MOG and AQP4 Antibodies among Children with Multiple Sclerosis and Controls.

OBJECTIVE: The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among patients with pediatric-onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG-IgG-associated disease (MOGAD), and identify clinical features associated with final diagnosis. METHODS: Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case-control study on POMS risk factors. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays. RESULTS: AQP4-IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG-IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty-five of 30 patients positive with MOG-IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re-review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p = 0.044), younger age (mean = 8.2 ± 4.2 vs 14.7 ± 2.6 years; p < 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p = 0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p < 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p = 0.002), serum Epstein-Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p < 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p < 0.001). INTERPRETATION: MOG-IgG and AQP4-IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4-IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2023;93:271-284.

Pediatric multiple sclerosis.

PURPOSE OF REVIEW: This review discusses the epidemiologic factors involved in the pathogenesis of pediatric multiple sclerosis (MS), which have been the focus of numerous studies in the last several years. We also review the clinical features (including diagnostic evaluation and differential diagnosis) of, treatment approach to, and prognosis of pediatric MS. RECENT FINDINGS: Up to 10% of patients with MS have their initial demyelinating before the age of 18 years. Over the past 15 years, international and collaborative studies have identified an increasing number of genetic and environmental risk factors for pediatric MS. Identification of these risks and their interplay allow for better understanding of the pathophysiology of pediatric MS, which may inform subsequent treatment and disease management. Careful attention to the management of relapses and chronic symptoms, including implementation of lifestyle modifications and pharmacologic interventions, enables improved school performance and quality of life. SUMMARY: Ongoing research in the field of pediatric MS aims to better understand the epidemiologic factors involved in the pathobiology, safety and efficacy of disease-modifying treatments, and long-term prognosis, particularly of cognitive development and academic potential. Collaborative, multinational studies will enable the advancements needed to truly optimize clinical care for this population.

Acute disseminated encephalomyelitis following meningoencephalitis: case report and literature review.

Meningoencephalitis and acute disseminated encephalomyelitis (ADEM) are both neurological disease processes, but there have been few cases of meningoencephalitis progressing to ADEM in the pediatric population. A case of a 4-year-old girl with an initial diagnosis of meningoencephalitis is presented here, whose initial presentation was manifested by prolonged fever, gray matter signal abnormality on brain magnetic resonance imaging, cerebrospinal fluid pleocytosis, and a markedly irritable mental status. As her neurological examination changed with focal abnormalities, a repeat magnetic resonance imaging demonstrated new areas of both gray and white matter signal abnormality, consistent with ADEM. Her symptoms and imaging findings completely resolved with a course of methylprednisolone. Based on the literature and this current case, it is our recommendation to consider ADEM as a diagnosis if meningoencephalitis is not improving.

The diagnostic workup of children with the radiologically isolated syndrome differs by age and by sex.

BACKGROUND: Cerebrospinal fluid (CSF) and spinal MRIs are often obtained in children with the radiologically isolated syndrome (RIS) for diagnosis and prognosis. Factors affecting the frequency and timing of these tests are unknown. OBJECTIVE: To determine whether age or sex were associated with (1) having CSF or spinal MRI obtained or (2) the timing of these tests. METHODS: We analyzed children (≤ 18 y) with RIS enrolled in an international longitudinal study. Index scans met 2010/2017 multiple sclerosis (MS) MRI criteria for dissemination in space (DIS). We used Fisher's exact test and multivariable logistic regression (covariates = age, sex, MRI date, MRI indication, 2005 MRI DIS criteria met, and race). RESULTS: We included 103 children with RIS (67% girls, median age = 14.9 y). Children ≥ 12 y were more likely than children < 12 y to have CSF obtained (58% vs. 21%, adjusted odds ratio [AOR] = 4.9, p = 0.03). Pre-2017, girls were more likely than boys to have CSF obtained (n = 70, 79% vs. 52%, AOR = 4.6, p = 0.01), but not more recently (n = 30, 75% vs. 80%, AOR = 0.2, p = 0.1; p = 0.004 for interaction). Spinal MRIs were obtained sooner in children ≥ 12 y (median 11d vs. 159d, p = 0.03). CONCLUSIONS: Younger children with RIS may be at continued risk for misdiagnosis and misclassification of MS risk. Consensus guidelines are needed.

Transition of Care to Adult Neuroimmunology.

A structured health care transition is essential for adolescents with chronic disease to ensure continuity of care without treatment lapse. Though rare, multiple sclerosis is diagnosed in children and adolescents and these patients will eventually require transition to adult care in late adolescence and early adulthood. Some barriers to transition include limited independence of the adolescent, fear of an unknown adult care model, and difficulty ending close relationships with longstanding pediatric providers. For optimal success, transition planning should be started in the early teenage years, and graduated independence and self-management skills should be fostered over time. Providers should also be aware of the developmental evolution of adolescents when assessing transition readiness and should screen for barriers during routine clinic visits to ensure that these are addressed prior to the time of transfer.

Invasive Multimodality Neuromonitoring to Manage Cerebral Edema in Pediatric Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an inflammatory disorder of the CNS with a variety of clinical manifestations, including cerebral edema. Case Summary: A 7-year-old boy presented with headaches, nausea, and somnolence. He was found to have cerebral edema that progressed to brainstem herniation. Invasive multimodality neuromonitoring was initiated to guide management of intracranial hypertension and cerebral hypoxia while he received empiric therapies for neuroinflammation. Workup revealed serum myelin oligodendrocyte glycoprotein antibodies. He survived with a favorable neurologic outcome. Conclusion: We describe a child who presented with cerebral edema and was ultimately diagnosed with MOGAD. Much of his management was guided using data from invasive multimodality neuromonitoring. Invasive multimodality neuromonitoring may have utility in managing life-threatening cerebral edema due to neuroinflammation.

Validation of claims-based diagnoses of adult and pediatric neuromyelitis optica spectrum disorder and variations in diagnostic evaluation and treatment initiation.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare demyelinating disease in need of more studies to determine effective treatment regimens. The rarity of the disorder, however, makes large randomized-controlled trials challenging. Validation of the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code for NMO could facilitate the use of large healthcare claims data for future research. We aimed 1) to determine the positive predictive value (PPV) of the ICD-9-CM code for NMO as well as evaluate case-finding algorithms for the identification of patients with NMO/NMOSD and 2) to compare the evaluation of and treatment for pediatric versus adult patients. METHODS: This was a multicenter retrospective cohort study of patients with ≥ 1 ICD-9 code for NMO seen at 3 pediatric and 2 adult United States medical centers from 2001-2016. Using a standardized data entry form, pediatric and adult neurologists and rheumatologists reviewed patients' medical records to determine whether patients fulfilled the 2006 criteria for NMO and/or the 2015 criteria for NMOSD in order to determine the positive predictive value (PPV) for the ICD-9-CM code. Demographic and clinical information was abstracted from patient medical records to ascertain variables then evaluated in case-based finding algorithms for further identification of patients with true NMO/NMOSD. We also evaluated differences in clinical characteristics between pediatric and adult patients using chi-squared or Fisher's exact tests, as appropriate, to assess for treatment variation. RESULTS: A single code for NMO had a PPV of 47% across all sites, with significant site variation (0-77%). The best case-finding algorithm included at least 5 codes as well as a documented hospitalization (PPV = =90% for children and PPV = 92% for adults). Children were more likely to be evaluated by a rheumatologist or ophthalmologist, undergo magnetic resonance imaging of the orbits, and receive immunosuppressive and biologic agents than their adult counterparts. Rituximab was administered similarly among the two groups. CONCLUSION: The ICD-9 code for neuromyelitis optica (NMO) is inaccurate for identification of NMO/NMOSD. Using case-finding algorithms increases the PPV. The initial diagnostic evaluation and treatment of NMOSD differs significantly between children and adults.

Validation of a symptom-based questionnaire for pediatric CNS demyelinating diseases.

PURPOSE: Optic neuritis is a manifestation of numerous neuroinflammatory disorders. Recognition of current and prior symptoms may facilitate identification of an underlying multifocal neurologic disease. The purpose of this study was to determine whether a symptom-based questionnaire could inform clinical decision making by identifying children with visual complaints who may have a systemic demyelinating disorder. METHODS: Children with visual changes from non-demyelinating disease were compared with patients with confirmed pediatric-onset multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD). Participants completed a 21-item questionnaire to capture their recent (<30 days) and remote (>30 days) symptoms of neurologic dysfunction. The questionnaire scores were compared using t tests, and the 95% confidence interval for each group was used to determine a threshold score suggesting demyelinating disease. RESULTS: We enrolled 51 participants (30 females [59%]) with a mean age of 14.6 years (range, 4-21): 25 in the non-demyelinating disease group and 26 with MS/NMOSD. The mean questionnaire score for the non-demyelinating group was 5.0 points (95% CI, 3.3-6.9); for the MS/NMOSD group, 9.4 points (95% CI, 7.4-11.4) for the MS/NMOSD group (P < 0.002). Questionnaire results were dichotomized using a score of ≥7 as indicative of demyelinating disease, with 69% sensitivity and 72% specificity. An abbreviated questionnaire, using 8 questions that differed between groups, had a sensitivity of 65% and specificity of 92%. CONCLUSIONS: A symptom-based questionnaire is sensitive and specific for identifying children with CNS demyelinating disease and may be useful as a screening tool for children with vision complaints and possible demyelination.

Oligoclonal bands increase the specificity of MRI criteria to predict multiple sclerosis in children with radiologically isolated syndrome.

BACKGROUND: Steps towards the development of diagnostic criteria are needed for children with the radiologically isolated syndrome to identify children at risk of clinical demyelination. OBJECTIVES: To evaluate the 2005 and 2016 MAGNIMS magnetic resonance imaging criteria for dissemination in space for multiple sclerosis, both alone and with oligoclonal bands in cerebrospinal fluid added, as predictors of a first clinical event consistent with central nervous system demyelination in children with radiologically isolated syndrome. METHODS: We analysed an international historical cohort of 61 children with radiologically isolated syndrome (≤18 years), defined using the 2010 magnetic resonance imaging dissemination in space criteria (Ped-RIS) who were followed longitudinally (mean 4.2 ± 4.7 years). All index scans also met the 2017 magnetic resonance imaging dissemination in space criteria. RESULTS: Diagnostic indices (95% confidence intervals) for the 2005 dissemination in space criteria, with and without oligoclonal bands, were: sensitivity 66.7% (38.4-88.2%) versus 72.7% (49.8-89.3%); specificity 83.3% (58.6-96.4%) versus 53.9% (37.2-69.9%). For the 2016 MAGNIMS dissemination in space criteria diagnostic indices were: sensitivity 76.5% (50.1-93.2%) versus 100% (84.6-100%); specificity 72.7% (49.8-89.3%) versus 25.6% (13.0-42.1%). CONCLUSIONS: Oligoclonal bands increased the specificity of magnetic resonance imaging criteria in children with Ped-RIS. Clinicians should consider testing cerebrospinal fluid to improve diagnostic certainty. There is rationale to include cerebrospinal fluid analysis for biomarkers including oligoclonal bands in planned prospective studies to develop optimal diagnostic criteria for radiologically isolated syndrome in children.

7T MRI Visualization of Cortical Lesions in Adolescents and Young Adults with Pediatric-Onset Multiple Sclerosis.

BACKGROUND: Cortical pathology in multiple sclerosis (MS) has been associated with prolonged and progressive disease. 7T magnetic resonance imaging (MRI) provides enhanced visualization of cortical lesions (CLs). Hence, we conducted a pilot study to explore whether CLs occur early in MS, as evidenced by pediatric-onset patients. METHODS: A total of 8 pediatric-onset MS patients were imaged using 7T MRI. CLs were annotated on T1-weighted magnetization-prepared rapid acquisition of gradient echoes images as leukocortical (LC), intracortical, or subpial. Total CLs, age at onset, age at scan, disease duration, total relapses, and Expanded Disability Status Scale (EDSS) score were recorded. RESULTS: A median of 120 (range: 48-144) CLs was identified in 8 MS patients (3 female, all with relapsing remitting MS, mean age at scan 21 years ± 3.5 SD, mean age of disease onset 15 years ± 2.3 SD, mean disease duration 5.3 years ± 3.4 SD, median EDSS 2.0). Nearly all the lesions identified were LC. CONCLUSIONS: Many CLs are detectable using 7T MRI in patients with pediatric-onset MS despite relatively brief disease duration, absence of progressive disease, and very limited physical disability-supporting early cortical involvement in MS.

Radiologically isolated syndrome in children: Clinical and radiologic outcomes.

OBJECTIVE: To describe clinical and radiologic outcomes of children with incidental findings on neuroimaging suggestive of CNS demyelination (termed "radiologically isolated syndrome" or RIS). METHODS: Clinical and radiologic data were obtained from a historical cohort of children with no symptoms of demyelinating disease who had MRI scans that met the 2010 MRI criteria for dissemination in space for MS. RESULTS: We identified 38 children (27 girls and 11 boys) with RIS now being prospectively followed at 16 sites in 6 countries. The mean follow-up time was 4.8 ± 5.3 years. The most common reason for initial neuroimaging was headache (20/38, 53%). A first clinical event consistent with CNS demyelination occurred in 16/38 children (42%; 95% confidence interval [CI]: 27%-60%) in a median of 2.0 years (interquartile range [IQR] 1.0-4.3 years). Radiologic evolution developed in 23/38 children (61%; 95% CI: 44%-76%) in a median of 1.1 years (IQR 0.5-1.9 years). The presence of ≥2 unique oligoclonal bands in CSF (hazard ratio [HR] 10.9, 95% CI: 1.4-86.2, p = 0.02) and spinal cord lesions on MRI (HR 7.8, 95% CI: 1.4-43.6, p = 0.02) were associated with an increased risk of a first clinical event after adjustment for age and sex. CONCLUSIONS: We describe the clinical characteristics and outcomes of children with incidental MRI findings highly suggestive of CNS demyelination. Children with RIS had a substantial risk of subsequent clinical symptoms and/or radiologic evolution. The presence of oligoclonal bands in CSF and spinal cord lesions on MRI were associated with an increased risk of a first clinical event.

New Perspectives in Pediatric Neurology-Multiple Sclerosis.

With the creation of consensus definitions for pediatric multiple sclerosis (MS) and other acquired demyelinating syndromes, there has been an increased recognition, improved collaboration, and expanded access to care for children with central nervous system demyelination. As a result, clinicians and researchers have been able to learn more about clinical features specific to pediatric MS, the associated genetic and environmental risk factors, and its prognosis and comorbidities. Treatment options have also expanded significantly in the past few years and insight has been gained into the challenges with adherence and tolerability of these medications in the pediatric population. Emerging therapies are now being studied in the context of pediatric clinical trials and may prove to be safe and effective options for patients with aggressive disease.

Pediatric multiple sclerosis: updates in epidemiology, clinical features and management.

Consensus definitions for acute demyelinating syndromes in children have led to increased recognition of pediatric multiple sclerosis and improved our understanding of its pathogenesis, epidemiology and treatment. An estimated 2-10% of MS patients experience their first clinical symptom in childhood. Multiple genetic and environmental risk factors have been identified in the pathogenesis of pediatric MS, although further research to determine their interplay is required. Clinical trials of emerging disease-modifying therapies in children are nearing completion. Additional treatment options are expected to bring associated challenges. As pediatric MS remains relatively uncommon overall, international collaboration is essential to facilitate research.

Pediatric Demyelination.

PURPOSE OF REVIEW: This review summarizes a general approach to pediatric demyelination as well as specific features of each of the acquired demyelinating syndromes to help clinicians in their evaluation of children with these disorders. Case studies are included to illustrate the expanding phenotype of many of these syndromes. RECENT FINDINGS: With the creation of consensus definitions for the pediatric acquired demyelinating syndromes, recognition of demyelination in children has increased, as has understanding of the clinical and radiologic features, prognosis, and response to treatment. Collaborative studies and multicenter clinical trials are ongoing and needed to appropriately evaluate emerging therapies for some of the chronic demyelinating disorders, such as multiple sclerosis and neuromyelitis optica (NMO) spectrum disorder. SUMMARY: This review will aid the clinician in identifying key features of the pediatric acquired demyelinating syndromes and highlights a general approach for the diagnosis and treatment of these disorders.

Treatment of multiple sclerosis in children and its challenges.

Though pediatric-onset multiple sclerosis (MS) is a rare disease, providers must be aware of the diagnosis, and of symptoms that herald demyelination, in order to initiate prompt workup and treatment in the appropriate clinical scenarios. Though children with MS do not have significant physical disability at onset, at least a third of patients have cognitive deficits at the time of diagnosis and demonstrate worsening cognitive functioning over time. Pediatric MS patients tend to have high relapse rates and high lesion volumes early in their disease course and warrant early initiation of disease modifying therapy. This review discusses the different treatment options available for pediatric patients with MS, emerging medications, and some of the challenges associated with treating this patient population.

Treatment of pediatric multiple sclerosis.

OPINION STATEMENT: The past 10 years have borne witness to increased recognition and diagnosis of pediatric multiple sclerosis (MS). Additionally, during this time period, the number of treatment options available for MS patients has increased significantly, as has the number of studies evaluating the use of these therapies in children. Though the U.S. Food and Drug Administration has not formally approved any of these therapies for use in pediatric MS, a number of injectable, oral, and intravenous treatments are currently being used off-label in these children. Disease modifying therapy should be initiated promptly following a diagnosis of MS. The patient and family should be engaged in the choice of therapy as this is likely to promote adherence. First-line options include any of the injectable therapies (glatiramer acetate, interferon beta), which have roughly similar efficacy (approximately 30 % reduction of clinical relapses). If a patient has breakthrough disease or persistent, unmanageable side effects, transition to a different first-line therapy or escalation to a second-line therapy, such as natalizumab, should be considered. Though the efficacy of second-line agents is higher, the potential risk of serious adverse effects also increases. New therapies, including oral agents, are now being rigorously studied with pediatric clinical trials and may provide safe alternatives for patients that are either unresponsive or intolerant to currently available medications. When necessary, acute exacerbations can be treated with corticosteroids. Intravenous methylprednisolone at a dosage of 30 mg/kg/day (maximum dose 1000 mg/day) for 3-5 days is recommended with severe attacks. If patients are unresponsive to corticosteroids, treatment with either intravenous immunoglobulin or plasma exchange may be required. Fatigue, spasticity, and pain can also occur in pediatric patients with MS. Medications are needed if symptoms are severe and impact quality of life.

Elevated cerebrospinal fluid opening pressure in a pediatric demyelinating disease cohort.

BACKGROUND: Cerebrospinal fluid opening pressure is elevated with central nervous system infection and vasculitis, but has not been studied in inflammatory demyelinating disease. This retrospective study sought to determine whether children with demyelinating disease demonstrate elevated cerebrospinal fluid opening pressure, and to explore possible clinical and radiologic correlates. METHODS: Pediatric patients with acute disseminated encephalomyelitis, multiple sclerosis, or a clinically isolated syndrome (including optic neuritis and transverse myelitis) who had a lumbar puncture within 1 month of presentation were eligible for inclusion, and were compared with a reference cohort of healthy children from the same institution. Regression analyses were used to determine the association of variables collected with opening pressure. RESULTS: Opening pressure was elevated in 15 of 53 (28%) children, which was significantly higher than the reference cohort (P = 0.001). There was no relationship between elevated opening pressure and any of the clinical or radiologic variables collected. CONCLUSION: Although almost one third of children with inflammatory demyelinating disease have an elevated cerebrospinal fluid opening pressure, the clinical and radiologic variables evaluated in this study did not explain this finding, and further understanding may require assessment of cerebrospinal fluid flow dynamics.

Status epilepticus and refractory status epilepticus management.

Status epilepticus (SE) describes persistent or recurring seizures without a return to baseline mental status and is a common neurologic emergency. SE can occur in the context of epilepsy or may be symptomatic of a wide range of underlying etiologies. The clinician's aim is to rapidly institute care that simultaneously stabilizes the patient medically, identifies and manages any precipitant conditions, and terminates seizures. Seizure management involves "emergent" treatment with benzodiazepines followed by "urgent" therapy with other antiseizure medications. If seizures persist, then refractory SE is diagnosed and management options include additional antiseizure medications or infusions of midazolam or pentobarbital. This article reviews the management of pediatric SE and refractory SE.