Innovation and optimization in autoimmune encephalitis trials: the design and rationale for the Phase 3, randomized study of satralizumab in patients with NMDAR-IgG-antibody-positive or LGI1-IgG-antibody-positive autoimmune encephalitis (CIELO).

Background: Autoimmune encephalitis (AIE) encompasses a spectrum of rare autoimmune-mediated neurological disorders, which are characterized by brain inflammation and dysfunction. Autoantibodies targeting the N-methyl-d-aspartic acid receptor (NMDAR) and leucine-rich glioma-inactivated 1 (LGI1) are the most common subtypes of antibody-positive AIE. Currently, there are no approved therapies for AIE. Interleukin-6 (IL-6) signaling plays a role in the pathophysiology of AIE. Satralizumab, a humanized, monoclonal recycling antibody that specifically targets the IL-6 receptor and inhibits IL-6 signaling, has demonstrated efficacy and safety in another autoantibody-mediated neuroinflammatory disease, aquaporin-4 immunoglobulin G antibody-positive neuromyelitis optica spectrum disorder, and has the potential to be an evidence-based disease modifying treatment in AIE. Objectives: CIELO will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of satralizumab compared with placebo in patients with NMDAR-immunoglobulin G antibody-positive (IgG+) or LGI1-IgG+ AIE. Study design: CIELO (NCT05503264) is a prospective, Phase 3, randomized, double-blind, multicenter, basket study that will enroll approximately 152 participants with NMDAR-IgG+ or LGI1-IgG+ AIE. Prior to enrollment, participants will have received acute first-line therapy. Part 1 of the study will consist of a 52-week primary treatment period, where participants will receive subcutaneous placebo or satralizumab at Weeks 0, 2, 4, and every 4 weeks thereafter. Participants may continue to receive background immunosuppressive therapy, symptomatic treatment, and rescue therapy throughout the study. Following Part 1, participants can enter an optional extension period (Part 2) to continue the randomized, double-blind study drug, start open-label satralizumab, or stop study treatment and continue with follow-up assessments. Endpoints: The primary efficacy endpoint is the proportion of participants with a ≥1-point improvement in the modified Rankin Scale (mRS) score from study baseline and no use of rescue therapy at Week 24. Secondary efficacy assessments include mRS, Clinical Assessment Scale of Autoimmune Encephalitis (CASE), time to rescue therapy, sustained seizure cessation and no rescue therapy, Montreal Cognitive Assessment, and Rey Auditory Verbal Learning Test (RAVLT) measures. Safety, pharmacokinetics, pharmacodynamics, exploratory efficacy, and biomarker endpoints will be captured. Conclusion: The innovative basket study design of CIELO offers the opportunity to yield prospective, robust evidence, which may contribute to the development of evidence-based treatment recommendations for satralizumab in AIE.

Brain Volumes in Opsoclonus-Myoclonus Ataxia Syndrome: A Longitudinal Study.

INTRODUCTION: Little is known about the longitudinal trajectory of brain growth in children with opsoclonus-myoclonus ataxia syndrome. We performed a longitudinal evaluation of brain volumes in pediatric opsoclonus-myoclonus ataxia syndrome patients compared with age- and sex-matched healthy children. PATIENTS AND METHODS: This longitudinal case-control study included brain magnetic resonance imaging (MRI) scans from consecutive pediatric opsoclonus-myoclonus ataxia syndrome patients (2009-2020) and age- and sex-matched healthy control children. FreeSurfer analysis provided automatic volumetry of the brain. Paired t tests were performed on the curvature of growth trajectories, with Bonferroni correction. RESULTS: A total of 14 opsoclonus-myoclonus ataxia syndrome patients (12 female) and 474 healthy control children (406 female) were included. Curvature of the growth trajectories of the cerebral white and gray matter, cerebellar white and gray matter, and brainstem differed significantly between opsoclonus-myoclonus ataxia syndrome patients and healthy control children (cerebral white matter, P = .01; cerebral gray matter, P = .01; cerebellar white matter, P < .001; cerebellar gray matter, P = .049; brainstem, P < .01). DISCUSSION/CONCLUSION: We found abnormal brain maturation in the supratentorial brain, brainstem, and cerebellum in children with opsoclonus-myoclonus ataxia syndrome.

Epstein-Barr Virus Strongly Associates With Pediatric Multiple Sclerosis, But Not Myelin Oligodendrocyte Glycoprotein-Antibody-Associated Disease.

Reported rates of Epstein-Barr virus (EBV) seropositivity in children meeting multiple sclerosis (MS) diagnostic criteria are considerably lower than those reported in adult-onset MS, putting in question a requisite role for EBV in MS development. As prior work preceded recognition of myelin oligodendrocyte glycoprotein-associated disease (MOGAD), we assessed viral serologies in 251 children with incident demyelination and prospectively ascertained diagnoses. When MOGAD was serologically accounted for, the prevalence of EBV infection among MS children exceeded 90%, whereas remote EBV infection was not associated with MOGAD risk. Together, these findings substantiate EBV's role across the MS spectrum, and support distinct pathobiological mechanisms in MS versus MOGAD. ANN NEUROL 2024;95:700-705.

Is it ethical to use teriflunomide as an active comparator in phase 3 trials?

Ethical concerns have been raised about the practice of using teriflunomide, an oral licensed disease-modifying therapy, as an active comparator in phase 3 multiple sclerosis (MS) trials. The assumption is based on the perceived low efficacy of teriflunomide as judged by its effect on relapses and focal MRI activity. However, when you look beyond focal inflammation, teriflunomide has a robust impact on disability progression and a similar effect to the anti-CD20 monoclonal antibody therapies on slowing down the accelerated brain volume loss associated with MS. Teriflunomide is also more effective when used second or third line. The other classes of disease-modifying therapies have problems with their use as active comparators in clinical trials. Using a non-inferiority or equivalence trial design has its own unique set of regulatory and ethical challenges and is not necessarily a solution. There are also economic, altruistic and pragmatic reasons for continuing to use teriflunomide as an active comparator in MS clinical trials. An online survey indicates that the majority of the MS community feels it is still ethical to randomise subjects to teriflunomide and that procedures can be put in place to protect trial subjects randomised to teriflunomide. Therefore, we still have equipoise, and teriflunomide comparator trials are ethical.

Chewing gum: alternative therapy to oxygen intolerance.

Rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome is a rare complex disorder associated with alterations in the endocrine system, autonomic nervous system, and respiratory system. Previously published case reports and studies have noted sleep-disordered breathing in patients with ROHHAD syndrome. Nocturnal respiratory manifestations, which if untreated early by respiratory support, may cause cardiorespiratory arrest and a life-threatening condition. More recently, it has been recognized that children with ROHHAD syndrome have central pauses during wakefulness associated with intermittent oxygen desaturations. We report novel findings of a child with ROHHAD syndrome displaying an irregular breathing pattern and significant central pauses associated with oxygen desaturations during wakefulness, whose respiratory status improved while chewing gum. This was used as an alternative to supplemental oxygen therapy. CITATION: Sunkonkit K, Selvadurai S, Yeh EA, Hamilton J, Narang I. Chewing gum: alternative therapy to oxygen intolerance. J Clin Sleep Med. 2022;18(6):1723-1726.

Diagnosis and Management of Opsoclonus-Myoclonus-Ataxia Syndrome in Children: An International Perspective.

BACKGROUND AND OBJECTIVES: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare disorder of the nervous system that classically presents with a combination of characteristic eye movement disorder and myoclonus, in addition to ataxia, irritability, and sleep disturbance. There is good evidence that OMAS is an immune-mediated condition that may be paraneoplastic in the context of neuroblastoma. This syndrome may be associated with long-term cognitive impairment, yet it remains unclear how this is influenced by disease course and treatment. Treatment is largely predicated on immune suppression, but there is limited evidence to indicate an optimal regimen. METHODS: Following an international multiprofessional workshop in 2004, a body of clinicians and scientists comprising the International OMS Study group continued to meet biennially in a joint professionals and family workshop focusing on pediatric OMAS. Seventeen years after publication of the first report, a writing group was convened to provide a clinical update on the definitions and clinical presentation of OMAS, biomarkers and the role of investigations in a child presenting with OMAS, treatment and management strategies including identification and support of long-term sequelae. RESULTS: The clinical criteria for diagnosis were reviewed, with a proposed approach to laboratory and radiologic investigation of a child presenting with possible OMAS. The evidence for an upfront vs escalating treatment regimen was reviewed, and a treatment algorithm proposed to recognize both these approaches. Importantly, recommendations on monitoring of immunotherapy response and longer-term follow-up based on an expert consensus are provided. DISCUSSION: OMAS is a rare neurologic condition that can be associated with poor cognitive outcomes. This report proposes an approach to investigation and treatment of children presenting with OMAS, based on expert international opinion recognizing the limited data available.

APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies.

OBJECTIVE: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations. METHODS: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes. RESULTS: A total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%. CONCLUSIONS: The modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to new research and practices regularly.

An upfront immunomodulatory therapy protocol for pediatric opsoclonus-myoclonus syndrome.

BACKGROUND: Treatment of opsoclonus-myoclonus syndrome (OMS) has historically involved corticosteroids and intravenous immunoglobulin (IVIG) for a duration of 6-12 months or longer. This study evaluated whether a brief upfront immunomodulatory therapy protocol with rituximab reduces the duration of OMS therapy without adversely affecting OMS outcomes. PROCEDURE: Retrospective chart review was performed for consecutive children diagnosed with OMS from 2006 to 2019 at The Hospital for Sick Children (Toronto, Canada). Children treated within 3 months of diagnosis with a treatment protocol involving pulse methylprednisolone (3-5 days, followed by an oral steroid taper), IVIG and/or plasma exchange, and rituximab (protocol group, n = 7) were compared to a historical group treated primarily with prednisone and IVIG (n = 8). RESULTS: The duration of corticosteroid treatment was shorter in the protocol (median 4.5 [range 3-12] months) compared to that in the historical group (median 21.5 [range 6-70] months, P = .005), and subjects in the protocol group received fewer cycles of IVIG (median 1 [range 0-7] cycle vs 7 [range 1-70] cycles, P = .01). The proportion of children with OMS relapse was similar between the protocol and historic groups (2/6 vs 5/8, P = .59). OMS symptom rating scales at 12-month follow-up were similar in the protocol group (median 2.5, range 0-3) compared to that in the historical group (median 1, range 0-7; P = .66). CONCLUSIONS: An upfront immunomodulatory therapy protocol with rituximab permits reduction in the duration of corticosteroid and IVIG therapy without a detrimental effect on OMS outcomes. Future studies with longer follow-up will have to determine whether neurocognitive and psychosocial outcomes are improved by this approach.

Evaluation and treatment of Langerhans cell histiocytosis patients with central nervous system abnormalities: Current views and new vistas.

Central nervous system (CNS) involvement in Langerhans cell histiocytosis (LCH) can include mass lesions of the hypothalamic pituitary axis, choroid plexus, cerebrum, and cerebellum or magnetic resonance imaging (MRI) signal abnormalities of the cerebellum, pons, and basal ganglia. The term neurodegenerative (ND) CNS-LCH has been given to the MRI signal abnormalities and neurologic dysfunction, although initially patients may have no clinical symptoms. Standardized evaluations to better understand the natural history and response to therapy are needed. We propose guidelines for clinical, radiologic, and physiologic tests as a framework for developing the best methods of evaluation, which can then be tested in prospective treatment protocols.

How to Treat Involvement of the Central Nervous System in Hemophagocytic Lymphohistiocytosis?

OPINION STATEMENT: Central nervous system (CNS)-hemophagocytic lymphohistiocytosis (HLH) is not a disease in itself, but it is part of a systemic immune response. The vast majority of patients with CNS-HLH also have systemic HLH and a large number of patients with primary and secondary HLH have CNS involvement. Reactivations within the CNS are frequent during the course of HLH treatment and may occur concomitant with or independent of systemic relapses. It is also important to consider primary HLH as an underlying cause of "unknown CNS inflammation" as these patients may present with only CNS disease. To initiate proper treatment, a correct diagnosis must be made. A careful review of the patient's history and a thorough neurological examination are essential. In addition to the blood tests required to make a diagnosis of HLH, a lumbar puncture with cerebrospinal fluid (CSF) analysis and magnetic resonance imaging (MRI) should always be done in all cases regardless of the presence or absence of neurological signs or symptom. Treatment options for CNS-HLH include, but are not limited to, those commonly used in systemic HLH, including corticosteroids, etoposide, cyclosporine A, alemtuzumab, and ATG. In addition, intrathecal treatment with methotrexate and corticosteroids has become a standard care and is likely to be beneficial. Therapy must be initiated without inappropriate delay to prevent late effects in HLH. An interesting novel approach is an anti-IFN-gamma antibody (NI-0501), which is currently being tested. Hematopoietic stem cell transplantation (HSCT) also represents an important CNS-HLH treatment; patients with primary HLH may benefit from immediate HSCT even if there is active disease at time of transplantation, though care should be taken to monitor CNS inflammation through HSCT and treat if needed. Since CNS-HLH is a condition leading to the most severe late effects of HLH, early expert consultation is recommended.

ROHHAD syndrome and evolution of sleep disordered breathing.

BACKGROUND: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) is a rare disease with a high mortality rate. Although nocturnal hypoventilation (NH) is central to ROHHAD, the evolution of sleep disordered breathing (SDB) is not well studied. The aim of the study was to assess early manifestations of SDB and their evolution in ROHHAD syndrome. METHODS: Retrospective study of children with ROHHAD at two Canadian centers. All children with suspected ROHHAD at presentation underwent polysomnography (PSG) to screen for nocturnal hypoventilation. PSG findings at baseline and follow-up were collected. Interventions and diagnostic test results were recorded. RESULTS: Six children were included. The median age of rapid onset obesity and nocturnal hypoventilation (NH) was 3.5 and 7.2 years respectively. On initial screening for ROHHAD 4/6 (66.7 %) children had obstructive sleep apnea (OSA), 1/6 (16.7 %) had NH and 1/6 (16.7 %) had both OSA and NH. Follow up PSGs were performed in 5/6 children as one child died following a cardiorespiratory arrest. All children at follow up had NH and required non-invasive positive pressure ventilation. Additionally, 3/6 (50 %) children demonstrated irregular breathing patterns during wakefulness. CONCLUSIONS: Children with ROHHAD may initially present with OSA and only develop NH later as well as dysregulation of breathing during wakefulness. The recognition of the spectrum of respiratory abnormalities at presentation and over time may be important in raising the index of suspicion of ROHHAD. Early recognition and targeted therapeutic interventions may limit morbidity and mortality associated with ROHHAD.