Clinical features and outcomes in children with seronegative autoimmune encephalitis.

AIM: To characterize the presenting features and outcomes in children with seronegative autoimmune encephalitis, and to evaluate whether scores at nadir for the Modified Rankin Scale (mRS) and Clinical Assessment Scale for Autoimmune Encephalitis (CASE) or its paediatric-specific modification (ped-CASE) are predictive of outcomes. METHOD: This observational study included children younger than 18 years of age with seronegative autoimmune encephalitis. Demographics and clinical data were collected. The mRS and CASE/ped-CASE scores were used to evaluate disease severity. Descriptive statistics and logistic regression were used for data analysis and to evaluate associations between scale scores and outcomes. RESULTS: Sixty-three children were included (39 [62%] females, median age 7 years, interquartile range [IQR] 4 years 1 months-11 years 6 months), with follow-up available for 56 out of 63 patients (median follow-up 12.2 months, IQR 13.4-17.8). The most frequent presenting neurological manifestation was encephalopathy (81%). Median CASE/ped-CASE and mRS scores at nadir were 12.0 (IQR 7.0-17.0) and 1.0 (IQR 0-2.0) respectively. Thirty-three patients (59%) had persistent neurological deficits at follow-up. Both scoring systems suggested good functional recovery (mRS score ≤2, 95%; CASE/ped-CASE score <5, 91%). CASE/ped-CASE score was more likely than mRS to distinguish children with worse outcomes. INTERPRETATION: Children with seronegative autoimmune encephalitis are likely to have neurological deficits at follow-up. CASE/ped-CASE is more likely to distinguish children with worse outcomes than MRS.

Rituximab for Pediatric Central Nervous System Inflammatory Disorders in Alberta, Canada.

BACKGROUND: Early and effective treatment of central nervous system (CNS) inflammatory disorders is vital to reduce neurologic morbidity and improve long-term outcomes in affected children. Rituximab is a B-cell-depleting monoclonal antibody whose off-label use for these disorders is funded in the province of Alberta, Canada, by the Short-Term Exceptional Drug Therapy (STEDT) program. This study describes the use of rituximab for pediatric CNS inflammatory disorders in Alberta. METHODS: Rituximab applications for CNS inflammatory indications in patients <18 years of age were identified from the STEDT database between January 1, 2012, and December 31, 2019. Patient information was linked to other provincial datasets including the Discharge Abstract Database, Pharmaceutical Information Network, and Provincial Laboratory data. Analysis was descriptive. RESULTS: Fifty-one unique rituximab applications were identified, of which 50 were approved. New applications increased from one in 2012 to a high of 12 in 2018. The most common indication was autoimmune encephalitis without a specified antibody (n = 16, 31%). Most children were approved for a two-dose (n = 33, 66%) or four-dose (n = 16, 32%) induction regimen. Physician-reported outcomes were available for 24 patients, of whom 14 (58%) were felt to have fully met outcome targets. CONCLUSION: The use of rituximab for pediatric CNS inflammatory disorders has increased, particularly for the indication of autoimmune encephalitis. This study identified significant heterogeneity in dosing practices and laboratory monitoring. Standardized protocols for the use of rituximab in these disorders and more robust outcome reporting will help better define the safety and efficacy of rituximab in this population.

Trends in the Epidemiology and Treatment of Pediatric-Onset Multiple Sclerosis in Alberta, Canada.

BACKGROUND: Fingolimod became the first disease-modifying therapy approved by Health Canada for pediatric multiple sclerosis in 2018, but the impact of that approval on treatment patterns in Canada is unknown. The aim of this study was to describe trends in the epidemiology and treatment of pediatric-onset multiple sclerosis in Alberta, Canada. METHODS: This study entailed a retrospective review of administrative health databases using 2 case definitions of multiple sclerosis. Those <19 years of age at a date of diagnosis between January 1, 2011, and December 31, 2020, were included. Incidence and prevalence estimates were calculated and stratified by sex and age cohort. Pharmacy dispenses of disease-modifying therapies were identified. RESULTS: 106 children met one or both case definitions. In 2020, the age-standardized incidence using the 2 case definitions was 0.47 and 0.57 per 100 000, and the age-standardized prevalence was 2.84 and 3.41 per 100 000, respectively. Seventy-nine incident cases were identified, 38 (48%) of whom were dispensed a disease-modifying therapy prior to age 19 years. Injectables accounted for all initial pediatric disease-modifying therapy dispenses prior to 2019, whereas in 2019-2020 injectables accounted for only 3 of 15 (20%) initial dispenses, and instead B-cell therapies were the most common initial disease-modifying therapy (6 of 15, 40%). In 2020, B-cell therapies were the most common disease-modifying therapy dispensed overall (9 of 22 dispenses, 41%) followed by fingolimod (6 of 22, 27%). CONCLUSION: The treatment of children with multiple sclerosis in Alberta has evolved, with a rapid shift in 2019 away from injectables to newer agents, although B-cell therapies-not fingolimod-are now most commonly dispensed.

Progressive retinal changes in pediatric multiple sclerosis.

Objectives To determine to what extent acute demyelinating episodes versus chronic degenerative phenomena drive retinal neuroaxonal damage in pediatric acquired demyelinating syndromes (ADS). Methods We acquired optical coherence tomography (OCT) data (follow-up range: 2 weeks - 5 years, at variable intervals from presentation) in pediatric participants who had multiple sclerosis (MS), monophasic ADS, or were healthy. Multivariable mixed effects models were used to assess the association of the number of demyelinating episodes (either optic neuritis [ON], or non-ON relapses) with changes in retinal nerve fiber layer (RNFL) or ganglion cell layer-inner plexiform layer (GCIPL) thickness. Results 64 OCT sans from 23 MS, and 33 scans from 12 monophasic ADS participants were compared with 68 scans from 62 healthy participants. The first ON episode had the biggest impact on RNFL or GCIPL thickness in monophasic ADS (RNFL: -7.9 µm, CI=5.5, p = 0.0056; GCIPL: -8.4 µm, CI=4.4, p = 0.0002) and MS (RNFL: -16 µm, CI = 3.7, p < 10-6; GCIPL: -15 µm, CI = 2.6, p < 10-6). Non-ON relapses were also associated with small but significant retinal thickness reductions in MS (RNFL: -2.6 µm/relapse, CI = 1.4, p = 0.0003; GCIPL: -2.8 µm/relapse, CI = 0.89, p < 10-6). MS participants showed progressive GCIPL thinning independent of acute demyelinating episodes (-2.7 µm/year, CI = 1.9, p = 0.0058). Conclusions We showed a prominent impact of early ON episodes on OCT measures of neuroaxonal structure in patients with ADS. We also demonstrated negative effects of non-ON relapses, and the presence of chronic retinal neurodegenerative changes, in youth with MS.

Rituximab in children with myelin oligodendrocyte glycoprotein antibody and relapsing neuroinflammatory disease.

The aim of this study was to evaluate tolerability of and response to rituximab in children with myelin oligodendrocyte glycoprotein (MOG) antibody-positive relapsing neuroinflammatory disease. This was an observational study of prospectively collected data on 12 consecutive children (eight females, four males; median age at onset 10y 6mo [interquartile range {IQR} 7y 2mo-12y 5mo], median follow-up 2y 1mo [IQR 1y 7mo-2y 6mo]) with central nervous system inflammation and persistent serum MOG immunoglobulin G positivity more than 12 weeks after clinical presentation. Patients received a standardized rituximab treatment protocol. MOG antibody testing was performed following standardized cell-based methods. Median clinical follow-up after rituximab induction was 2 years (IQR 1y 7mo-2y 10mo). The relapse rate in the first 12 months posttreatment was 0 (IQR 0-0). After rituximab, two patients relapsed during B-cell suppression and four showed clinical or radiological disease recurrences at B-cell reconstitution. Mild-to-moderate infusion related adverse events occurred in two patients. Leukopenia developed in seven patients and serum immunoglobulin suppression in five patients with no significant age effect on the risk of their development. None developed severe life-threatening events. Rituximab-induced B-cell suppression was associated with absence of relapses in 10 patients who were MOG-positive with recurrent disease. Rituximab was well tolerated. The most frequent adverse effects were hypogammaglobulinemia and leukopenia. We recommend monitoring of complete blood counts and immunoglobulins in this population. WHAT THIS PAPER ADDS: Rituximab appears to control disease in most anti-myelin oligodendrocyte glycoprotein-positive patients with relapsing neuroinflammatory disease. Rituximab was associated with transitory, mild-to-moderate infusion-related effects. Half of patients treated with rituximab developed leukopenia or hypogammaglobulinemia. No opportunistic infections were observed.

Early neuroaxonal injury is seen in the acute phase of pediatric optic neuritis.

BACKGROUND: Thinning of the retinal nerve fiber layer (RNFL) and ganglion cell/inner plexiform layer (GCIPL) occur in the chronic phase after optic neuritis (ON) in children and reflect neuroaxonal injury. The objective of this study was to describe changes in RNFL and GCIPL thickness in the acute phase following pediatric ON. METHODS: Data were collected prospectively from consecutive children presenting with ON as part of an incident acquired demyelinating event. Children with a final diagnosis of multiple sclerosis (n = 9, 10 ON-affected eyes) or monophasic demyelination (n = 16, 25 ON-affected eyes) who underwent spectral-domain optical coherence tomography (OCT) testing within 30 days of symptom onset were included. Standardized visual assessment was performed at presentation and 6-18 months follow-up. OCT measures were compared to those of healthy controls (n = 25, 50 eyes). RESULTS: Median (interquartile range [IQR]) global RNFL thickness was increased in ON-affected eyes (155 µm [114-199 µm]) compared to control eyes (104 µm [98.5-107.5 µm]; p < 0.0001). Compared to controls, fellow eyes demonstrated a reduced temporal quadrant RNFL thickness (59 µm [53-72 µm] versus 71.5 µm [65-81 µm]; p = 0.013) and lower GCIPL thickness (80.5 µm [74-88 µm] versus 87 µm [85-89 µm]; p = 0.003). The ON-affected eyes of children with monophasic demyelination demonstrated a greater global RNFL thickness (183.5 µm [146.5-206 µm]) compared to the ON-affected eyes of children with multiple sclerosis (108.5 µm [95-124 µm]; p = 0.01). OCT measures at presentation did not predict low-contrast visual acuity nor color vision at 6-18 months follow-up. CONCLUSION: Children with multiple sclerosis show less RNFL swelling in their ON-affected eyes at onset compared to children with monophasic demyelination. Lower GCIPL and temporal RNFL thickness in the clinically unaffected eyes of those children with unilateral ON suggests the presence of pre-existing neuroaxonal injury in children presenting with a first episode of ON. This finding may be driven by the subset of children with multiple sclerosis.

Improving Outcomes in Pediatric Multiple Sclerosis: Current and Emerging Treatments.

Pediatric-onset multiple sclerosis (MS) comprises 2-5% of MS cases, and is known to be associated with high disease activity and the accumulation of disability at an earlier age than their adult-onset counterparts. Appropriate therapy leading to disease control has the potential to alter the known trajectory of adverse long-term physical, cognitive, and psychosocial outcomes in this population. Thus, optimizing treatment for children and adolescents with MS is of paramount importance. The last decade has seen a growing number of disease-modifying therapies approved for relapsing MS in adults, and available agents now include oral, injectable, and infusion therapies. Recently, the development of randomized controlled MS trials in youth has led to the first agent approved by the US FDA for the treatment of pediatric MS-fingolimod. With this, we have entered a new era of knowledge and treatment in this population and ongoing pediatric trials are expected to further inform clinical management. With the emergence of highly effective therapies targeting the inflammatory component of the disease, there has been increased interest in identifying treatment strategies that instead target mechanisms such as remyelination/repair, neuroprotection, or rehabilitation. The potential role for such emerging therapies in the treatment of pediatric MS remains an important area of study. In this review, we discuss current evidence for MS therapies in children including the treatment of acute relapses, disease-modifying therapies, and symptomatic management. We will also discuss evidence for emerging therapies, including remyelinating and neuroprotective agents.

PANDAS/PANS in childhood: Controversies and evidence.

Since first defined in 1998, paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and its later, broader iteration, paediatric acute-onset neuropsychiatric syndrome (PANS), have garnered significant attention and controversy. The role of streptococcal infection in children with explosive onset obsessive-compulsive disorder and new onset tics, the natural history of this entity, and the role of symptomatic and disease-modifying therapies, including antibiotics, immunotherapy, and psychoactive drugs, are all issues that have yet to be definitively addressed. While definitive proof of the autoimmune hypothesis of PANDAS is lacking, given the heightened attention to this entity and apparent rise in use of this diagnostic category, addressing questions around diagnosis, treatment, and etiology is imperative. In this paper, we review current working definitions of PANDAS/PANS, discuss published evidence for interventions related to this entity, and propose a clinical approach to children presenting with acute symptoms satisfying criteria for PANDAS/PANS.

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.

Radiologically isolated syndrome in children: Current knowledge and future directions.

As the use of magnetic resonance imaging (MRI) grows in clinical practice, clinicians are increasingly faced with the difficult task of interpreting the significance of incidental findings on brain MRI. Among individuals found to have incidental brain MRI findings, a small number have white matter abnormalities on MRI that resemble the demyelinating lesions of multiple sclerosis (MS) in the absence of a history of relevant clinical symptoms. This has been termed radiologically isolated syndrome (RIS). Recent years have seen growing interest in RIS, with observational studies that have specifically focused on answering questions regarding the subsequent risk of future clinical events and diagnosis of MS in adults and children with these findings. Given the high rate of subsequent clinical events seen in adult studies, knowledge related to RIS in children is paramount, particularly given the higher disease activity and burden in children with MS. This review examines this question, providing an overview of RIS with a focus on its significance in children including current definitions, its association with MS, and knowledge related to therapeutic interventions for RIS. We conclude with suggestions for an approach to assessment of and subsequent surveillance in children fulfilling criteria for RIS and directions for future study.

The Spectrum of Inflammatory Acquired Demyelinating Syndromes in Children.

Acquired demyelinating syndromes in childhood comprise a spectrum of monophasic and recurrent inflammatory conditions of the central nervous system. Examples of monophasic conditions include, clinically isolated syndromes such as optic neuritis and transverse myelitis, as well as acute disseminated encephalomyelitis, whereas recurrent disorders include entities such as multiple sclerosis and neuromyelitis optica spectrum disorder. Knowledge about these disorders has expanded due to rigorously evaluated diagnostic criteria, magnetic resonance imaging features, outcomes, and serum biomarkers in these disorders. This review aims to provide a summary of clinical developments in pediatric acquired demyelinating syndromes, with a special focus on diagnostic criteria, neuroinflammatory markers, burden of disease in addition to current and potential future treatment options.

An Infant With Epilepsy and Recurrent Hemiplegia due to Compound Heterozygous Variants in ATP1A2.

BACKGROUND: Pathogenic heterozygous variants in the ATP1A2 gene have most commonly been associated with familial hemiplegic migraine. However, a wide spectrum of phenotypes that include alternating hemiplegia of childhood and epilepsy have been described. PATIENT DESCRIPTION: We describe a boy who presented at age three months with a complex phenotype that included epilepsy, nonepileptic paroxysmal events, and recurrent hemiplegia. Magnetic resonance imaging demonstrated unilateral cortical edema during a severe episode of hemiplegia that was followed by a persistent mild hemiparesis. RESULTS: Whole-exome sequencing identified a previously reported ATP1A2 missense variant (p.Arg548Cys) classified as pathogenic and a novel missense variant (p.Arg1008Trp) classified as a variant of uncertain significance. After this genetic diagnosis, treatment with flunarizine was initiated and no further episodes of hemiplegia have occurred. CONCLUSIONS: This is only the second report of compound heterozygosity of the ATP1A2 gene. It demonstrates the spectrum of paroxysmal neurological events that can arise as a result of ATP1A2 variants, with unique features overlapping alternating hemiplegia of childhood, hemiplegic migraine, and epilepsy. This child illustrates the diagnostic challenges that these disorders can present and the importance of genetic diagnosis in guiding management.

Opsoclonus-Myoclonus Syndrome: A New Era of Improved Prognosis?

BACKGROUND: Opsoclonus-myoclonus syndrome is an autoimmune neurological disorder characterized by opsoclonus, myoclonus, ataxia, and behavioral changes. Although long-term outcomes have historically been poor, including motor and cognitive disabilities, the advent of new and more aggressive immunotherapy regimens may be improving prognosis in opsoclonus-myoclonus syndrome. METHODS: We retrospectively reviewed the records of all children diagnosed with opsoclonus-myoclonus syndrome at BC Children's Hospital from 2000 to 2010. Neurological outcomes were compared with those previously reported in the literature. RESULTS: Twelve children with opsoclonus-myoclonus syndrome were identified, four of whom had an associated neuroblastoma. Two thirds of patients received initial treatment with a combination of corticosteroids, intravenous immunoglobulin (IVIG), and an additional immunosuppressant agent. After a median follow-up of three years from diagnosis, ten patients had no or minimal neurological abnormalities. Two patients had poor outcome with significant cognitive impairment. CONCLUSIONS: Most patients in this series were treated with early multimodal immunotherapy, and neurological outcomes were better than those in most historical reports. This finding is consistent with recent studies that suggest multimodal immunotherapy regimens may be improving the prognosis in this challenging disease. However, some individuals did well with less aggressive treatment, and further studies are required to determine optimal treatment approach.

Manifestations of Tuberous Sclerosis Complex: The Experience of a Provincial Clinic.

BACKGROUND: Tuberous sclerosis complex (TSC) is a neurocutaneous disorder with a wide spectrum of manifestations. Recent consensus recommendations stress the importance of multidisciplinary management of children with TSC. The objective of this study was to examine the manifestations of TSC at a large referral centre to determine the care needs of this population. METHODS: A retrospective, systematic chart review was performed of children with TSC managed at British Columbia Children's Hospital. Patients were identified through epilepsy and clinical neurophysiology databases. RESULTS: The study population comprised 81 patients, born between 1987 and 2014, who were a median of 10 years (range, 0.2-23.2) at most recent follow-up. Epilepsy occurred in 91% of patients, including 32% with a history of infantile spasms. Nineteen patients underwent epilepsy surgery, nine (47%) of whom were seizure-free at most recent follow-up. Overall, 61% of epilepsy patients had been seizure-free for at least 1 year at the time of last follow-up. Neuropsychiatric disorders were diagnosed in 49% of children, with autism (25%), attention deficit hyperactivity order (19%) and anxiety (16%) being the most common. Cardiac rhabdomyomata occurred in 35% of children and renal angiomyolipomas were seen in 43%. A total of 91% had skin manifestations. CONCLUSION: This study outlines the multisystem manifestations of TSC, observed through a large pediatric referral center. Epilepsy and neuropsychiatric disorders are the major source of morbidity in this age group and provide many challenges to the treating clinician. Because a subset of the study population is still quite young, the prevalence of neuropsychiatric disorders is likely underestimated.