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Small vessel primary angiitis of the central nervous system is a rare and often severe disease characterized by central nervous system-restricted inflammatory vasculitis on histopathology. Diagnosis requires brain biopsy for confirmation and is suggested prior to starting immunotherapy when feasible. However, emerging evidence suggests that other neuroinflammatory conditions may have a clinical and radiographic phenotype that mimics small vessel primary angiitis, at times with overlapping pathologic features as well. Such diagnoses, including myelin oligodendrocyte glycoprotein antibody-associated disease and central nervous system-restricted hemophagocytic lymphohistiocytosis, can be non-invasively diagnosed with serum antibody or genetic testing that would prompt different monitoring and treatment paradigms. To determine the ultimate diagnosis of patients who were suspected prior to biopsy to have small vessel primary angiitis, we reviewed the clinical, radiographic, and pathological features of a cohort of patients at a single center undergoing brain biopsy for non-oncologic indications.Clinical data were retrospectively extracted from the medical record. Pathology and neuroimaging review was conducted.We identified 21 patients over a 19-year time-period, of whom 14 (66.7%) were ultimately diagnosed with entities other than small vessel primary angiitis that would have obviated the need for brain biopsy. Diagnoses included anti-myelin oligodendrocyte glycoprotein antibody associated disease (n = 9), central nervous system-restricted hemophagocytic lymphohistiocytosis (n = 3), anti-GABAThis study highlights the importance of pursuing now readily available non-invasive testing for mimicking diagnoses before performing a brain biopsy for suspected small vessel primary angiitis of the central nervous system. ANN NEUROL 2022.

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.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.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).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 2022.

Pediatric-onset multiple sclerosis (POMS) shows earlier axonal involvement and greater axonal loss than in adults. We aim to characterize the white matter (WM) microstructural changes in POMS using a diffusion compartment imaging (DCI) model and compare it to standard diffusion tensor imaging (DTI).Eleven patients (2 males, mean age 18.8 ± 3.9 years) with a diagnosis of relapsing and remitting POMS (mean age at disease onset 13.8 ± 2.9 years, mean duration 5.1 ± 1.9 years) and healthy controls (8 males, mean age 26.4 ± 6.5 years) were recruited and imaged at 3 T. A 90-gradient set Cube and Sphere acquisition and a novel DCI model known as DIstribution of Anisotropic MicrOstructural eNvironments with Diffusion-weighted imaging (DIAMOND) were used to calculate a single anisotropic compartment, an isotropic compartment, and a free diffusion compartment. Lesions and contralateral normal-appearing white matter (NAWM) in patients and whole brain WM for controls were labeled.Eleven patients and 11 controls were recruited. When comparing lesions and contralateral NAWM in patients using DCI, compartmental axial diffusivity, radial diffusivity (cRD), and mean diffusivity (cMD) were higher in lesions. Conversely, compartmental fractional anisotropy (cFA) and heterogeneity index were lower in lesions. An analysis of DTI equivalents showed the same trends. In whole-brain NAWM of patients compared to controls, cRD and cMD were higher and cFA was lower in patients.Lesions in POMS can be accurately characterized by a DCI model. Incipient changes in NAWM seen in DCI may not be readily observable by DTI.

Mendelian and early-onset severe psychiatric phenotypes often involve genetic variants having a large effect, offering opportunities for genetic discoveries and early therapeutic interventions. Here, the index case is an 18-year-old boy, who at 14 years of age had a decline in cognitive functioning over the course of a year and subsequently presented with catatonia, auditory and visual hallucinations, paranoia, aggression, mood dysregulation, and disorganized thoughts. Exome sequencing revealed a stop-gain mutation in RCL1 (NM_005772.4:c.370 C > T, p.Gln124Ter), encoding an RNA 3′-terminal phosphate cyclase-like protein that is highly conserved across eukaryotic species. Subsequent investigations across two academic medical centers identified eleven additional cases of RCL1 copy number variations (CNVs) with varying neurodevelopmental or psychiatric phenotypes. These findings suggest that dosage variation of RCL1 contributes to a range of neurological and clinical phenotypes.

Febrile‐infection related epilepsy syndrome (FIRES) is a devastating neurological condition characterized by a febrile illness preceding new onset refractory status epilepticus (NORSE). Increasing evidence suggests innate immune dysfunction as a potential pathological mechanism. We report an international retrospective cohort of 25 children treated with anakinra, a recombinant interleukin‐1 receptor antagonist, as an immunomodulator for FIRES. Anakinra was potentially safe with only one child discontinuing therapy due to infection. Earlier anakinra initiation was associated with shorter duration of mechanical ventilation, ICU and hospital length of stay. Our retrospective data lay the groundwork for prospective consensus‐driven cohort studies of anakinra in FIRES.

ObjectiveRapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), is a severe pediatric disorder of uncertain etiology resulting in hypothalamic dysfunction and frequent sudden death. Frequent co-occurrence of neuroblastic tumors have fueled suspicion of an autoimmune paraneoplastic neurological syndrome (PNS); however, specific anti-neural autoantibodies, a hallmark of PNS, have not been identified. Our objective is to determine if an autoimmune paraneoplastic etiology underlies ROHHAD.MethodsImmunoglobulin G (IgG) from pediatric ROHHAD patients (n=9), non-inflammatory individuals (n=100) and relevant pediatric controls (n=25) was screened using a programmable phage display of the human peptidome (PhIP-Seq). Putative ROHHAD-specific autoantibodies were orthogonally validated using radioactive ligand binding and cell-based assays. Expression of autoantibody targets in ROHHAD tumor and healthy brain tissue was assessed with immunohistochemistry and mass spectrometry, respectively.ResultsAutoantibodies to ZSCAN1 were detected in ROHHAD patients by PhIP-Seq and orthogonally validated in 7/9 ROHHAD patients and 0/125 controls using radioactive ligand binding and cell-based assays. Expression of ZSCAN1 in ROHHAD tumor and healthy human brain tissue was confirmed.InterpretationOur results support the notion that tumor-associated ROHHAD syndrome is a pediatric PNS, potentially initiated by an immune response to peripheral neuroblastic tumor. ZSCAN1 autoantibodies may aid in earlier, accurate diagnosis of ROHHAD syndrome, thus providing a means toward early detection and treatment. This work warrants follow-up studies to test sensitivity and specificity of a novel diagnostic test. Last, given the absence of the ZSCAN1 gene in rodents, our study highlights the value of human-based approaches for detecting novel PNS subtypes. ANN NEUROL 2022;92:279-291.

AIM To determine predictors of full-scale IQ (FSIQ) in an international pediatric opsoclonus myoclonus syndrome (OMS) cohort. METHOD In this retrospective and prospective cohort study at three academic medical centers (2006-2013), the primary outcome measure, FSIQ, was categorized based on z-score: above average (≥+1), average (+1 to -1), mildly impaired (-1 to -2), and impaired (

ObjectiveTo create an international consensus treatment recommendation for pediatric NMDA receptor antibody encephalitis (NMDARE).MethodsAfter selection of a panel of 27 experts with representation from all continents, a 2-step Delphi method was adopted to develop consensus on relevant treatment regimens and statements, along with key definitions in pediatric NMDARE (disease severity, failure to improve, and relapse). Finally, an online face-to-face meeting was held to reach consensus (defined as ≥75% agreement).ResultsCorticosteroids are recommended in all children with NMDARE (pulsed IV preferred), with additional IV immunoglobulin or plasma exchange in severe patients. Prolonged first-line immunotherapy can be offered for up to 3–12 months (oral corticosteroids or monthly IV corticosteroids/immunoglobulin), dependent on disease severity. Second-line treatments are recommended for cases refractory to first-line therapies (rituximab preferred over cyclophosphamide) and should be considered about 2 weeks after first-line initiation. Further immunotherapies for refractory disease 1-3 months after second-line initiation include another second-line treatment (such as cyclophosphamide) and escalation to tocilizumab. Maintenance immune suppression beyond 6 months (such as rituximab redosing or mycophenolate mofetil) is generally not required, except for patients with a more severe course or prolonged impairments and hospitalization. For patients with relapsing disease, second-line and prolonged maintenance therapy should be considered. The treatment of NMDARE following herpes simplex encephalitis should be similar to idiopathic NMDARE. Broad guidance is provided for the total treatment duration (first line, second line, and maintenance), which is dictated by the severity and clinical course (i.e., median 3, 9 and 18 months in the best, average, and worst responders, respectively). Recommendations on the timing of oncologic searches are provided.ConclusionThese international consensus recommendations for the management of pediatric NMDARE aim to standardize the treatment and provide practical guidance for clinicians, rather than absolute rules. A similar recommendation could be applicable to adult patients.

Author(s): Greenberg, Benjamin M; Casper, Theron Charles; Mar, Soe S; Ness, Jayne M; Plumb, Patricia; Liang, Shannon; Goyal, Manu; Weinstock-Guttman, Bianca; Rodriguez, Moses; Aaen, Gregory S; Belman, Anita; Barcellos, Lisa F; Rose, John W; Gorman, Mark P; Benson, Leslie A; Candee, Meghan; Chitnis, Tanuja; Harris, Yolanda C; Kahn, Ilana L; Roalstad, Shelly; Hart, Janace; Lotze, Timothy E; Rensel, Mary; Rubin, Jennifer P; Schreiner, Teri L; Tillema, Jan-Mendelt; Waldman, Amy Tara; Krupp, Lauren; Graves, Jennifer; Drake, Kaylea; Waubant, Emmanuelle | Abstract: Background and objectiveThe objective of this study was to determine whether family members of patients with pediatric multiple sclerosis (MS) have an increased prevalence of autoimmune conditions compared with controls.MethodsData collected during a pediatric MS case-control study of risk factors included information about various autoimmune diseases in family members. The frequency of these disorders was compared between cases and controls.ResultsThere was an increased rate of autoimmune diseases among family members of pediatric MS cases compared with controls with first-degree history of MS excluded (OR = 2.27, 95% CI 1.71-3.01, p l 0.001). There was an increased rate of MS among second-degree relatives of pediatric MS cases compared with controls (OR = 3.47, 95% CI 1.36-8.86, p = 0.009). The OR for MS was 2.64 when restricted to maternal relatives and 6.37 when restricted to paternal relatives.DiscussionThe increased rates of autoimmune disorders, including thyroid disorders and MS among families of patients with pediatric MS, suggest shared genetic factors among families with children diagnosed with pediatric MS.

Background and ObjectivesOpsoclonus-myoclonus syndrome (OMS) is a rare autoimmune disorder associated with neuroblastoma in children, although idiopathic and postinfectious etiologies are present in children and adults. Small cohort studies in homogenous populations have revealed elevated rates of autoimmunity in family members of patients with OMS, although no differentiation between paraneoplastic and nonparaneoplastic forms has been performed. The objective of this study was to investigate the prevalence of autoimmune disease in first-degree relatives of pediatric patients with paraneoplastic and nonparaneoplastic OMS.MethodsA single-center cohort study of consecutively evaluated children with OMS was performed. Parents of patients were prospectively administered surveys on familial autoimmune disease. Rates of autoimmune disease in first-degree relatives of pediatric patients with OMS were compared using Fisher exact t test and χ2 analysis: (1) between those with and without a paraneoplastic cause and (2) between healthy and disease (pediatric multiple sclerosis [MS]) controls from the United States Pediatric MS Network.ResultsThirty-five patients (18 paraneoplastic, median age at onset 19.0 months; 17 idiopathic, median age at onset 25.0 months) and 68 first-degree relatives (median age 41.9 years) were enrolled. One patient developed systemic lupus erythematosus 7 years after OMS onset. Paraneoplastic OMS was associated with a 50% rate of autoimmune disease in a first-degree relative compared with 29% in idiopathic OMS (p = 0.31). The rate of first-degree relative autoimmune disease per OMS case (14/35, 40%) was higher than healthy controls (86/709, 12%; p < 0.001) and children with pediatric MS (101/495, 20%; p = 0.007).DiscussionIn a cohort of pediatric patients with OMS, there were elevated rates of first-degree relative autoimmune disease, with no difference in rates observed between paraneoplastic and idiopathic etiologies, suggesting an autoimmune genetic contribution to the development of OMS in children.

Neurobeachin (NBEA) was initially identified as a candidate gene for autism. Recently, variants in NBEA have been associated with neurodevelopmental delay and childhood epilepsy. Here, we report on a novel NBEA missense variant (c.5899G > A, p.Gly1967Arg) in the Domain of Unknown Function 1088 (DUF1088) identified in a child enrolled in the Undiagnosed Diseases Network (UDN), who presented with neurodevelopmental delay and seizures. Modeling of this variant in the Caenorhabditis elegans NBEA ortholog, sel-2, indicated that the variant was damaging to in vivo function as evidenced by altered cell fate determination and trafficking of potassium channels in neurons. The variant effect was indistinguishable from that of the reference null mutation suggesting that the variant is a strong hypomorph or a complete loss-of-function. Our experimental data provide strong support for the molecular diagnosis and pathogenicity of the NBEA p.Gly1967Arg variant and the importance of the DUF1088 for NBEA function.

ROHHAD (Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation) is a rare, yet severe pediatric disorder resulting in hypothalamic dysfunction and frequent sudden death. Genetic and other investigations have failed to identify an etiology or diagnostic test. Frequent co-occurrence of neuroblastic tumors (NTs) and cerebrospinal fluid inflammation point to an autoimmune paraneoplastic neurological syndrome (PNS); however, specific anti-neural autoantibodies, a hallmark of PNS, have not been identified. Here, we screened antibodies from a curated cohort of ROHHAD patients (n=9) and controls (n=150) using a programmable phage display of the human peptidome (PhIP-Seq). Our ROHHAD cohort exhibited frequent association with NTs (8/9) and features consistent with autoimmune etiology. Autoantibodies to Zinc finger and SCAN domain-containing protein 1 (ZSCAN1) were discovered and orthogonally validated in 7 of 9 ROHHAD patients, all of whom had NTs, and shown to be absent in non-ROHHAD pediatric patients with NTs. Notably, human ZSCAN1 expression was confirmed in ROHHAD tumor and healthy human hypothalamus. Our results support the notion that tumor-associated ROHHAD is a pediatric PNS, potentially initiated by an immune response to peripheral NT. ZSCAN1 autoantibodies may aid in an accurate diagnosis of ROHHAD, thus providing a means toward early detection and treatment. Lastly, given the absence of the ZSCAN1 gene in rodents, our study highlights the value of human-based approaches in addition to the classical rodent-based approaches for detecting novel PNS subtypes.

Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM)1-6. Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF)2. CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM.

Children with pediatric-onset multiple sclerosis and pediatric controls were enrolled across 16 pediatric multiple sclerosis centers in the United States and completed questionnaires that addressed time of first unaided walking and acquisition of 2-word phrases. A total of 467 (308 female) cases and 428 (209 female) controls were enrolled. Pediatric multiple sclerosis (n = 467) were not delayed in walking or using 2-word phrases compared to healthy controls (n = 428) (2.2% vs 5.7%, respectively). Children with disease onset before age 11 versus onset at 11 years or after were more likely to need an individualized education plan ( P = .002), reading assistance ( P = .0003), and math assistance ( P = .001). Children with multiple sclerosis onset prior to age 18 are not delayed in meeting the 2 major early developmental milestones but do have a significantly increased use of special services or learning assistance at school. Further research will need to address whether other measures of development (eg, rate of language acquisition or fine motor skills) differ between pediatric multiple sclerosis and controls.

Background: There are limited data on the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among pediatric-onset MS (POMS) patients and healthy controls. Using a prospective cohort of POMS patients and healthy controls, we aimed to determine the frequency of MOG-IgG and AQP4-IgG in both groups, compare clinical characteristics and outcomes in seronegative vs seropositive children, and identify predictors of final diagnosis. Methods: POMS patients and controls were enrolled at 14 US sites through a case-control study on POMS risk factors. Follow-up data were prospectively collected. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays. Medical records were re-reviewed in seropositive cases to confirm final diagnosis. Findings: We included 1196 participants, 493 POMS and 703 controls. AQP4-IgG was negative in all participants. MOG-IgG was positive in 30/493 cases (6%) and 0/703 (0%) controls. Twenty-five of 30 MOG-IgG positives (83%) were determined to have MOG-IgG-associated disease (MOGAD) while 5/30 (17%) maintained a diagnosis of MS. The MOG-IgG false-positive rate was 1%. MOGAD cases, compared with MS, were more commonly female (84% vs 64%; p=0.044), presented at younger age (mean 8∙2±4∙2 vs 14∙7±2∙6 years; p

Importance: Overall, immunotherapy has been shown to improve outcomes and reduce relapses in individuals with N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis (NMDARE); however, the superiority of specific treatments and combinations remains unclear. Objective: To map the use and safety of immunotherapies in individuals with NMDARE, identify early predictors of poor functional outcome and relapse, evaluate changes in immunotherapy use and disease outcome over the 14 years since first reports of NMDARE, and assess the Anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score. Data Sources: Systematic search in PubMed from inception to January 1, 2019. Study Selection: Published articles including patients with NMDARE with positive NMDAR antibodies and available individual immunotherapy data. Data Extraction and Synthesis: Individual patient data on immunotherapies, clinical characteristics at presentation, disease course, and final functional outcome (modified Rankin Scale [mRS] score) were entered into multivariable logistic regression models. Main Outcomes and Measures: The planned study outcomes were functional outcome at 12 months from disease onset (good, mRS score of 0 to 2; poor, mRS score greater than 2) and monophasic course (absence of relapse at 24 months or later from onset). Results: Data from 1550 patients from 652 articles were evaluated. Of these, 1105 of 1508 (73.3%) were female and 707 of 1526 (46.3%) were 18 years or younger at disease onset. Factors at first event that were significantly associated with good functional outcome included adolescent age and first-line treatment with therapeutic apheresis, corticosteroids plus intravenous immunoglobulin (IVIG), or corticosteroids plus IVIG plus therapeutic apheresis. Factors significantly associated with poor functional outcome were age younger than 2 years or age of 65 years or older at onset, intensive care unit admission, extreme delta brush pattern on electroencephalography, lack of immunotherapy within the first 30 days of onset, and maintenance IVIG use for 6 months or more. Factors significantly associated with nonrelapsing disease were rituximab use or maintenance IVIG use for 6 months or more. Adolescent age at onset was significantly associated with relapsing disease. Rituximab use increased from 13.5% (52 of 384; 2007 to 2013) to 28.3% (311 of 1100; 2013 to 2019) (P

Febrile infection-related epilepsy syndrome (FIRES) is characterized by new onset refractory status epilepticus in a previously healthy child that is associated with poor cognitive outcomes and chronic epilepsy. Innate immune system dysfunction is hypothesized to be a key etiologic contributor, with a potential role for immunotherapy blocking pro-inflammatory cytokines, such as interleukin-1β and interleukin-6. We present a case of FIRES refractory to anakinra, an interleukin-1 receptor antagonist, subsequently treated with the ketogenic diet and tocilizumab, an interleukin-6 receptor antagonist, temporally associated with seizure cessation and a favorable 1-year outcome.

Rasmussen encephalitis (RE) is a disorder characterized by drug-resistant seizures and progressive unihemispheric atrophy, hemiparesis, and varying degrees of cognitive decline. The pathophysiology of RE remains elusive, with hypotheses suggesting underlying autoimmune- and T cell-mediated processes. In this case report, we describe a single patient's clinical course from the first day of presentation until definitive treatment for atypical Rasmussen encephalitis at a tertiary care pediatric center. The patient exhibited several atypical features of Rasmussen encephalitis, including a posterior predominance of initial seizure onset with the development of severe choreoathetosis and ipsilateral cerebellar atrophy. He subsequently developed coexistent autoimmune disorders in the form of psoriasis and uveitis, and underwent multiple forms of immunotherapy with limited benefit. This patient shows an association of RE with other autoimmune conditions supporting an autoimmune mechanism of disease while exhibiting several atypical features of RE. Rarely, occipital lobe seizures have been documented as the presenting semiology of this syndrome. This case highlights the need to be mindful of atypical features that may delay hemispherectomy, which remains the definitive treatment. It also suggests that children may be predisposed to the development of autoimmune disorders in later stages of the disease., Highlights • Occipital seizure localization and semiology should not dissuade the diagnosis of Rasmussen's encephalitis • Movement disorders, can accompany Rasmussen's encephalitis • Ipsilateral cerebellar atrophy has been described in Rasmussen's encephalitis • Children with Rasmussen's encephalitis may be predisposed to autoimmune disorders in the later stages of the disease

Phenotypic and biological characterization of rare monogenic disorders represents 1 of the most important avenues toward understanding the mechanisms of human disease. Among patients with SH3 and multiple ankyrin repeat domains 3 (SHANK3) mutations, a subset will manifest neurologic regression, psychosis, and mood disorders. However, which patients will be affected, when, and why are important unresolved questions. Authors of recent studies suggest neuronal SHANK3 expression is modulated by both inflammatory and hormonal stimuli. In this case series, we describe 4 independent clinical observations of an immunotherapy responsive phenotype of peripubertal-onset neuropsychiatric regression in 4 girls with pathogenic SHANK3 mutations. Each child exhibited a history of stable, mild-to-moderate lifelong developmental disability until 12 to 14 years of age, at which time each manifested a similar, subacute-onset neurobehavioral syndrome. Symptoms included mutism, hallucinations, insomnia, inconsolable crying, obsessive-compulsive behaviors, loss of self-care, and urinary retention and/or incontinence. Symptoms were relatively refractory to antipsychotic medication but improved after immunomodulatory treatment. All 4 patients exhibited chronic relapsing courses during a period of treatment and follow-up ranging from 3 to 6 years. Two of the 4 girls recovered their premorbid level of functioning. We briefly review the scientific literature to offer a conceptual and molecular framework for understanding these clinical observations. Future clinical and translational investigations in this realm may offer insights into mechanisms and therapies bridging immune function and human behavior.

Author(s): Mar, Soe; Liang, Shannon; Waltz, Michael; Casper, T Charles; Goyal, Manu; Greenberg, Benjamin; Weinstock-Guttman, Bianca; Rodriguez, Moses; Aaen, Gregory; Belman, Anita; Barcellos, Lisa F; Rose, John; Gorman, Mark; Benson, Leslie; Candee, Meghan; Chitnis, Tanjua; Harris, Yolanda; Kahn, Ilana; Roalsted, Shelly; Hart, Janace; Lotze, Timothy; Moodley, Manikum; Ness, Jayne; Rensel, Mary; Rubin, Jennifer; Schreiner, Teri; Tillema, Jan-Mendelt; Waldman, Amy; Krupp, Lauren; Graves, Jennifer S; Waubant, Emmanuelle; U.S. Network of Pediatric Multiple Sclerosis Centers | Abstract: BackgroundThere is limited information about the potential associations of multiple sclerosis (MS) and commonly used household chemicals.MethodsWe performed a case-control study of exposures to common household chemicals during childhood in children with MS and healthy pediatric controls. Exposures to household products were collected from a comprehensive questionnaire (http://www.usnpmsc.org/Documents/EnvironmentalAssessment.pdf) completed by parents at the time of enrollment in the study. Cases included children diagnosed with MS or clinically isolated syndrome with at least two silent T2 bright lesions on MRI, recruited within 4nyears of disease onset from 16 pediatric MS clinics in the USA. Multivariate analyses using logistic regression were adjusted for possible confounders including age, sex, race, ethnicity, mother's highest level of education, and urban versus rural living.ResultsQuestionnaire responses to household chemicals were available for 312 eligible cases (median age 15.7nyears, 63% girls) and 490 healthy controls (median age 15.0, 57% girls). Exposure to rodenticides (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.35-3.26, Pn≤n0.001), weed control agents (OR 1.99, 95% CI 1.36-2.92, Pn≤n0.001) and products for plant/tree disease control (OR 2.72, 95% CI 1.54-4.82, Pn≤n0.001) anytime during childhood were associated with an increased risk for pediatric-onset MS in adjusted and multiple comparisons analyses.ConclusionsOur findings suggest that exposure to specific household chemicals during early childhood is associated with the risk of developing pediatric-onset MS. Future studies are needed to elucidate a causal relationship and the exact agents involved.

Familial hemophagocytic lymphohistiocytosis (HLH) is an immune hyperactivation syndrome caused by mutations in genes associated with cytotoxic T-cell and NK-cell function. While neurological manifestations frequently accompany systemic inflammation at initial presentation, isolated central nervous system (CNS) involvement is rare, and the histological correlates are not well described. We present 3 patients (ages 5, 6, and 7 years) with CNS-isolated familial HLH, who presented with a variety of neurological symptoms and underwent brain biopsies for multifocal enhancing supratentorial and infratentorial lesions. Biopsy slides from all 3 patients revealed similar findings: perivascular lymphocytes, predominantly CD3+ T-cells (CD4>CD8) with occasional intramural infiltration of small vessels; scattered histiocytes without hemophagocytosis; parenchymal and leptomeningeal inflammation varying from mild and focal to severe and sheet-like with associated destructive lesions. There was no evidence of demyelination, neoplasia, or infection. Genetic testing identified compound heterozygous mutations in PRF1 (Patients 1 and 2) and UNC13D (Patient 3), with no evidence of systemic disease except decreased NK-cell function. All 3 patients were treated with hematopoietic stem cell transplantation with marked improvement of symptoms. These findings combined with the poor outcomes associated with delayed diagnosis and lack of aggressive treatment highlight the need to consider HLH in the differential diagnosis of inflammatory brain lesions.

Vessel wall MR imaging may be helpful in diagnosing and monitoring the treatment of vasculitic complications from CNS infections.

Background The differential diagnosis in pediatric patients presenting with concern for CNS infections and/or autoimmune disorders is broad. Despite recent advances in diagnostic modalities, many cases may remain undiagnosed. For example, approximately 50% of pediatric patients with encephalitis do not have an identified etiology. Use of metagenomic next-generation sequencing (mNGS) may improve the diagnostic yield. This study evaluated etiologies in a cohort of pediatric patients who underwent CSF mNGS. Methods Retrospective cohort study of all hospitalized patients < 21-years-old who underwent CSF mNGS at a tertiary pediatric hospital from June, 2017 - February, 2020. Final diagnosis was assigned by two independent study physician reviewers (pediatric infectious disease and neurologist) based on documentation including discharge summaries, consult notes, and subsequent clinic notes where available. Results Thirty-seven patients (59% female, median age 9 (1–17) years) were identified (21 with encephalitis). Twenty-six (70%) had a definite diagnosis – 10 (27%) infectious, 11 (30%) autoimmune, 5 (14%) other. The most common etiology was anti-MOG antibody associated meningoencephalitis (n=4, 11%). Among infections, Powassan virus encephalitis (n=3, 8%) was most common; other infectious etiologies included EBV, neuroborreliosis, rubella, and Eastern Equine encephalitis. Eight (22%) had a positive result on CSF mNGS; 7 were clinically significant including change in management in 5 of 8 (63%) patients. Conclusion In this cohort of pediatric patients who underwent CSF mNGS, an etiology was identified in 70%. Eight patients had a positive result on mNGS which resulted in change in management for the majority of patients. These data suggest that CSF mNGS is high-yield and impacts clinical care. However, given the significant cost of mNGS, future directions include cost analyses to determine when and in whom CSF mNGS should be sent. Disclosures Asim A. Ahmed, MD, Karius (Employee)

Significance The study addresses a basic immunology topic with considerable clinical relevance, namely the nature of the pathogenic T helper cells that drive autoimmune disorders like multiple sclerosis (MS) and inflammatory arthritis. Using mouse MS, we identify precursors of the encephalitogenic/pathogenic T cells based on their dependence on the protease inhibitor SerpinB1. Newly identified signature genes reveal the unusual nature of these T cells that combine ( i ) inflammatory cytokine secretion, ( ii ) a cytolytic system, and ( iii ) extreme rapid proliferation. We demonstrate that their survival/expansion depends on SerpinB1 and involves regulation of a proliferation-associated protease-mediated cell suicide mechanism. Importantly, we discovered that cell surface CXCR6 is an exquisite marker of pathogenic T helper cells and demonstrated that anti-CXCR6 treatment has potential to prevent or mitigate MS.

Phenotypic and biological characterization of rare monogenic disorders represents 1 of the most important avenues toward understanding the mechanisms of human disease. Among patients with SH3 and multiple ankyrin repeat domains 3 (SHANK3) mutations, a subset will manifest neurologic regression, psychosis, and mood disorders. However, which patients will be affected, when, and why are important unresolved questions. Authors of recent studies suggest neuronal SHANK3 expression is modulated by both inflammatory and hormonal stimuli. In this case series, we describe 4 independent clinical observations of an immunotherapy responsive phenotype of peripubertal-onset neuropsychiatric regression in 4 girls with pathogenic SHANK3 mutations. Each child exhibited a history of stable, mild-to-moderate lifelong developmental disability until 12 to 14 years of age, at which time each manifested a similar, subacute-onset neurobehavioral syndrome. Symptoms included mutism, hallucinations, insomnia, inconsolable crying, obsessive-compulsive behaviors, loss of self-care, and urinary retention and/or incontinence. Symptoms were relatively refractory to antipsychotic medication but improved after immunomodulatory treatment. All 4 patients exhibited chronic relapsing courses during a period of treatment and follow-up ranging from 3 to 6 years. Two of the 4 girls recovered their premorbid level of functioning. We briefly review the scientific literature to offer a conceptual and molecular framework for understanding these clinical observations. Future clinical and translational investigations in this realm may offer insights into mechanisms and therapies bridging immune function and human behavior.

BackgroundSince 2014, the United States has experienced a biennial spike in pediatric acute flaccid myelitis (AFM). Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF) and only inconsistently identified from the respiratory tract, serum, or stool.MethodsWe interrogated CSF from children with AFM (n=42) and pediatric controls with other neurologic diseases (OND) (n=58). Samples were incubated with T7 bacteriophage expressing 481,966 sixty-two amino acid peptides with a fourteen amino acid overlap tiled across all known vertebrate virus and arbovirus genomes, an adaption of the VirScan method. Antibody-bound phage were deep sequenced to quantify enriched peptides with normalized counts expressed as reads per hundred thousand (rpK). EV antibody findings were confirmed with ELISA using whole viral protein 1 (VP1) from contemporary enterovirus (EV) A71 and D68 strains. Separately, metagenomic next-generation sequencing (mNGS) of CSF RNA, both unbiased and with targeted enrichment for EVs, was performed.ResultsThe most significantly enriched viral family by VirScan of CSF in AFM versus OND controls wasPicornaviridae(mean rpK 11,266 versus mean rpK 950, p-adjusted < 0.001, Wilcoxon signed-rank test with Bonferroni adjustment). EnrichedPicornaviridaepeptides belonged almost entirely to the genusEnterovirus.The mean EV VP1 ELISA signal in AFM (mean OD 0.51) was significantly higher than OND controls (mean OD 0.08, p-value < 0.001, Mann-Whitney test). mNGS did not detect additional enterovirus RNA in CSF.ConclusionDespite the rare detection of EV RNA in the CNS of patients with AFM, a pan-viral serologic assay identified high levels of CSF EV antibodies in AFM CSF compared to CSF from OND controls. These results provide further evidence for a causal role of non-polio enteroviruses in AFM.

Key Points Familial HLH can present as chronic isolated neuroinflammation. CNS-isolated HLH responds to hematopoietic cell transplantation.

Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles., Author summary Multiple sclerosis (MS) is an autoimmune disease that is mostly found in populations with northern European ancestry. Our study investigates whether there is evidence that the difference in MS prevalence around the globe could be explained by European MS genetic risk factors in African Americans, Hispanics, or Asian Americans. Our work first established that most alleles associated with MS are not necessarily European, but are in fact, cosmopolitan. However, we also observed in African Americans that European HLA-DRB1*15:01 conferred three times the odds of MS compared to the African allele. The allele HLA-DRB1*15:01 has been shown to be a major genetic risk factor in Europeans and other admixed populations. In addition, we observed genetic variations between European and African HLA-DRB1*15:01 alleles that, based on location, could influence the function of antigen-binding proteins involved in MS. Consequently, it is plausible that ancestry could explain the risk or protective effects of other MS-associated alleles. Additionally, our study found on chromosome 8 in Hispanics a region where MS cases have more European ancestry than controls, implicating there may be new MS risk alleles to be discovered in Hispanics. In conclusion, our study found evidence that the difference in MS prevalence could be explained by European ancestry and established that the ancestry of MS genetic risk factors is complex.

Importance Acute flaccid myelitis (AFM) is an emerging poliolike illness of children whose clinical spectrum and associated pathogens are only partially described. The case definition is intentionally encompassing for epidemiologic surveillance to capture all potential AFM cases. Defining a restrictive, homogenous subpopulation may aid our understanding of this emerging disease. Objective To evaluate the extent to which the US Centers for Disease Control and Prevention (CDC) case definition of AFM incorporates possible alternative diagnoses and to assess the plausibility of a case definition that enriches the biological homogeneity of AFM for inclusion in research studies. Design, Setting, and Participants Retrospective case analysis of children younger than 18 years diagnosed as having AFM between 2012 and 2016 using the CDC case definition. Group 1 included patients recruited from the United States and Canada based on the CDC case definition of AFM. Group 2 included patients referred to the Johns Hopkins Transverse Myelitis Center for evaluation of suspected AFM. Patients’ records and imaging data were critically reviewed by 3 neurologists to identify those cases with definable alternative diagnoses, and the remaining patients were categorized as having restrictively defined AFM (rAFM). Clinical characteristics were compared between patients with rAFM (cases) and those with alternative diagnoses, and a case description distinguishing these AFM groups was identified. Interrater reliability of this description was confirmed for a subset of cases by a fourth neurologist. Data were analyzed between May 2017 and November 2018. Main Outcomes and Measures Proportion of patients with possible alternative diagnosis. Results Of the 45 patients who met the CDC AFM case definition and were included, the mean age was 6.1 years; 27 were boys (60%); and 37 were white (82%), 3 were Asian (7%), 1 was Hispanic (2%), and 4 were mixed race/ethnicity (9%). Of the included patients, 34 were classified as having rAFM, and 11 had alternate diagnoses (including transverse myelitis, other demyelinating syndromes, spinal cord stroke, Guillain-Barre syndrome, Chiari I myelopathy, and meningitis). Factors differing between groups were primarily asymmetry of weakness, lower motor neuron signs, preceding viral syndrome, symptoms evolving over hours to days, absence of sensory deficits, and magnetic resonance imaging findings. A case description was able to reliably define the rAFM group. Conclusions and Relevance We present an approach for defining a homogeneous research population that may more accurately reflect the pathogenesis of the prototypical poliomyelitis-like subgroup of AFM. The definition of rAFM forms a blueprint for inclusion criteria in future research efforts, but more work is required for refinement and external validation.

A Boy with Seizures A 3-year-old boy was admitted to the hospital because of a seizure. Decreased language output, lethargy, mood lability, unsteady gait, and abnormal movements developed. CSF anal...

ObjectiveTo identify molecular correlates of primary angiitis of the CNS (PACNS) through proteomic analysis of CSF from a biopsy-proven patient cohort.MethodsUsing mass spectrometry, we quantitatively compared the CSF proteome of patients with biopsy-proven PACNS (n = 8) to CSF from individuals with noninflammatory conditions (n = 11). Significantly enriched molecular pathways were identified with a gene ontology workflow, and high confidence hits within enriched pathways (fold change >1.5 and concordant Benjamini-Hochberg–adjusted p < 0.05 on DeSeq and t test) were identified as differentially regulated proteins.ResultsCompared to noninflammatory controls, 283 proteins were differentially expressed in the CSF of patients with PACNS, with significant enrichment of the complement cascade pathway (C4-binding protein, CD55, CD59, properdin, complement C5, complement C8, and complement C9) and neural cell adhesion molecules. A subset of clinically relevant findings were validated by Western blot and commercial ELISA.ConclusionsIn this exploratory study, we found evidence of deregulation of the alternative complement cascade in CSF from biopsy-proven PACNS compared to noninflammatory controls. More specifically, several regulators of the C3 and C5 convertases and components of the terminal cascade were significantly altered. These preliminary findings shed light on a previously unappreciated similarity between PACNS and systemic vasculitides, especially anti-neutrophil cytoplasmic antibody–associated vasculitis. The therapeutic implications of this common biology and the diagnostic and therapeutic utility of individual proteomic findings warrant validation in larger cohorts.

The central nervous system (CNS) has a dedicated network of blood vessels to support the physiological activity of the brain, spinal cord and meninges. Consequently, inflammation of CNS vasculature can have devastating effects on neurological function. A lack of understanding regarding the molecular pathology of CNS vasculitis impedes the development of better diagnostics and effective therapies. Here, we analyze the proteome of cerebrospinal fluid from patients with biopsy-confirmed Primary Angiitis of the Central Nervous System (PACNS) relative to non-inflammatory control patients and patients with Reversible Cerebral Vasoconstrictive Syndrome (RCVS), a syndrome that clinically mimics PACNS in several aspects. In PACNS, we find significant elevation of apolipoproteins, immunoglobulins and complement cascade components. Notably, we find a bias towards activation of the alternative complement pathway with elevated levels of the terminal cascade component, complement C5. Given the recent treatment successes of Anti-Neutrophil Cytoplasmic Antibody (ANCA) vasculitis with the C5 receptor inhibitor, CCX168 (Avacopan), our results suggest that complement C5 inhibitors may also prove useful as therapeutic interventions for PACNS.

Background: Recognizing the cause of optic neuritis (ON) affects treatment decisions and visual outcomes. Objective: We aimed to define radiological features of first-episode demyelinating ON. Methods: We performed blinded radiological assessment of 50 patients presenting with first-episode myelin oligodendrocyte glycoprotein (MOG) antibody-associated ON (MOG-ON; n=19), aquaporin-4 (AQP4) antibody-associated ON (AQP4-ON; n=11), multiple sclerosis (MS)-associated ON (MS-ON; n=13), and unclassified ON ( n=7). Results: Bilateral involvement was more common in MOG-ON and AQP4-ON than MS-ON (84% vs. 82% vs. 23%), optic nerve head swelling was more common in MOG-ON (53% vs. 9% vs. 0%), chiasmal involvement was more common in AQP4-ON (5% vs. 64% vs. 15%), and bilateral optic tract involvement was more common in AQP4-ON (0% vs. 45% vs. 0%). Retrobulbar involvement was more common in MOG-ON, whereas intracranial involvement was more common in AQP4-ON. MOG-ON and AQP4-ON had longer lesion lengths than MS-ON. The combination of two predictors, the absence of magnetic resonance imaging brain abnormalities and a higher lesion extent score, showed a good ability to discriminate between an autoantibody-associated ON (MOG or AQP4) and MS. AQP4-ON more frequently had severe and sustained visual impairment. Conclusion: MOG-ON and AQP4-ON are more commonly bilateral and longitudinally extensive. MOG-ON tends to involve the anterior optic pathway, whereas AQP4-ON the posterior optic pathway.

Background Central nervous system complications of bone marrow transplant are a common occurrence and the differential diagnosis is quite broad, including opportunistic infections, medications toxicities, graft versus host disease, and other autoimmune processes. Patient Description We summarize previously reported cases of autoimmune myelitis in post-transplant patients and discuss a 17-year-old boy who presented with seronegative neuromyelitis optica after a bone marrow transplant for acute myeloid leukemia. Our patient had a marked improvement in symptoms after plasmapheresis. Conclusion Including our patient, there have been at least eight cases of post-transplant autoimmune myelitis presented in the literature, and at least three of these are suspicious for neuromyelitis optica. Several of these patients had poor outcomes with persistent symptoms after the myelitis. Autoimmune processes such as neuromyelitis optica should be carefully considered in patients after transplant as aggressive treatment like early plasmapheresis may improve outcomes.

To determine the yield of neuroimaging in children presenting to the emergency department with acute ataxia in the post–varicella vaccine era, we conducted a cross-sectional study between 1995 and 2013 at a single pediatric tertiary care center. We included children aged 1-18 years evaluated for acute ataxia of

Autoimmunity is being increasingly recognized as a cause of neurologic presentations both inside and outside the intensive care unit (ICU) setting. Pediatric autoimmune neurologic diseases likely to be seen in the ICU include autoimmune encephalitidies such as N-Methyl-D-aspartate (NMDA) receptor encephalitis, central nervous system vasculitis, demyelinating disorders, and neurologic involvement of systemic autoimmune disorders. In addition, there are conditions of suspected autoimmune etiology such as febrile infection-related epilepsy syndrome (FIRES) and rapid-onset obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) syndrome that are rare, but when they do present, it is often to the ICU. Refractory seizures, altered mental status, and disordered breathing are the most common indications for intensive care for these patients.

Objective:To report the clinical features, comorbidities, receptor subunit targets, and outcome in patients with anti-GABAA receptor (GABAAR) encephalitis.Methods:Clinical study of 26 patients, including 17 new (April 2013–January 2016) and 9 previously reported patients. Antibodies to α1, β3, and γ2 subunits of the GABAAR were determined using reported techniques.Results:Patients' median age was 40.5 years (interquartile range 48.5 [13.75–62.35] years; the youngest 2.5 months old; 13 female). Symptoms included seizures (88%), alteration of cognition (67%), behavior (46%), consciousness (42%), or abnormal movements (35%). Comorbidities were identified in 11 (42%) patients, including 7 tumors (mostly thymomas), 2 herpesvirus encephalitis (herpes simplex virus 1, human herpesvirus 6; coexisting with NMDAR antibodies), and 2 myasthenia without thymoma. Brain MRI was abnormal in 23 (88%) patients, showing in 20 (77%) multifocal, asynchronous, cortical-subcortical T2/fluid-attenuated inversion recovery abnormalities predominantly involving temporal (95%) and frontal (65%) lobes, but also basal ganglia and other regions. Immunologic or tumor therapy resulted in substantial improvement in 18/21 (86%) assessable patients; the other 3 (14%) died (2 status epilepticus, 1 sepsis). Compared with adults, children were more likely to have generalized seizures (p = 0.007) and movement disorders (p = 0.01) and less likely to have a tumor (p = 0.01). The main epitope targets were in the α1/β3 subunits of the GABAAR.Conclusions:Anti-GABAAR encephalitis is characterized by frequent seizures and distinctive multifocal cortical-subcortical MRI abnormalities that provide an important clue to the diagnosis. The frequency of symptoms and comorbidities differ between children (more viral-related) and adults (more tumor-related). The disorder is severe but most patients respond to treatment.

Auto-antibodies that bind to conformational extracellular epitopes of neuronal receptors or synaptic proteins have provided clinicians with essential biomarkers in acute neurology. This review summarizes the current status and challenges in the field. In children, anti-N-methyl-D-aspartate receptor encephalitis remains the most identifiable autoimmune encephalitis, although many patients have a clinical syndrome of brain inflammation in which no antibodies are identified. Anti-myelin oligodendrocyte glycoprotein antibody associated demyelination is now recognized as a major cause of monophasic and relapsing demyelination, often presenting with encephalopathy. We discuss the importance of auto-antibody detection methodology and the possible influence of intrathecal antibody synthesis on the speed of recovery and response to immune therapy. The current, often pragmatic rather than evidence-based therapeutic pathway will be discussed, highlighting key challenges such as the timing of second-line therapy, monitoring of disease activity, and identifying the patient who is responding poorly to treatment. Although there have been significant developments, future priorities include the need for paediatric-specific consensus definitions for seronegative suspected autoimmune encephalitis, novel tools for monitoring patients with autoimmune encephalitis, consensus treatment recommendations, and neuroprotective strategies.

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context., European Research Council (GA 309449: Fellowship to Y.J.C.), ERA-NET Neuron (MR/M501803/1), and a state subsidy managed by the National Research Agency (France) under the “Investments for the Future” (ANR-10-IAHU-01)

A 19-year-old woman was admitted to the pediatric ICU because of a headache, fever, photophobia, neck stiffness, and mental-status changes. She was drowsy and disoriented with respect to year. She had truncal ataxia and rotatory nystagmus, and her face and right arm were numb.

Objective: To assess the utility and safety of rituximab in pediatric autoimmune and inflammatory disorders of the CNS. Methods: Multicenter retrospective study. Results: A total of 144 children and adolescents (median age 8 years, range 0.7-17; 103 female) with NMDA receptor (NMDAR) encephalitis (n = 39), opsoclonus myoclonus ataxia syndrome (n = 32), neuromyelitis optica spectrum disorders (n = 20), neuropsychiatric systemic lupus erythematosus (n = 18), and other neuroinflammatory disorders (n = 35) were studied. Rituximab was given after a median duration of disease of 0.5 years (range 0.05-9.5 years). Infusion adverse events were recorded in 18/144 (12.5%), including grade 4 (anaphylaxis) in 3. Eleven patients (7.6%) had an infectious adverse event (AE), including 2 with grade 5 (death) and 2 with grade 4 (disabling) infectious AE (median follow-up of 1.65 years [range 0.1-8.5]). No patients developed progressive multifocal leukoencephalopathy. A definite, probable, or possible benefit was reported in 125 of 144 (87%) patients. A total of 17.4% of patients had a modified Rankin Scale (mRS) score of 0-2 at rituximab initiation, compared to 73.9% at outcome. The change in mRS 0-2 was greater in patients given rituximab early in their disease course compared to those treated later. Conclusion: While limited by the retrospective nature of this analysis, our data support an off-label use of rituximab, although the significant risk of infectious complications suggests rituximab should be restricted to disorders with significant morbidity and mortality. Classification of evidence: This study provides Class IV evidence that in pediatric autoimmune and inflammatory CNS disorders, rituximab improves neurologic outcomes with a 7.6% risk of adverse infections.

ObjectiveTo highlight a novel, treatable syndrome, we report 4 patients with CNS-isolated inflammation associated with familial hemophagocytic lymphohistiocytosis (FHL) gene mutations (CNS-FHL).MethodsRetrospective chart review.ResultsPatients with CNS-FHL are characterized by chronic inflammation restricted to the CNS that is not attributable to any previously described neuroinflammatory etiology and have germline mutations in known FHL-associated genes with no signs of systemic inflammation. Hematopoietic stem cell transplantation (HCT) can be well tolerated and effective in achieving or maintaining disease remission in patients with CNS-FHL.ConclusionsEarly and accurate diagnosis followed by treatment with HCT can reduce morbidity and mortality in CNS-FHL, a novel, treatable syndrome.Classification of evidenceThis study provides Class IV evidence that HCT is well tolerated and effective in treating CNS-FHL.