AMJ Neurology 1.1 2024

Article

Optic Coherence Tomography

Angiography in Multiple Sclerosis

Yaakov Stern, Jacqueline A. French, and Chia-Chun Chiang Interviews

Editorial Board

Editorial Board

Prof Amos Korczyn Tel-Aviv University, Israel

Dr Natan Bornstein Shaare-Zedek Medical Center, Israel

Prof Nils Erik Gilhus University of Bergen, Norway

Dr Giuseppe Lanza University of Catania, Italy

Dr Simy Parikh Thomas Jefferson University, Pennsylvania, USA

Dr Kenneth Mack Mayo Clinic, Minnesota, USA

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AMJ Neurology is an open-access, peer-reviewed eJournal committed to publishing the highest quality medical research concerning all aspects of the function and disease of the nervous system to help advance the development of this field.

The journal is published annually approximately 6 weeks after the American Academy of Neurology (AAN) Annual Meeting, and features highlights from this event, alongside interviews with experts in the field, reviews of abstracts presented at the event, as well as in-depth features on congress sessions. The journal also 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.

AMJ 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.

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This Publication

Launch Date: 2024

Frequency: Annually Online ISSN: 3033-375X

All information obtained by AMJ and each of the contributions from various sources is as current and accurate as possible. However, due to human or mechanical errors, AMJ and the contributors cannot guarantee the accuracy, adequacy, or completeness of any information, and cannot be held responsible for any errors or omissions. AMJ is completely independent of the review event (AAN 2024) and the use of the organisations does not constitute endorsement or media partnership in any form whatsoever. The cover photo is of Denver.

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Dear Readers,

Evgenia Koutsouki Editor

It is with great pleasure that I welcome you to the inaugural issue of AMJ Neurology, bringing you key coverage and insights from the American Academy of Neurology (AAN) Annual Meeting, which this year took place in Denver, Colorado, USA. Highlights from the event include results of trials on Niemann-Pick disease Type C, Alzheimer's disease-related agitation, and chronic inflammatory demyelinating polyneuropathy, among other key insights. We have covered in-depth sessions that discussed emerging neuroinfectious diseases, and new treatment approaches in Alzheimer’s disease.

We are delighted to also bring you interviews with prominent experts covering a spectrum of topics, ranging from the intriguing cognitive reserve hypothesis in Alzheimer’s disease, to headache management and innovations in the treatment of epilepsy.

Be sure not to miss our insightful articles spotlighting topics like optic coherence tomography angiography in multiple sclerosis, an innovative tool valuable for mapping vascular change; a case report of hereditary hemochromatosis; and a compelling case series on tics associated with mild traumatic brain injury in pediatric patients.

In closing, I would like to thank our Editorial Board and peer reviewers for their support, and our contributors and interviewees for providing insightful content for this first issue. I trust you will find this content informative, and eagerly anticipate your feedback and suggestions for future editions. Until next year’s AMJ Neurology, be sure not to miss our upcoming issue of the European journal, EMJ Neurology, set to be published later this summer!

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AAN 2024

Review of the 76ᵗʰ American Academy of Neurology (AAN) Annual Meeting

Location: Denver, Colorado, USA

Date: April 13–18, 2024

Citation: Neurol AMJ. 2024;1[1]:8-16. https://doi.org/10.33590/neurolamj/RAYA5561.

DENVER, Colorado, USA, was the backdrop for the 2024 American Academy of Neurology (AAN) Annual Meeting. Coined as the Mile High City, sitting at 5,280 feet above sea level, it posed as the perfect setting to host an event for an academy with the mountainous mission of promoting brain health for all.

With a combined in-person and online attendance of 10,575 neurology professionals, the meeting spanned 6 days, included >500 programs, and had representation from 105 countries. This year, attendees were offered the opportunity to step outside of traditional educational sessions into hubs, for a unique way to learn and network. These hubs covered a variety of topics, from academics and innovation to leadership and wellness.

Hope O’Brien, Vice Chair of the AAN Meeting Management Committee, expressed excitement to welcome all attendees to the 76ᵗʰ AAN Annual Meeting and drew attention to several new additions to this year’s meeting, including the Educator’s Room where delegates could network and attend courses, childcare, hydration stations, and the Leadership Little Library, stocked with books recommended by leadership alumni.

In the official Welcome, O’Brien highlighted the Society Spotlight sessions, which showcased top

abstracts from subspecialty meetings, and drew attention to the daily Plenary sessions, which featured presentations from neurology leaders on the latest and greatest in the field, including breakthrough research and controversial issues.

The Presidential Plenary Session, which took place on Day 2 and was hosted by the 2024 AAN President, Carlayne E. Jackson, was packed with delegates excited to hear from experts in the Presidential Lecture and the winners of the George C. Cotzias Lecture: Maiken Nedergaard, Center for Translational Neuromedicine, University of Copenhagen, Denmark; the Sidney Carter Award in Child Neurology: Susan J. Hayflick, Oregon Health and Science University, Portland, USA; and the Robert Wartenberg Lecture: Mark Hallett, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, Maryland, USA.

Jackson kicked off the Presidential Plenary by giving recognition to the select members who have been invited to become AAN Fellows in recognition of their outstanding achievements and contributions to the field of neurology. Before displaying the names of newly invited AAN Fellows on the screen, Jackson commended the new members, commenting: “We celebrate their remarkable accomplishments and commitment to excellence in neurology.”

Jackson further commended those who have been dedicated AAN members for >50 years, contributing a profound legacy of service and excellence. She reflected that these individuals embody core values of the AAN, and have demonstrated unwavering dedication to patient care, education, research, and advocacy throughout their distinguished careers.

Subsequently, Jackson bestowed the 2024 AAN President’s Award to Ann Tilton, Chair of the Meeting Management Committee. Jackson spotlighted Tilton’s dedication to the AAN, having been a member for 43 years. Zoning in on her recent work with the Meeting Management Committee, Jackson emphasized how instrumental Tilton has been in the reimaging of the program following emergence from the COVID-19 pandemic. After joining the stage, Tilton discussed how rewarding it has been to watch sections expand, see members get a voice in their areas of interest, and be involved in the development of strategy and direction, before thanking the AAN for the incredible honor and imploring the audience to “take advantage of the exceptional people around you and enjoy them, because every minute is a privilege.”

Jackson also referenced the AAN’s new 5-year strategic plan and updated mission statement to

enhance member career fulfilment and promote brain health for all, before welcoming Natalia Rost, AAN President Elect, to the stage for the 2024 Annual Meeting Presidential Lecture. This lecture saw Sanjay Gupta, Associate Professor of Neurosurgery at Emory University Hospital, Atlanta, Georgia, USA, reflect on his journey and the brain health revolution.

When discussing some of the lessons learned over his career, Gupta commented that the stories clinicians come across are “the stories of humanity”, and highlighted the impact these have on people outside of the profession. He also stressed the need for clinicians to find the balance between uncertainty and providing patients with useful information.

Rost highlighted that we are currently amid the brain health revolution, and Gupta discussed how brain health is much more than just the absence of brain disease. He touched on the fact that we live in more of a sick care than health care system, and utilizing brain health as an example, he stated that brain maladies are only treated once a problem has occurred. He further suggested that moving forwards, preventive neurologist input could be a meaningful way to intervene before problems arise.

"We have to be voices for the voiceless. We have to be able to tell a more complete story.”

Gupta discussed that the mechanistic understanding of how the brain functions has been one of the main challenges in getting the public focused on brain health, noting that as our understanding has improved, the perception that we can do something about it is now changing. Moving forward, improved research and translation of this research to the bedside will require funding, advocacy, and careful messaging about what someone with good brain health looks like and how their life will be better with improved brain health, both acutely and in the long term. Furthermore, in keeping with the AAN belief in brain health for all, Gupta stressed the importance of looking at brain health universally and the relevance of research to the broader population. He poignantly stated: “We have to be voices for the voiceless. We have to be able to tell a more complete story.”

This section of the Presidential Lecture also discussed sleep as one of the five pillars of brain health. The trio discussed that to inject meaningful change into primary and neurological care, clinicians need to emphasize that healthy sleep can reduce cognitive decline and stroke risk, explaining the ‘why’ and the ‘how’. The section concluded with Jackson thanking Gupta and highlighting how his thoughts will resonate with members as the AAN moves forward with their mission towards brain health.

Building on the importance of sleep, Paul George, AAN Science Committee Chair, joined the stage to introduce the recipient of the George C. Cotzias Lecture for excellence in neuroscience, Nedergaard, for her work on the glymphatic system.

Nedergaard emphasized that “lack of sleep changes focus, judgement, and mental state,” highlighting that several studies have recently shown that subjects who have ≤6 hours of sleep per night have an approximately 30% increased risk of developing dementia as they age.

Exploring why the brain is exquisitely sensitive to sleep deprivation, Nedergaard’s

team hypothesized that sleep fulfils an essential function that cannot occur in the awake state. Interestingly, compared to all other organs, the brain lacks a lymphatic system despite being a metabolically active tissue. Detailing the findings from research so far, Nedergaard discussed how the glymphatic system was uncovered, its function in CSF recirculation and clearance of proteins such as β-amyloid and tau, how it is affected by aging, and how its activity is suppressed in the awake state.

Exploring research reviewing sleep deprivation, findings showed that the human glymphatic system is affected by sleep deprivation with the effect of reduced clearance activity still present after 48 hours. Nedergaard noted that studies now suggest it may take days to weeks for the brain to recover from one night of sleep deprivation. Furthermore, she displayed research that has shown the vascular system drives the glymphatic system, stressing that reduced flow leads to increased protein aggregation and neuroinflammation, leading to neurodegeneration and subsequently, dementia. In reference to research showing that glymphatic failure is the common final path to dementia, Nedergaard highlighted that several factors, including sedentary lifestyle, aging, and reduced sleep quality, impact the function of the glymphatic system. However, there is the possibility for intervention here. If these factors are addressed earlier by increasing activity and improving sleep, onset of dementia could be delayed. Nedergaard concluded her insightful and highly topical lecture by stating that sleep is non-negotiable and that the brain is uniquely sensitive to a healthy cardiovascular system.

The AAN 2024 Annual Meeting was a hub of activity, cutting-edge research, and inspiring collaboration. We look forward to participating in the 77th AAN Annual Meeting, which will take place in San Diego, California, USA, April 5–9, 2025. For now, read on for further scientific insights from 2024’s Annual Meeting. ●

Novel Treatment for Niemann-Pick Disease Type C

NEIMANN-PICK disease Type C (NPC) is a slow-progressing, ultimately fatal genetic lysosomal disorder characterized by inability to adequately transport lipids, such as cholesterol. This results in the accumulation of fatty material around tissues, causing increasing damage to these areas and, accordingly, progressive deterioration of functionality.

The extreme burden of disease, and premature mortality, associated with NPC makes it a significant health concern. Despite its gravity, there are, as yet, no effective treatments for NPC, with the course of medication only extending so far as to alleviate symptoms and improve quality of life.

A recent clinical trial conducted by Michael Strupp, Department of Neurology, Ludwig Maximilians University, Munich, Germany, and colleagues, puts forth a novel therapy in the form of the active L-enantiomer N-acetyl-L-leucine (NALL), for pediatric (≥4 years) and adult patients alike. Data were presented at the 2024 AAN Annual Meeting.

The trial in question was a Phase III, doubleblind, randomized, placebo-controlled crossover trial with 53 subjects randomly assigned (1:1) to receive orally-administered NALL three times a

day, or a placebo, over two consecutive 12-week periods. Of the results presented, one of the most profound findings was a significant improvement to muscle control in the limbs, measured according to the Scale for the Assessment and Rating of Ataxia (SARA). Where ataxia is a prominent feature of NPC, patients treated with NALL saw a 1.97 SARA change from baseline, compared to 0.60 SARA change from baseline in the placebo cohort.

NPC is not the sole condition to benefit from the administration of NALL. As an extension of this trial, Strupp and team sought to evaluate the efficacy of NALL in the treatment of gangliosidosis, a progressive genetic disorder that destroys neurons of the brain and spinal cord. Promisingly, NALL was shown to produce similar treatment outcomes as in NPC.

Of note, none of the participants suffered any serious adverse effects, and the frequency of adverse effects between the experimental and placebo groups were comparable. ●

"Despite its gravity, there are, as yet, no effective treatments

for NPC."

Efgartigimod in Patients with Chronic Inflammatory Demyelinating Polyneuropathy

RECENT developments of the ADHERE trial were presented at the 2024 Annual Meeting of the AAN, which took place April 13–18 in Denver, Colorado, USA.

Jeffrey A. Allen, Department of Neurology, University of Minnesota, Minneapolis, USA, opened his discussion with a summary of what chronic inflammatory demyelinating polyneuropathy (CIDP) is, the current treatment options available, and the promise of the ADHERE trial. CIDP is an autoimmune, inflammatory condition characterized by distal/proximal weakness and sensory deficits. Common treatments include corticosteroids, intravenous immunoglobulin, and subcutaneous immunoglobulin or plasma exchanges. Whilst these treatment options are effective, they carry a significant treatment burden, such as the frequency and duration of infusions, dependency on donors, and residual neurological impairment and disability.

"Efgartigimod is a human IgG1Fc fragment that outcompetes endogenous IgG."

Evidence supports the role of pathogenesis IgGs in the pathogenesis of CIDP. Efgartigimod is a human IgG1Fc fragment that outcompetes endogenous IgG, preventing recycling, and promoting lysosomal degradation of IgG, without impacting IgG production. Based on this, efgartigimod PH20 subcutaneous (SC) was developed, a coformulation of efgartigimod and recombinant human hyaluronidase PH20, which, as explained by Allen, “allows for rapid (30–90s single injection) SC administration of larger volumes.”

ADHERE is a multicenter, multi-stage, randomizedwithdrawal, double-blinded, placebo-controlled trial of efgartigimod in CIDP. Notably, the trial showed that regardless of prior CIDP therapy, participants treated with efgartigimod PH20 SC demonstrated considerable clinical benefits, with evidence of rapid clinical improvement, maintained clinical response to treatment, and a 61% reduced risk of relapse compared with placebo.

Looking to the future, Allen highlighted the potential of a single, rapid (30–90s) injection of weekly efgartigimod PH20 SC as a therapeutic option to reduce treatment burden in patients with CIPD. ●

Positive Results of AXS-05 Efficacy and Safety in Alzheimer's Disease Agitation

NEW findings from the ACCORD study have revealed that AXS-05 significantly delayed time to and prevented relapse of Alzheimer's diseaserelated agitation (AD agitation). The results from this study were presented at the 76ᵗʰ AAN Annual Meeting.

AD agitation is a common disease phenotype, reported in up to 70% of patients with AD and characterized by emotional distress, aggressive behaviors, and disruptive irritability. The increased caregiver burden, accelerated cognitive decline, earlier institutionalization, and increased mortality, in conjunction with the limited efficacy of first-line therapy treatments for AD agitation, highlight the need for effective pharmacological alternatives.

AXS-05, a novel oral N-methyl-D-aspartate receptor antagonist, was demonstrated to rapidly, substantially, and significantly improve AD agitation in the ADVANCE-1 study, as measured by the Cohen-Mansfield Agitation Inventory (CMAI) score.

The ACCORD study was a double-blind, placebo-controlled, multi-center, randomized discontinuation study designed to assess the efficacy and safety of AXS-05. The study was divided into two phases: an open-label and a double-blind period. A total of 178 study participants with probable AD and clinically significant agitation were treated with AXS-

05 for up to 9 weeks until a sustained clinical response was observed, defined as a 30% or more significant reduction in CMAI score. In the doubleblind phase, the study organizers implemented a 1:1 randomization of the 108 sustained clinical responders between a placebo and AXS-05 group. The double-blind phase extended for up to 26 weeks or until an agitation relapse.

Results from Phase III of the ACCORD trial showed an early and rapid reduction in CMAI score in the open-label phase, statistically significant from entry CMAI, with 80% of participants recognized as clinical responders by Week 6. The double-blind phase revealed that participants receiving AXS-05 had a significantly delayed time and decreased risk of agitation relapse, with the risk of relapse 3.6fold lower with AXS-05 compared with placebo. Furthermore, AXS-05 was well tolerated, generally safe, and not found to be associated with cognitive impairments or significant adverse events.

The safety results and clinically meaningful improvements in AD agitation led Anton Porsteinsson, director of the Alzheimer's Disease Care, Research and Education Program at University of Rochester, New York, USA, to conclude that AXS-05 has the potential “to fulfill a high unmet need for the pharmacological treatment of AD agitation.” ●

"AXS-05 has the potential to fulfill a high unmet need for the pharmacological treatment of AD agitation."

Does Dexamethasone Improve Outcomes in Herpes Simplex Virus Encephalitis?

RESULTS from a randomized controlled trial assessing the effect of the corticosteroid dexamethasone on herpes simplex virus (HSV) encephalitis outcomes were presented at the 2024 AAN Meeting, held in Denver, Colorado, USA.

Tom Solomon, Walton Centre NHS Foundation Trust, Liverpool, UK, and colleagues, enrolled a total of 94 patients (aged >16 years) with HSV encephalitis, confirmed by cerebrospinal fluid (CSF) PCR, in the trial, and randomized participants 1:1 to an intervention group or control group. The intervention group (n=47; mean age: 64 years; 43% female; 87% HSV-1) was allocated to intravenous dexamethasone 40 mg every 24 hours for 4 consecutive days, and standard care. The control group (n=47; mean age: 67 years; 51% female; 100% HSV-1) were allocated to no drug, and standard care. The primary outcome was an improvement in auditory memory, as determined by the Weschler Memory Scale IV (WMS-IV) assessed at 6 months. Auditory memory is consistently impaired in HSV encephalitis, and often the most severely impaired domain. At Days 1–7, baseline data and baseline biomarker samples were collected, and daily Glasgow Coma Scale (GCS) was measured. At Day 14, a repeat MRI brain scan was performed, as well as a repeat CSF examination for HSV PCR as a safety outcome.

The team found no significant difference in the WMS-IV Auditory Memory Index between the dexamethasone group (mean: 71; standard deviation: 26) and control group (mean: 69; standard deviation: 25; P=0.756). Furthermore, secondary neuropsychological outcomes, such as WMS-IV Visual Memory Index, Immediate Memory Index, and Delayed Memory Index, were not significantly different between the two groups. There was also no difference in MRI scan results at Day 14, with similar percentage changes of total edema, cytotoxic edema, and vasogenic edema between the two groups. Finally, results from the safety outcome showed no increase in detectable HSV in CSF at 2 weeks in the dexamethasone group compared to the control group.

The authors stated that a higher dose of dexamethasone, closer to the dose used for inflammatory disease, or earlier administration, could perhaps have affected patient outcomes, but further research will be required. However, complete lack of signal across any of the parameters suggests that dexamethasone does not improve patient outcomes. ●

"Auditory memory is consistently impaired in HSV encephalitis, and often the most severely impaired domain."

Embolization of the Middle Meningeal Artery to Treat Subdural Hematoma

NEW research conducted by Jason Davies, State University of New York, Buffalo, USA, and colleagues, indicates that embolization of the middle meningeal artery (MMA) with a liquid embolic agent reduces the recurrence rate of subacute and chronic subdural hematomas in elderly patients following surgical operation. These data were presented at the 2024 AAN Annual Meeting.

Subdural hematoma (SDH) is a serious and urgent medical condition that requires emergency surgery, most typically a craniotomy or burr hole surgery. Old age and consumption of anticoagulant medications are risk factors for SDH, and thereby informed the inclusion criteria of this trial.

As one of the most common neurosurgical diseases, with increasing prevalence correlated with an increasing average life expectancy, SDH represents a prominent and growing health concern. Indeed, by 2030, it is estimated that SDH will become the most common neurosurgical disease. Furthermore, SDH has a recurrence rate between 12–20% up to 90 days post-surgery, indicating the necessity of effective recurrence prevention.

In their prospective cohort study, Davies and team evaluated the safety and effectiveness of MMA embolization with a liquid embolic agent in an elderly cohort. The experimental and control arms of the study were divided into those treated with liquid embolic agent alongside standard surgical management, and those treated solely

"By 2030, it is estimated that SDH will become the most common neurosurgical disease."

with standard surgical management, respectively. Homogeneity between the two groups at baseline was extensive, though the prominence of male candidates in both groups (72.6% and 73.4%, respectively) may limit generalizability of the data.

Overall, the results indicated a three-fold reduction in recurrence requiring surgical intervention in the experimental cohort compared to the control cohort (4.1% versus 11.3%; risk ratio: 0.36; p=0.0081).

Davies and team highlighted the potential underrepresentation of this effect due to confounding factors. Some members of the experimental arm were ineligible for treatment with liquid embolic agent on account of dangerous anatomical variants, and three members of the control arm were embolized outside of trial protocol.

Of the experimental cohort, 15.7% experienced serious adverse events (SAE) up to 30 days following embolization and surgery, but none experienced any SAEs related to use of the liquid embolic agent. This figure was greater in the control group, with 21.7% recording SAEs post-surgery. All neurological deaths up to 90 days post-operation were related to SDH alone. Notably, some of the SAEs observed are typical in elderly patients following neurosurgery, although the balance of SAEs attributable to this effect versus the operation itself is unclear. ●

New Frontiers in Alzheimer’s Disease

Authors: Victoria Antoniou, EMJ, London, UK

Citation: Neurol AMJ. 2024;1[1]:17-19. https://doi.org/10.33590/neurolamj/SKOE9169.

THIS YEAR’s American Academy of Neurology (AAN) Annual Meeting, held in Denver, Colorado, USA, from April 13–18, featured an insightful session on Alzheimer’s Disease (AD), hosted by Liliana Ramirez-Gomez, Harvard Medical School, Boston, Massachusetts, USA. The session included fascinating insights into the diagnosis, management, and implementation of new therapies in AD, presented by Ramirez-Gomez herself; Julio Rojas-Martinez, University of California, San Francisco, USA; and Jeremy Pruzin, Banner Alzheimer’s Institute, Phoenix, Arizona, USA.

THE USE OF BIOMARKERS FOR DIAGNOSIS AND STAGING

The necessity of biomarkers in diagnosing AD is often misunderstood outside of the field of neurology, according to Rojas-Martinez. Despite this, he emphasized as he opened his discussion that they are vital when it comes to increasing diagnostic certainty, which helps both patients and their families; planning for long-term care, especially considering the financial and emotional burden of the disease; and guiding therapeutic decisions. Rojas-Martinez went so far as to advocate for biomarkers to always be used in diagnosing AD, saying that relying on clinical assessment alone is not enough.

"The necessity of biomarkers in diagnosing AD is often misunderstood outside of the field."

He went on to discuss the origin of biomarkers in disease diagnosis, before addressing the current available and approved AD biomarkers, including neuroimaging, cerebrospinal fluid, and blood biomarkers. Delving into the specifics of how β-amyloid plaques (Aβ) and tau tangles are analyzed, he highlighted that many of these can

be considered simplistic, limited biomarkers, and, for example, some blood tests involving mass spectrometry, have limited access for patients and practitioners. More analysis methods are constantly being approved, and becoming more relevant as therapies evolve.

Biomarkers are analyzed in those with mild cognitive impairments (MCI) or mild amnestic dementia, as these patients respond to diseasemodifying therapies better than those with later stages of the disease. The same goes for patients with early-onset dementia who are suspected to have AD, as well as those with atypical dementia. Biomarkers, Rojas-Martinez explained, are tested once a patient has received a full evaluation and diagnosis. He went on to describe the process of implementing biomarkers, addressing what can be gleaned from positive tests for AD biomarkers; for example, diagnosing not only AD but copathologies, as well as how to address nonamnestic MCI compared to amnestic MCI.

Interpreting AD biomarkers is not simple; for cerebrospinal fluid biomarkers, for example, several years of research have gone into figuring out that using Aβ42ELISA and TauELISA methods in conjunction yields the highest accuracy. Many other tests will produce equivocal results, which until recently were non-specific, and therefore

not helpful in diagnosing AD. However, newer methods for handling such results have since been developed, and Rojas-Martinez emphasized the importance of relying on ratios in these equivocal situations. The ever-evolving practice of interpreting biomarkers in AD, and the potential for higher accuracy in the future, was underlined as Rojas-Martinez discussed the increasingly important role of blood biomarkers in disease prognosis and staging, along with current and future research, focusing on novel analytical platforms and diverse populations.

EMERGING THERAPIES FOR ALZHEIMER’S DISEASE TREATMENT

Diagnostic methods are not the only area in which AD care and research is progressing. Pruzin’s portion of this enlightening session covered several of the new and emerging therapies for treatment of AD. Some of the treatments discussed were treatments already on the market, such as semaglutide, a hormone that activates receptors in the gut, liver, and pancreas, approved for the treatment of diabetes and obesity. Semaglutide is used to lower cardiovascular adverse outcomes in people at risk, and to stimulate insulin release, as well as restore insulin sensitivity. AD is often associated with mixed pathology, commonly with cerebrovascular disease, and evidence has been found for brain insulin resistance in patients. A retrospective study of the treatment of other diseases using semaglutide showed that patients with the disease were significantly less likely to develop dementia. These results inspired the Phase III

clinical trials (EVOKE and EVOKE+) currently underway to investigate the effectiveness of this drug in treating cognitive disorders, with results expected in 2026.

Pruzin then gave an overview of several other ongoing trials, all in various stages, from early Phase II to nearly approved. Donanemab, for example, is nearing approval, and though the trial was limited by a lack of diverse participants, the drug shows significant clinical cognitive benefits, slowing rate of decline, and driving down biomarkers.

"Prevention goes beyond drug development; however, modifiable risk factors matter."

However, new treatments for existing patients with AD are not the only exciting development, Pruzin was quick to point out. Preventative treatments are also coming onto the market; drugs which have shown benefit in those with early symptomatic AD, including donanemab, are now being given to individuals with brain Aβ but who are cognitively normal, in the hope that it will prevent, or at least delay, the onset of disease.

Prevention goes beyond drug development; however, modifiable risk factors matter, emphasized Pruzin. A large proportion of dementia cases could be delayed or prevented if clinicians addressed several modifiable risk factors, including depression, obesity, social isolation, smoking, diabetes, and hypertension, among others. Several of these can be addressed early in life, from an

educational standpoint, and others at later stages. The importance of this approach was reinforced in Pruzin’s closing statement, as he highlighted the benefits not only of single treatments, but of a combination of treatments, involving pharmacological ones, as well as more lifestylebased methods, both for symptomatic patients, and as a preventative measure for others.

IMPLEMENTATION OF NEWLY APPROVED DISEASEMODIFYING THERAPIES

Development of new medications is only one step in the process of treating AD. RamirezGomez rounded up the individual presentations by elaborating on what neurologists are doing in the clinic to implement these new therapies and monitor patients. Lecanemab, the first diseasemodifying therapy for AD, approved for those with MCI or mild dementia, is now given to patients with AD by clinicians. Due to the nature of the medication, Ramirez-Gomez underscored the importance of knowing exactly what stage of disease each patient is at, in order to treat them effectively. She also pointed out the need for clinicians to be aware of the costs of the treatment for the patient, and how this may affect them.

In order to address this, at Massachusetts General Hospital, the Alzheimer Therapeutics Program

(ATP) has been developed with a protocol for the administration and safety of AD treatment. Patients are referred from several departments, when they show MCI or mild dementia, have had a brief cognitive screening test, a brain MRI, and a continued follow-up plan. The safety of the treatment is monitored, and Ramirez-Gomez emphasized the importance of interdisciplinary work at the program to provide this care for patients. The focus of the program is to provide timely and appropriate treatment for patients with AD, considering the family expectations, costs to the patient, and the effect of treatment on the individual. After the team has confirmed that the patient meets the eligibility criteria and that all their personal factors have been considered, the patient starts lecanemab, and their results are constantly monitored.

Programs such as the ATP demonstrate the rapid development of AD treatment and diagnosis, and as therapies continue to evolve and change, so will the diagnostic tools used in clinical practice, and the approach to treatment taken by clinicians.

Following Ramirez-Gomez’s fascinating talk, the three speakers remained to answer questions on emerging therapies in AD, novel methods for interpreting biomarkers, and the various trials taking place today, as well as those still to come. ●

Emerging Neuroinfectious Diseases

Authors: Helena Bradbury, EMJ, London, UK

Citation:

Neurol AMJ. 2024;1[1]:20-23. https://doi.org/10.33590/neurolamj/TTAH5347.

THIS YEAR’S American Academy of Neurology (AAN) Annual Meeting, in Denver, Colorado, USA, held from April 13–18, 2024, delved into research regarding newly recognized pathogens, and the challenges they present to global health. Discussions explored a range of microorganisms, from viruses to bacteria, fungi, and parasites, each with unique clinical presentations, diagnostic approaches, and implications for public health.

EMERGING VIRUSES

Powassan Virus

Daniel Pastula, University of Colorado, Aurora, USA, opened with three insightful case studies, followed by a vote asking the audience to choose the virus they believed to be the cause of each clinical case. With 64% of votes, the first case study was of the Powassan virus (POWV).

As explained by Pastula, this virus has two main viral lineages, which are clinically and serologically indistinguishable: POW, identified in Ontario, Canada, in 1958; and POW2, identified in Northern Colorado, USA, in 1952.

Notably, POWV cases peak during May/June, with an evident male predominance in infection rates. Its incubation period typically spans 1–4 weeks, with 25% of cases progressing to neuro-invasive meningoencephalitis, carrying a 10% mortality rate and a 50% risk of long-term neurological sequelae. Diagnosis primarily relies on serologic tests, necessitating a screening for POWV IgM followed by a confirmatory POWV neutralizing antibody test (e.g., PRNT).

Unfortunately, as highlighted by Pastula, there is currently no specific disease-modifying treatment against POWV. Alternatively, Pastula shared recommendations to mitigate tick bite infections,

advocating for measures such as wearing longsleeved shirts and pants, utilizing U.S Environmental Protection Agency (EPA)-approved tick repellent, and avoiding densely vegetated areas.

Mpox Virus

The second case study focused on Mpox. This is a double-stranded DNA virus hailing from the Poxviridae family, and is notably large, measuring 200x300 nm, with a genome length of 170–250 kb. It features two distinct clades: I (Central African) and II (West African). Transmission occurs through various means, including direct contact with infected rashes or scabs, respiratory droplets, fomites, or via bites or consumption of an infected animal. Pastula highlighted the 2003 Mpox outbreak in the USA, triggered by the importation of African rodents infecting prairie dogs sold as pets nationwide. Presently, a significant outbreak is underway in the Democratic Republic of the Congo, primarily affecting children in over two-thirds of cases.

Clinical features include an incubation period of 3–17 days and classical symptoms such as fever, fatigue, myalgia, and a widespread vesiculopustular rash, typically lasting 2–4 weeks. Neurological manifestations mainly present as headaches (>50%), with seizures, confusion, and encephalitis being rarer occurrences

(approximately 3%, 2%, and 2%, respectively). Diagnosis primarily relies on PCR testing of skin lesions or fluid by Mpox virus nucleic acid. Several antiviral therapies exist, including tecovirimat, vaccinia immune globulin intravenous, cidofovir, and brincidofovir.

Pastula emphasized the importance of raising awareness to target specific subgroups during outbreaks, as it can prompt people to change their behavior to reduce infection rates. For instance, during a 2022–2023 Mpox outbreak in the UK, infections were notably prevalent among gay males. Upon alerting the community, an online survey was later conducted among gay, bisexual, and other males who have sex with males between August 5–15, 2022. Respondents reported deliberately altering their behavior to minimize the risk of infection. For example, 48% decreased their number of sexual partners, 50% reduced one-time sexual encounters, and an equal percentage decreased sexual activity with partners met on dating apps. These proactive behavioral changes resulted in a decline in cases.1

Japanese Encephalitis Virus

For the third case study, Pastula detailed the Japanese encephalitis virus (JEV), an arthropodborne virus closely linked to Murray Valley

encephalitis, St. Louis encephalitis, Usutu, and West Nile viruses. It primarily spreads through mosquitoes, particularly Culex tritaeniorhynchus, which originates from northern Asia. These mosquitoes thrive in low-lying water-logged areas with a temperature of around 23 °C, commonly found near rice farms, or around pigs and wading birds, acting as amplifying hosts. Diagnosis typically involves testing JEV IgM serum or cerebrospinal fluid (CSF). Although there is no disease-modifying treatment available, Pastula reiterated the importance of using EPA-approved insect repellent, wearing long sleeves, and utilizing air conditioning/screens to deter mosquitoes.

Notably, there was a sudden outbreak of JEV in southeast Australia from February–April 2022, resulting in 37 cases and three deaths. It was found to be linked to pig farms located along the Murray Valley, and extreme rainfall that preceded the outbreak. In his concluding remarks, Pastula urged for continued vigilance and research to better understand emerging viruses, and noted several other emerging viruses such as Bourbon virus, La Crosse virus, Ross River virus, Zika virus, and many others.

"Pastula emphasized the importance of raising awareness to target specific subgroups during outbreaks."

EMERGING BACTERIA, FUNGI, AND PARASITES

Neurosyphilis

Felicia Chow, University of California, San Francisco, USA, subsequently discussed syphilis, citing some troubling statistics; in 2022 there was a total of 207,255 syphilis cases reported in the USA, representing an 80% increase since 2018. Congenital syphilis has also seen a dramatic epidemic; in 2022 there were over 3,000 cases of congenital syphilis, a 10-fold increase from 300 in 2013.

Chow explored the various testing and treatment approaches for syphilis. For instance, there are two types of tests: non-treponemal (e.g., rapid plasma regain and venereal disease research laboratory) and treponemal tests (e.g., treponema pallidum particle agglutination assay and fluorescent treponemal antibody absorption). Treponemal tests detect antibodies specifically against the syphilis bacterium and remain positive for life; whereas,

non-treponemal tests detect antibodies produced in response to infection and may become negative after treatment.

Chow elaborated on the array of treatment options for neurosyphilis, highlighting intravenous penicillin (administered at 18–24 million units per day, given as 3–4 million units intravenously every 4 hours for 10–14 days) as the preferred choice, with ceftriaxone (2 g intravenously daily for 10–14 days) as a suitable alternative. Referring to UK and European guidelines, she underscored that doxycycline is also considered a viable alternative for treating neurosyphilis. Quoting a supporting 2021 retrospective single-center study involving 87 patients (median age: 35 years), she noted that oral doxycycline administered for 30 days may present a reasonable substitute for intravenous penicillin in early neurosyphilis, as evidenced by clinical and serological response.2 Additionally, she referenced a recent 2023 trial, which demonstrated the effectiveness of doxycycline as postexposure prophylaxis in reducing the incidence of sexually transmitted infections, including syphilis, gonorrhea, and chlamydia.3

"In 2022 there was a total of 207,255 syphilis cases reported in the USA, representing an 80% increase since 2018."

Balamuthia Mandrillaris

Cases of Balamuthia encephalitis predominantly emerge from South America (Peru) and the USA, with infection typically occurring through respiratory exposure or skin injury. A total of 109 cases were documented in the USA from 1974–2016, with 68% affecting males and 39% involving individuals with compromised immune systems.4 The subcutaneous presentation can include confusion, fever, and seizures, with many patients also developing a distinct facial skin lesion earlier on as well. Regarding treatment, a combination therapy involving various drugs with proven in vitro efficacy and strong penetration into the central nervous system is typically employed. This treatment regimen, which may include pentamidine, fluconazole, and flucytosine, often extends for a duration of 12–18 months.

Cryptococcus gattii Infection

Finally, Chow delved into Cryptococcus gattii infection, which accounts for roughly 20% of all cryptococcal infections worldwide. This pathogen, associated with trees, resides in soil, bark, and other tree-related debris. Initially viewed as a tropical or subtropical ailment, it is now increasingly recognized as an emerging threat in temperate climates. Moreover, a compelling study linking land use to the rise of C. gattii infections, revealed a direct correlation between deforestation/tree harvesting and the incidence of this pathogen.

References

1. Delaney KP et al. Strategies adopted by gay, bisexual, and other men who have sex with men to prevent Monkeypox virus transmission - United States, August 2022. MMWR Morb Mortal Wkly Rep. 2022;71(35);1126-30.

Clinical presentations often feature a robust inflammatory response, significantly impacting morbidity and mortality rates. Symptoms may include cerebral edema, headache, neck stiffness, encephalopathy, seizures, and cranial neuropathies. Additionally, around 50% of cases present with concurrent pulmonary infections.

While CSF culture remains the gold standard for diagnosis, it can be a time-consuming process, taking days to weeks. Alternatively, the Cryptococcal antigen test demonstrates excellent sensitivity and specificity in blood and CSF for both C. neoformans and C. gattii. However, its sensitivity may be slightly lower in patients without HIV (86% versus 100%).

CONCLUSION

In closing, these talks on emerging pathogens, be that viral, bacterial, parasitic, or fungal, highlight the need for continued awareness and preparedness. By better understanding the complexities of emerging pathogens, and developing effective clinical treatment strategies, we are more equipped for future outbreaks. ●

2. Girometti N et al. Clinical and serological outcomes in patients treated with oral doxycycline for early neurosyphilis. J Antimicrob Chemother. 2021;76(7):1916-19.

3. Luetkemeyer AF et al. Postexposure doxycycline to prevent bacterial sexually transmitted infections.

N Engl J Med. 2023;388(14): 1296-306.

4. Cope JR et al. The epidemiology and clinical features of Balamuthia mandrillaris disease in the United States, 1974-2016. Clin Infect Dis. 2019;68(11):1815-22.

Updated Study Data for Ozanimod in Relapsing Multiple Sclerosis

A summary of selected data presented at the 9th Joint European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)ACTRIMS Meeting held in Milan, Italy, between October 11–13, 2023; and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum held in West Palm Beach, Florida, USA, between February 29–March 2, 2024

Authors: John DeLuca,1,2 Massimo Filippi,3 Ralf Gold,4 Krzysztof W. Selmaj,5,6 Robert Zivadinov7

1. Kessler Foundation, East Hanover, New Jersey, USA

2. Departments of Physical Medicine and Rehabilitation, and Neurology, Rutgers-New Jersey Medical School, Newark, USA

3. Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, Neurorehabilitation Unit, and Neurophysiology Service, IRCCS San Raffaele Scientific Institute, and Vita-Salute San Raffaele University, Milan, Italy

4. Neurologische Universitätsklinik, St. Josef Hospital, Bochum, Germany

5. Centre for Neurology, Łódź, Poland

6. Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland

7. Buffalo Neuroimaging Analysis Centre, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, USA

Disclosure:

DeLuca has received consultancy fees from Biogen Idec, Bristol Myers Squibb (BMS), Janssen Pharmaceuticals, and Novartis; speaker fees for Consortium of MS Centres; and grant funding from Biogen Idec, Canadian MS Society, Consortium of MS Centers, EMD Serono, and National MS Society. Filippi is the editor-in-chief of the Journal of Neurology and associate editor of Human Brain Mapping, Neurological Sciences, and Radiology; has received compensation for consultancy services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, and Sanofi; speaker fees from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen Pharmaceuticals, Merck Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and Teva; has participated in advisory boards for Alexion, Biogen, BMS, Merck, Novartis, Roche, Sanofi, SanofiAventis, Sanofi-Genzyme, and Takeda; has provided scientific direction for educational events for Biogen, BMS, Celgene, Lilly, Merck, Novartis, Roche, and Sanofi-Genzyme; and receives research support from Biogen Idec, Fondazione Italiana Sclerosi Multipla, Italian Ministry of Health, Merck Serono, Novartis, and Roche. Gold has received research support and speaker fees from Abbott, Bayer Schering, Biogen, BMS, Chugai, Eisai, Janssen, Merck Serono, Novartis, Nikkiso Pharma, Roche, SanofiGenzyme, and Teva; consultancy fees from ZLB Behring,

Baxter, and Talecris; and personal stock options in Bayer, Merck, Novartis, Pfizer, and Roche. Selmaj is a consultant for Biogen, Celgene, Genzyme, Merck, Novartis, Ono Pharma, Roche, Synthon, and Teva. Zivadinov has received speaker/consultancy fees from BMS, EMD Serono, Janssen Pharmaceuticals, Mapi Pharma, Novartis, Sanofi, and 415 Capital, and financial support for research activities from BMS, CorEvitas, EMD Serono, Mapi Pharma, Novartis, Protembis, and V-Wave Medical.

Acknowledgements: Writing assistance was provided by Nicola Humphry, Nottingham, UK.

Support: The publication of this article was supported by Bristol Myers Squibb.

Disclaimer: The opinions expressed in this article belong solely to presenters.

Keywords: Brain volume, cognitive functioning, long-term, relapse, relapsing multiple sclerosis (RMS), rebound effect, ozanimod, safety.

Citation: Neurol AMJ. 2024;1[1]:24-33. https://doi.org/10.33590/neurolamj/ZRZL5766.

Meeting Summary

Ozanimod is an approved treatment for relapsing multiple sclerosis (RMS) that has been shown to reduce relapses, new brain lesions, and brain volume loss relative to intramuscular interferon (IFN) β-1a.

This article summarizes the latest data, and several new analyses, of clinical trials of ozanimod in RMS, which were presented at the 9th Joint European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)-ACTRIMS Meeting in 2023, and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024.

ENLIGHTEN is a prospective, open-label study of ozanimod in patients with early RMS (≤5 years after diagnosis of multiple sclerosis [MS]) who have received ≤1 MS disease-modifying therapy (DMT). In an ad hoc interim analysis, conducted after 1 year, cognitive processing speed improved or remained stable in the majority of patients. This suggests that ozanimod may prevent cognitive decline during the first year of use. In addition, decline in whole brain volume (WBV), which is often accelerated in patients with MS, was minimal, indicating that brain volume was preserved during the first year of ozanimod treatment in patients with early RMS.

Final data were presented for the completed open-label extension (OLE) study of ozanimod in adults with RMS (DAYBREAK). Long-term follow-up of participants indicated that the majority remained free of confirmed disability progression (CDP), and a post hoc analysis found no evidence of disease rebound in participants who discontinued ozanimod. Ozanimod was generally well tolerated with sustained efficacy over a treatment period of approximately 6 years, demonstrating a low relapse rate and control of disability progression.

Introduction

Ozanimod is a modulator of spingosine-1-phosphate (S1P) receptor 1 and 5. It is approved in multiple countries for the treatment of adults with RMS or moderately-to-severely active ulcerative colitis.1,2

Four clinical trials of ozanimod in RMS have been completed, including a Phase I pharmacokinetic and pharmacodynamic study,3 a Phase II study with an extension period,4,5 and two Phase III trials.6,7

In the completed Phase III trials (RADIANCE and SUNBEAM), oral ozanimod 0.92 mg/day for up to 24 months was associated with significantly fewer relapses, fewer lesions on brain MRI, and slowed brain volume loss relative to intramuscular IFN β-1a 30 μg/week.6,7 Ozanimod was well tolerated, with fewer treatment-emergent adverse events (TEAE) leading to discontinuation compared with IFN β-1a.

Data from the ongoing Phase III study ENLIGHTEN, and the OLE study DAYBREAK, were presented at ECTRIMS-ACTRIMS 2023 and ACTRIMS 2024.

Interim Analyses from the ENLIGHTEN Study

The ongoing ENLIGHTEN study (NCT04140305)8 is a prospective, multicenter, longitudinal, open-label study in the USA and Canada. It aims to describe changes in cognitive processing speed, disease biomarkers, and patient-reported outcomes, over 3 years, in adults with early RMS treated with ozanimod 0.92 mg.

ENLIGHTEN includes adults aged 18–65 years at screening, with a diagnosis of MS within the last 5 years; ≤1 MS DMT (none within 1 month of enrolment); an Expanded Disability Status Scale (EDSS) score ≤3.5 at screening; no relapses within 30 days before screening; ≤10 gadoliniumenhancing lesions on baseline brain MRI scan; and no history of developmental disorders, or motor or sensory defects, that could interfere with cognitive test performance.8,9

ENLIGHTEN assesses cognitive functioning, in a very early RMS patient population, through the Brief International Cognitive Assessment

for Multiple Sclerosis (BICAMS). The BICAMS is a cognitive battery that assesses cognitive processing speed, auditory/verbal learning, and visuospatial memory via the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test Second Edition (CVLT-II), and Brief Visuospatial Memory Test, Revised (BVMT-R), respectively.10,11 Higher test scores indicate greater cognitive functioning.

The primary outcome measure of the ENLIGHTEN study is the proportion of subjects with improvement in SDMT score, defined as an increase in raw score of ≥4 points or 10% from baseline.8 Changes in CVLT-II and BVMT-R scores were exploratory endpoints.12

An ad hoc interim analysis was conducted after 1 year, with a data cut-off of February 14, 2023. Baseline characteristics of participants with data at Year 1 included an average age of approximately 40 years, approximately 79% were female, and the majority (approximately 88%) were White. Roughly 65% of patients were DMT-naïve. Characteristics varied slightly between analyses, depending on the number of participants with available measurements.9,13

Changes in Cognitive Functioning over 1 Year

Impairments in cognitive functioning can begin in the early stages of MS14,15 and are associated with subsequent disease progression and decreased quality of life.16-18

At data cut-off for the ad hoc interim analysis, SDMT data were available at both baseline and Year 1 for 116 participants, CVLT-II data for 102 participants, and BVMT-R data for 93 participants.12

During the first year of ozanimod use, cognitive processing speed remained stable or improved in the majority (73.3%) of participants (Figure 1).13 Almost half of the participants (47.4%) experienced an improvement in cognitive processing speed. While mean SDMT and CVLT-II scores increased from baseline after 1 year of ozanimod treatment, BVMT-R scores remained relatively stable: least squares mean changes in scores were 3.3 for

SDMT, 3.2 for CVLT-II, and 0.8 for BVMT-R, generated using a mixed-effects model with repeated measures.12

In conclusion, among participants with early RMS, many of whom were DMT-naïve, interim data suggest that ozanimod treatment may prevent cognitive decline during the first year of use.13

Figure 1: Change in Symbol Digit Modalities Test over 1 year of treatment.

Reproduced with permission from DeLuca et al.12

*Improvement was defined as a ≥4-point or ≥10% increase in SDMT raw score relative to baseline.

†Stable cognitive processing speed was defined as <4 point and <10% change in SDMT.

‡Worsening was defined as a ≥4-point or ≥10% decrease in SDMT.

§Generalized estimating equation model.

CI: confidence interval; RMS: relapsing multiple sclerosis; SDMT: Symbol Digit Modalities Test.

Brain Volume Changes over 1 Year

While WBV declines with normal ageing at a rate of around 0.27% per year,19 this decline is often accelerated in patients with MS, and may correlate with cognitive impairment.19,20 Alongside these changes, lateral ventricle volume (LVV) increases with atrophy of brain parenchyma in patients with MS.21

The assessment of brain volume using MRI is a secondary outcome of the ENLIGHTEN study.8 At the interim analysis, MRI data were available at baseline and Year 1 for 101 participants.12

The percentage change in WBV and brain region volumes over 1 year were analyzed using the following methods:9

• WBV: Structural Image Evaluation using Normalization of Atrophy (SIENA).

• Cortical grey matter volume (CGMV): A modified hybrid of SIENA and SIENA crosssectional (SIENAX) methods (mSIENAX multitimepoint).

• Thalamic volume (TV) and medulla oblongata volume (MOV): FreeSurfer open-source brain imaging software.

• LVV: SIENAX at baseline, and the SIENA method to measure ventricular enlargement (VIENA) on 3D T1-weighted MRI at 1 year.

Over the first year of ENLIGHTEN, observed mean changes in brain volume were minimal: WBV decreased at a rate similar to that seen in healthy controls;19 CGMV, TV, and MOV did not significantly decrease from baseline; and LVV did not significantly increase from baseline (Figure 2).9 It was noted that the observed increase in CGMV may suggest a central effect related to ozanimod S1P receptor selectivity.12

In conclusion, these findings indicate that brain volume was preserved during the first year of ozanimod treatment in patients with early RMS.9

New Data from the DAYBREAK Open-Label Extension Study

Participants who completed any of the four RMS trials of ozanimod3-7 were eligible to enroll in DAYBREAK (NCT02576717), a Phase III, singlearm, OLE study of ozanimod 0.92 mg/day.23,24 An interim analysis of the DAYBREAK OLE showed that ozanimod treatment provided sustained control of disability progression for up to 5 years in participants with RMS.25

Figure 2: Change in whole brain volume and brain region volumes over 1 year in patients with early relapsing multiple sclerosis treated with ozanimod 0.92 mg.

Reproduced with permission from Zivadinov et al.22

For least squares mean change, a mixed-effect model with repeated measures was used with the baseline volume, baseline age, and time point (treated as a categorical variable) as fixed effects; and individual patients as a random effect.

Kenward and Rogers’ adjustment for the degrees of freedom was applied.

CI: confidence interval; CGMV: cortical grey matter volume; LS: least squares; LVV: lateral ventricular volume; MOV: medulla oblongata volume; RMS: relapsing multiple sclerosis; TV: thalamic volume; WBV: whole brain volume.

Relapse-Associated Worsening and Progression-Independent Relapse Activity

There are currently considered to be two main mechanisms for the accumulation of disability during the early stages of MS: relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA).26

The Phase III RADIANCE study (NCT02047734)27 was a multicenter, randomized, double-blind, double-dummy trial comparing oral ozanimod 0.46 mg/day and 0.92 mg/day with intramuscular IFN β-1a 30 μg/week in adults with RMS.23 Primary findings from the study indicated that ozanimod treatment was associated with significantly fewer relapses than IFN β-1a.6

In a long-term analysis of participants from the RADIANCE Phase III study who entered DAYBREAK (data cut-off: February 1, 2022), the two treatment groups were those who received continuous ozanimod 0.92 mg/day (n=363) across both studies and those who switched from IFN β-1a to ozanimod 0.92 mg/day (n=346) upon entering the DAYBREAK OLE. Data from this analysis, reported at the 2023 ECTRIMS-ACTRIMS meeting, showed that the two treatment groups had similar demographic and baseline disease characteristics, with a mean age of approximately 36 years. Around 68% of participants were female, and approximately 99% were White.22

Participants were assessed for 6-month CDP, defined as a ≥1-point increase in EDSS score from baseline confirmed at 6 months.23 Participants were considered to have RAW if CDP onset occurred ≤90 days after a relapse, or to have PIRA if CDP onset occurred without relapse or >90 days after a relapse. For any relapse with incomplete recovery, baseline EDSS was reset >90 days after relapse onset, to allow for identification of the next PIRA event.23 In addition, WBV and CGMV were measured using SIENAX, and TV using ThalamicVolume software.22

On long-term follow-up (up to 8 years), approximately 76% of all participants remained free of 6-month CDP (Figure 3).22 Overall, data indicated that RAW and PIRA contributed similarly to disability progression. Of those participants with

6-month CDP who were treated with continuous ozanimod, 44.3% had RAW, 54.5% had PIRA, and 8.0% had both, relative to RADIANCE baseline. 23 Of those participants with 6-month CDP who switched from IFN β-1a to ozanimod, 57.8% had RAW, 43.4% had PIRA, and 4.8% had both, relative to RADIANCE baseline.23

Relative to baseline at enrolment in the DAYBREAK OLE, participants who were treated with continuous ozanimod experienced numerically less 6-month CDP compared with participants who switched from IFN β-1a (14.0% versus 17.9%, respectively). In addition, among patients treated with continuous ozanimod, the proportion of PIRA contributing to 6-month CDP was higher relative to DAYBREAK baseline (70.6%) than in the analysis relative to RADIANCE baseline (54.5%).22

In both treatment groups, EDSS at RADIANCE baseline was positively associated with the incidence of RAW; and WBV, CGMV, and TV thalamic volumes were negatively associated (P<0.05). However, these variables were not found to be predictors of PIRA.23

In conclusion, these data suggest that while controlling relapses is essential early in the MS disease course, other processes such as lesion development and brain volume loss may also be important.22

Absence of Rebound Effect Following Ozanimod Discontinuation

Rebound is described as a severe relapse of disease following discontinuation of therapy. Discontinuation of MS DMT has been associated with a risk of disease reactivation, particularly if treatment with another DMT is not initiated, and some cases have been reported in which increased MRI activity has occurred.28-32 To assess the risk of rebound (characterized by severe disease reactivation and physical disability) after ozanimod discontinuation, an exploratory, post hoc analysis was conducted on data from the DAYBREAK OLE study (database lock April 7, 2023).33

Participants were included in the analysis if they had at least 1 day of post-treatment safety followup in DAYBREAK, and they did not transition to

Figure 3: Time to onset of sustained disability progression: 6-month confirmed disability progression during RADIANCE and the DAYBREAK open-label extension.

*Kaplan-Meier analyses of the intention-to-treat population.

CDP: confirmed disability progression; IFN: interferon; KM: Kaplan-Meier; M: month; PIRA: progression independent of relapse activity; OLE: open-label extension; RAW: relapse-associated worsening.

commercial ozanimod within the safety follow-up period (initially 28 days but increased to 75 days in 2018 and 90 days in 2019).12 A total of 1,679 participants were included, of whom 55 (3.3%) had a known post-discontinuation relapse. The mean ozanimod exposure during DAYBREAK was 61 months.33

This analysis found no evidence of rebound in participants who permanently discontinued

ozanimod: only one patient relapse was reported as severe by the investigator, and most patients who relapsed had an EDSS category change of 0.5 (40.0%) or 1.0 (25.5%). Relapse predominantly occurred during the second and third months after ozanimod discontinuation (median time from last dose to relapse: 61 days), was most common in untreated participants, and was generally mild or moderate.33

In conclusion, most DAYBREAK participants did not have MS disease reactivation characterized by relapses within 90 days of permanent ozanimod discontinuation.

Long-Term Efficacy and Safety of Ozanimod

The DAYBREAK OLE study was completed in January 2023, and final safety and efficacy results of extended exposure to ozanimod were reported at the ACTRIMS Forum (database lock: April 7, 2023).12

Of 2,494 participants who enrolled in DAYBREAK and received at least one dose of ozanimod 0.92 mg, 1,950 (78.2%) completed the study.33,34 Of the 21.8% of participants who discontinued treatment during the study, 14.6% discontinued due to the Russian invasion of Ukraine, and 3.9% discontinued due to TEAEs.12,34 The mean age of participants was 37.7 years, 67% were female, and 99% were White. Baseline demographics and disease characteristics were generally consistent across parent trial treatment groups.12 The mean exposure to ozanimod in DAYBREAK was 61 months;34 while the mean exposure to any dose of ozanimod across the parent trials and DAYBREAK was 75 months, with a maximum of 117 months.12

Ozanimod treatment demonstrated sustained efficacy, with most participants remaining relapse free during DAYBREAK. At Months 60 and 72, 69% and 67% of participants, respectively, were relapse free. Participants who continuously received ozanimod through both a parent trial and DAYBREAK experienced the lowest annualized relapse rate (ARR) compared to other groups. The greatest numerical reduction in ARR from the Phase III parent trial to DAYBREAK occurred among those who switched from IFN β-1a to ozanimod 0.92 mg.12

During DAYBREAK, 17.2% of participants had 3-month CDP and 15.2% had 6-month CDP by the end of the study.34 Across the Phase III parent trials and DAYBREAK together, 22.5% of participants had 3-month CDP and 19.8% had 6-month CDP by the end of DAYBREAK.12

The majority (89.0%) of participants experienced a TEAE during DAYBREAK; 15.3% had a serious TEAE (SAE), and 3.9% discontinued due to a TEAE. Similar

rates of TEAEs and serious TEAEs occurred when assessed by the parent trial treatment group.34

Two participants died due to malignancies during the study; two due to accidents; two due to pulmonary embolism; and one each due to abscess of the right lung, COVID-19, COVID-19 bilateral pneumonia, COVID-19 infection, COVID-19 pneumonia, heart failure, intracerebral hemorrhage, pneumonia, and sudden death.12

Infections were reported in 64% of participants, most commonly nasopharyngitis (21.3%), COVID-19 (16.5%), and upper respiratory tract infection (12.4%); 4.3% of participants experienced a serious infection. Opportunistic infections were reported in 6.4% of participants, most commonly oral herpes (2.3%) and herpes zoster infections (2.0%). Only one serious opportunistic infection occurred during DAYBREAK (progressive multifocal leukoencephalopathy)12,25

Macular edema was reported in 10 (0.4%) participants, of which five cases were confirmed by the Macular Edema Review Panel. Cardiac TEAEs occurred in 103 (4.1%) DAYBREAK participants, 11 of whom had serious events. Absolute lymphocyte count (ALC) <0.2x109 /L was reported in 369 of 2,488 participants with available ALC data, of whom 44 had a consecutive ALC <0.2x109 /L on retest within 30 days.12

Across the parent trials and DAYBREAK together, 50 (1.8%) participants exposed to either dose of ozanimod developed treatment-emergent malignancies, including one with malignant melanoma (0.04%), 17 non-melanoma skin cancers (0.6%), and 31 non-cutaneous malignancies (1.1%).12

In conclusion, ozanimod demonstrated sustained efficacy over a treatment period of approximately 5 years, with a low relapse rate, low numbers of new/enlarging lesions on brain MRI, and control of disability progression. Ozanimod is generally well tolerated, with a small percentage of patients discontinuing treatment due to TEAEs, and it continues to demonstrate a strong safety profile over 5 years1,2,6,7,12

References

1. Bristol Myers Squibb (BMS). ZEPOSIA (ozanimod). FDA package insert. 2023. Available at: https://www.accessdata. fda.gov/drugsatfda_docs/ label/2023/209899s006s009lbl.pdf. Last accessed: 15 April 2024.

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Abstract Highlights

The following highlights spotlight selected abstracts presented at the American Academy of Neurology (AAN) 2024 Annual Meeting. Covering a range of topics, from cognitive decline impacting speech behavior to assisted reproductive technologies in multiple sclerosis, read on for this year’s most innovative new research in neurology.

Citation: Neurol AMJ. 2024;1[1]:34-44. https://doi.org/10.33590/neurolamj/CMMH8341.

How Does Age-Related Cognitive Decline Affect Speech Behavior?

AGE-related cognitive decline leads to greater entropic descriptiveness in connected speech tasks, according to new research presented at the AAN Annual Meeting 2024, held from April 13–18 in Denver, Colorado, USA.

A complex array of cognitive processes is required for speech production; age-related decline slows down these processes, leading to language changes. To address previously conflicting data on the patterns of connected speech in aging individuals, Michael J. Kleiman, University of Miami Miller School of Medicine, Florida, USA, and team, enrolled 53 healthy participants (age range: 55–85 years; mean: 70.3±8.1 years) to measure the continuous trajectory of decline, and examine language changes due to aging.

Participants were administered three connected speech tasks: picture descriptions, narrative recall,

"Participants

and open-ended responses. Transcribed speech was analyzed to produce measures of lexical complexity, lexical diversity, lexical frequency, parts of speech ratios, entropy, disfluencies, and speech rate. Each measure was examined continuously using linear regressions and correlations.

Across all tasks, the team observed increases in entropy and filled disfluency rate, and decreases in closed-to-open class word ratios. They also found increases in adjective-to-verb ratio differences found in picture description tasks.

Post-disfluency latencies and open-class word use also increased continuously.

Overall, the study found that increasing age was associated with a tendency towards less complex language, with a decline in conciseness, a tendency to over-describe, and an increase in processing time when searching for these descriptions. ●

were administered three connected speech tasks: picture descriptions, narrative recall, and open-ended responses."

Suicidal Ideation in Patients with Spinocerebellar Ataxias

PATIENTS with spinocerebellar ataxias (SCA) have been shown to be at an increased risk of suicidal ideation, according to new research presented at the AAN Annual Meeting 2024. Though suicidality has been linked to a variety of neurological disorders in previous research, it has not been extensively studied in individuals with SCAs.

Levi Peppel, Baylor College of Medicine, Houston, Texas, USA, and team, analyzed 781 patients with genetically confirmed SCAs from the Clinical Research Consortium for the Study of Cerebellar Ataxia cohort. They looked at the prevalence of suicidal ideation in those with SCA Types 1, 2, 3, and 6. These results were compared to those of the general population using Fisher’s exact test to generate an odds ratio. The clinical characteristics that may contribute to suicidal ideation included age, disease duration,

"Peppel and colleagues found that suicidal ideation was present in 11.8% of patients with SCAs."

sex, ataxia severity, and Personal Health Questionnaire Depression Scale (PHQ-8) scores, which were measured over a period of 2 weeks.

Overall, Peppel and colleagues found that suicidal ideation was present in 11.8% of patients with SCAs, compared to 9.2% of historical controls from the general population (odds ratio [OR]: 1.32; P=0.002). The group with SCA3 displayed the most prominent cases of suicidal ideation (OR: 1.74; P=0.003). Patients with SCA and suicidal ideation were found to have longer years of disease duration (11.48±6.88 versus 9.93±8.63; P=0.015), more severe ataxia as rated by the scale for the assessment and rating of ataxia (17.40±8.76 versus 12.94±7.83; P<0.001), and more severe depression (10.38±5.72 versus 4.95±4.80; P<0.001) than those without suicidal ideation.

The team concluded that suicidal ideation is more common in those with SCAs than in the general population. This research emphasizes the need for screening suicidal risk as part of the clinical evaluation for SCAs. Earlier screening and increased awareness may allow for earlier intervention, reducing impact on patients and their families. ●

Early Predictors for Future Synucleinopathy Diagnosis

CHANGES in idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) serve as an effective early indicator for manifesting neurodegenerative disorders, even up to over a decade prior to diagnosis, according to new research presented at the AAN Annual Meeting 2024. In patients with iRBD, mild motor and nonmotor prodromal manifestations can already be detected years before a diagnosis of a synucleinopathy, such as Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy.

In the study, 85 people with iRBD (mean age at inclusion: 69.2±8.7 years; 23 females) were followed longitudinally until they fulfilled clinical diagnostic criteria (phenoconversion) for either Parkinson’s disease (n=40), dementia with Lewy bodies (n=39), or multiple system atrophy (n=6). Comprehensive clinical assessments of motor and non-motor symptoms were performed annually, and the range of follow-up time was 1–12 years. Tracing backwards from phenoconversion, clinical outcomes of iRBD were compared with expected

scores for age-matched healthy controls, and between iRBD subgroups, at each time point.

Six years before phenoconversion, motor symptoms and signs showed significant worsening in patients with iRBD compared to healthy aging, while quantitative motor function tests showed abnormalities 4–5 years ahead. Smell showed the earliest changes with detection of hyposmia 11 years prior to phenoconversion. Cognitive impairment and abnormal color vision were identified 5 and 2 years before diagnosis, respectively.

These findings highlight that, in comparison to healthy aging, patients with iRBD showed evident motor and non-motor impairment years before a clinical diagnosis of a synucleinopathy. This underscores the potential for early detection and intervention in patients with iRBD, paving the way for more effective treatments and improved outcomes for those at risk of developing synucleinopathies in the future. ●

"In comparison to healthy aging, patients with iRBD showed evident motor and non-motor impairment years before a clinical diagnosis."

Assisted Reproductive Technologies and Multiple Sclerosis Relapse

RISK of multiple sclerosis (MS) relapse after undergoing assisted reproductive technologies (ART) is low, according to research presented at the AAN Annual Meeting 2024. Previous data showed that there may be an increased risk of relapse; however, newer research suggests this could be untrue. This study, from Ruhr University, Bochum, Germany, investigated whether ART would impact risk of relapse in females with MS, as well as the benefits of maintaining diseasemodifying therapy during ART.

Participants were recruited from the ART and MS sub-registry of the German Multiple Sclerosis and Pregnancy Registry (DMSKW). The team conducted telephone interviews using a standardized questionnaire, which collected data on stimulations, pregnancy, and disease course during and after ART. Annualized relapse rates and relapse ratios were analyzed, comparing

"There was no link between pregnancy and reduced relapse rate."

the 3 months after ART (risk period) to the period 12 months before ART, or between stimulations (no risk period).

A total of 126 females that accounted for 344 stimulations, 229 of whom were under diseasemodifying therapies (DMT; 72.93% first line and 27.07% second line), participated in the study. The team noted relapses after 20 stimulations (5.81%); of these, only seven (35%) were under DMTs, compared to 13 (65%) without DMT (p=0.005).

Use of any DMT during ART was associated with a statistically significantly lower relapse rate ratio. The team, however, did not find age, BMI, disease duration, disease course, stimulation protocol, and ART outcome, to be associated with occurrence of relapse after ART. Notably, there was no link between pregnancy and reduced relapse rate.

The team concluded that risk of relapse after ART is low, and that ART is not linked to an increased risk of relapse. Furthermore, maintaining DMTs was identified as the only modifiable factor linked to relapse risk reduction. These reassuring data emphasize the need to closely manage disease, and counsel regarding pregnancy-safe DMTs throughout patients’ reproductive journey. ●

Phenotyping Multiple Sclerosis with Digital Mobility Outcome Measures

NEW research by teams across the UK, Italy, and Germany, which was presented at the AAN Annual Meeting 2024, has highlighted the effectiveness of using digital mobility outcome (DMO) measures in the phenotyping of multiple sclerosis (MS). Several symptoms of MS lead to loss of mobility, including weakness in the legs and difficulty walking.

Currently, the Expanded Disability Status Scale (EDSS) is used in both clinical settings and research; however, the scale provides no differentiation between disease subtypes, and also does not have an appropriate level of sensitivity to allow the recording of meaningful disease changes. The newly-created unsupervised digital mobility assessment (DMA) has the goal of objectivity measuring the real-world mobility of this patient group.

Mobilise-D is a comprehensive system that monitors and evaluates the gait of patients with MS using digital technologies. Its aims are to substantiate DMOs, and to outline baseline gait quality characteristics in those with both progressive and relapsing MS.

Researchers conducted the largest longitudinal study to date of unsupervised walking in patients with MS. In total, the study recruited 602 adult patients (mean age: 52 years; 64% female) with MS (EDSS score: 3.0–6.5, with 30 days since their last relapse, and disability worsening over the last 2-year period) from four centers across Europe. Six-monthly clinical assessments took place,

followed by a 7-day interval of patients wearing a device on their waist, for a total of 2 years.

"Mobilise-D is a comprehensive system that monitors and evaluates the gait of patients with MS."

To be valid, DMA had to be used for ≥12 hours wear time per day for ≥3 days. A Mann-Whitney U test and Spearman rank correlation were used when apposite (significance: p<0.05). Median EDSS score was 5.0. In the cohort, 10% were diagnosed with primary progressive MS, 35% with secondary progressive MS, and 54% with relapsing-remitting MS.

Baseline DMA data were valid in 92.4% of cases; of these, mean wear time was 6.7 days, with 294 mean walking spells per day. Researchers found that DMOs varied with severity of disease, which was measured with both patient-reported data and EDSS, and also differed between relapsing and progressive types.

Lead study author Gavin Brittain, Sheffield Teaching Hospitals NHS Trust, and the University of Sheffield, UK, underscored the utility of DMOs in this patient group: “Mobility monitoring is acceptable to patients, and can objectively discriminate between patients of different subtypes and disease severity.” ●

Improving Sleep in Neurology Inpatients

TARGETING each cause of sleep deprivation in general neurology inpatients with a combined approach can improve sleep duration and quality, according to research presented at the AAN Annual Meeting 2024. Inpatients get significantly less sleep compared to when they are at home, which can negatively impact their experience and clinical outcomes. Researchers therefore investigated whether this could be improved in the inpatient neurology population.

This study aimed to characterize baseline sleep data, and identify an intervention targeting the drivers of poor sleep in neurology inpatients. The team used patient surveys, actigraphy devices, and direct observation to identify the key disruptors of sleep, and find ways to address these disruptors.

"Main causes of poor sleep included patient discomfort and anxiety."

Data revealed that the main causes of poor sleep included patient discomfort and anxiety, provider-driven interruptions, and lack of provider awareness around sleep deprivation. The team identified three interventions to address

these. The first involved a sleep-friendly order set in patients who are at low-risk for clinical deterioration, which retimed care such as vitals, phlebotomy, neuro checks, and medications to outside of protected sleeping hours, as well as providing standing melatonin, and adjusting delivery of venous thromboembolism prophylaxis. The second was a patient-centric sleep menu offering interactions, such as guided meditation, and comfort items, such as aromatherapy. Finally, for the third intervention, individual sleep reports were created and distributed to clinicians every morning, including actigraphy data and patient commentary on their sleep experience.

The team noted a total sleep duration increase of 75% in patients who received these interventions, on average. Furthermore, actigraphy sleep quality scores increased by 33%, overnight charted interruptions decreased by 51%, and 71% of patients slept at least 6 hours each night, compared to only 25% before intervention.

Researchers concluded that there are multiple factors causing sleep deprivation in general neurology inpatients, and that a combined approach targeting each of these factors improves sleep quality and duration. ●

Exploring Sleep and Pain in Neuropathy

THE RELATIONSHIP between sleep and pain modulation is well-established, with evidence suggesting that treating disordered sleep in patients with neuropathic pain could enhance how they perceive pain. However, according to a study presented at the AAN Annual Meeting 2024, research on the factors contributing to poor sleep, and the social factors influencing the health of patients with peripheral neuropathy, is limited.

In this study, 24 individuals who were diagnosed with peripheral neuropathy underwent a cross-sectional examination to determine the connections between disrupted sleep, pain perception, and neuropathic symptoms. Various validated scales, such as the Pittsburgh Sleep Quality Index (PSQI), the Brief Pain Inventory (BPI), the Pain Catastrophizing Scale (PCS), the Michigan Neuropathy Screening Instrument (MNSI), and the Perceived Stress Scale (PSS) were utilized. Out of the 24 participants, 18 were female (75%), four were participants from a nonWhite background (16.7%), and the average age was 66.9 years (SD±10.5).

Results showed that there was a clear correlation between higher perceived stress, as measured by the PSS, and worse sleep quality, according to the PSQI (p=0.017). Even after adjusting for factors like age, sex, race, and history of major depression, and the PCS and PSS, the cross-sectional association remained significant (p=0.009) in participants with distal symmetric polyneuropathy.

This study underscores a strong link between perceived stress and diminished sleep quality in individuals with peripheral neuropathy. The findings suggest that addressing sleep disturbances that are modifiable could potentially lead to improvements in both sleep and neuropathic pain management. Understanding the root causes of poor sleep, including social determinants of health, is crucial for developing targeted interventions to address both sleep impairment and neuropathic pain effectively. ●

"Understanding the

root causes

of poor sleep, including social determinants of health, is crucial."

Brain Care Score: A Key to Predicting Brain Health

HIGHER Brain Care Score (BCS) mitigates conferred genetic risk of stroke, dementia, and depression, according to research presented at the AAN Annual Meeting 2024. BCS, a 21-point novel tool, encourages lifestyle adjustments to lower dementia, stroke, and late-life depression risks. A lower BSC is associated with a higher risk of these outcomes. The team aimed to investigate whether the association between BCS and outcomes is independent of genetic predisposition for the same outcomes. They also investigated whether improving BCS could mitigate the effect of high genetic risk of the outcomes.

Data from 176,693 UK Biobank participants with primary care records were utilized, with baseline and 12-year follow-up BCS data collected. Polygenic risk scores for stroke and depression were generated using polygenic prediction via continuous shrinkage priors and genome-wide association study summary data. All-cause dementia risk was determined using the APOE gene, stratified by APOE e4 alleles. Sex and ageadjusted Cox proportional hazard models were performed to assess associations between BCS at baseline, and changes in BCS over time.

It was found that participants with high BCS exhibited lower hazards: stroke (hazard ratio [HR]: 0.55; 95% confidence interval [CI]: 0.48–0.62), depression (HR: 0.48; 95% CI: 0.45–0.52), and dementia (HR: 0.80; 95% CI: 0.70–0.91). This was true even among participants with high genetic risk. Similarly, a 5-point longitudinal increase in total BCS during follow-up lowered the risks among those at the highest genetic risk of stroke (HR: 0.69; 95% CI: 0.59–0.81) and depression (HR: 0.57; 95% CI: 0.51–0.63).

"A higher BCS mitigates the conferred genetic risk for stroke, dementia, and depression."

These findings indicate that a higher BCS mitigates the conferred genetic risk for stroke, dementia, and depression, strengthening the case for utilizing BCS as a tool for brain care. ●

Are Patients With Essential Tremor More Likely to Develop Dementia?

ACCORDING to research presented at the AAN Annual Meeting 2024, patients with essential tremor (ET) are three-times more likely to develop dementia than the general population. Although mild cognitive impairment (MCI) as a consequence of ET has garnered growing interest in recent months, Elan Louis, University of Texas Southwestern Medical Center, Dallas, USA, and colleagues, are among the first to identify conversion rates from MCI to dementia in individuals diagnosed with ET.

"The overall prevalence of MCI amongst the experimental group was placed at 26.6%."

The team conducted detailed cognitive assessments of 222 individuals (mean age: 79.3±9.7 years). These participants would, according to their respective performances, be assorted into one of three of categories: normal cognition, MCI, or dementia. Of these 222 individuals, 177 took part in subsequent evaluations at 18, 36, 54, and 72 month intervals,

with the resultant data being compared to that of historical controls and patients with Parkinson’s disease (PD). The results of this study indicated 18.5% prevalence of dementia amongst the experimental group, and a 12.2% average annual conversion rate of MCI to dementia within this same cohort; almost three-times that of the general population, and half the magnitude of the values reported in patients with PD. The overall prevalence of MCI amongst the experimental group was placed at 26.6%, almost twice that of the general population, though not quite as extensive as that found in PD.

Louis and colleagues concluded that the prevalence of, and conversion rates to, dementia in patients with ET exceed those found in healthy individuals, but do not meet the severity found in patients with PD. The lack of corresponding research into the connection between ET and secondary dementia indicates the need for further study to establish the specifics of this relationship. Likewise, the findings of this study indicate the importance of early testing and diagnosis of dementia amongst cohorts with ET. ●

Long-Term Outcomes of Patients With New-Onset

Refractory Status Epilepticus

A RECENT prospective cohort study, presented at the AAN Annual Meeting 2021, has identified positive long-term outcomes amongst patients with cryptogenic new-onset refractory status epilepticus (C-NORSE) following treatment with first-line immunotherapy. Despite the gravity of this condition, comprehensive understanding of the long-term phenotypical characteristics and prognostic markers of C-NORSE is largely incomplete.

"Unfavourable outcomes were correlated with both hippocampal atrophy and extra-limbic lesions."

The study, conducted by Yoonhyuk Jang and colleagues at Seoul National University Hospital, South Korea, examined 74 patients with C-NORSE (median age: 32.7 years [interquartile range: 23.5–47.3]; 36 [48.6%] male), diagnosed according to the International League Against Epilepsy (ILAE) criteria between January 1, 2014–March 31, 2023. Jang and team recorded modified Rankin Scale, Global Assessment of Severity of Epilepsy (GASE) score, seizure frequency, MRI, and serial brain volumetric data from their cohort, and proceeded to prescribe first-line immunotherapy (steroids or intravenous immunoglobulin therapy), following which 83.8% (62/74) of patients regained mental function within a median duration of 30 days (interquartile

range: 14–56). Patients were then examined at 3-month, 1-year, and 2-year intervals.

Jang and peers ascertained a positive outcome (modified Rankin Scale=0, 1, and 2) in 37.1% of 70 patients with C-NORSE 1 year posttreatment, which subsequently rose to 50% of 62 patients with C-NORSE 2 years post-treatment. Unfavourable outcomes were correlated with both hippocampal atrophy and extra-limbic lesions evident 3-months post-treatment (odds ratio: 1.295; 95% confidence interval [CI]: 1.086–1.544; P=0.006) in combination with prolonged (>60 days) unconsciousness (odds ratio: 1.426; 95% CI: 1.101–1.847; P=0.010). Rates of hippocampal atrophy, determined by longitudinal MRI brain volumetric analysis, were found to significantly differ between the ‘favourable’ and ‘unfavourable’ outcome cohorts (β=-44.2; 95% CI: -69.69–-16.71; P=0.002). Notably, Jang and colleagues determined that continuous immunotherapy served as an effective treatment 18 weeks postC-NORSE onset, but were unable to ascertain its efficacy beyond this point.

The team concluded that hippocampal atrophy and the presence of extra-limbic regions serve as poor prognostication factors for C-NORSE. Likewise, continuous immunotherapy may provide an opportunity for effective treatment of C-NORSE 18 weeks post-onset. ●

Interviews

We spoke with Yaakov Stern, Jacqueline A. French, and Chia-Chun Chiang to gain insights into their inspiring careers in research and clinical practice. Topics covered include the cognitive reserve hypothesis, improving clinical trial development in epilepsy, headache in patients with vascular disorders, and artificial intelligence.

Featuring: Yaakov Stern, Jacqueline A. French, and Chia-Chun Chiang

Citation:

Q1Yaakov Stern

Florence Irving Professor of Neuropsychology, Departments of Neurology, Psychiatry, and Psychology, Columbia University Vagelos College of Physicians and Surgeons, New York, USA; Taub Institute for Research in Alzheimer's Disease and the Aging Brain, and Gertrude H. Sergievsky Center, Columbia University, New York, USA.

Citation: Neurol AMJ. 2024;1[1]:46-52. https://doi.org/10.33590/neurolamj/GSLY6570.

After completing your BA in psychology, what inspired you to undertake a PhD exploring cognition in Parkinson’s disease, and subsequently focus your research on cognition in aging?

When I was doing my BA in psychology, I found myself more interested in the research side of the subject; a lot of people who were studying psychology wanted to be therapists, but that didn't interest me as much as the research. So, I found this program called Experimental Cognition that was up at the City College of New York, USA. I applied, and truthfully, I really didn't know a lot about what they were doing in the program. There were two things going on: there were people

doing rat research, and then there were people doing something called neuropsychology. At that point, neuropsychology was a relatively new field, and I became very interested in it. I started to learn how to test patients.

"When we started, Alzheimer's disease was considered a very rare disease."

In my second year or third year, they brought in a new professor, Jeff Rosen, to work with the graduate students that were interested in

neuropsychology. Rosen told me that in Boston, his student had been working with Richard Mayeux, a neurologist who had done his residency at the Columbia University Irving Medical Center in New York. Now, he had just come back to New York, to Columbia University, as a new assistant professor. Rosen suggested that I meet with him, and we started working together. At that point, Mayeux was studying depression and Parkinson's disease. I was good with statistics, and I offered to help him with his data, which included cognitive testing. I started to realize that while the people with mild Parkinson's disease were well functioning, they had subtle cognitive deficits. That was a very new and controversial idea at the time, and it drove the studies that I did for my doctoral dissertation.

Mayeux and I continued studying Parkinson's disease. And then, there was a point in time where the world began to realize that Alzheimer's disease was very prevalent. Alzheimer had described dementia that is seen in younger people; and older people who had severe cognitive problems were not recognized as having Alzheimer's disease. But suddenly, several investigators were showing that these people had amyloid plaques in their brain, and they had the same kinds of brain changes that Alzheimer's had

described. So, we were pushed by the field to move towards studying Alzheimer's, and that research set me up for a lot of the work I did subsequently.

This was in the 1970s? It sounds like you were right at the forefront of all these major advancements.

It was; it's hard to think of it now, because everyone recognizes Alzheimer's disease not just as a prevalent disease, but as such an important one to research. However, when we started, Alzheimer's disease was considered a very rare disease. Once it became clear that that was not the case, The National Institute on Aging (NIA), which supports research in the USA, started to push very hard for research in the area, because they realized that this was a major problem.

Q2You have championed the cognitive reserve hypothesis to explain the individual differences in performance and deficits resulting from neuropathological insults. Can you give a brief overview of the hypothesis?

I first thought about cognitive research in the context of Alzheimer's disease, where we know that there are underlying pathologies, including

"Cognitive

reserve suggests that, when people begin to develop Alzheimer's pathology, some can cope with that pathology better than others."

plaques and tangles caused by amyloid and tau. As these pathologies get worse, a person starts to have cognitive problems. The concept of cognitive reserve suggests that some people can cope with those pathologies better than others; you could have two people that could have the same amount of plaques and tangles, and one would have more cognitive issues than the other.

One observation that sparked my interest was made by Robert Katzman, who was very influential in publicizing the idea that Alzheimer's was a prevalent disease. He was following elderly people over time and was doing autopsies on them when they died. He wrote a paper about 10 women who were cognitively normal while they were alive, but their autopsies found that they had a lot of amyloid in their brains, and he was wondering how that could be. What he speculated was that they had larger than average brains, and that somehow allowed them to cope with that pathology better. He called that brain reserve. That's a concept that is still prevalent today, and there's another related concept called brain maintenance, where some people maintain their brains better than others, allowing them to age more successfully. But I thought about it in a different way; I thought that maybe two people could have the same amount of Alzheimer's pathology, and one could show less cognitive change than the other, because some aspect of their cognitive functioning in some way allowed them to cope with the pathology better. I did a few early studies confirming that idea, which I called cognitive reserve in contrast to Katzman’s brain reserve.

The concept of cognitive reserve suggests that, when people begin to develop Alzheimer's pathology, some can cope with that pathology better than others. Similarly, even in normal aging, there are brain changes that occur throughout our lifetime. Those changes in the brain cause the cognitive changes seen in normal aging. In both normal aging and dementia, cognitive reserve moderates the impact of brain changes on cognitive changes.

Q3How has research in this area developed over the course of your career?

You start with an idea. In the beginning, the goal was to try to firm up this concept. In the first paper I wrote on this topic I explored this idea: if you had two patients with Alzheimer's disease who had the same level of cognitive and functional problems, and one had higher and the other had lower education, a proxy measure of cognitive reserve, the person with higher education should have more plaques and tangles in the brain. However, we didn't have the kinds of autopsy studies that are quite common now to do that. We were doing a study of patients with Alzheimer’s disease where they were receiving a brain scan that measured the severity of their Alzheimer's pathology. We matched patients for clinical severity and showed that the people with higher education had indication of more advanced pathology. So, this study showed that the patients with higher education could cope with Alzheimer’s disease pathology better. That was the first paper I published on this topic. We also tried to look at it in different ways, using epidemiologic approaches. One study showed that people with higher educational attainment had less risk of developing Alzheimer’s disease over time. Another showed that in healthy elders without dementia, those with higher education or IQ showed less cognitive decline over time. Once the concept was confirmed, then we started to ask questions such as: “How does it work?” and “What's going on in the brain that allows some people to cope better than others with age-related changes or disease pathology?” It's one thing to say that people with higher education or higher occupation do better, but what's going on in their brains that allows them to do that?

This was right around the time when people started doing functional MRI (fMRI), a technique where you can actually look at the areas of the brain that are involved in that task and look at the degree to which those areas are used. I was very taken up with the idea that I could use fMRI to understand the neural implementation of cognitive research. That's something that I'm still doing today. What's fun about research is that one question leads to another.

Q4

What are the key take-home messages from the recent paper you co-authored entitled, ‘Brain reserve affects the expression of cognitive reserve networks?’

This is the other side of cognitive reserve. Cognitive reserve is a very hopeful concept; there are things that we do across the lifespan that can help us age more successfully and allow us to deal better with disease pathology, and it's not just education and occupation, which I previously mentioned. Throughout the lifespan, there is a whole set of exposures that impact reserve: the environment we grow up in when we're children, the kind of schools we go to, the kind of jobs we have, our leisure activities, and whether we exercise. So, it's a very positive concept.

"I think that we understand cognitive aging quite well, but we still don't understand it completely."

The truth is that you can have the most brilliant person, and if they develop severe Alzheimer's disease pathology, they're going to lose cognitive function. We have been able to show that they can cope with the pathology longer, and once they get it, they have Alzheimer's for a shorter amount of time, because the disease is so severe that it progresses more rapidly. However, we have never done a study to understand how the brain changes that occur in normal aging, or Alzheimer's disease, impact on the cognitive reserve networks themselves. So, this latest paper talks to the point that age- or disease-related brain changes can impact the cognitive reserve networks as well.

Q5With over 700 publications, and four decades of experience, in your opinion, what are the unmet research needs that should be addressed to further understand cognition in normal aging and Alzheimer’s disease?

Any information just opens up new questions. I think that we understand cognitive aging quite well, but we still don't understand it completely. Over time, there are new techniques, like fMRI,

that you can use to study aging and dementia. But there are always new things that you can add into your research, and different questions to ask. There are now things we can do that we just couldn't do before. When I first started, we didn't know whether someone had pathology in their brain until they’d had an autopsy, but at some point, they developed PET scans and PET tracers that allow you to see whether someone had amyloid plaques or tangles in their brain during life. Those are the two big, bad actors in Alzheimer's disease. Now there are also bloodbased biomarkers. All of a sudden, we have gone from an extremely expensive PET scan to a relatively inexpensive blood test, which allows us to look at those kinds of pathologies and see the presence of them very easily. The field is expanding tremendously, and that opens up new research opportunities. Now, for example, we're working with someone who can take blood and do what's called exposomics. This allows you to get a record of any kind of pollution or any exposure someone has had to a bad chemical throughout their lifetime. We can then relate those measures to brain and cognitive changes. And I'm just touching the surface, there's always more to do.

The other thing that I've been interested in for a very long time is the large variability in the presentation and course of Alzheimer's disease. It's quite typical for people to have a memory problem, although Alzheimer’s doesn't always start that way. However, some people with Alzheimer's disease also have what are called delusions; they have strange beliefs, like someone is stealing from them, whereas others don't. Some people have sleep problems; some don't. Some people have depression; some don't. These differences in the disease presentation are associated with variability in how it progresses.

Q6

What is the Reference Ability Neural Network Study? What are the aims of this study, and what does your role as Director entail?

The Reference Ability Neural Network is aimed at better understanding the cognitive changes in normal aging. The term ‘reference ability’ is

"There are a lot of people who die with some pathology but were never affected by the disease. The reserve puts off the onset of the disease."

interesting. An investigator named Tim Salthouse examined multiple cognitive tests in elders followed over time and suggested that we could summarize cognitive aging into four domains: memory, reasoning, speed of processing, and vocabulary. He called these reference abilities. With fMRI, we can look at the networks underlying any cognitive task. I wondered whether we could do the same thing that Salthouse did using imaging: could we summarize cognitive changes, but on the imaging level? Salthouse showed that many memory tasks can be summarized into this one variable: can we take the imaging data from three memory tasks and find a common task-related activation pattern in the brain that underlies them? This would be a reference ability neural network. That's the basis for the title of the project.

What it's turned into over time is a large study of cognitive aging. We started with about 500 people aged 20 to 80 and have followed them. We have completed 5-year follow up, and now we're

doing a 10-year follow up. We do a lot of cognitive testing, but we also measure the structural changes in the brain. As we age, our brains shrink, and the white matter that connects things gets affected. There are all these things that we can measure with imaging.

I think the thing that many people don't realize is that cognitive aging is not just something that happens in older people. We see changes in cognition and memory from ages 20‒25. This does not happen to everybody, but on average, people are getting a little worse over time. Because we have these longitudinal data, we can use our data to ask important questions about the causes of cognitive aging. It also helps us with our cognitive reserve studies as well, because it gives us a basis where we have 5- and now 10-year changes in the same people; we can see the changes in their brains in terms of atrophy and the like, or whether they're developing Alzheimer's pathology, and at the same time, we can see changes in cognition.

What moderates those changes is the cognitive reserve question.

Q7

What are some of the nonpharmacological and preventative brain health interventions that can be implemented to help reduce the risk of developing cognitive impairment, or improve cognition as we age?

There is a lot of research that has been done, and there are some good answers to that question. It's been quite clear that something like the Mediterranean diet is very helpful, and so is exercise. Both help to maintain the brain. Then, there is a whole set of variables, a lot of which I’ve spoken about previously. In younger people, the nature of their education and cognitively stimulating activities they were exposed to, contribute to successful aging. In older people, being active in some way is useful. This doesn't mean taking a course in particle physics, but just being active, with whatever people enjoy doing. In middle age, the kind of work people do really makes a difference. Some work is more physical, and some is more interpersonal or cognitively demanding. Engaging with people and having social networks are also useful. There's a whole set of things that seem to be very useful for promoting successful cognitive aging. I always try to be careful when I talk about this; doing all these things doesn’t mean I won't

get Alzheimer's. If you do develop the disease, it is going to win at some point. However, there are a lot of people who die with some pathology but were never affected by the disease. The reserve puts off the onset of the disease.

Q8Biomarkers for the diagnosis of cognitive disorders are becoming more prevalent. Are there any biomarkers in particular that you are excited to see utilized in the future?

We have biomarkers for Alzheimer's changes, such as plaques and tangles, including amyloid and tau, as well as biomarkers for other aspects of the disease. This allows us, in a relatively inexpensive way, to understand to what degree cognitive changes are associated with those pathologies, as opposed to what I would call normal aging and the normal range of changes that occur in aging. So, that's been very powerful. It has also changed the way people think about Alzheimer's disease. With most diseases, you talk about the problem that you have in the body or brain; not the outcome of that problem. More recently, there have been proposals that Alzheimer's disease should not be based on cognitive or functional changes, but whether people have amyloid and tau in the brain. But for me, I think it allows us to measure something that we just didn't have before. And, as I mentioned, there are unbelievable amounts of things that now,

with these blood-based measures you can look at, such as seeing all the chemicals people have been exposed to. There are others that give us hints about lifelong diet. There are several measures that use blood-based analyses to look at the rate of aging. There are just tremendous numbers of things you study.

Q9

The field of artificial intelligence (AI) has exploded in recent years. Do you think there is a role for it in predicting and identifying patients at risk of developing Alzheimer’s disease, or stratifying when patients are likely to develop certain behavioral, psychiatric, or cognitive features?

I think so. Statistics have become much more sophisticated and can really capture numerous variables. There are many kinds of analyses one can do, especially if you have a lot of data and a lot of people. This is very different from when I started. AI is another powerful way to deal with large amounts of information. It's not a magic bullet; but I would not be surprised if, over a short amount of time, new and unique kinds of relationships are discovered with it. It's just a matter of having the right data to evaluate.

Q10Are you using AI currently?

No. I work with people who are using AI, and approaches close to AI for quite a while. Now, again, it's a matter of having access to very, very

large datasets. And then hopefully, you'll discover something new.

Q11To conclude, what are your hopes for the legacy of your work, and what direction would you like to see it taken in the future?

My work in cognitive reserve has been very satisfying. I think it's an accepted concept. I've worked with people for a long time on coming up with consensus definitions for these types of concepts, and I think these are now built into people's thinking about aging and dementia. When you start to do research, especially where I am at Columbia, where there are so many amazing researchers around, it's sort of like being a kid in a candy shop; there are so many things going on, and so many new ideas. There are things that you really want to do, and there's only so much time to do them. The kind of things we're thinking about right now include approaches to perhaps imparting cognitive reserve in people. There's a technique called transcranial magnetic stimulation, a way of stimulating the brain. Can we use that to modify existing brain networks in order to impart reserve?

The way that a researcher’s life, like mine, is set up is, you need grants to support projects, and then you need to make those projects work. In some ways, the legacy that you leave is the early ideas you helped promote and the papers that you write. Hopefully, those ideas and papers are useful to others in helping them design research that will make more contributions in the future. ●

Q1

Jacqueline A. French

Professor, Department of Neurology, Comprehensive Epilepsy Center, NYU Grossman School of Medicine, NYU Langone Health, New York, USA

Citation: Neurol AMJ. 2024;1[1]:53-59. https://doi.org/10.33590/neurolamj/FSDQ4926.

Neurology covers a broad spectrum of disorders. How did you come to specialize in the field of epilepsy?

I feel like epilepsy is the ‘window’ into the brain, because when people have a seizure, their onset tells you a lot about that area of the brain, and the way people describe their seizures is so interesting. What other field can you go into where you hear people describe: “At the beginning of my seizure, I hear all the music in the world at once?”

In addition, epilepsy has so many facets, that you can go down a number of different pathways depending on your interests. If you're interested in pharmacology, phenomenology, patient outcomes, surgery, devices, electrophysiology, neuroimaging, and I can continue to go on, all of those touch on epilepsy.

Finally, I think another really important thing is that, not only can you make a profound difference in people’s lives, but the therapy for epilepsy is not rote. You have to really take the person and the options for therapy into account. There is a lot of individual decision-making between you and the person you are treating. I really like the fact that the relationships you make with people can last for decades. I started seeing people as young as 8 years old, and followed them into their 30s. So, that's a lot of evolution, where you see the impact of the disease on people at different stages in their life. That part is quite fascinating to me, and also quite rewarding.

Q2

You are Founder and Director of The Epilepsy Study Consortium (TESC). What inspired you to set up this academic group, and how has the group directly impacted clinical practice and patient outcomes?

The TESC is a non-profit that tries to work with people who are developing either new therapies or new diagnostics to improve the conduct of trials and development, and speed therapies in the right direction for people who need them. There are probably two main impetuses for starting it over 15 years ago. First, back in the 90s, you could maybe run an epilepsy trial with 10 centers, all of them being the most prominent centers in the field, and each of the centers would enroll 10 patients or more. A decade later, when new therapies were available and had made an impact on people, and therefore seizure frequencies were lower, it would take 100 centers. Now, it takes more like 300 centers. The number of individuals that each center can enroll has dropped, and that means there are so many centers that can't be the experts. And so, they needed some assistance in terms of finding and enrolling the right patients, because as this was happening, noise was building in the system, and the placebo responder rate was rising. We actually lost a drug or two that I think were effective drugs, because the placebo response overwhelmed the treatment effect. I think we have good reason to believe that by adjudicating patients, and by training all of the sites on the type of patients they should enroll, we're keeping the placebo rate down, and we're increasing the purity of the signal, so that people

can really understand whether a drug is beneficial or not.

I think the other real impetus was that, back when I started doing trials, the operations part of the study was handled in-house by companies. As time went on, that was divested, and Contract Research Organizations came in, and these are not epilepsy experts. A lot was lost in translation. We felt that there needed to be some sort of intermediary there, who cared about what the outcome of the study was, that it was positive, and that the signal was true. Now, we are adjudicating for scores and scores of studies, both in the pediatric and adult realms. I do believe that the impact of the consortium has allowed new therapies, not only to get to the clinic faster, but to get to the clinic for the right indications; and again, for the study results to be interpretable, the signal to be more pure, and the placebo rate to be a little lower than it otherwise would be.

It has been extremely rewarding, and I think it's rewarding for the people who work there. We are a small group, but we have seven people now

working in the consortium. My executive director reminded me the other day that in all of the duration of time that the consortium has been in existence, not one person has left for another job.

Q3

You are also Chief Medical Officer at the Epilepsy Foundation. What does this role entail, and what are your hopes for the future direction of the organization?

I think that, working with the Epilepsy Foundation, I always keep the person with epilepsy, and their family, very foremost in my mind. I work primarily with the research group at the foundation, and we run a couple of meetings that really tie in well with the other hat that I have, at TESC. So, this allows us to sit at the table with the innovators of the drugs, the U.S Food and Drug Administration (FDA), potentially other agencies that are relevant, as well as the patient voice, very importantly, to make sure that all of those are incorporated into thoughts about improving development, and both what the patient’s need is, and what the family’s need is.

"The impact of the consortium has allowed new therapies, not only to get to the clinic faster, but to get to the clinic for the right indications."

We just started a second research roundtable, for tracking and monitoring devices; right now, there is an explosion of devices, because people with epilepsy can't really track their seizures very well. They may be unconscious, they may forget about the seizure, and if their loved one is not standing right next to them, then the loved one is constantly anxious that the person is having a serious seizure, and that there might be life-threatening consequences. So there is an urgent need for the ability for a device to either count seizures, or detect seizures, and then alert someone if it's a serious seizure. Companies are really struggling right now in terms of how they are actually going to get to market, and how they are going to get reimbursed once they get to market. We have a second roundtable where we're bringing not only the FDA, which is a really important aspect about how they get approved, but also payers, like Medicaid, Centers for Medicare and Medicaid Services (CMS), and others that ultimately have to see the value of these interventions. So that is going to be very exciting as well; we have 27 companies for the monitoring and tracking roundtable, and we have 29 companies for the therapeutic roundtable, which just demonstrates that there's an enormous amount of activity in the field.

On top of that, our new initiative at the Epilepsy Foundation is that we are starting a patient

research bootcamp. The idea is that we will bring in all varieties of voices from the community, including those from underrepresented communities, and explain to them a little bit about research, clinical trials, and the FDA, and turn them into research ambassadors. They will then be informed and able to contribute more, not only to telling the FDA and other organizations necessary things, but also to going back and talking to their own communities about why it's important to enroll in trials, and why it's particularly important for underrepresented communities to be represented in trials. We're very excited about that initiative.

Our research roundtable also includes representatives from the other major players in the field, such as the American Epilepsy Society (AES), Cure Epilepsy, and the Rare Epilepsy Network, so that we can incorporate all voices into the considerations during each of these initiatives.

Q4A novel way in approaching the treatment of epilepsy is to work towards disease-modifying therapeutics. What are the challenges associated with this type of therapy for epilepsy?

We're all extremely excited about the fact that disease-modifying therapies are in the clinic as

we speak, both for rare and common epilepsies. These trials will take an extremely long time. Usually, particularly for the non-seizure outcomes, it may take a year before you get to a point where you can measure a difference. One issue is that if you do a placebo-controlled intervention, you can't ask somebody with active epilepsy, with so many therapies available, not to change any therapy for a year, particularly children. We're considering enrolling children as young as 1, 2, or 3 years old; they will not have had time to fail all of the appropriate therapies that are available, and if they get randomized to the placebo arm, you can't just say: “Okay, this child is now doomed to spend maybe 25% of their life waiting to find out whether they were enrolled in the active arm.” And of course, the active arm might not work.

We have to find ways to look at the seizure outcome in a shorter term, and then the non-seizure outcomes in a longer term. That's something that we discussed at a previous research roundtable a few years ago on anti-epileptogenesis and diseasemodifying therapies, in anticipation that they would be coming very soon. It was really interesting to hear our perception, even in terms of vocabulary: “What does disease modification mean? Does it mean anything?”

I think the other major challenge is that, particularly in the rare epilepsies, which tend to be in the category of what is called developmental and epileptic encephalopathies, often as a result of a monogenetic mutation, the children present with an enormous variability, both in symptomatology and severity. If we are trying to enroll them very, very early, we may not know what their course would be, even without therapy. So, we hope that variability, in what is likely to be very small trials, will not prevent us from reaching a positive outcome.

There have been circumstances in diseases where the FDA has said, “You can compare against a natural history,” but in those cases, they actually usually want a circumstance where children who are receiving the drug, for example, achieve a milestone that children who don't receive the drug never achieve. So, if you look at a disease where a child will never walk, and now they walk, you can compare it to natural history;

but when you have variability, then it's very difficult to say: “Okay, no child will ever do X, Y, or Z.” So we have to really seriously consider that there may be things that we find, and we have to make sure that we identify them properly so that they are acceptable endpoints.

Q5Currently, artificial intelligence (AI) is a hot topic across multiple medical and surgical specialties. Do you see a role for AI in diagnosing or identifying those at risk of developing epilepsy?

There are many groups that are currently investigating this. One problem I see with diagnosing epilepsy, is that somebody has presented to the medical system, and I'm trying to decide if they had a syncope, an epilepsy, or a migraine. There is a problem there, but another problem is that many people with epilepsy don't realize that what they're having is an epileptic seizure. When I talk to people about that, I say that the lay person with epilepsy only understands what I call the ‘television’ seizure, which is where you fall on the ground, you shake all over, and you’re frothing at the mouth. And most epilepsy starts not with the ‘television’ seizure, but with more subtle seizures, where you may have just a little bit of confusion, or déjà vu, or some strange twitching of your mouth; and people do not even present to the hospital, so it's hard for AI to diagnose them.

A potential role is that when people try and Google those symptoms, epilepsy doesn't even come up, so if there was some way that AI could identify what people are googling, and say: “Consider going to a neurologist for the symptoms,” that might help. I Googled ‘dreams while awake’ and I found a website called ‘The Doctor’s Lounge’, where people were talking about their symptoms. There was a person who was describing what I, as an epileptologist, was pretty sure was a seizure. And what I was very impressed with is that there were 100 people below saying: “Oh, my goodness, I have that too. You just described exactly what I have.” So it's definitely out there.

I think the future will bring something at some point, but how to implement and train an algorithm for that will be quite challenging. There are also algorithms underway in the epilepsy space for differentiating seizures. A colleague of mine is using AI for differentiating epileptic from nonepileptic seizures. There are also other people who are working on algorithms, once epilepsy has been diagnosed, to differentiate whether an individual is going to have an easy course with treatment responsiveness, or a difficult course, because sometimes identifying treatment resistance, or inability of treatment to control the seizures, can take 2 or 3 years to conclude. In the past, I worked on the definition of treatment-resistant epilepsy, and it requires failure of two drugs, because a percentage of people can respond to the second that didn't respond to the first, but that means that there's a long delay. If you could identify them early, then you could give them maybe slightly more risky therapies, but therapies that are more likely to intervene or be successful under those circumstances. So, we're working on all of those things with AI.

"90% of people with epilepsy never see an epilepsy specialist."

Q6

Having received multiple awards, including the 2017 American Epilepsy Society (AES) Lennox Award; co-authored over 200 publications; contributed to several novel clinical trial designs; and presented on the topic internationally, where do you see yourself in the next 5 years?

I'm going to continue to do the things that I'm doing, and the things that I am excited about. One of the things I think was most rewarding for me, in my academic role, was working on The Human Epilepsy Project, which includes three related studies that followed different groups of patients over a long period of time to see what their outcome was. We did one in newly diagnosed focal epilepsy, one in treatment-resistant focal epilepsy, and a third in generalized epilepsy. What really interests me is

how the selection of therapy is so individual, and how we can do better at getting people to the right outcome faster, because sometimes it takes so long; and there are ways to do that with AI. But I am also very concerned that all of those three studies were done at academic epilepsy centers, because that's where we enrolled patients, and 90% of people with epilepsy never see an epilepsy specialist. I know from my role at the Epilepsy Foundation, a lot more now than I ever did about how people with epilepsy receive care when they're not being seen by a specialist. So, I think my goal for the next 5 years and beyond is to figure out ways to improve the care of epilepsy beyond the epilepsy center. We can spend 90% of our dollars spent on epilepsy on the 10% most sick, whereas we spend very little money, attention, or time on the 60% that actually have a fantastic opportunity to get on the right drug and lead a perfectly normal life, so I would like to focus on that.

Q7

One recent paper you co-authored was an International League Against Epilepsy (ILAE) position paper looking at the terminology used to describe medications in epilepsy treatment. What are the take-away messages for healthcare professionals from this review?

I think everybody in the epilepsy community has already switched over, they switched over even before the official wording change from “Antiepileptic drug” to “anti-seizure medication” was official. We think it's a really important change, because anti-epileptic drug implies that the drug is treating the epilepsy, and that is also an implication that seeps down into conversations with patients. If patients understand that their epilepsy is being treated, then they may not understand that medication is needed every day, forever, potentially in some cases. The way I try and describe it to my patients, as I tell them about the new wording, is to imagine the difference between having pneumonia, and treating the pneumonia, versus giving cough medicine. Antiseizure medicines are basically like treating the cough, where the seizure is the cough. Seizures can be caused by any number of different things, and these medications, whether you have epilepsy or not and you're just temporarily at risk for

"I’m a huge proponent for discussing adherence with patients, and I don’t think that it’s discussed enough."

seizures, will suppress the seizure itself. You may get benefits from not having seizures in terms of your cognition and ability to function, but it is not a treatment for the underlying disease. Now we have to decide what the name of the other medication group is, that actually can modify the disease. We thought about disease-modifying epilepsy medications, or DMEMs, but we have to meet as a group and decide on an official name.

Q8You previously chaired the American Academy of Neurology (AAN) and the AES committee that developed guidelines for the treatment of both newly diagnosed and treatment-resistant epilepsy. How did you become involved with this, and as Chair, what were your responsibilities?

It was probably one of the more formative things I did in my career. Very early on, when I was a junior faculty member, somebody from the AAN who was then Chair of the Guideline Committee, came and gave a talk at the University of Pennsylvania, Philadelphia, USA, which is where I was, and I was really interested in the process. I was concerned that maybe they didn't have epilepsy expertise on the committee, so I sort of very brashly went up and said: “You should probably include an epileptologist.” So, I got on the committee very early, worked on the guidelines for anti-epileptic drugs, which of course, were widely disseminated and widely used. Ultimately, I stayed on the committee, became the Co-Chair, and then stayed on after that, so it was a very long period of time.

I saw lots of evolution of the committee, and it's evolving even more now. It was a really good opportunity to learn two things. One, is that I learned some of the methodology that I really needed to learn, because, unlike today, when everybody gets a Master's in clinical investigation, back in my day, there was no such thing, so you had to get your learning elsewhere. And this was like a Master's in clinical investigation,

because there was an enormous attention to all of the different aspects that made a study high quality. On the other hand, I also learned that a randomized, placebo-controlled, highly rigorous trial can only get you so far; and it doesn't tell you the whole truth. The whole truth has to come from elsewhere as well. One of the things that I repeat over and over again is, if you think about a randomized, placebo-controlled trial, the best scenario where that would be useful is what I call the ‘seatbelt example’, where there is just one thing you want to know: is it better to do it, or to not do it. For example, either use a seatbelt, or don't use a seatbelt. If you use a seatbelt, you reduce death; therefore, we should use it.

On the other hand, at least in epilepsy, and in many fields now, it's not the seatbelt, it is more along the lines of: “How do I get from New York to Washington, with the choice of a plane, train, car, or bicycle.” You could do a study of a bicycle to get there, or no bicycle to get there, and you could say that a bicycle gets you to Washington, but that doesn't mean that that's the best way to get there. Then if you consider that you personally own a car, maybe a car is better for you, but somebody else doesn't own a car, or somebody's claustrophobic, or somebody has to get there faster. When I say a plane gets you to Washington, this is how much it costs; this is how long it takes; and it's better than no plane, how does that tell me how I personally should get from New York to Washington? That is the constant struggle with guidelines. It's so fascinating that the language is proscriptive and pre-determined. If something is positive in a placebo-controlled trial, if it's very high quality evidence, the language used in guidelines says that you must offer it. It doesn't say you must offer it only if it seems like it's a good idea. If it's slightly lower level evidence, the language suggests that you may offer it. But I always thought, are you supposed to stand in front of a person with epilepsy and say: “There are 20 drugs that I must offer you?” Guidelines may suggest the three newest, or disease-modifying treatments, but

this doesn’t mean that those that aren’t on the list shouldn’t be offered. It becomes complicated, and guidelines are evolving. They are much more nuanced than when I first started, and they need to continue to evolve.

Q9Finally, what do you feel are the unmet needs that require further research or attention to advance patient outcomes in the future?

Top on the list is trying to put together a roadmap for the non-epilepsy specialist to advise on the things they need to do in order to give the best care to someone with epilepsy, as it’s very difficult for them to find that information in terms of diagnosis, treatment, and other things such as

adherence. I’m a huge proponent for discussing adherence with patients, and I don’t think that it’s discussed enough. For example, for other conditions, if someone takes 80–100% of their pills, they’re considered to be highly adherent. In epilepsy, 100–100% is highly adherent. So, if you’re going to say that somebody needs to raise their behavior to that level, then there need to be additional tools given to them. Adding to that, epilepsy is a condition where memory is a problem. Every single person with epilepsy should use a pill box, because if you don’t use one, you don’t know whether you’ve taken the medication or not. So, it’s these little things that make a difference, and most review articles do not discuss giving patients a pill box, and a rescue plan or rescue therapy if they need it; it’s very pragmatic, but very important. ●

Chia-Chun Chiang

Consultant and Assistant Professor of Neurology, Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA; Visiting Scholar, Stanford University, California, USA; Faculty Member, Scientific Program Committee and Electronic Media Committee and Resident Education for Assessment and Care for Headache Program, American Headache Society; Representative of the Headache and Stroke Division, Neurology Artificial Intelligence Program, Mayo Clinic, Rochester, Minnesota, USA

Citation:

Neurol AMJ. 2024;1[1]:60-63. https://doi.org/10.33590/neurolamj/10300987.

Q1 What, or who, inspired you to undertake a career in neurology?

My father, a dedicated neurosurgeon, played a significant role in my choice. He tirelessly shared stories of the lives he had saved, and the individuals he had helped through his work. My fascination with the intricate and enigmatic nervous system began at a young age. As a high school student, I had the opportunity to delve into neuroscience in a lab, particularly focusing on memory formation, which deeply intrigued me.

During my time in medical school, surrounded by various medical specialties, neurology emerged as the most compelling and intellectually stimulating field to me. My hospital rotations during clerkship and internship exposed me to the harsh realities of debilitating neurological diseases, but they also highlighted the potential for groundbreaking discoveries and advancements in the treatment of neurological conditions. The experiences solidified my unwavering determination to pursue a career in neurology.

Q2 You completed your medical degree and internship in Taiwan before moving to the USA for neurology training. What factors influenced your decision to practice in the USA?

I was born and raised in Taiwan, where I attended medical school at the National Yang Ming

University in Taipei. During this time, I immersed myself in research, guided by Arthur Chiou, and had the privilege to present my research findings at international conferences, where I won awards. Additionally, I had the opportunity to work at a bioengineering laboratory at University of California, San Diego, USA, under the mentorship of Shu Chien. This experience greatly resonated with me, and I found myself drawn to the vibrant research environment in the USA.

My aspiration had always been to pursue an academic career as a clinician-scientist, collaborating with some of the brightest minds worldwide. The prospect of working in the USA, which is renowned for its cutting-edge research and innovation, seemed like the ideal path to realize this ambition. Consequently, I made the decision to pursue my medical career in the USA.

Q3 You now specialize in managing headache in patients with vascular disorders. Could you discuss research updates exploring the association between migraine with aura, atrial fibrillation, and stroke risk?

Migraine, especially migraine with aura, is linked to approximately a two-fold increased risk of ischemic stroke. Additionally, research indicates an elevated risk of other cardiovascular conditions, such as myocardial infarction and atrial fibrillation, in individuals experiencing migraine with aura.

In females under the age of 50, migraine with aura is associated with a higher likelihood of experiencing ischemic stroke, and this risk is further exacerbated in individuals who smoke or use oral contraceptives. Onset of migraine with aura at the age of 50 years or older is associated with ischemic stroke occurring later in life. Furthermore, migraine with aura is linked to a greater risk of cardioembolic stroke, and a higher incidence of atrial fibrillation, when compared to migraine without aura. Various mechanisms, such as endothelial dysfunction, microembolism, paroxysmal embolism through a right-to-left shunt, a hypercoagulable state, and vasospasm, have been suggested as potential explanations for the connection between migraine with aura and stroke, and cardiovascular diseases. I have published a review article on this topic.1

Q4Another research focus of yours is the use of artificial intelligence (AI) to improve patient outcomes. Could you share the main areas in which you think AI can be utilized to optimize patient care in neurology?

I believe that leveraging AI can offer significant benefits in optimizing patient care within the field of neurology, addressing various aspects of healthcare delivery. Taking the headache medicine field, for example, AI can enhance diagnostic precision; a study has shown that an AI algorithm can enhance diagnostic accuracy among nonheadache specialists.2 Given the high prevalence of migraine and other headache disorders, and the

limited number of headache specialists we have, such tools could empower patients to receive appropriate diagnoses, mitigate the burden of

"AI can offer significant benefits in optimizing patient care within the field of neurology."

severe headaches, and reduce the necessity for a referral to a neurologist.

AI can also help derive valuable insights from real-world patient data, for both clinicians and researchers. For example, we have leveraged big data from a smartphone electronic headache diary application, to compare the patient-reported treatment effectiveness of acute migraine medications.3 AI can improve the prediction of outcomes, like forecasting migraine attacks, predicting treatment responses, or predicting which patients with migraine would develop other comorbidities. Furthermore, AI can be applied to streamline clinical workflows. Since the emergence of large language models, like ChatGPT (OpenAI, San Francisco, California, USA), many researchers, including myself, have devoted time to how we could utilize these techniques to improve clinical workflow and research productivity. This includes using language models to extract essential information from electronic health records,4 improving efficiency for clinicians in gathering information,5 or exploring the potentials of using those tools to draft clinical notes and reduce the

time clinicians spend on documentation. Finally, in the realm of digital health, language models have the potential to significantly enhance access to care, particularly in regions where there is a scarcity of neurologists and headache specialists. By providing telemedicine support, these models can bridge geographical gaps, enabling patients to consult with experts remotely.

Q5 What do your roles as a Faculty Member for the Scientific Program Committee and Electronic Media Committee, and the Resident Education for Assessment and Care for Headache (REACH) Program at the American Headache Society (AHS) entail?

The AHS Scientific Program Committee plans and arranges details and logistics of the annual AHS scientific meeting. We plan out the meeting sections and contents, select speakers, review abstracts, and review the feedback from attendees. The Electronic Media Committee helps to raise awareness for migraine and other headache disorders on social media and the Internet. The REACH program helps the AHS faculty to deliver grand round presentations and resident educations to hospitals or healthcare institutions, where more headache education is desired.

Q6

In 2023, you presented at the American Academy of Neurology (AAN) Annual Meeting on the use of big data to study the efficacy of different migraine treatments. Are you attending the 2024 AAN Annual Meeting, and if so, what sessions are you most looking forward to?

Yes. I look forward to the 2024 AAN meeting, and cannot wait to hear about the updates from the plenary sessions, and research updates in headache and vascular neurology. I received the 2024 Harold Wolff–John Graham Award, and will be presenting a research study using AI to predict migraine attacks in the 2024 AAN Hot Topics in Headache section.

Q7

In 2022, you received the Early Career Award from the American Headache Society. What research did you receive this award for, and what were the key findings?

Using a cutting-edge AI-ECG algorithm in a comprehensive study, we have found that the atrial fibrillation (AF) prediction model output of those with migraine with aura was significantly higher than those with migraine without aura. This finding indicates a higher likelihood of concurrent paroxysmal or impending AF in individuals with migraine with aura, both among females and males. Our results underscore that migraine with aura serves as an independent risk factor for AF, particularly in patients under the age of 55 years. This implies that AF-related cardioembolism could be a key contributor to the connection between migraine and stroke for certain patients. The research also demonstrated how we could use modern computer technologies, like the AI algorithm, to study association between diseases, such as migraine and AF.

Q8 Do you feel there are any gaps in the current literature, or topics that warrant greater attention in headache and vascular disorder research?

Certainly, there are several areas within headache and vascular disorder research that could benefit from further exploration. Firstly, I believe there is a need for more in-depth investigation into the treatment of headaches in patients with vascular conditions. Specifically, we should delve into the risk-benefit profiles of various medications in this context. Currently, the risks associated with many migraine medications remain unclear, and it is equally important to establish a clearer understanding of their therapeutic benefits in this particular patient population.

Secondly, I would emphasize the importance of studying migraine aura in greater detail. This includes cases of aura occurring without the typical headache symptoms, and late-onset migraine aura. We should determine the criteria and guidelines for when to be concerned, and when to recommend vascular evaluations in

these scenarios. Additionally, understanding the optimal timing and approach to treatment for these specific migraine manifestations is crucial for improving patient care and outcomes in the field of headache and vascular disorder research.

Q9 You are involved in educating and training medical students, residents, and fellows. What are three pieces of advice you would suggest to students or younger clinicians aspiring towards a career in neurology?

Firstly, I would suggest a detail-oriented approach to history taking and examinations. In the realm of neurology, meticulous attention to detail is paramount when conducting patient interviews and physical examinations. Second, I would recommend persistence and perseverance. Neurology, and academic medicine overall, can be a challenging and intricate field. Like any other career path, a strong sense of persistence is important to pursue success. Finally, prioritization is key. While hard work is crucial, it is equally essential to work smart and prioritize. A career in academic neurology demands not only diligence, but also strategic decision-making. Prioritize your tasks, set clear

References

1. Chiang MC et al. Migraine with visual aura and the risk of stroke- a narrative review. J Stroke Cerebrovasc Dis. 2021;30(11):106067.

2. Katsuki M et al. Developing an artificial intelligence-based headache diagnostic model and its utility for non-specialists'

"Migraine with aura serves as an independent risk factor for AF."

goals, and focus on what truly resonates with your interests and career objectives.

Q10 As a clinician, researcher, and educator, where do you see your focus lying in the next 5 years?

In the coming 5 years, my primary focus will be on pioneering the integration of AI within the fields of headache medicine and vascular neurology. I aim to leverage AI technology to develop innovative tools that can deliver precision medicine to our patients, tailoring treatments and interventions to their unique needs and conditions. Additionally, I am committed to using AI to enhance patient access to care, especially for those in underserved areas who may not have easy access to specialized medical expertise. By combining my roles as a clinician, researcher, and educator, I aspire to contribute to the advancement of healthcare in these areas, and make a meaningful impact on patient outcomes and wellbeing. ●

diagnostic accuracy. Cephalalgia. 2023;43(5):3331024231156925.

3. Chiang CC et al. Simultaneous comparisons of 25 acute migraine medications based on 10 million users' self-reported records from a smartphone application. Neurology. 2023;101(24):e2560-e2570.

4. Chiang CC et al. A large language model-based generative natural

language processing framework finetuned on clinical notes accurately extracts headache frequency from electronic health records. medRxiv. 2023;10.1101/202 3.10.02.23296403.

5. Fleming SL et al. MedAlign: A clinician-generated dataset for instruction following with electronic medical records. arXiv. 2023;10.48550/arXiv.2308.14089.

Ozanimod Long-Term Safety and Efficacy

Results from the recently completed DAYBREAK extension

Ozanimod

S1P receptor 1 and 5 modulator for relapsing forms of MS in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease1,2

Administration leads to dose-dependent redistribution of lymphocytes to lymph nodes3

DAYBREAK OLE Final Analysis

• At DAYBREAK start: N=736 switched from IFNb-1a/week, N=877 switched from OZA 0.46 mg/day

• N=881 took OZA 0.92 mg/day continuously from parent trial start through OLE

74.8 Months’ mean exposure 15,556.2 Patient year’s exposure

Safety

Rates of TEAEs for all participants in DAYBREAK4,5 The safety findings were consistent with phase 3 trials5,6

N=2,494 Phase I−III trial completers enrolled in DAYBREAK OLE trial and received OZA 0.92 mg/day

OLE Study Design

Most common TEAEs

Nasopharyngitis (21.3%),

Headache (17.1%), COVID-19 (16.5%), URTI (12.4%), Lymphopenia (10.3%),

(>5%)

Back Pain (9.6%), ALC decreased (9.4%),

Hypertension (9.2%), GGT increased (8.0%), UTI (6.8%), RTI (6.6%),

17 deaths at DAYBREAK end due to:

Arthralgia (6.5%), Bronchitis (6.3%), Treatment-related depression (5.9%), Viral RTI (5.8%), ALT increased (5.1%)

• COVID-19 and related pneumonia (n=4), malignancies (n=4), accidents (n=2), pulmonary embolisms (n=2), right lung abscess, heart failure, intracerebral hemorrhage, pneumonia, sudden death (n=1 each)

Baseline Demographics

• 66.9% female, 99.2% White, 90.1%

• Mean age at symptom onset: 29.5 (SD: mean age at DAYBREAK baseline: 37.7

In a post hoc analysis conducted in the patients trials to DAYBREAK (n=2,256), safety over

Infection TEAEs

Only 1 serious opportunistic infection (a previously reported

infection

Malignancy TEAEs

Hepatic TEAEs

Phase III SUNBEAM (Total n=1,203) (Continuous n=398)

Phase III

(Total n=1,053) (Continuous n=364)

7 patients who went from Phase III over time was evaluated by year.

infection has occurred in DAYBREAK reported case of PML)

Serious infection

The publication of this infographic was supported by

Citation: Neurol AMJ. 2024;1[1]:64-65. https://doi.org/10.33590/neurolamj/IYAW3561.

This infographic was first published online 30th May 2024. Since then an erratum was made, which can be found here.

Efficacy

Sustained treatment efficacy in DAYBREAK participants continuously taking OZA 0.92 mg/day from parent trial start4

0.09

Adjusted ARR (n=879)

77.9% Showed no 3-CDP up to 7 years (N=760)

Gadolinium Enhancing Lesions

(n=447)

(n=433)

New/Enlarging T2 Lesions

22.1%

Experienced 3-CDP (N=760)

(OZA 0.92mg/day arm)

Trial Month 12 (n=705)

Month 60 (n=565)

Key: ALC: absolute lymphocyte count; ALT: alanine transaminase; ARR: annualized relapse rate; GdE: gadolinium-enhancing; GGT: gamma-glutamyltransferase; IR: interquartile range; OLE: open label extension; OZA: ozanimod;

1. European Medicines Agency (EMA). ZEPOSIA® (ozanimod) Summary of productcharacteristics. Available at: https://www.ema.europa.eu/en/documents/ productinformation/zeposia-epar-product-information_en.pdf. Last accessed: 16 May 2024.

2. Bristol Myers Squibb (BMS). ZEPOSIA® US Prescribing Information. 2023. Available at: https://packageinserts.bms.com/pi/pi_zeposia.pdf. Last accessed: 16 May 2024.

3. Harris S et al. Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS. Neurol Neuroimmunol Neuroinflamm. 2020;7(5):e839

4. Selmaj KW et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: final analysis of the DAYBREAK open-label extension study. P090.

ACTRIMS Forum 2024, February 29-March 2, 2024.

5. Selmaj KW et al. Safety patterns over time with ozanimod during an open-label extension trial in patients with relapsing multiple sclerosis. Presentation P012. AAN Annual Meeting, April 13-18, 2024.

6. Cohen JA et al. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15:373-81.

7. Cree BA et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: up to 5 years of follow-up in the DAYBREAK open-label extension trial. Mult Scler. 2022;28(12):1944-62.

Optic Coherence Tomography Angiography in Multiple Sclerosis: A Tool for Evaluation of Neuroinflammation

Authors: *Cansu Elmas,1 Mine Öztürk,2 Belgin Petek Balcı1

1. Neurology Department, University of Health Sciences, Haseki Research and Training Hospital, Istanbul, Türkiye

2. Department of Ophtalmology, Haseki Research and Training Hospital, Istanbul, Türkiye

*Correspondence to cansuelmastunc@gmail.com

Disclosure: The authors have declared no conflicts of interest.

Received: 30.03.23

Accepted: 29.01.24

Keywords: Multiple sclerosis (MS), optic coherence tomography angiography (OCTA), optic neuritis (ON), vascular density.

Citation: Neurol AMJ. 2024;1[1]:66-77. https://doi.org/10.33590/neurolamj/11000019.

Abstract

Purpose: This study aims to evaluate changes in retinal microvasculature in patients with multiple sclerosis (MS) by means of optic coherence tomography angiography (OCTA).

Material and Methods: A total of 60 patients with MS (18 clinically isolated syndrome [CIS], 27 relapsing remitting MS [RRMS], 15 secondary progressive MS [SPMS]) and 56 healthy controls participated in the study. Demographic and clinical data, including optic neuritis history, ophthalmic examination findings, and OCTA parameters, were recorded. OCTA parameters included the following vascular structures: vascular density (VD) in the retinal superficial capillary plexus, deep capillary plexus, and radial peripapillary capillaries. Retinal nerve fiber layer as a structural spectral domain optic coherence tomography parameter was also evaluated.

Results: Superficial and peripapillary vascular plexus densities and retinal nerve fiber layer thickness values were significantly reduced in patients with MS (p=0.0001). Deep capillary plexus densities showed no difference between groups (p=0.279). Patients with a previous history of optic neuritis (ON+) showed significant reduction in VD, compared to patients without a previous history of optic neuritis (ON-), and control groups (p=0.0001). The SPMS group had lower perifoveal values than patients with RRMS and CIS, and patients with RRMS had lower levels than the CIS group (p=0.012; p=0.03; p=0.035). Expanded disability status scores and VD values inversely correlated (r=0.264; p=0.003). No significant difference between MS and control groups in the foveal avascular zone was found (p=0.296).

Conclusion: OCTA findings showed reduced peripapillary and superficial vascular plexus densities in patients with MS. While this reduction was more prominent in patients with

SPMS and history of optic neuritis, patients with CIS and without history of optic neuritis still showed significant reduction compared to healthy controls. These results indicate vascular regression caused by reduced metabolic demand, and microvascular damage caused by chronic inflammation.

Key Points

1. This study uses optic coherence tomography angiography (OCTA) to assess retinal microvasculature in multiple sclerosis (MS), providing insights into neuroinflammation and hypoperfusion in optic nerve involvement in different disease stages.

2. OCTA reveals significant reductions in vascular parameters in patients with MS, including those without optic neuritis history. Prognostically, these changes correlate with disability scores, emphasizing OCTA's potential.

3. OCTA is emerging as a valuable tool, revealing vascular changes that correlate with clinical parameters, which may provide insight for prognosis and treatment decisions.

INTRODUCTION

Multiple sclerosis (MS) is an autoimmune disease that occurs mostly in females, typically in young adults aged between 20–30 years, and is characterized by central nervous system inflammation, demyelination, and axonal damage. The prevalence of MS ranges from 5–300/100,000 worldwide.1 Clinical presentation may vary depending on the location of central nervous system lesions, with the most common symptoms being weakness in the extremities, sensory deficits, ataxia, dysarthria, visual deficits, and fatigue. Optic neuritis (ON) is reported as the initial symptom in 15–20% of patients with MS, and up to 70% of patients with MS are affected by ON during their lifetime.2,3

Optic nerve involvement without a clinical ON history has been demonstrated in patients with MS through the visual evoked potential and post-mortem studies.4 Optic coherence tomography (OCT) has been increasingly used in clinical practice, as peripapillary retinal nerve fiber layer (RNFL) thickness correlates with visual acuity, visual field, and contrast sensitivity.5 Additionally, studies have shown that it correlates with disease duration, clinical course, disability, and MRI findings, such as thalamus and brain parenchymal volume, and development of contrast-enhancing lesions.6

Optical coherence tomography angiography (OCTA) is a state-of-the-art imaging technique that measures retinal vascular densities via sequential OCT scans of a particular retinal area, where motion contrast of the erythrocytes within the vessel provides detailed visualization of retinal and choroidal vasculature, without the use of contrasting agents.7 A thorough assessment of the microvascular network in MS holds promise in detecting early optic involvement without retinal atrophy, and understanding the role of hypoperfusion in the pathogenesis of ON.

This study aims to assess variations in retinal microvasculature among individuals with MS by examining OCTA parameters across three distinct clinical groups: clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and secondary progressive MS (SPMS). The authors hypothesize that the observed changes in retinal microvasculature are indicative of neuroinflammation, a hallmark of MS progression.

METHODS

Patient Cohort

This study was carried out at the University of Health Sciences Haseki Research and Training

Hospital, Istanbul, Türkiye, in accordance with the principles of the Declaration of Helsinki. The procedure was approved by the Clinical Research Ethics Committee, and all participants gave written informed consent after detailed explanation of the nature of the study. From March 2020–March 2021, the authors recruited 60 patients with MS, and 56 healthy controls.

For this study, the authors recruited patients with MS aged between 18–55 years, with no other neurological or psychiatric diagnosis. The authors used the 2017 McDonald criteria for MS diagnosis. The exclusion criteria were history of MS relapse 6 months prior and after recruitment, the use of corticosteroids within the last 30 days, the presence of systemic diseases that may confound the assessment (such as hypertension, diabetes, and ischemic heart disease), glaucoma (intraocular pressure >21 mm Hg), refractive error >+3/-7 diopters, and any retinal or optic disc disease. The authors ensured that each patient in the MS group was sex- and age-matched with a healthy control.

The authors enrolled 60 patients with MS (120 eyes) and 56 healthy participants (107 eyes) for this study. Five eyes were excluded from the analysis due to the presence of drusen, visual loss resulting from amblyopia sequelae, and traumatic ON.

Clinical Data

The authors collected clinical data, such as age, sex, MS subtype, disease duration, Expanded Disability Status Scores (EDSS), history of ON, medication use, and cerebrospinal fluid findings (presence of oligoclonal bands and IgG index, if available). The EDSS assessment was carried out by a neurologist certified at level C, the highest score for EDSS certification. The authors also recorded the demographic characteristics of the control group.

Optical Coherence Tomography Angiography Data Acquisition Protocol

The ophthalmological examination comprised of the best-corrected visual acuity expressed as a decimal value; intraocular pressure measurement; fundus examination after pupil dilatation was done to exclude conditions mentioned in the exclusion criteria; and OCTA results obtained using

the Optovue Angiovue System, software ReVue XR version 2017.1.0.151 (Optovue Inc., Fremont, California, USA).

The OCTA analysis, based on a split spectrum amplitude decorrelation algorithm,8 divided the macular region into the whole image, fovea, and parafovea in each vascular network of the retina.9 Retinal vascular density (VD), the percentage of the imaging region occupied by blood vessels, was divided into two vascular plexuses (superficial capillary plexus [SCP] and deep capillary plexus [DCP]) from the macular 6x6 mm2 OCTA images. The foveal avascular zone (FAZ) was estimated from the macular 3x3 mm2 OCTA images and determined in micrometers. A signal strength index and composite quality index (QI) were used to assess image quality.9 The QI had a range of 1–10 and accounted for signal strength, as well as motion artifacts and image sharpness. The scans were repeated if signal strength index or QI was <7/10. The upper limit for evaluating the superficial plexus was set as the internal limiting membrane, and the lower limit was set as 9 μm below the inner plexiform layer (IPL). To evaluate the deep plexus, 9 μm below the IPL, and 9 μm above the outer plexiform layer were taken (Figure 1). Using the same software, the RNFL thickness was calculated along a 3.45 mm diameter circle around the optic disc. Measurements of the disc and the rim areas, as well as the cup-to-disc ratio, were used.

Statistical Analysis

The authors performed statistical analyses using the Number Cruncher Statistical System (NCSS) 2007 statistical package program (NCSS, LLC, Kaysville, Utah, USA). They examined the distribution of variables such as mean, standard deviation, median, and interquartile range. The Shapiro–Wilk test determined the normality. For normally distributed variables, the authors used a one-way analysis of variance (ANOVA) for intergroup comparisons, Tukey multiple comparison tests for group comparisons, and an independent t test for paired group comparisons. Non-normally distributed variables underwent Kruskal–Wallis and the Mann–Whitney U test for intergroup and paired comparisons, respectively. The authors used the χ2 test to compare qualitative data. The Pearson correlation test was used to determine the relationship between variables. For the comparison

SCPD and DCPD

Peripapillary capillary plexus density

Superficial capillary plexus density

Deep capillary plexus density

of MS subtypes, the restricted maximum likelihood method for mixed effect regression analysis was done with the Statistical Package for the Social Sciences (SPSS) Statistics 25 (IBM, Armonk, New York, USA). The significance level for all tests was determined at p<0.05.

RESULTS

There were 120 eyes from 60 patients in the MS group (mean age: 35.74±9.99; 23 male; 37 female), and 107 eyes from 56 healthy subjects in the control group (mean age: 34.78±10.93; 32 female; 24 male). Demographic and clinical characteristics are detailed in Table 1. After

analyzing the data from the patient cohort, the authors aimed to evaluate the variations in retinal microvasculature among patients with MS, and the authors’ hypothesis posited that the decrease in vascular parameters would be more prominent in progressed disease states.

Retinal fiber layer thickness, and all retinal vascular parameters, except for the peripapillary capillary density inside the disc, and the densities of the deep vascular plexus, were significantly lower in the MS group (Table 2). Notably, the mean perifoveal nasal density of the DCP in the MS group was statistically significantly higher than that in the control group (p=0.029).

DCPD: deep capillary plexus density; SCPD: superficial capillary plexus density.

Figure 1: Retinal nerve fiber layer thickness and capillary plexus density percentages.

Table 1: Demographic and clinical data.

Ave: average; CIS: clinically isolated syndrome; EDSS: Expanded Disability Status Score; IQR: interquartile range; MS: multiple sclerosis; MSSS: MS Severity Score; N/A: not applicable; ON: optic neuritis; RRMS: relapse remitting MS; SD: standard deviation; SPMS: secondary progressive MS.

Table 2: Vascular parameters in the multiple sclerosis and control group.

RNFL Thickness (µm)

Retinal Thickness (µm) Whole image

Parafoveal whole image

Parafoveal temporal

Parafoveal superior

Parafoveal nasal 326.55±14.20

0.0001

0.0001

0.0310

0.0001

0.0001

0.0001

0.0001

Parafoveal inferior 324.40±13.13 312.56±17.3 0.0001

Perifoveal whole image

Perifoveal temporal

Perifoveal superior 284.75±10.61

Perifoveal nasal

Perifoveal inferior

0.0001

0.0010

0.0001

0.0001

0.0001 PPCD (%) Whole image

0.0001

0.0001

0.0001

0.0001

0.0001 SCPD

Parafoveal superior 54.66±3.21 52.55±4.39 0.0001

Parafoveal nasal 53.11±3.41 51.02±4.51 0.0001

Perifoveal

Perifoveal temporal 48.75±2.94 46.77±4.15 0.0001

Perifoveal superior 51.90±2.84 49.07±4.74 0.0001

Perifoveal nasal 55.84±2.25 52.98±4.49 0.0001

Perifoveal inferior 52.48±3.24 49.9±4.82 0.0001

2 (continued)

DCPD (%) Whole image

Parafoveal whole image

Parafoveal temporal

Parafoveal superior

Parafoveal nasal

Parafoveal inferior

Perifoveal whole image

Perifoveal temporal

Perifoveal superior

Perifoveal nasal

Perifoveal inferior 55.67±7.03

0.7890

0.1020

0.1710

0.0710

0.4010

0.0550

0.2760

0.6340

0.8770

0.0290

0.2320

*Independent t test.

DCPD: deep capillary plexus density; MS: multiple sclerosis; PPCD: peripapillary capillary density; RNFL: retinal nerve fibre layer; SCPD: superficial capillary plexus density.

The mean thickness of the RNFL in the study group was significantly lower compared to that in the control group (p=0.0001). When analyzing the relationship between RNFL thickness and vascular densities in the MS group, a positive correlation was observed between the densities of the peripapillary and SCPs (p<0.0001; r=0.4193; r=0.5455; Figure 1). However, no correlation was found between the densities of the DCP (p=0.914).

Although no statistically significant correlation was found between disease duration and the mean density of the SCP (SCPD), a negative tendency was observed (r=0.03090; p=0.1717).

There was a significant difference in all optic nerve head and retinal vascular parameters (p=0.0001) between the ON+, ON-, and control groups, except for foveal retinal thickness, and values of the density of the deep vascular plexus (Table 3). When comparing these groups individually, the parameters were lower in the ON+ group than in the ON- group (p=0.0001), and lower in the ON-

group than in the control group (p=0.0001). No statistically significant difference was observed between the mean size of the FAZ of the control and study groups (p=0.296).

The comparison between different MS subtypes showed statistical significance in whole vascular density of the SCP, as well as superior and inferior hemispheres, in which SPMS eyes had lower densities (p=0.019; p=0.026; p=0.019). The same correlation was found in perifoveal SCP values (p=0.028; p=0.038; p=0.027), while no statistically significant difference was found in parafoveal SCP and DCP parameters.

When examining the correlation between SCPD and EDSS, no correlation was observed in ON+ eyes. However, significant but weak negative correlations were found for ON- eyes between the whole image, perifoveal, and parafoveal SCPD, and EDSS (r=0.1003 and p=0.0031 for whole image SCPD; r=0.1103 and p=0.0019 for perifoveal SCPD; r=0.1026 and p=0.028 for parafoveal SCPD).

Table

Table 3: Vascular parameters according to history of optic neuritis.

A statistically significant negative correlation was observed between the EDSS score and values of RNFL, as well as retinal thickness (r=-0.288; p=0.001; r=-0.264; p=0.003). A similar negative correlation was observed with values of superficial parafoveal and perifoveal vascular plexus densities (r=-0.221; p=0.014; r=-0.188; p=0.036). However, no statistically significant correlation was observed for the values of DCPD (p>0.05). EDSS and MS Severity Score (MSSS) values did not correlate with the values of FAZ (r=-0.097; p=0.290; r=-0.097; p=0.290).

Table 3 (continued).

*One way analysis of variance.

DCPD: deep capillary plexus density; ON-: patients with no history of optic neuritis; ON+: patients with history of optic neuritis; PPCD: peripapillary capillary density; RNFL: retinal nerve fiber layer; RT: retinal thickness; SCPD: superficial capillary plexus density.

DISCUSSION

Retinal perfusion has been extensively researched in many neurological diseases, because the brain and retina share the same embryonic origin, and receive blood from the same vessels. ON in MS has also been extensively studied due to its high incidence rates, and the accessibility of the affected demyelinated area. Various MS studies have reported microvascular changes and global hypoperfusion, and several hypotheses, such as neurodegeneration caused by diffuse inflammation, trans-synaptic degeneration, and ischemia, have been proposed.

Several publications have reported decreased blood flow in normal-appearing white matter,10 and the observation that these changes were noted as early as in CIS highlights the potential causal connection. One theory is that releasing nitric oxide and cytokines, due to widespread inflammation or vasoconstriction caused by elevated astrocyte calcium levels, could contribute to this condition.11

Alterations in vascular structures in MS have been previously identified through various techniques before the availability of OCTA. For instance, Akarsu et al.12 used Doppler ultrasound to investigate retrobulbar hemodynamics, and discovered reduced blood flow and elevated resistance in the central retinal and posterior ciliary arteries. The authors suggested this could be due to vasospasm triggered by increased levels of endothelin-1.12

In an autopsy study of the retinas of patients with MS, Green et al.13 discovered ganglion cell loss and varying degrees of axonal damage that were not correlated with the disease severity. Moreover, damage beyond the retinal nerve fiber and ganglion cell layers has been documented, with histopathological investigations revealing changes that extend to the inner nuclear layer, a finding that OCT studies have corroborated. Because these changes are focal, they have been linked to retrograde trans-synaptic degeneration, not neurodegeneration caused by diffuse inflammation.14

The neurosensory retina receives blood from the two distinct vascular plexuses, originating from the central retinal artery. The superficial vascular

plexus supplies the retinal nerve fiber and ganglion cell layers, while the deep vascular plexus supplies the outer plexiform and inner nuclear layers. The peripapillary vascular plexus, on the other hand, supplies the nerve fiber layer. Recent reviews have indicated that thinning of the RFNL and ganglion cell layer in patients with ON is accompanied by a decrease in superficial and peripapillary capillary plexus density.15-18 Vascular regression due to reduced metabolic demand, and endothelial damage caused by inflammation, have been proposed as potential causes.

Consistent with previous literature, the authors’ study revealed a reduction in RNFL thickness, and a decrease in SCPD parameters, with a positive correlation between these parameters in patients with MS. Moreover, the authors observed a decrease in mean superficial plexus density and retinal thickness in eyes with ON+ compared to those with ON- and the control group, and in ON- eyes compared to the control group. While some studies have found no significant differences between ON+ and ON- eyes, suggesting that retinal microvascular damage is a primary effect of the disease rather than a secondary change due to ON,19,20 others have reported no significant differences in superficial vascular densities between MS ON- eyes and the control group.17,18,21,22 However, consistent with the authors’ findings, some studies have also reported a decrease in mean RNFL thickness and superficial vessel densities in eyes without a history of ON compared to the control group, suggesting that microvascular damage is secondary to diffuse inflammation, and independent of demyelinating attacks.23-26

Another study that included patients with RRMS, SPMS, and primary progressive MS in more advanced stages of the disease observed a negative correlation with the EDSS scores in all eyes, regardless of a history of ON.23 Detecting damage independently of the ON history in the later stages of the disease supports the idea that it is a secondary outcome of chronic inflammation. This study also revealed a significant reduction in superficial perifoveal capillary plexus densities in the SPMS group compared to the RRMS and CIS groups, and in the RRMS group compared to the CIS group. In line with the literature, the authors also identified a negative correlation between disability scores such as EDSS and MSSS, and SCPD literature.23,25 Notably,

there was no correlation between SCPD values and EDSS in ON+ eyes, whereas SCPD showed a negative correlation with EDSS in ON- eyes.

In this study, peripapillary capillary plexus density (PCPD) parameters were also found to be significantly lower in ON+ eyes compared to ON- and the control group, in four quadrants. In addition, PCPD values positively correlated with RNFL thickness. Since PCPD is associated with the retinal nerve layer, its decline in eyes without a history of ON may predict axonal loss.26 The radial peripapillary capillary network cannot be evaluated by fundus fluorescein angiography. Therefore, the findings obtained from OCTA are very important.7,27

Macular ganglion cell loss is a well-established characteristic of MS, and parafoveal VD and retinal thickness values are critical for demonstrating the loss. Lanzillo et al.28 reported, in a prospective study, that the mean parafoveal plexus density declined over time, which was linked to increased disability. In the authors’ study, they discovered that the mean parafoveal plexus density was significantly lower in the ON+ group than in the ON- group, and it was negatively correlated with EDSS and MSSS.

Since the deep vascular plexus is associated with the outer plexiform and inner nuclear layers, it is not anticipated to be affected following ON. Anatomically, the deep vascular plexus comprises the anastomoses of the superficial vascular plexus. In the event of primary vascular damage, a decrease in density is expected in both layers. However, the literature does not support this, including the authors’ study.15,25,26,29

The widening of the FAZ, and a reduction in its circularity, indicate macular ischemia. This finding is considered a marker of microvascular damage in OCTA studies, since it correlates directly with the severity of glaucoma and diabetic retinopathy, and is associated with decreased visual acuity. The lack of a significant difference in FAZ parameters in patients with MS compared to the control group contradicts the theory of precursor microvascular damage in MS.20,30 Likewise, the authors’ study revealed no significant increase in FAZ parameters.

Limitations of this study include the lack of an additional OCT evaluation, which would have

allowed comparison between ganglion cell IPL and vessel densities. Furthermore, due to its crosssectional design, this study cannot demonstrate the prognostic value of OCTA assessment. Prospective studies are required to establish the clinical usefulness of OCTA for prognosis and treatment decisions.

The most critical distinguishing aspect of the authors’ study is the inclusion of patients with CIS and SPMS in the cohort. As of writing, no publications have statistically compared OCTA parameters in patients with CIS, RRMS, and SPMS. More comprehensive prospective studies are necessary to determine the progression of vascular changes over time.

CONCLUSION

This study demonstrates a reduction in both peripapillary and SCP density, and retinal thickness values, in patients with MS, compared to the control group. This discovery was evident in all four quadrants when perifoveal and parafoveal areas were analyzed separately. However, no disparity was observed in DCP density.

A decrease in vascular parameters was observed in eyes with a previous history of ON, compared to those without. This observation may be attributed to reduced metabolic demand caused by retinal nerve layer atrophy, following a demyelinating attack. Nonetheless, the discovery of a decrease in eyes without a history of ON compared to the control group implies the presence of microvascular damage, believed to occur due to inflammation independent of the demyelinating attack.

The reduction in perifoveal VD values, along with the negative correlation between peripapillary and SCP density values, and disability scores such as EDSS and MSSS, was observed in patients with SPMS when compared to RRMS and CIS groups. These findings indicate that OCTA possesses promising prognostic value.

In conclusion, this study discovered decreased peripapillary and superficial vascular plexus densities in patients with MS using OCTA. While this decline was more significant in patients with

SPMS and eyes with a history of ON, it was also evident in eyes without ON, and patients with CIS. These observations suggest a regression caused by decreased metabolic demand, and microvascular damage caused by diffuse inflammation. Furthermore, the reduced VD values

References

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2. Balcer LJ. Clinical practice. Optic neuritis. N Engl J Med. 2006;354(12):1273-80.

3. Toosy AT et al. Optic neuritis. Lancet Neurol. 2014;13(1):83-99.

4. Leocani L et al. Visual evoked potentials as a biomarker in multiple sclerosis and associated optic neuritis. J Neuroophthalmol. 2018;38(3):350-7.

5. Sakai RE et al. Vision in multiple sclerosis (MS): the story, structurefunction correlations, and models for neuroprotection. J Neuroophthalmol. 2011;31(4):362-73.

6. Britze J, Frederiksen JL. Optical coherence tomography in multiple sclerosis. Eye (Lond). 2018;32(5):884-8.

7. Kashani AH et al. Optical coherence tomography angiography: a comprehensive review of current methods and clinical applications. Prog Retin Eye Res. 2017;60:66-100.

8. Jia Y et al. Split-spectrum amplitudedecorrelation angiography with optical coherence tomography. Opt Express. 2012;20(4):4710-25.

9. Sampson DM et al. RTVue XR AngioVue optical coherence tomography angiography software up-grade impacts on retinal thickness and vessel density measurements. Transl Vis Sci Technol. 2020;9(3):10.

10. D’haeseleer M et al. Vascular aspects of multiple sclerosis. Lancet Neurol. 2011;10(7):657-66.

11. Varga AW et al. White matter hemodynamic abnormalities precede sub-cortical gray matter changes in multiple sclerosis. J Neurol Sci. 2009;282(1-2):28-33.

12. Akarsu C et al. Color Doppler

were negatively associated with disability scores, indicating that OCTA may provide information on disease progression. More comprehensive studies are necessary to show the evolution of vascular damage over time.

imaging in optic neuritis with multiple sclerosis. Graefes Arch Clin Exp Ophthalmol. 2004;242(12):990-4.

13. Green AJ et al. Ocular pathology in multiple sclerosis: retinal atrophy and inflammation irrespective of disease duration. Brain. 2010;133(Pt 6):15911601.

14. Petzold A et al.; ERN-EYE IMSVISUAL. Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurol. 2017;16(10):797-812.

15. Liu J et al. Microvascular impairments detected by optical coherence tomography angiography in multiple sclerosis patients: a systematic review and meta-analysis. Front Neurosci. 2023;16:1121899.

16. Kleerekooper I et al. Optical coherence tomography angiography (OCTA) in multiple sclerosis and neuromyelitis optica spectrum disorder. Front Neurol. 2020;11:604049.

17. Aly L et al. Optical coherence tomography angiography indicates subclinical retinal disease in neuromyelitis optica spectrum disorders. Mult Scler. 2022;28(4):522-31.

18. Khader SA et al. Evaluation of optical coherence tomography angiography findings in patients with multiple sclerosis. Indian J Ophthalmol. 2021;69(6):1457-63.

19. Cordon B et al. Angiography with optical coherence tomography as a biomarker in multiple sclerosis. PLoS One. 2020;15(12):e0243236.

20. Balıkçı A et al. Optical coherence tomography and optical coherence tomography angiography findings in multiple sclerosis patients. Neuroophthalmology. 2021;46(1):1933.

21. Feucht N et al. Optical coherence tomography angiography indicates associations of the retinal vascular

network and disease activity in multiple sclerosis. Mult Scler. 2019;25(2):224-34.

22. Kallab M et al. Retinal oxygen metabolism and haemodynamics in patients with multiple sclerosis and history of optic neuritis. Front Neurosci. 2021;15:761654.

23. Lanzillo R et al. Optical coherence tomography angiography retinal vascular network assessment in multiple sclerosis. Mult Scler. 2018;24(13):1706-14.

24. Montorio D et al. Retinal and choriocapillary vascular changes in early stages of multiple sclerosis: a prospective study. J Clin Med. 2021;10(24):5756.

25. Murphy OC et al. Alterations in the retinal vasculature occur in multiple sclerosis and exhibit novel correlations with disability and visual function measures. Mult Scler. 2020;26(7):815-28.

26. Rogaczewska M et al. Macular vessel density differs in multiple sclerosis and neuromyelitis optica spectrum disorder: an optical coherence tomography angiography study. PloS One. 2021;16(6):e0253417.

27. Campbell JP et al. Detailed vascular anatomy of the human retina by projection-resolved optical coherence tomography angiography. Sci Rep. 2017;7:42201.

28. Lanzillo R et al. Retinal vascular density in multiple sclerosis: a 1‐year follow‐up. Eur J Neurol. 2019;26(1):198-201.

29. Cennamo G et al. Peripapillary vessel density as early biomarker in multiple sclerosis. Front Neurol. 2020;11:542.

30. Yilmaz H et al. Assessments of vessel density and foveal avascular zone metrics in multiple sclerosis: an optical coherence tomography angiography study. Eye (Lond). 2020;34(4):771-8.

Movement Disorder: Initial Manifestation of Hereditary Hemochromatosis – A Case Report

Authors: Oscar Javier Diaz Alcendra,1 Muriel Marrugo Fernandez,2 Jesus Chaves Pineda,3 Tatiana Marrugo4

1. Department of Internal Medicine, Universidad Libre Seccional Barranquilla, Ayudas Diagnósticas SURA IPS, Colombia

2. Department of Emergency Medicine, Clínica La Asunción, Barranquilla, Colombia

3. Ayudas Diagnósticas SURA IPS, Medellín, Colombia

4. San Vicente Fundación CES, Medellín, Colombia

*Correspondence to oscarj-diaza@unilibre.edu.co

Disclosure: The authors have declared no conflicts of interest.

Received: 29.01.24

Accepted: 11.04.24

Keywords: Case report, hemochromatosis, parkinsonism, tremor.

Citation: Neurol AMJ. 2024;1[1]:78-82. https://doi.org/10.33590/neurolamj/ZPPU7223.

Abstract

Hereditary hemochromatosis is a condition resulting in tissue damage by pathological iron deposition due to genetic alterations. The clinical manifestations are diverse, and depend on the involvement of the affected organ. Complications such as cirrhosis, heart failure, diabetes, and arthritis are described. Iron deposition in brain tissues with neurological damage and presence of symptoms is not a usual finding. Some case series describe movement disorders as the clinical manifestation. The authors report a patient with movement disorder due to hepato-cerebral hemochromatosis, who showed clinical improvement after diagnosis and treatment. Hereditary hemochromatosis should be considered in the differential diagnosis of movement disorders in patients with signs of iron overload.

Key Points

1. Hereditary hemochromatosis is a condition that does not usually affect the nervous system; very few cases have been described that present with movement disorders.

2. Unusually, hereditary hemochromatosis can present with a phenotype of cerebral iron overload, increased deposition in the basal nuclei, and associated parkinsonism.

3. Hereditary hemochromatosis should be considered in the differential diagnosis of movement disorders with pathological iron deposition in the brain.

INTRODUCTION

Hemochromatosis is a genetic disorder characterized by pathological tissue iron deposition with multiple organ involvement.¹ Hereditary hemochromatosis (HH) is one of the most common inherited disorders. The prevalence varies worldwide, and is more common in people from Northern Europe.² It is associated with tissue iron deposition, leading to functional alterations in several organs, with potential irreversible damage. This can lead to complications such as cirrhosis, heart failure, diabetes, arthritis, and a high risk of hepatocellular carcinoma.³ Nervous system involvement is uncommon, with a few reported cases manifesting as movement disorders.⁴ The authors present the case of a patient with movement disorders as the initial manifestation of hereditary hepato-cerebral hemochromatosis.

PATIENT INFORMATION

The patient was a 75-year-old male, with Type 2 diabetes and hypertension, without alcoholism. There was no family history of HH. He consulted for symptoms of 6 months of evolution characterized by tremor at rest, exacerbated after movements; loss of dexterity in both upper limbs; facial hypomimia; and rigidity and bradykinesia of the upper and lower limbs bilaterally, with increased support perimeter. The patient reported impairment in the ability to perform activities of daily living.

CLINICAL FINDINGS

Upon admission, the patient’s vitals revealed a temperature of 36.6 °C, a blood pressure of 130/75 mmHg, a heart rate of 76 beats per minute, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 97% on room air. His cognition was preserved. Heart and lung auscultation had no alterations. The patient had a normal physical examination, except for rest tremor in both upper extremities. There was no ataxia. No significant alterations in pain sensitivity or sensitivity level were detected. In addition, the patient presented facial hypomimia, and rigidity and bradykinesia of the upper and lower limbs bilaterally, with increased support perimeter.

DIAGNOSTIC ASSESSMENT

Labs showed hemoglobin of 18.3 g/dL, hematocrit of 54.8%, leukocytes of 6,410 mm3, platelet count of 508,000 mm3, glycated hemoglobin of 6.3%, albuminuria/creatinuria ratio of 4.4 mg/g, and serum creatinine of 0.99 mg/dL. The brain CT scan was normal; therefore, a brain MRI scan was performed, which showed hypointensity in the echo gradient of the globus pallidus and midbrain, suggestive of iron deposition (Figure 1).

Complementary studies were performed, showing serum ceruloplasmin of 22 mg/dL, serum aspartate aminotransferase of 56 U/L, serum alanine aminotransferase of 26 U/L, total bilirubin of 0.2 mg/dL, normal thyroid-stimulating hormone, serum ferritin of 703.81 ng/mL, total serum iron of 255 ug/DL, transferrin saturation of 58%, hepatitis B surface antigen negative, antibody to hepatitis B core antigen negative, antibody to hepatitis C virus negative, and HIV negative. The study was complemented with hepatic MRI, which showed liver with decreased T2 signal and decreased signal in the phase sequence with R2* measurement of 95.4 s-1 ms, corresponding to intrahepatic iron concentration of 2.9 mg/g of dry liver by the Garbowski formula. Transthoracic Doppler echocardiogram was without segmental alterations, with good bilateral ventricular function, normal atrial dimensions, and normal valvular structures.

In view of the elevated ferritin and transferrin saturation levels, with the findings in the cerebral and hepatic MRI, a genetic panel was performed with positivity for homozygous HFE C282Y mutation, which confirmed the diagnosis of hereditary hemochromatosis.

THERAPEUTIC INTERVENTION

Management with phlebotomy was indicated, starting with induction of 500 mL in each extraction every 2 weeks, until serum ferritin lower than 50 ng/mL was reached. The phlebotomy protocol was continued every 4 months, and serum ferritin was monitored.

FOLLOW-UP AND OUTCOMES

After 3 months of treatment, improvement in neurological symptoms with functional independence was observed. Serum ferritin levels showed gradual decrease: 528 ng/mL, 374 ng/mL, 139 ng/mL, 45 ng/mL, and 34 ng/ml. The patient reported improved ability to perform activities of daily living.

DISCUSSION

HH is an inherited disorder characterized by increased dietary iron absorption with tissue accumulation, with potential for direct toxicity damage.⁵ The broad spectrum of tissue toxicity can result in diverse clinical manifestations, including cirrhosis, endocrine and exocrine pancreatic insufficiency, polyarthritis, skin hyperpigmentation, hypogonadism, adrenal insufficiency, hypothyroidism, and heart failure.²‚⁶

Iron is an essential element in various metabolic processes. In the brain, a sufficient amount of iron is particularly necessary for myelin synthesis, neurotransmitters, and energy production. Iron concentrations are highest in structures such as the globus pallidus, substantia nigra, putamen, and dentate nucleus.7 It has been suggested that excessive amounts of iron in the brain cause alterations in particularly susceptible tissues, leading to the generation of free radicals that exceed the capacity of cellular detoxification systems to scavenge them.8,9

The diagnosis of hemochromatosis is usually suspected in patients with elevated serum ferritin and transferrin saturation levels. Serum ferritin levels above 300 ng/mL in males, or 200 ng/mL in females, are usually considered elevated.5

Assessment of hyperferritinemia should include consideration of other possible etiologies, such as acute or chronic inflammatory states, liver disease,

Brain MRI scan shows T2 hypointensity in the globus pallidus and midbrain.

Figure 1: Brain MRI scan.

infectious diseases, and secondary iron overload. Certain environmental conditions, such as alcohol consumption, can also elevate ferritin.6 In the case presented, significant elevation of ferritin levels and elevation of transferrin saturation were found. On the other hand, there was no evidence of secondary causes of iron overload, nor a history of alcoholism that could predispose to the condition.

MRI findings suggestive of pathological iron deposition are characterized by a low T2-weighted signal. In fact, whenever available, iron excess should be confirmed by MRI with iron measurement protocol.10 In the present case, a decrease in the T2 signal and a drop in the signal in phase sequence with an R2* measurement of 95.4s-1 ms, corresponding to an intrahepatic iron concentration of 2.9 mg/g of dry liver by Garbowski’s formula, were observed.

Brain MRI typically shows T2 hypointensities and T1 hyperintensities, as well as low signal artefacts in susceptibility weighted imaging, mainly in the basal ganglia, dentate nucleus, and white matter.11 The case presented is notable for alterations in resonance imaging, especially in the globus pallidus and midbrain. MRI alterations may also be present in asymptomatic patients.12

Coexistence of hemochromatosis with diabetes and liver disease is rare, except in the presence of chronic alcoholism.3 Fracanzani et al.13 reviewed a prospective cohort of patients with hemochromatosis diagnosed between 1976–2007. Those patients with milder iron overload also had a lower prevalence of cirrhosis and extrahepatic manifestations, such as diabetes.13 The patient in question was diagnosed with diabetes 15 years earlier, with no history of alcoholism; it is uncertain whether iron deposition and tissue damage in the pancreas triggered the onset of diabetes in the present case.

In the general population, the allelic presentation of p.Cys282Tyr is estimated at 6.2%. The prevalence of the homozygous allele in patients with clinically recognized hemochromatosis is as high as 80.6%. Heterozygosity for the C82Y/His63Asp compound was reported in 5.3% of cases, and 19.4% of cases were unrelated to the gene.14

In the genetic panel performed in the clinical case presented, the presence of homozygous HFE C282Y mutation was confirmed.

Contrary to reports in the literature, the initial manifestation of hemochromatosis was neurological symptoms. The clinical case presented an iron overload phenotype with increased deposition in the basal nuclei and associated parkinsonism. Neurological involvement with movement disorders has been described in patients with HH, including parkinsonism, Parkinson’s syndromes, chorea, myoclonus, ataxia, dystonia, and tremor, with a mean age of onset at 57 years.4

The trend towards reversibility of neurological disorders with stabilization of iron stores through phlebotomy is highly suggestive of a causal relationship between HH and movement disorders. The patient showed significant improvement after 3 months of phlebotomy protocol.

CONCLUSION

This article presents a case of hereditary hemochromatosis due to homozygous mutation of HFE C282Y with movement disorder as initial manifestation. The presence of hepatic deposits was confirmed by MRI; however, a better clinicalradiological correlation was observed between the cerebral deposits and the patient’s symptoms. The favorable response to the phlebotomy protocol reinforces the premise of brain iron toxicity involvement. Hereditary hemochromatosis should be considered in the differential diagnosis of movement disorders in patients with signs of iron overload.

PATIENT PERSPECTIVE

Despite not being able to share a written perspective on the diagnosis, the patient expressed his bewilderment after the explanation of the atypical clinical presentation of his condition. The patient expressed full agreement with phlebotomy treatment, especially after noticing clinical improvement. On outpatient follow-up, he reported improved ability to perform activities of daily living. He continues to be followed up by the treating medical team.

References

1. Janssen MCH, Swinkels DW. Hereditary haemochromatosis. Best Pract Res Clin Gastroenterol. 2009;23(2):171-83.

2. Salgia RJ, Brown K. Diagnosis and management of hereditary hemochromatosis. Clin Liver Dis. 2015;19(1):187-98.

3. Powell LW et al. Haemochromatosis. Lancet. 2016;388(10045):706-16.

4. Kumar N et al. Movement disorders associated with hemochromatosis. Can J Neurol Sci. 2016;43(6):801-8.

5. Murphree CR et al. Diagnosis and management of hereditary haemochromatosis. Vox Sang. 2020;115(4):255-62.

6. Brissot P et al. Haemochromatosis. Nat Rev Dis Primers. 2018;4(1):1-15.

7. Dusek P et al. Iron dysregulation in movement disorders. Neurobiol Dis. 2012;46(1):1-18.

8. Rosana A, La Rosa L. A case of hereditary haemochromatosis in a patient with extrapyramidal syndrome. Blood Transfus. 2007;5:241-3.

9. Aquino D et al. Age-related iron deposition in the basal ganglia: quantitative analysis in healthy subjects. Radiology. 2009;252(1):165-72.

10. Wood JC. Estimating tissue iron burden: current status and future prospects. Br J Haematol. 2015;170(1):15-28.

11. Nielsen JE et al. Hereditary haemochromatosis: a case of iron accumulation in the basal ganglia associated with a parkinsonian syndrome. J Neurol Neurosurg Psychiatry. 1995;59(3):318-21.

12. Berg D et al. The basal ganglia in haemochromatosis. Neuroradiology. 2000;42(1):9-13.

13. Fracanzani AL et al. Hemochromatosis in Italy in the last 30 years: role of genetic and acquired factors. Hepatology. 2010;51(2):501-10.

14. European Association for the Study of the Liver (EASL). EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010;53(1):3-22.

Neurological Presentation of Lead Toxicity: A Case Report

Authors:

Rakshit Gupta,1 Praveen Kumar,2 Suresh Gupta1

1. Department of Pediatrics, Institute of Child Health, Sir Ganga Ram Hospital, New Delhi, India

2. Division of Pediatric Neurology, Institute of Child Health, Sir Ganga Ram Hospital, New Delhi, India

*Correspondence to rockingrakshitgupta3@gmail.com

Disclosure: The authors have declared no conflicts of interest.

Acknowledgments: R. Gupta contributed to the case description and initial draft, Kumar to the literature research and editing, and S. Gupta to the supervision and final editing. Written parental/guardian consent was obtained.

Received: 16.06.23

Accepted: 28.03.24

Keywords: Acute disseminated encephalomyelitis (ADEM), chelation, encephalopathy, lead poisoning, pica.

Citation: Neurol AMJ. 2024;1[1]:83-88. https://doi.org/10.33590/neurolamj/XFQN6712.

Abstract

Acute encephalopathy, caused by infectious agents, metabolic or mitochondrial dysfunction, brain tumor, or prolonged exposure to toxic elements, is a significant cause of morbidity and mortality in young children. Lead encephalopathy that occurs due to prolonged lead ingestion or exposure in children is not uncommon, and many such cases have been reported in the past. This report shares the authors’ experience of the missed diagnosis of lead encephalopathy, its red flags, and its relation to pica as a root cause. A 14-month-old boy, resident of Delhi, India, was admitted with vomiting, irritability, and two episodes of abnormal limb movements, with the first symptom starting when he was 11 months old. His case was initially treated as acute disseminated encephalomyelitis, but he showed no improvement. The child was then referred to the Sir Ganga Ram Hospital, New Delhi, India. The boy presented with severe anemia, along with basophilic stippling on the peripheral smear during routine investigations. Suspecting lead poisoning, blood lead levels were checked, and were found to be grossly elevated. The child was then started on chelation therapy. Multiple doses of chelation (dimercaprol and D-penicillamine) were given, and sequential blood lead levels were monitored, which showed a marked decrement. The child was discharged, and is being monitored routinely. Lead poisoning remains a neglected public health issue, especially in children, and delay in identification can cause significant morbidity and mortality. Pediatricians and general practitioners must be aware of this risk, especially in children with iron deficiency anemia exhibiting pica.

Key Points

1. Despite being treatable, lead poisoning and lead encephalopathy are still critical public health concerns, especially among children, primarily due to delayed diagnosis.

2. This case report aims to demonstrate how lead encephalopathy can clinically mimic other encephalopathic conditions, like acute disseminated encephalomyelitis (ADEM), potentially causing oversight and delay in diagnosis.

3. Children with symptoms of lead encephalopathy may show clinical similarities to conditions like ADEM or viral encephalitis. Thus, when conventional therapies fail, clinicians should consider lead poisoning as a potential differential diagnosis.

INTRODUCTION

Acute encephalopathy is a significant cause of morbidity and mortality in young children. It can be caused by infectious agents, metabolic or mitochondrial dysfunction, brain tumors, or prolonged exposure to toxic elements like lead, which can result in poisoning, leading to severe consequences, including encephalopathy.

Lead is a naturally occurring heavy metal found in the earth’s crust. It can gain entry into the body through various pathways, including lead-based paints, contaminated soil, construction dust, and water.1 The Global Burden of Disease (GBD) dataset 2019 estimated that nearly 800 million children worldwide have unsafe levels of lead in their bodies, with more than 50% living in Southeast Asia.2 The Institute for Health Metrics and Evaluation (IHME) estimated that in 2019, lead exposure accounted for 900,000 deaths, and 21.7 million years of healthy life lost (disability-adjusted life years) worldwide, due to long-term effects on health, with the highest burden in low- and middle-income countries.3 Young children, particularly toddlers, are vulnerable to lead exposure and toxicity due to their handto-mouth behaviors, and increased absorption rates. This case report aims to illustrate how lead encephalopathy can clinically resemble other encephalopathic conditions, such as acute disseminated encephalomyelitis (ADEM), potentially leading to oversight and delayed diagnosis.

CLINICAL DESCRIPTION

A 14-month-old boy with normal birth and development, relatively asymptomatic, had one episode of afebrile generalized tonic-clonic seizure as an 11-month-old, when awake. The seizure lasted for a duration of 5–10 minutes, and subsided without active intervention, followed by postictal drowsiness. The child was stabilized at a local hospital and was administered anti-epileptics intravenously. Brain MRI revealed no pathology. One week later, the child had another episode of afebrile seizure during feeding. He was admitted to hospital, where he was started on intravenous (IV) anti-epileptics and antibiotics. A repeat brain MRI suggested ADEM. Electroencephalography (EEG) was reported to be normal. Lumbar puncture report showed a cell count of 4 /µl (100% lymphocytes), 24 mg/dL of protein, 90 mg/dL of glucose, herpes simplex virus PCR negative, culture and sensitivity sterile. The child was discharged after 10 days on oral anti-epileptics. The child remained well for subsequent days but, 1 month later, developed vomiting (refractory to oral antiemetics) and intermittent irritability. He was admitted again, and a repeat brain MRI was done; the results were consistent with previous MRI findings. The child was referred to the authors’ centre due to persistent vomiting and irritability.

The child on examination was found to be mildly dehydrated, underweight, irritable, afebrile, had tachycardia (heart rate: 128 /min), pallor, and decreased muscle tone in both lower and upper limbs, plantar reflexes going down, and showed no signs of meningeal irritation.

On Day 1 of admission, the child was started on parenteral drug therapy, which included IV fluids (to maintain a urine output of 1 mL/kg/hour), ceftriaxone, and levetiracetam.

As vomiting was persistent and refractory to IV antiemetics, the child was started on tube feedings, and the pediatric gastrology team were involved. Gastrografin swallow was done to rule out gastroesophageal reflux disease, which revealed no gross abnormality.

On Day 2, an opinion of pediatric neurology was taken, given the child’s persistent irritability and history of seizures. The neurologist modified the child’s anti-epileptics, and suggested a repeat brain MRI and EEG for the child. Initial investigations, which were sent on admission, showed hemoglobin and total leucocyte levels to be at 6 g/dL and 9,870 /µl, respectively. A normal level of C-reactive protein, iron, and ferritin (iron: 119 mcg/dL, ferritin: 75.30 ng/ dL) were noted. Peripheral smear showed anisopoikilocytosis with severe microcytic hypochromic anemia with basophilic stippling. Based on the peripheral smear report, the child was suspected to have lead poisoning. This led to the review of the child’s environmental history.

The father of the child works at a local paint factory in New Delhi, that uses lead in its manufacturing process. He often brought home painted toys from the factory for the child to play with, and observed the child chewed on the toys

numerous times. Additionally, the child resided in an area with multiple small factories and ongoing construction works. The mother had observed the child ingest dust particles from these construction activities, which settled on the floors and windows of their home. Considering these potential lead exposure sources, a lead encephalopathy diagnosis was inferred. Diagnostic investigations included blood lead level (BLL) analysis, urine toxicology screening, urine coproporphyrin analysis, abdominal X-ray (to detect lead flakes), and X-rays of long bones (to identify lead lines).

MANAGEMENT AND OUTCOME

On Day 5 of admission, the urine toxicology screen was normal, but blood lead levels were grossly elevated (BLL: 71 mcg/dL). X-ray of the abdomen showed fecal loading; the X-ray of long bones showed dense metaphysis suggesting lead lines (Figure 1). Urine coproporphyrin was within the normal range.

MRI of the brain with MR spectroscopy was suggestive of toxic encephalopathy, and EEG findings were consistent with cerebral dysfunction.

On Day 8 of admission, the repeat blood lead levels were 80 mcg/dL (Figure 2); hence, a plan was made to start IV chelation therapy. The child’s anemia was treated by transfusing packed red blood cells. The pre-chelation work-up included complete blood counts; serum electrolytes,

Figure 1: X-ray of long bones showing dense metaphysis suggestive of lead lines.

including magnesium, urine routine and microscopy; G6PD levels; and liver enzymes.

On Day 10, the pre-chelation work-up came back normal; thus, the child was started on dimercaprol intramuscular injection (5 mg/kg/dose), given after every 4 hours, for a total of 30 doses, and 50 mg D-penicillamine tablets, once a day, orally. Complete blood counts, liver enzymes, serum electrolytes, and urine routines were monitored every alternate day as per the standard treatment protocol.

On Day 3 of chelation therapy, the child became inconsolably irritable; the opinion of a pediatric neurologist and toxicologist was sought. Antiepileptics were modified, and D-penicillamine was stopped. The blood lead level after the chelation therapy was still at 83 mcg/dL, so the child was

started again on dimercaprol therapy for 5 days (30 doses).

Repeat blood lead levels after chelation therapy came down to 5 mcg/dL. The child was discharged on oral anti-epileptics and multivitamins, and was advised to attend regular follow-ups.

DISCUSSION

Lead encephalopathy is a severe but avoidable neurological disorder that is characterized by the toxic effects of lead on the central nervous system. It is a serious public health concern with global implications, particularly in low- and middle-income nations, where environmental lead poisoning is still a significant issue.

There are numerous sources of lead exposure attributable to its extensive utilization and environmental pollution, the most significant being the ingestion of lead-containing materials, which is especially prevalent among younger children. These sources encompass contaminated dust or soil, lead paint flakes, tainted food and spices,

water passing through lead service lines, and lead-containing traditional medicines or foreign bodies.4 In India, the primary source of lead exposure often stems from contaminated lead dust and soil, and this is particularly prevalent in metro cities undergoing rapid construction. Additionally, numerous local paint manufacturing companies

Figure 2: Trend of blood lead levels during hospital stay.

continue to incorporate high levels of lead in their manufacturing processes, resulting in the distribution of painted toys that easily find their way into homes with children.

While searching PubMed and MEDLINE, the authors found multiple cases of lead poisoning in children with a history of pica who ate paint peelings, herbal medicines, and lead-containing dust. In a case study from Africa, a 3-year-old girl diagnosed with lead encephalopathy had a history of pica, and consumption of herbal medications.5 In the authors’ case, the 14-month-old boy resides in New Delhi, where his father is employed at a local paint factory, utilizing lead in its paint manufacturing process. The father frequently brought home painted toys from the factory for the child to play with and observed on numerous occasions the child chewed on these toys. Another potential source of lead exposure for the child could have been household dust, which he might have ingested due to the habitual hand-to-mouth contact. As shown in previous studies, analyses of the dust samples obtained from residential areas in Delhi, and different parts of India, have revealed notably elevated lead levels.6,7.

Lead poisoning in children initially presents with vague symptoms like vomiting, and abdominal pain, mimicking viral illness. With continuous exposure, children can have systemic involvement, including cognitive delay, encephalopathy, and anemia. Children with lead encephalopathy exhibit symptoms that resemble other forms of encephalopathy, such as viral, autoimmune, or metabolic etiologies. As a result, diagnosis can be delayed or overlooked, leading to prolonged illness and increased health expenditure. The same was exemplified in the authors’ case, where the child initially received treatment for ADEM at multiple hospitals, before ultimately being diagnosed with lead encephalopathy at the authors’ hospital. After receiving the treatment, the child has been doing well.

Lead poisoning in an individual is diagnosed based on the presence of relevant clinical features and high blood lead levels. There are no known safe blood lead levels, and concentrations as low as 3.5 mcg/dL may cause decreased intelligence in children, behavioral difficulties, and learning problems.1 Other valuable investigations include a

complete blood count and ferritin to identify iron deficiency anemia, a peripheral smear to look for basophilic stippling, raised urinary coproporphyrin, presence of lead flakes on abdominal X-ray, lead lines on X-ray of long bones, and neuroimaging to look for encephalopathic changes. Studies have shown that children with underlying iron deficiency anemia, and exhibiting pica, are more prone to lead toxicity.8

As per the World Health Organization (WHO), primary treatment measures for all children with suspected or confirmed lead exposure include source removal and correction of underlying anemia; while chelation therapy, either oral or parenteral, is recommended for children with BLL >45 mcg/dL.4 Primary chelators include injectable calcium disodium edetate (CaNa2EDTA) and oral succimer, along with injectable dimercaprol and oral D-penicillamine.9 During chelation therapy, it is essential to monitor complete blood counts, liver enzymes, serum electrolytes, and urine routine and microscopy. Children and adolescents with significant neurological features of lead toxicity or lead encephalopathy require urgent admission and parenteral chelation therapy.4

Prevention of lead exposure stands as the cornerstone in decreasing the incidence and mitigating the risks of lead poisoning among children. This necessitates a multidisciplinary approach, involving health workers, governmental bodies, and the general populace. Several countries have enacted legislation, limiting the quantity of lead in paints. Additional methods entail screening asymptomatic children for blood lead levels, conducting dust clearance tests to assess lead levels in household dust, regular maintenance of lead service lines transporting drinking water, and stringent quality regulations for traditional medicines in the market.10

In conclusion, lead poisoning continues to pose a significant threat in current times, and can prove fatal if not promptly identified; hence, it is imperative to conduct blood lead level screenings for children exhibiting nonspecific symptoms and a history of pica.

Furthermore, it is noteworthy that children displaying symptoms of lead encephalopathy may exhibit clinical similarities to conditions

such as ADEM or viral encephalitis. Therefore, in cases where a child is suspected of having encephalopathy, and remains unresponsive to

References

1. Yang Y et al. Chronic lead poisoning induced abdominal pain and anemia: a case report and review of the literature. BMC Gastroenterol. 2020;20(1):335.

2. Global Burden of Disease (GBD) 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the global burden of disease study 2019. Lancet. 2020;396(10258):120422. Erratum in: Lancet. 2020;396(10262):1562.

3. UNICEF. The toxic truth: children’s exposure to lead pollution undermines a generation of future potential. 2020. Available at: https://

conventional therapies, lead poisoning should be considered as a potential differential diagnosis.

www.unicef.org/reports/toxictruth-childrens-exposure-to-leadpollution-2020. Last accessed: 29 June 2023.

4. World Health Organization (WHO). Guideline for clinical management of exposure to lead. 2021. Available at: https://www.who.int/publications/i/ item/9789240037045. Last accessed: 1 March 2024.

5. Rouzi L et al. Lead poisoning with encephalic and neuropathic involvement in a child: case report. Pan Afr Med J. 2022;42:276.

6. Bedi N. Lead toxicity: the unbeaten menace. Indian Pediatr. 2023;60(1):67-9.

7. Sharma S et al. Blood lead level in school going children of Jodhpur,

Rajasthan, India. Turk J Biochem. 2021;46(4):393-8.

8. Słota M et al. Effects of environmental and occupational lead toxicity and its association with iron metabolism. Toxicol Appl Pharmacol. 2022;434:115794.

9. Centre for Disease Control and Prevention (CDC). 2021. Childhood lead poisoning, guidelines and recommendations. Available at: https://www.cdc.gov/nceh/lead/ resources/guidelines.html. Last accessed: 15 January 2023.

10. Council on Environmental Health. Prevention of childhood lead toxicity. Pediatrics. 2016;138(1):e20161493. Erratum in: Pediatrics. 2017;140(2). Erratum in: Pediatrics. 2020;145(6).

Tics Temporally Associated with Mild Traumatic Brain Injury in Pediatric Patients: A Sui Generis Case Series

Authors: S.M. Taslima Yasmin,1 S.M. Taniya Yasmin,1 Mary E. Jenkins,2 *Farah Abdulsatar3,4

1. Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada

2. Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada

3. Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada

4. Children’s Health Research Institute, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada

*Correspondence to fabduls@uwo.ca

Disclosure:

Acknowledgements:

The authors have declared no conflicts of interest. There are no financial relationships relevant to this article to disclose from all the identified authors. Written consents from the families were obtained.

The authors would like to express their gratitude to their patients and their families for recognizing the importance of sharing their clinical cases, thereby contributing to the expansion of knowledge among healthcare providers.

Received: 18.01.24

Accepted: 11.04.24

Keywords: Case report, children, movement disorders, traumatic brain injury (TBI), tics.

Citation: Neurol AMJ. 2024;1[1]:89-93. https://doi.org/10.33590/neurolamj/EPTH6543.

Abstract

Traumatic brain injury (TBI) is a major public health concern in Canada, with falls, blows to the head, car accidents, and sports-related injuries being the leading causes. Post-traumatic movement disorders, such as tics, can occur after a TBI, but their association with mild TBIs has been less explored. This manuscript presents two pediatric cases of de novo tics following mild TBIs, shedding light on this unique phenomenon. Possible mechanisms linking mild TBI and tics, such as genetic predisposition and stress-induced activation of the hypothalamic-pituitary-adrenal axis, are discussed. This paper emphasizes the importance of recognizing tics as a potential consequence of mild TBIs in children, and underscores the need for further research to shed light on the mechanism involved.

Key Points

1. This case report highlights the rare occurrence of de novo tics following mild traumatic brain injury in children, emphasizing the need for clinical awareness, and for differentiation from other movement disorders, which are often misdiagnosed as tics.

2. The manuscript delves into potential mechanisms, such as genetic predisposition and stress-induced hypothalamic-pituitary-adrenal axis activation, illustrating how these factors may contribute to the development of tics after mild traumatic brain injuries.

3. Key takeaways include the importance of considering tics as a potential outcome when evaluating children after concussions, and the need for additional research to develop more effective treatment strategies for these patients.

INTRODUCTION

Traumatic brain injury (TBI) is a significant public health concern in Canada, with falls, blows to the head, car accidents, and sportsrelated injuries being the most common causes.1 TBIs are categorized by severity ranging from mild to severe, based on the presence and intensity of loss of consciousness, cognitive impairment, memory loss, and brain damage.2 Following a TBI, some patients may experience involuntary movements, which can be attributed to various factors, such as immediate injury to the basal ganglia and its connections, delayed consequences of hemosiderin deposits, and abnormal neuroplasticity.3 While tremors, dystonia, chorea, and tics are well known to occur after a severe TBI, tics have been reported in less than 1% of cases.3,4 Post-traumatic tics can either start early, within a few weeks, or late, after several months following TBI.4 The article describes two unique pediatric cases of de novo tics following mild TBIs. These cases are significant, as they demonstrate a close temporal association between concussions and the development of tics, which has not been previously described in the literature. Understanding the potential relationship between mild TBI and tics is important for effective management and care of patients, particularly those with a family history of tics or who may display signs of psychological distress post-TBI. In this paper, the authors discuss the possible etiological factors and potential therapeutic approaches for post-traumatic tics. Additionally, existing theories that attempt to explain the link

between TBI and the onset of tics are explored, considering both genetic predisposition and stress-induced mechanisms.

CASE DESCRIPTION

Case 1

This case involves an 8-year-old girl who presented to the pediatric movement disorders outpatient clinic with a 2-year history of repeated abnormal movements. The patient first exhibited movement disorders approximately 2 years ago, in 2018, when she was 6 years old, following a concussion due to a fall at a park. Post-concussion, she showed symptoms mostly in the form of anxiety, and school refusal, which lasted about 9 months. She did develop headaches that lasted for about 3 weeks, and was tired early on when she developed the concussion. A month after the injury, her parents noticed her repeatedly blinking her eyes, raising her eyebrows, and stretching her face. Over time, these movements intensified, with the blinking of the eye being the initial symptom, followed by facial stretching. The patient did not exhibit any vocal tics, repetitive sounds, or words. According to her parents, the movements worsened when she was focused, stressed, or when these movements were discussed; but they improved when she was engaged in activities such as playing with friends or sports, although they still occurred during these times. The patient herself reported that the movements were triggered when she was excited, and that she felt a sense of relief after they occurred. The patient

herself was aware of her eye blinking tic, which she described as an attempt to “unstick her face.” The tics could be bothersome, especially when reading, but they did not prevent her from carrying out tasks. In the video recordings sent by her parents, she showed repeated blinking, as well as a few episodes of stretching her eyes, mouth, and face, and scratching her nose. These videos were recorded when she was lying down and watching TV, and she was aware that the family was filming her for the tics. There is no family history of any movement or diagnosed psychiatric disorders. The neurological examination was unremarkable, aside from observing motor tics in the form of puckering the lips, consistent with the diagnosis of persistent motor tic disorder. Despite the persistent tics, as the patient reported no disruption in their daily activities at home or school, no medications were initiated. The patient is currently on an annual follow-up with the pediatric movement disorders outpatient clinic.

Case 2

The second case involves a 15-year-old transgender male, who was referred to the concussion clinic due to a year’s history of persistent post-concussion symptoms following a fall from a swing at home. The patient developed concussion symptoms immediately, which included stuttering, dizziness, periods of spacing out, and memory lapses. Additionally, they experienced persistent headaches, which worsened on days with more activities, and poor sleep. Following the concussion, they developed verbal and motor tics soon after, which were absent prior to the incident. The verbal tics include coprolalia, and sounds such as clicks, beats, or ‘hoops’; while the motor tics manifest as head-turning and copropraxia (raising their middle finger). The patient reported that although they could suppress them momentarily, they found it mentally and physically challenging. Releasing the tics provided them with relief. The tics worsened when stressed, when they thought or talked about them, when speaking to strangers, and were triggered by frustration during their art activities; but they improved when they were engaged in non-frustrating art or other activities they enjoyed. At the time of consultation, they reported no significant concern regarding their ability to take part in daily life activities. The patient had a past medical history significant

for gender dysphoria, depression, anxiety, and attention deficit hyperactivity disorder. They had no history of other movement disorders, and denied having any tics prior to the concussion. The patient’s family history was positive for depression, anxiety, migraines, and learning disability. Neurological examination was unremarkable, aside from observed motor and vocal tics, mostly in the form of turning of the head to one side and raising fingers, including the middle finger. Verbal tics included some sounds of coprolalia, as well as some clicking sounds. Given the severity of their tics and the atypical age of onset, an MRI was conducted, which was unremarkable. The patient was started on clonidine, which helped improve their tics. The patient was also started on sertraline, and was referred to psychology for counseling. Eventually, the patient reported improvement in their post-concussion symptoms, and was discharged from the concussion clinic. Their tics persisted, but were managed with clonidine, and they continued to follow-up with their pediatrician.

DISCUSSION

This article presents two unique cases of de novo tics temporally associated with mild TBIs in pediatric patients, which have not been extensively described in the literature. Acquired tics, which include tics due to head trauma, have been reported to be less common in children. Few reports have previously documented tics followed by severe TBI in the pediatric population, while in many cases, other movement disorders, such as chorea, stereotypies, myoclonus, and psychogenic movements have been wrongly labeled as tics. It is important that tics are differentiated from other movement disorders.5

The diagnosis of post-traumatic tics requires a history of documented head trauma, the absence of tics prior to the injury, and the presence of other TBI sequelae.3 While some studies have reported normal brain imaging in patients who developed tics following TBIs,6 an MRI in a case described by Krauss and Jankovic revealed diffuse sub-cortical white matter changes, potentially disrupting connections between basal ganglia and frontal cortex.3

The cause-and-effect relationship between TBI and tics remains uncertain, partly due to the delayed onset of tics post-TBI, but various theories attempt to elucidate this association.

Studies showed that tic disorders occurring 2 weeks–3 months after a mild-to-moderate TBI, with normal brain imaging, may result from altered neuronal receptor sensitivity following the trauma in genetically or behaviourally predisposed individuals.4 Even subtle neuroanatomic or neurophysiologic changes induced externally by mild TBI, can trigger tic disorders in predisposed individuals, which might have otherwise manifested later in life.6-8 A case described by Eriksson et al.9 discusses the emergence of de novo tics 2 months post-injury in a 3-year-old child with a family history of tics, following a rightsided temporal bone fracture.8,9 The underlying genetic processes in such cases remain unclear. In contrast, patients with severe TBI may develop tics several months after the initial injury. These delayed tics may be caused by abnormal neuronal regeneration, or by the delayed impact of injury on the neural circuits connecting the thalamus, basal ganglia, and frontal cortex.3,6 In both the cases discussed above, despite the absence of evident tic predisposition, tics manifested only after mild TBI.

TBI of any severity can lead to various neurobehavioral and psychiatric consequences. Moderate and severe TBI can lead to personality changes, such as irritability, apathy, affective instability, and impulsivity. Even mild TBIs, typically deemed benign, have been associated with psychological distress, such as acute stress disorder, anxiety, and post-traumatic stress disorder.10,11 The causal mechanism linking stress to tic disorders remains elusive, but theories suggest a functional relationship, wherein tics are exacerbated by psychological stress, likely via hypothalamic-pituitary-adrenal (HPA) axis activation due to injury-related stress.12,13 Savino et al.14 presented three pediatric patients without predisposing factors who developed de novo tics after COVID-19 infection, theorizing that overwhelming psychological stress from

the infection hyperstimulated the HPA axis. Dopamine, a crucial neurotransmitter in HPA axis activation, is released during stress, and changes in dopaminergic neurotransmission can influence the expression of tics.15 Dopamine release due to psychological stress may also enhance immunological responses, which can lead to the onset or exacerbation of tics. Additionally, it is possible that individuals with a history of mild TBI have an impaired adaptive ability to environmental stressors and increased perceived stress, with their symptoms being reactions to stress.16 In both of these patients, it is plausible that the tic disorder was triggered by stress from the trauma, and persistent concussion symptoms.

CONCLUSION

Understanding the potential relationship between TBI and tics is vital for better patient management and care. While the neurophysiological link between mild TBI and tics remains unclear, possible mechanisms involving genetic predisposition and stress-induced activation of the HPA axis have been proposed. Clinicians need to be aware of the possibility of tics following mild TBIs in children, especially in those with a family history of tics, or signs of psychological distress post-TBI. Awareness of the latter is particularly important, as it underscores the importance of managing mild TBI as rigorously as other forms of TBI. HannaPlady et al.17 proposed that individuals with a mild TBI history, who are in the post-acute recovery phase and show no symptoms, could benefit from cognitive-behavioral therapies and a structured biofeedback-assisted relaxation program, further suggesting that this approach might prevent the development of post-concussion symptoms. The authors propose that the management of post-traumatic tics should be similar to tics not associated with TBI, as there is a lack of literature that suggests otherwise. Further research in this area is warranted to gain a deeper understanding of the underlying mechanisms, and effective therapeutic approaches for post-traumatic tics.

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17. Hanna-Pladdy B et al. Stress as a diagnostic challenge for postconcussive symptoms: sequelae of mild traumatic brain injury or physiological stress response. Clini Neuropsychol. 2001;15(3):289-304.

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