperative for heightened clinical vigilance and expertise in their identification and management.
This case report delineates a rare instance of a cervical ISCA caused by Streptococcus intermedius. It underscores the importance for prompt identification and intervention to mitigate the risk of significant morbidity and mortality. Additionally, the report highlights the crucial role of rehabilitative measures in enhancing recovery and functional restoration for patients afflicted by this uncommon condition.
CASE PRESENTATION
In this case report, the authors detail the clinical presentation of a 67-year-old male who presented to the emergency department with an acute onset of rightsided weakness, preceded by a protracted
history of cervical discomfort and persistent bilateral shoulder pain lasting several months. The patient’s medical history is notable for seronegative granulomatosis with polyangiitis, manifesting as recurrent respiratory and renal involvement. For the past 8 years, the patient has been maintained on an immunosuppressive therapy regimen comprising cyclophosphamide, methotrexate, mycophenolate mofetil, azathioprine, and prednisolone. This regimen has been meticulously adjusted and modified by his rheumatology team to address and manage recurrent disease relapses. Additionally, the patient exhibited a confirmed colonisation with Mycobacterium avium, for which he received antituberculosis therapy including ethambutol, azithromycin, and rifampicin for a period of 2 years. Moreover, he also had a history of a right-sided cerebrovascular accident manifesting as a transient ischaemic attack, which resolved spontaneously without residual focal neurological deficits.
Upon admission, a comprehensive neurological assessment revealed motor strength graded at 2 out of 5 across the myotomes from C5 to T1 in the right upper limb, and 3 out of 5 in the myotomes from L2 to S1 in the right lower limb, according to the Medical Research Council (MRC) scale for muscle strength. Additionally, a sensory deficit was observed in the right upper limb from C5 to T1, and throughout the entire right lower limb.
The differential diagnosis for this patient’s presentation was extensive and multifaceted. While ISCA was a consideration, particularly given his immunosuppressed state and chronic M. avium infection, transverse myelitis was also strongly considered, especially in the context of his autoimmune condition, granulomatosis with polyangiitis, which typically presents with acute or subacute motor and sensory changes. The chronic cervical and shoulder pain, coupled with acute neurological symptoms, suggested the possibility of a spinal cord tumour, such as meningiomas, schwannomas, or metastatic lesions. Additionally, the presentation was indicative of potential cervical spondylotic
myelopathy, particularly considering his age and chronic cervical discomfort. Given his history of transient ischaemic attack, vascular myelopathy or a spinal cord infarction were critical differentials, as both conditions are known to present with sudden-onset weakness and pain. Furthermore, Brown–Séquard syndrome was considered due to the specific distribution of neurological deficit. However, the absence of any noted trauma made this diagnosis less likely.
Comprehensive clinical examination, imaging, and relevant laboratory investigations were essential to accurately diagnose and effectively manage this case. MRI with gadolinium contrast of the cervical spine (Figure 1A and 1B) revealed a welldefined, bi-loculated intramedullary ovoid lesion, localised to the posterior aspect of the spinal cord at the C2/C3 level on T2-weighted images. Correspondingly, T1-weighted images (Figure 1C and 1D) demonstrated a rim-enhancing lesion at the same anatomical level. The lesion consisted of a large, left sided locule measuring 23.3 x 10.1 mm and a smaller right sided locule measuring 10.5 x 10.1 mm. Based on his culture results identifying S. intermedius and its antibiotic sensitivities, including sensitivity to vancomycin and penicillin, and resistance to clindamycin, the patient was treated with ceftriaxone for a duration of 1 month. In addition, the patient underwent a C2–C4 laminectomy and abscess aspiration. Despite the initial surgical intervention, he subsequently developed weakness in all four of his limbs, accompanied by bladder and bowel incontinence.
Subsequent examination revealed that muscle strength across all myotome distributions of both the left upper and lower limbs was uniformly assessed at Grade 3 out of 5 on the MRC scale. A repeat MRI scan with gadolinium on the third post-operative day demonstrated a re-accumulation of the bi-loculated abscess, measuring 22 x 18 mm, accompanied by extensive oedema both above and below the lesion (Figure 2A and 2B). Consequently, the patient underwent a revision surgical procedure, involving drainage of the intramedullary abscess via myelotomy.
Figure 1: MRI with gadolinium contrast of the cervical spine and T1-weighted images.
A) T2-weighted MRI Cervical Spine with Gadolinium (Sagittal section): relatively well-circumscribed, biloculated intramedullary, ovoid lesion centred in the posterior aspect of the cord at the C2 and C3 level keeping with a spinal cord abscess. B) T2-weighted MRI Cervical Spine with Gadolinium (Axial section): the lesion consists of a large left sided locule (20.3x10.1 mm) and a small right sided locule (10.5x10.1 mm). C) T1-weighted MRI (Sagittal section): ring enhancing right sided cervical cord lesion at the C3 level. D) T1-weighted MRI (axial section): ring enhancing right sided cervical cord lesion at the C3 level
Over the ensuing 2–3 weeks postmyelotomy, there was a marked improvement in muscle strength across
all myotomal distributions of the left upper and lower limbs, progressing to Grade 4 out of 5 on the MRC scale.
Figure 2: Repeat MRI scan with gadolinium on the third post-operative day.
A B
A) T2-weighted MRI cervical spine with Gadolinium (Sagittal section) 3 days post laminectomy and aspiration: recollection of biloculated C2/C3 intramedullary abscess, which has increased in size (22x18 mm). B) T2-weighted MRI cervical spine with Gadolinium scan (Axial section) 3 days post laminectomy and aspiration: extensive oedema noted at the C2 and C3 level with recollection of abscess
The patient’s ongoing immunosuppressive therapy and antituberculosis medication significantly elevated his risk for abscess formation throughout the body, which may also explain the absence of fever at the time of presentation. Streptococcus, the organism isolated from the intramedullary abscess, likely disseminated following transient bacteraemia from an indeterminate source. Initially, the patient exhibited asymmetric weakness predominantly affecting the right side of his body. This asymmetry correlated with the pressure effects exerted by the intramedullary abscess, likely due to the oedema distribution favouring the right side of the cervical cord, proximal to the abscess location.
Once stability was established, the patient was transferred to a specialised tertiary spinal rehabilitation centre for further rehabilitation. Upon admission, a comprehensive neurological examination classified him as C5 American Spinal Injury Association Impairment Scale (AIS) Grade D according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNSCI).
Motor function assessment using the MRC scale revealed a muscle strength Grade of 2 out of 5 in all myotomes of the right upper limb, and 3 out of 5 in all myotomes of the right lower limb. The left upper and lower limbs demonstrated muscle power of 4 out of 5 on the MRC scale. Both anal tone and voluntary anal contraction were present, though weak, and deep anal pressure was also present.
Throughout the neurorehabilitation process, which employed a comprehensive multidisciplinary approach involving rehabilitation physicians, specialists, nurses, physiotherapists, occupational therapists, psychologists, dietitians, and volunteers, the patient exhibited gradual improvement. He participated in daily physiotherapy sessions lasting 1–2 hours, with gradual progressions in both gym and pool settings to enhance his mobility. Additionally, he engaged in weekly occupational therapy sessions aimed at improving dexterity and daily living activities. These interventions were designed to equip him with the necessary skills to return to his optimal state and establish a new baseline for engaging in everyday life.
During his 3-month tenure at the rehabilitation unit, he progressed from relying on an assistant-propelled wheelchair to standing unaided for brief intervals. Additionally, he advanced to taking several assisted steps and regained bowel continence. A repeat MRI scan performed 4 months after the initial presentation revealed a reduction in the lesion size to 14 x 6 mm, with features more indicative of myelitis rather than an abscess (Figure 3A–3C). Although his overall neurological level remained unchanged 6 months postadmission to the rehabilitation centre, a significant improvement in the functional capabilities of his lower limbs was observed. Throughout his tenure at the rehabilitation unit, the patient demonstrated incremental progress across all domains of the Spinal Cord Independence Measure (SCIM), encompassing self-care activities (such as feeding, grooming, bathing, and dressing), respiration and sphincter management, as well as patient mobility, including transfers to and from bed, and navigating indoor and outdoor environments.2,5,6 His SCIM on admission was 26, which subsequently improved to 68 at 6 months. Upon discharge, he continued to require catheterisation, with a plan in place to transition to a supra-pubic catheter at an appropriate future date. Given the persisting weakness in his upper limb strength, he was evaluated and considered unsuitable for selfintermittent catheterisation. Additionally, he remained continent with bowels.
DISCUSSION
ISCA is an exceptionally rare condition, largely attributable to the spinal cord tissue’s inherent resistance to infection. Its infrequent documentation in the literature further limits comprehensive understanding. The exceptional nature of this case is underscored by the involvement of the cervical cord and the patient’s immunosuppressive condition; while intramedullary abscesses typically present with acute neurological deficits and initial dorsal pain followed by the onset of neurological deficits, the patient exhibited a more insidious presentation resembling a spinal tumour or other conditions causing chronic myelopathy.
ISCA predominantly affects males and has a median onset age of 45 years.1 Remarkably, 31% of cases occur in the absence of any identifiable predisposing conditions.1 The clinical manifestation of ISCA is categorised based on the duration of symptoms into acute (less than 1 week), subacute (1–6 weeks), and chronic (more than 6 weeks) phases.2 Motor and sensory impairments constitute the predominant clinical manifestations of ISCA, with most patients initially presenting with symptoms of weakness, pain, and bladder dysfunction. Furthermore, a substantial proportion of these patients are nonambulatory at the time of initial presentation.1 Fever is observed in less than 50% of cases as an initial symptom.3 The most frequently reported symptoms at presentation include fever, pain, and neurological deficits, collectively referred to as the ISCA triad. Yet, fever is observed in less than 50% of cases as an initial symptom, and this triad is often not present in patients with subacute and chronic stages of ISCA.3 In the absence of febrile response or other definitive indicators of infection, as demonstrated in this patient, differentiating ISCA from other acute to subacute aetiologies of myelopathy, such as immunological or neoplastic processes, presents a significant diagnostic challenge. Therefore, it is imperative that clinicians maintain a high degree of suspicion for ISCA, even in the absence of classic infectious manifestations. This vigilance is critical to ensuring timely and accurate diagnosis, thereby facilitating appropriate therapeutic interventions.
The pathological evolution of an ISCA begins within the grey matter, which is rich in neuronal cell bodies, and progressively extends into the peripheral white matter, characterised by myelinated nerve fibers.4,5,7 This expansion follows a rostro-caudal trajectory, disrupting and separating the spinal cord’s fibre tracts. Notably, compression of spinal cord structures, a critical phase in the disease progression, manifests in the advanced stages of abscess development. Concurrently, the infection precipitates fibrous proliferation and gliosis around the affected area, indicative of the body’s reparative response to inflammation and injury, albeit contributing to pathological alterations within the spinal cord.
Figure 3: A repeat MRI scan performed 4 months after the initial presentation.
A) T2WI MRI cervical spine (sagittal section) 4 months post initial laminectomy and aspiration: further reduction in size of the intramedullary lesion. Features consistent with myelitis rather than abscess. Maximum diameters 14x6 mm. B) T2WI MRI cervical spine (axial section): maximum diameter of the lesion measures 14x6 mm. C) T1WI MRI cervical spine (sagittal section) 4 months post initial laminectomy and aspiration: absent rim enhancing lesion seen in initial T1WI.
WI: weighted image.
This process is further compounded by meningeal thickening, reflecting the extensive inflammatory response. In later stages, vascular complications arise, including thrombosis of adjacent veins, which compromises blood flow and exacerbates the condition’s severity.4
This suppurative condition is akin to the pyogenic brain abscess, with similar progressive changes in MRI finding in the
spinal cord as one would observe in the brain in pyogenic abscesses.8,9 The lesion presents as hyperintense on T2-weighted imaging with poorly defined enhancement observed in post-contrast T1-weighted imaging initially. Additionally, in literature, post-treatment initiation, the lesion typically exhibits a reduced hyperintense appearance on T2-weighted imaging and manifests welldemarcated enhancement in post-contrast T1-weighted imaging.8,9 In majority of cases,
this is not identified in earlier stages as the disease process is still under evolution. The return of function in those with intramedullary abscess is in clear contrast to those with epidural abscess,7 whereby a good functional outcome is either unknown or less, once the conduction is affected in individuals with epidural abscesses.10 Comparatively, a centrally placed abscess is less likely to cause irreversible vascular changes in the cord.
The aetiology of ISCA was identified predominantly as contiguous spread via a sinus tract opening, particularly noted in the lumbar region, though it can affect any segment of the spinal cord.5 Additional pathways for infection include haematogenous dissemination, complications following neurosurgical interventions, and cryptogenic origins.3 Specifically, cryptogenic ISCA predominantly manifests in the cervical and thoracic segments. This predilection is supported by findings that the blood supply, and correspondingly the number and calibre of blood vessels, in the upper spinal segments surpasses that of the lower segments.6 Furthermore, studies have posited that cryptogenic brain abscesses may arise from transient bacteraemia originating from an odontogenic source,2,3 suggesting a similar pathogenic mechanism for ISCA. In the era following the widespread use of antibiotics, the majority of ISCA cases have been cryptogenic, attributed to transient bacteraemia potentially leading to the colonisation of regions within the spinal cord previously compromised by subclinical injury or microinfarction.3
A recent systemic review noted there to be 202 cases of ISCA reported in literature.2 Between 1830–1944 (pre-antibiotic era), mortality rate was found to be 90%.10 The initiation of antibiotics improved the mortality rate, with subsequent mortality rates of 24% for cases reported between 1944–1977.11 In the pre-antibiotic era, over 50% of patients had haematogenous spread of infection from extraspinal focus, and more than 20% of patients had underlying suppurative lung disease. The other sites included soft tissue infections and infective endocarditis.12 Staphylococcus was found
to be the most common organism followed by Streptococcus, Escherichia Coli, Proteus, Listeria, Bacteroides, Pseudomonas, Brucella, Histoplasma, Actinomyces, Candida albicans, and Mycobacterium.10,13-20 Since the advent of antibiotics, the incidence of ISCA originating from haematogenous dissemination of infection from extraspinal sources has declined to less than 10%.3 This reduction can be attributed to the broader accessibility and effectiveness of antibiotics in treating the primary infection sites. Furthermore, a study by Hoche et al.,21 involving the introduction of micro-organisms into the circulatory system of experimental animals, revealed that ISCA did not develop unless thrombi were also introduced. This led to the conclusion that vascular disruption plays a pivotal role, suggesting that thrombi might either promote the localisation of circulating pathogens within the spinal cord, or compromise its blood supply, thus fostering an environment suitable for abscess formation. Gupta et al.21 reported a case of a patient with Pott’s spine who, failing to respond to anti-tuberculous treatment, developed ISCA, necessitating surgical decompression alongside antibiotic therapy. Conversely, Kurita et al.22 reported successful treatment with antibiotics alone. They reported no difference in the neurological manifestations in those treated with surgically treated patients when compared to the medically managed patients.22 Another study highlighted a mortality rate of 13.6% among surgically treated cases.20 Historical data further illustrate that, prior to the widespread use of antibiotics (before 1929), 34 patients treated non-operatively succumbed to the condition, 31 of whom had not received antibiotic treatment, underscoring the transformative impact of antibiotic therapy on the management of ISCA.20
In the era following the widespread use of antibiotics, coupled with advancements in diagnostic and surgical techniques, surgical drainage has been recommended to prevent neurological deficits. Early detection of the condition, followed by prompt surgical intervention alongside antibiotic therapy, is regarded as the optimal treatment approach.11,19,23 If left unaddressed, the natural progression of ISCA culminates
in irreversible neurological impairment due to the abscess’s capacity to occupy space, significantly contributing to the ensuing tissue damage.24,25 Consequently, it is imperative that ISCA be treated as a medical emergency, necessitating surgical decompression. Overall, there has been considerable reduction in the morbidity and mortality since the era of antibiotics, growing awareness, and prompt neurosurgical intervention.11,8,26
In the authors’ patient, the neurological status post-initial procedure, which encompassed laminectomy and aspiration, may have been compromised due to post-operative oedema and potentially incomplete abscess evacuation. Gradual neurological improvement was observed following a subsequent myelotomy, which provided further decompression of the cord abscess. The combined approach of surgical decompression, antibiotic therapy, and rehabilitation contributed significantly to the patient’s recovery, enabling independence in wheelchair mobility over extended distances, the ability to walk a few steps with assistance, and the restoration of bowel continence.
In individuals afflicted with severe spinal cord infections, the ensuing complications can precipitate profound, life-altering consequences. There is a lack of literature documenting the importance of rehabilitation, but implementing fundamental rehabilitation strategies during the preoperative, post-operative, and home-based care phases can significantly enhance patient outcomes by improving sensory and motor functions, fostering greater independence in activities of daily living.27 This rehabilitation journey, albeit arduous and protracted, necessitates the concerted efforts of patients, their families, and the rehabilitation team. An effective rehabilitation program aims to facilitate early mobilisation, alleviate pain, augment muscle strength, prevent muscle deconditioning, ensure stabilisation and proper posture, enhance trunk mobility, and offer education to avert secondary complications like pressure ulcers and additional medical problems. Critical to this process is the continuous
re-evaluation of the therapeutic regimen and the adaptation of goals to reflect the patient’s evolving needs. Paramount among these considerations is fostering patient compliance, education, and support, thereby maximising the potential for regaining independence, particularly significant in the case of the patient under study.
CONCLUSION
This case of a patient with cervical ISCA highlights several important implications for clinical practice and research. ISCA represents a rare pathology, with cervical occurrences being particularly scarce. The misleading symptoms often necessitate early detection and immediate treatment through surgical and/or antibiotic means to mitigate morbidity and mortality. The role of immunosuppressive therapy and antituberculosis treatment in predisposing to ISCA emphasises the need for careful infection monitoring in immunocompromised patients. The patient’s atypical presentation, mimicking other neurological disorders, underscores the need for heightened diagnostic vigilance, especially in the absence of typical infectious symptoms like fever. Prompt surgical intervention was critical, as evidenced by the patient’s improvement following myelotomy. The prognosis significantly depends on the timeliness of intervention; however, the importance of rehabilitation and a multidisciplinary team approach is crucial for the patient’s optimal reintegration into society. This case also contributes valuable insights to the limited literature on cervical ISCA, calling for further research into its pathophysiology, management, and outcomes. Additionally, it serves as an educational tool for clinicians, demonstrating the complexities of diagnosing and managing rare spinal cord infections. Public health strategies should include guidelines for monitoring infections in immunosuppressed individuals and preventive measures. Finally, the establishment of a registry for rare spinal infections is recommended to facilitate research and inform clinical guidelines.
References
1. Harrold GK et al. Clinical features and diagnosis of intramedullary spinal cord abscess in adults. Neurol. 2023;101(8):e836-44.
2. Jabbar R et al. Intramedullary spinal cord abscess with concomitant spinal degenerative diseases: a case report and systematic literature review. J Clin Med. 2022;11(17):5148.
3. Kurita N et al. Intramedullary spinal cord abscess treated with antibiotic therapy -case report and review-. Neurol Med Chir. 2009;49(6):262–8.
4. Patrick Keefe, Joe M. Das, Sunil Munakomi, Mohammed A. Al-Dhahir. Spinal cord abscess (2023). Treasured Island: StatPearls. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK532939/. Last accessed: 14 March 2024.
5. Dawson J et al. A structured review of outcome measures used for the assessment of rehabilitation interventions for spinal cord injury. Spinal Cord. 2008;46(12):768–80.
6. Catz A et al. The Catz-Itzkovich SCIM: a revised version of the spinal cord independence measure. Disabil Rehabil. 2001;23(6):263–8.
7. Fekete C et al. Development and validation of a self-report version of the spinal cord independence measure (SCIM III). Spinal Cord. 2013;51(1):40–7.
8. Candon E, Frerebeau P. Bacterial abscesses of the spinal cord. Review of the literature (73 cases). Rev Neurol. 1994;150(5):370–6.
9. Hoche A. Experimentelle beiträge zur pathologie des rückenmarks. Archiv für Psyl. 1899;32:947–1008.
10. Chan CT, Gold WL. Intramedullary abscess of the spinal cord in the antibiotic era: clinical features, microbial etiologies, trends in pathogenesis, and outcomes. Clin Infect Dis. 1998;27(3):619–26.
11. Sverzut JM et al. Spinal cord abscess in a heroin addict: case report. Neuroradiology. 1998;40(7):455–8.
12. Carus MEM et al. Intramedullary spinal cord abscess. J Neurol Neurosurg Psychiatry. 1992;55(3):225–6.
13. Murphy KJ et al. Spinal cord infection: myelitis and abscess formation. Am J Neuroradiol. 1998;19(2):341–8.
14. Bavdekar SB et al. Intramedullary spinal cord abscess. Indian J Pediatr. 1997;64(3):428–31.
15. Gillilan LA. The arterial blood supply of the human spinal cord. J Comp Neurol. 1958;110(1):75–103.
16. Wispelwey B SWM, Mandell GL, Bennett JE, Dolin R (eds), Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases (1995) 4ᵗʰ edition, New York: Churchill Livingstone, pp.887–900.
17. ARZT PK. Abscess within the spinal cord. Arch Neurol Psychiatry. 1944;51(6):533.
18. Menezes AH et al. Spinal cord abscess: a review. Surg Neurol. 1977;8(6):461–7.
19. Hart J. Case of encysted abscess in the spinal cord. Med Chir Rev. 1831;14(27):284–6.
20. Çokça F et al. An intramedullary dermoid cyst abscess due to Brucella abortus biotype 3 at T11-L2 spinal levels. Infect. 1994;22(5):359–60.
21. King SJ, Jeffree MA. MRI of an abscess of the cervical spinal cord in a case ofListeria meningoencephalomyelitis. Neuroradiology. 1993;35(7):495–6.
22. Ushikoshi S et al. Spinal intrathecal actinomycosis: a case report. Surg Neurol. 1998;50(3):221–5.
23. Cheng KM et al. Tuberculous intramedullary spinal cord abscess. Acta Neurochir. 1997;139(12):1189–90.
24. Hanci M et al. Intramedullary tuberculous abscess. Spine (Phila Pa 1976). 1996;21(6):766–9.
25. Lindner A et al. Magnetic resonance image findings of spinal intramedullary abscess caused by candida albicans. Neurosurgery. 1995;36(2):411–2.
26. Bartels RH et al. Intramedullary spinal cord abscess- a case report. Spine (Phila Pa 1976). 1995;20(10):1199–204.
27. Barbarawi MA et al. Management of intramedullary spinal cord abscess: experience with four cases, pathophysiology and outcomes. Eur Spine J. 2009;18(5):710–7.
Bromocriptine in the Management of Central Hyperthermia
Authors: *Krishnaprasad Ittilavalappil Narayanankutty,1 Atiq Ur Rehman,1 Mohammed Hossein Al Hamawi,1 Fatma Jasim S.J. Al Kuwari1
1. Qatar Rehabilitation Institute, Hamad Medical Corporation, Doha, Qatar *Correspondence to knarayanankutty@hamad.qa
Disclosure: The authors have declared no conflict of interest.
Acknowledgements The patient has provided informed written consent to publish his case in medical literature, after proper anonymisation of specific patient identifiers in text and images. It was submitted to and approved by the institutional review board.
Received: 10.01.24
Accepted: 10.04.24
Keywords: Bromocriptine, central fever, hyperthermia of central origin.
Central fever, or hyperthermia of central origin, is a not so rare cause of hyperthermia in neurological rehabilitation units, characterised by persistent fever without any recognisable cause, and poor response to conventional antipyretics. This article reports a case of central fever in a patient with tuberculous meningitis, treated with dopamine agonist bromocriptine in conventional doses, which resulted in fever remission. The current literature is also reviewed.
Key Points
1. Central hyperthermia in neurological diseases is a diagnosis of exclusion, postulated to be due to dysfunction of central temperature regulatory mechanisms. The treatment of this condition is empirical, and largely based on anecdotal evidence. Even the commonly used drugs like bromocriptine, baclofen, propranolol, etc., have different dosing regimens in literature. This article attempts to revisit the literature, and suggest a low-dose treatment option.t
2. The authors present a case of central fever in a patient with tuberculous meningitis and neurological disability, treated with dopamine agonist bromocriptine in smaller doses, which resulted in fever remission. The authors also reviewed the different treatment options for central fever available in literature.
3. Central hyperthermia shall be considered as a differential diagnosis in a patient with central neurological diseases, presenting with fever refractory to other measures. A few treatment options are available with limited evidence. Bromocriptine is an effective agent as per the authors’ experience in the case described. Other options are also available in the literature, which clinicians can choose based on their experience and availability.
INTRODUCTION
Fever is a common medical issue encountered in neurorehabilitation units. The most common cause of fever is infection; the common sources could be genitourinary tract, respiratory tract, gastrointestinal system, skin and soft tissue, and so on. The presence of fever in such patients warrants a rigorous search for the possible source of infection. Immune system impairment, which is observed after any central nervous system insult, also contributes to higher chances of infection. In addition to infections, hyperthermia can be related to the underlying brain insult. The common causes of such central hyperthermia are subarachnoid, intraventricular, and intracerebral haemorrhages; central nervous system tumours; traumatic brain injury; ischaemic stroke; tuberculous meningitis; traumatic spine injuries; and so on. Central hyperthermia is characterised by rapid persistent elevation of temperatures, with marked fluctuations and poor response to the conventional antipyretics. It may be the result of damage or dysfunction of central temperature control centres, which can dysregulate the thermoregulation.1 Fever due to any cause will adversely affect the prognosis of patients with neurological
injuries, and need to be addressed with appropriate treatment strategies.
In this paper, the authors present a 35-yearold male with persistent central fever after a tuberculous meningitis and obstructive hydrocephalus. The fever was difficult to control with the conventional antipyretics, but responded well with the conventional doses of bromocriptine.
PATIENT INFORMATION
A 35-year-old male with no significant pre-existing illnesses presented with acute headache, dizziness, vomiting, and mild left-sided weakness. CT examination revealed supratentorial hydrocephalus, atlantoaxial hemispinal deformity with basilar invagination, and multiple left cervical chain lymph nodes. MRI confirmed the ventriculomegaly and narrowing of the spinal canal at C1 level, with compressive myelopathy at the cervicalmedullary junction (Figure 1), along with basilar invagination and atlantoaxial subluxation. External ventricular drainage of cerebrospinal fluid (CSF) was done, which revealed lymphocytic predominant leucocytosis, and tuberculous bacilli DNA was isolated.
Comprehensive myelopathy at the cervical-medullary junction
Ventriculomegaly
Figure 1: Compressive myelopathy with obstructive hydrocephalus.
The patient was started on the conventional four-drug regimen for extra-pulmonary tuberculosis (rifampicin, isoniazid, pyrazinamide, and ethambutol). He started to vomit, and was noted to have a rising trend of transaminases while on first-line agents. Hence, the first-line agents were stopped, and he was started on second-line agents (amikacin, moxifloxacin, cycloserine, and linezolid). Vomiting subsided, and transaminase level improved.
CLINICAL FINDINGS AND DIAGNOSTIC ASSESSMENT
The patient developed another episode of fever with desaturation. Blood pressure, pulse rate, and respiratory rate were normal. General examination was unremarkable, except mild pallor. Cardiorespiratory examination, abdominal examination, and genitourinary examination did not reveal any abnormalities. Neurological examination showed generalised weakness, wasting with normal reflexes, and normal sensorium. Higher mental functions and cranial nerves functioned normally. Blood culture showed Klebsiella pneumonia, but no source could be identified despite extensive search. He was treated with ertapenem as per sensitivity for 14 days, but fever persisted.
Blood cultures after that failed to demonstrate any further growth. Chest X-ray, abdominal ultrasound, and echocardiogram were normal. The patient was otherwise vitally stable, and labs did not reveal any significant pathology. CT scan of the head was repeated to rule out any occult subdural empyema. It showed an interval increase in the size of the supratentorial ventricular system, with no evidence of any infection, and no change in previous findings. Those findings were reviewed by the neurosurgeon to rule out any neurosurgical interventions.
THERAPEUTIC INTERVENTION AND OUTCOME
Since there was no clear focus of infection despite extensive work-up, the team decided to treat him as hyperthermia of central origin, and started him on bromocriptine 2.5 mg daily in divided doses. Fever started trending down from the next day, and no further fever spikes happened (Figure 2). Bromocriptine was continued at the same dose for a period of 3 weeks, and then tapered off and discontinued. There was no fever recurrence, and other vitals and laboratory parameters were within normal limits. Also, no significant side effects in relation to bromocriptine use were noticed.
Figure 2: Temperature trend after bromocriptine therapy.
DISCUSSION
Fever or hyperthermia, defined as oral temperature greater than 37.5 °C, is a common situation in patients who have suffered neurological injuries, and are undergoing rehabilitation.2 Fever is a symptom of which differential diagnoses are extensive, the most common being infective aetiology. Common differential diagnosis of fever happening in a rehabilitation unit are enumerated in Table 1, but this is not an exhaustive list. Persistent fever can adversely affect the neurological outcome, extend the length of stay, increase the cost of care, and sometimes can lead to nonjudicious use of broad-spectrum antibiotics, leading to microbial resistance.
Table 1: Differential diagnosis of fever.
Infectious causes
Non-infectious causes
Neurological diseases
Drugs/toxins
Endocrine diseases
Hence, making an early diagnosis and instituting appropriate management is imperative.
Central fever, also known as neurogenic fever or hyperthermia of central origin, is a not so rare cause of fever encountered in rehabilitation units.3 It can occur alone, or as part of the clinical syndrome of paroxysmal sympathetic hyperactivity. It is characterised by rapid-onset persistent fever, with marked fluctuations and poor response to conventional antipyretics.4 It was first described in 1939 by Theodore C. Erickson.
The origin of central fever is hypothesised to be due to the involvement of central thermoregulatory pathways mediated by
Aspiration pneumonia
Sinusitis
Meningitis
Encephalitis
Catheter-related sepsis
Clostridium difficile diarrhoea
Abdominal sepsis
Complicated wound infections
Urinary tract infection
Drug fever
Connective tissue disease
Pancreatitis
Cholecystitis
Gastrointestinal bleed
Gout/pseudo-gout
Phlebitis/thrombophlebitis
Neoplastic fever
Venous thrombosis
Increased intracranial pressure
Non-convulsive status epilepticus
Autonomic dysreflexia
Agitation
Dystonia
Malignant catatonia
Paroxysmal sympathetic hyperactivity
Delirium
Serotonin syndrome
Acute drug withdrawal (intrathecal baclofen, dopamine agents)
Narcotic withdrawal
Neuroleptic syndrome
Drug overdoses (e.g., aspirin, anticholinergic drugs)
Pheochromocytoma
Thyroid storm
Adrenal insufficiency
various hypothalamic centres, like the lateral parabrachial nucleus and pre-optic area. The pathways involving the brain stem have also been described, which play a role in the pathogenesis of central fever.1 The subject has all probability of either of these areas having been affected by his obstructive hydrocephalus, causing the compression of the brain stem, and a chronic central nervous system infection with associated inflammatory damage.
Central fever is a diagnosis of exclusion. Most common neurologic injuries predisposing to central fever are brain haemorrhages, traumatic brain injury, ischaemic stroke, tuberculous meningitis, and so on. A high index of suspicion is warranted when any patient with above neurological conditions presents with persistent high-grade fever, negative cultures, no definite identifiable source, and failure to respond to conventional antipyretics. Sometimes the coexistence of another infection or physiologic stress of neurologic insult can lead to an elevation of inflammatory markers and leucocytosis, which can cloud the diagnosis. However, the inflammatory response will be of a lower grade compared to infections, and the response to empirical antibiotic therapy will not be observed in central fever.
Controlling fever is important, due to the negative effects of hyperthermia in the injured brain. Since the response to conventional antipyretics has been poor, other methods have been explored in the management of central fever. Several physical methods have been tried with limited efficacy, and sometimes with patient discomfort. They include rotary fans, sponging, surface cooling devices, hypothermia blankets, intravenous infusion of cold saline, inhaled cooling systems, and local brain cooling systems. Various medications have also been tried anecdotally, including morphine, chlorpromazine, baclofen, bromocriptine, growth hormone, and IL-1 antagonists.5
Bromocriptine is a dopamine D2 agonist that acts on the hypothalamus and corpus striatum, and has shown some effect in symptomatic management of paroxysmal
sympathetic hyperactivity.6 There are no systematic studies regarding the use of bromocriptine in central hyperthermia; however, a few case reports have demonstrated some benefit using different doses of bromocriptine.7 In a case report, a patient with traumatic brain injury and high-grade fever, diagnosed as central hyperthermia, was treated with 0.025 mg/ kg bromocriptine, which was later increased to 0.05 mg/kg. A comparison of mean daily temperatures before and after bromocriptine revealed significant lowering of body temperature, and the patient was weaned off over the next 5 weeks without any relapse of fever.8 Other similar case reports have been reported in the literature.9-11
CONCLUSION
This case report describes a case of central hyperthermia managed with a minimal dose of bromocriptine. Central fever should be considered as a possible differential in any patients who are neurologically injured, in which no other source for hyperthermia is identified. Bromocriptine could be an effective therapeutic option, but more structured studies are needed to evaluate its efficacy and safety in the management of central fever.
STRENGTH AND LIMITATIONS
As mentioned elsewhere, central hyperthermia is a challenging clinical entity, and not many pharmacological agents have been identified conclusively of any benefit. The researchers used bromocritine based on anecdotal reports, but with lesser doses, and became successful in managing the patient. Identifying the role of bromocriptine, even in small doses, could open the door for identifying other agents with a similar mechanism of action in the management of central hyperthermia. Having said that, this being a single case, it has limited value to suggest it as a therapeutic agent to be included in management algorithms of central fever.
PATIENT PERSPECTIVE
Once the fever started settling down, the patient started participating in the therapies well, which translated to better functional gains at discharge.
References
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4. Honig A et al. Central fever in patients with spontaneous intracerebral
His psychological state also improved, and he expressed his pleasure at the outcome of treatment. He finished his rehabilitation successfully, and was discharged from the inpatient rehabilitation service after he attained all the functional goals.
hemorrhage: predicting factors and impact on outcome. BMC Neurol. 2015;15:6.
5. Reinert JP, Kormanyos Z. Pharmacologic management of central fever: a review of evidence for bromocriptine, propranolol, and baclofen. J Pharm Technol. 2023;39(1):29-34.
6. Naz F et al. Bromocriptine therapy: review of mechanism of action, safety and tolerability. Clin Exp Pharmacol Physiol. 2022;49(8):903-22.
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8. Amin S et al. Bromocriptine for central hyperthermia after acute brain injury: a retrospective cohort study. Res Square. 2023;DOI:10.21203/ rs.3.rs-2386683/v1.
9. Yu KW et al. Effectively managing intractable central hyperthermia in a stroke patient by bromocriptine: a case report. Neuropsychiatr Dis Treat. 2013;9:605-8.
10. Natteru P et al. Central hyperthermia treated with bromocriptine. Case Rep Neurol Med. 2017;2017:1712083.
11. Ge X, Luan X. Uncontrolled central hyperthermia by standard dose of bromocriptine: a case report. World J Clin Cases. 2020;8(23):6158-63.
