A 2024 Clinical Preview: What Are Neurologists Excited About?

As the clinical community steps further into 2024, the field of neurology is set on moving forward with advancements and potential treatments that can change the landscape of care for patients. Clinicians are showing their anticipation, fueled by the promise of novel technologies and therapies, and a deeper understanding of neurological conditions including movement disorders, migraine, epilepsy, neuromuscular diseases, sleep disorders, and multiple sclerosis (MS), among others.

Movement Disorders

The field of movement disorders is expecting new research updates and pending approvals on potential therapies for conditions such as tardive dyskinesia, Huntington disease, and Parkinson disease (PD). Clinical trials for PD research have advanced the field over the years, shedding new light on the cellular pathways that contribute to the pathogenesis of PD and offer increasingly compelling targets for potential therapeutics.¹Despite the progress in research and investigations of therapies for patients with PD, though, there remains to be a disease-modifying treatment approved to slow, stop, or reverse disease progression.

"I think this is a truly exciting time to be part of the movement disorders community in any capacity. There are a lot of eyes on the field of movement disorders, especially PD right now. That means it's a win for us because more research is being completed, providing numerous opportunities for hope for people living with PD. More than ever, this is one of the most exciting aspects of 2024,” Kelly Papesh, DNP, APRN, FNP-BC, the clinical director of the Parkinson & Movement Disorder Alliance (PMD Alliance), told NeurologyLive^®.

Key Clinical Takeaways

Movement Disorders: The movement disorders community is awaiting potential breakthroughs in Parkinson disease therapy, emphasizing the urgent need for disease-modifying treatments amid ongoing research and evolving therapeutic landscapes.

Migraine and Headache Disorders: Migraine treatment has seen a paradigm shift with the advent of novel therapies targeting calcitonin gene-related peptide and pituitary adenylate cyclase-activating polypeptide, promising better outcomes and expanded treatment options for patients.

Epilepsy and Seizure Disorders: With advancements in epilepsy therapeutics, including novel medications and focal delivery of disease-modifying treatments, clinicians anticipate improved seizure control and tailored approaches for drug-resistant epilepsy, enhancing patient outcomes and quality of life.

Neuromuscular Disorders: The neuromuscular community is awaiting potential game-changers in CIDP therapy, such as Fc receptor and complement inhibitors, heralding new treatment avenues and improved outcomes for patients with challenging-to-treat neuromuscular diseases.

Sleep Disorders: Novel oral therapies for sleep apnea offer hope for patients intolerant to traditional treatments, signaling a potential shift in management strategies and improved outcomes for those with various sleep disorders.

Multiple Sclerosis: Anticipation surrounds revisions to MS diagnostic criteria and the development of Bruton tyrosine kinase (BTK) inhibitors, promising more accurate diagnoses and innovative treatments to halt disease progression and improve patient outcomes.

Researchers are continuing their pursuit in 2024 to study active and passive immunotherapy approaches with the goal of modifying the spread of α-synuclein pathology in the brain in patients with PD. According to a review previously published in the journal Neurotherapeutics,¹ currently available treatments proposed to have potential disease-modifying effects for PD included calcium channel blockers, antioxidants, anti-inflammatory agents, iron-chelating agents, glucagon-like peptide 1 agonists, and c-Abl tyrosine kinase inhibitors. Investigators noted that these treatments offer mechanistic diversity and hope for patients, however, trials assessing them have not produced significant findings.

“There are pipeline therapies currently under FDA review and hopefully coming to market, offering hope for our community. This presents an opportunity for clinicians to provide new therapies, potentially offering solutions for patients who previously weren't responding to the right treatment,” Papesh said. “When we consider the therapies in the pipeline, including many pumps and oral therapeutics, having these options gives us more tools to better manage patients. Without these advanced therapies and the new research being done, we would continue to utilize many of the same formulations and therapies in new ways. This novelty, especially in the US market, is one significant aspect we're looking forward to in 2024."

Migraine and Headache Disorders

Headache medicine is anticipating new research updates and pending approvals on potential therapies for headache disorders, including migraine, status migrainous, posttraumatic headache, and others. Headache, a common ailment that afflicts patients worldwide, can have debilitating impacts on the quality of life and productivity of those with the condition.² Over the recent years, the medical community has made significant strides to understand the complexities of headache, with a greater focus on novel approaches for diagnosis, treatment, and management.

“I would say probably over the last quarter century, there have been many human and animal models in migraine that have provided crucial data and understanding of the mechanisms of migraine attacks. Studies have identified the involvement of 2 neuropeptides. The first is calcitonin gene-related peptide [CGRP] and the other is pituitary adenylate cyclase-activating polypeptide [PACAP],” Brian Grosberg, MD, FAHS, director of the Hartford Healthcare Headache Center in Connecticut, told NeurologyLive. “Both induce migraine attacks in patients when they're given intravenously and can cause dilation of arteries in the head. Findings have contributed to the development of what we know and the marketing of monoclonal antibodies that block the CGRP signaling pathway. This is fantastic because it's really spearheaded treatment for people with migraine.”

Investigators are continuing their pursuit in 2024 to understand more of the determinants, interactions, and biological mechanisms of headache to uncover innovative and better management strategies. In a recent editorial published in Frontiers in Pain Research, researchers showcased some of the latest advancements in the field, shedding light on various aspects of the condition and their implications for care.³ These included CGRP, a peptide that participates in the transmission of pain signals, and the new class of therapies that prevent migraine attacks. As more new therapies become introduced for patients, researchers are raising questions about real-world experiences, as well as the intentional and unintentional effects of combinations and interactions.

“Over the past decade, there’s been more evidence accumulating that PACAP plays a critical role in migraine pathophysiology. Ultimately, the PACAP pathway seems to be distinct from the CGRP pathway. There’s potential that antagonism of PACAP may be a novel therapeutic target of particular interest in patients who are not responding optimally to the CGRP antagonizing therapies,” Grosberg, also a professor of neurology at the University of Connecticut School of Medicine, said. “In the past couple of years, there have been a couple of studies under development targeting PACAP to study it. I'm hopeful that this new class of medications will be helpful for many patients with migraine. Another agent that has been studied is oxytocin, a hormone and neurotransmitter in the hypothalamus that has an important antinociceptive or antipain role through its binding to oxytocin receptors among other functions. This effect inhibits the trigeminal nerve neurons excitability and is also being studied right now for prevention of migraine.”

Epilepsy and Seizure Disorders

Those in epilepsy medicine are hopeful for new research updates and approval of therapies for epilepsy and seizure disorders, including those with various epilepsy types and rare syndromes such as Dravet syndrome and Lennox-Gastaut syndrome, and others. The field is currently still challenged by issues with drug-resistant epilepsy, adverse reactions and therapy interactions, earlier identification of epileptic syndromes, and limited prevention therapies for epilepsy as well as its comorbidities.⁴ Despite these challenges, investigators are continuing their pursuit to understand more of the determinants, interactions, and biological mechanisms of seizures to discover better management options for patients.

"There's a lot of new exciting therapeutics for patients with epilepsy. I believe we're in a year where new, highly effective medications are coming to the market for epilepsy patients. There are medications in the pipeline with mechanisms of action different from any of our currently available antiseizure medications for focal epilepsy, such as potassium channel modulators, many of which are being studied,” Claude Steriade, MD, CM, an epileptologist at NYU Langone Health and associate professor in the department of neurology at NYU Grossman School of Medicine, told NeurologyLive. “Additionally, there are serotonergic drugs, like the one just approved for Lennox-Gastaut syndrome. What I'm really excited about is having drugs with proven efficacy for patients.”

Currently, there are many treatment options for seizures that center on the condition's symptoms rather than the cause, meaning there are still several patients with difficult epilepsy to treat that need effective therapies. This is the case, especially for patients who live with autoimmune epilepsy, which presents specific clinical manifestations. According to a review published in the Journal of Clinical Neurology,⁵ research shows that the type of autoimmune epilepsy is a critical factor to consider when selecting from among various immunotherapy options for patients. In addition, researchers suggest that clinicians should additionally take the characteristics of antiepileptic treatment into account when using them as adjuvant therapy for those with autoimmune epilepsy.

“Another exciting aspect is our growing understanding of the mechanisms of autoimmunity in patients with epilepsies having an autoimmune cause. A lot of work, particularly from Europe, focuses on neuropathological findings in patients with autoimmune-associated epilepsies. We are starting to understand better why these patients have a poor response to immunotherapies,” Steriade said. “From a therapeutic perspective, there are new approaches beyond medications, including focal delivery of potentially disease-modifying treatments. Overall, the epilepsy community is receiving a wealth of new and exciting information, even beyond my specific research realm."

Neuromuscular Disorders

In 2024, those in neuromuscular medicine are anticipating new research updates and pending approvals on potential therapies for certain disorders, including amyotrophic lateral sclerosis, myasthenia gravis, Duchenne muscular dystrophy, chronic inflammatory demyelinating polyneuropathy (CIDP), and others. Neuromuscular diseases, like CIDP, have experienced challenges in the clinical setting with the diagnosis of subtypes of the diseases and prescribing the most effective therapies for patients that improve outcomes.

CIDP is characterized as progressive weakness and reduction in the senses of the arms and legs caused by damage to the fat-based protective covering on nerves.⁶Over the recent years, the neuromuscular community has made significant strides to understand the complexities of CIDP, with a greater focus on novel approaches for diagnosis, treatment, and management.

"There are 2 new potentially new treatments that are being explored in CIDP the Fc receptor inhibitors, which showed a favorable response with efgartigimod (Vyvgart; Argenx), and the complement inhibition that was reported to have an effect in a smaller phase 2 trial. Both of those are exciting potential new treatment avenues that may change the landscape and then there are other things that need to be explored in terms of immune therapy,” Richard Lewis, MD, director of the electromyography laboratory and professor of neurology at Cedars-Sinai Medical Center, told NeurologyLive. “Remission rates and CIDP are very low in general, probably a third can go into short-term remission, and probably 10% or less can go into long-term remission. We still don't have the treatment that will stop the disease and allow you to live life without being treated but maybe CAR-T will at some point have some benefits for some of these disorders.”

Investigators are continuing their pursuit in 2024 to understand more of the determinants, interactions, and biological mechanisms of CIDP to discover innovative and improved management strategies. In a recent literature review published in Medicina, researchers established that the destruction of peripheral nerves and nerve roots typifies CIDP and is an autoimmune disease that influences the myelinating constructions of the peripheral nervous system. Although several treatments for CIDP show promising results, researchers recommend that treatment decisions be personalized for each patient’s needs.⁷

“Gene therapy is a promising avenue for various disorders, particularly genetic diseases, where its potential is evident. However, its excitement for immune and inflammatory disorders remains uncertain. The sheer abundance of genetic diseases makes it challenging to predict when specific conditions will benefit from gene therapy. Despite this uncertainty, there is considerable enthusiasm in the scientific community about the potential of gene therapy, and that's truly exciting,” Lewis said.

Sleep Disorders

Clinicians in sleep medicine anticipate the latest updates in research and the pending approval of therapies in sleep disorders, including obstructive sleep apnea, cataplexy, narcolepsy, insomnia, excessive daytime sleepiness, and others. The field of sleep disorders is cross-disciplinary challenged, requiring the collaboration of healthcare professionals to build a solid framework for diagnosis and treatment.⁸ Although growing research has provided clinicians with more understanding of sleep disorders, researchers suggest that several trends are dominated by outdated paradigms.

“I'm particularly excited this year about the novel oral therapies that are coming out for treating sleep apnea as there's been some promising work over the last couple of years. But a lot of the time patients will tell us they can't tolerate continuous positive airway pressure or they can't afford a dental appliance, or weight loss is insufficient. We don't really have an avenue to treat sleep apnea and we know that it's so harmful and can be associated with vascular risk with dementia, poor quality of life, and so forth,” Mark I. Boulos, MD, BSc, FRCP, CSCN, MSc, an associate professor, in the department of medicine and division of neurology at the Institute of Medical Science of the University of Toronto, told NeurologyLive. “It would be really cool to see if these oral medications will have promise in treating sleep apnea not only in the general populations but also in other populations as well that are high risk for sleep apnea, like stroke, dementia, and other various neurological populations.”

According to a previous review published in Frontiers in Neurology, researchers highlighted that the evolution of diagnosis and treatments in sleep medicine has a continuous push and pull between several forces.⁸Despite previously failed trials, the research has contributed to a better understanding of the condition, leading to updated treatment guidelines. In addition, the different specialties in sleep disorders may sometimes intertwine with other neurological disorders and thus increase the knowledge of those conditions as well.

“I think 2024 will be a year where we see a lot of novel therapies come out for various sleep conditions like neurostimulation for treating restless leg syndrome. I think that's very promising for this condition since it’s a sleep disorder where a lot of patients almost run out of options as well. We're running a trial right now that's looking at cannabis use for treating refractory restless legs, funded by the RLS foundation. Overall, I think there are going to be some cool therapies coming out for this condition with neurostimulation, potentially cannabis, and maybe other pharmacological agents. There are also novel therapies coming out for narcolepsy. With these therapies, we just have to make sure that they're safe for patients,” Boulos said.

Multiple Sclerosis

Medical professionals anticipate the latest updates in research and continue to advance the therapeutic options for patients with MS including relapsing MS and progressive MS, as well as related and demyelinating disorders such as neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease. The field has experienced significant positive gains over the past couple of decades with understanding the fundamental drivers of the disease, identification of risk genes, having a more precise account of epidemiology, and the development of effective treatments.⁹ Currently, relapses in MS can be safely eliminated in most patients with the latest therapies, and treatment-resistant progressive symptoms have partially slowed.¹⁰

“I'm excited about the upcoming MS diagnostic criteria revisions. There was a large group of clinicians and scientists that met a few months ago to discuss proposed revisions and it does seem like there will be some dramatic changes coming up in the next year. Overall, I think this is positive because I think the diagnostic criteria consider all the emerging science on what we're thinking about MS. Some of these changes will essentially allow for an appropriate diagnosis for patients but we'll also prevent misdiagnosis with some of the proposed tools that will be used. I think it will be a big change in comparison to prior versions of the diagnostic criteria, and all positive changes and good news for people living with MS,” Jiwon Oh, MD, PhD, staff neurologist and medical director of the Barlo Multiple Sclerosis Program at St. Michael's Hospital and the University of Toronto, told NeurologyLive.

Among the recent advancements in therapeutics, Bruton tyrosine kinase (BTK) inhibitors, a cytoplasmic tyrosine kinase expressed by B cells and myeloid cells, show promise in curtailing disease progression by targeting immune cells on both sides of the blood–brain barrier. According to a recent review published in Nature Reviews Neurology, there are several BTK inhibitors currently under investigation for MS that differ in selectivity, strength of inhibition, binding mechanisms, and ability to modulate immune cells.¹¹ These BTK inhibitors include evobrutinib (Merck KGaA/EMD Serono), tolebrutinib (Sanofi), and orelabrutinib (Biogen/InnoCare Pharma), and the reversible inhibitors fenebrutinib (Roche) and BIIB091 (Biogen).¹²

“I think the world was a bit disappointed with the very high-level results that were reported for evobrutinib, but we're still very excited about that class of therapy. Just because at least the early clinical trial data, as well as many kinds of preclinical studies, show some intriguing findings, including the fact that it probably has a good effect on peripherally mediated inflammation."

“There are also some intriguing studies showing that not only do these drugs get into the brain, but they may have an effect on some of the pathological processes that we think are responsible for progression in MS. This year, we're anticipated to hear likely the results of the second BTK inhibitor that has been widely studied in MS, which is tolebrutinib,” Oh said.