Predictors of a relapsing course in myelin oligodendrocyte glycoprotein antibody-associated disease.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described demyelinating disorder, and children represent about 50% of all cases. Almost half of the patients experience relapses, but very few studies have evaluated predictors of relapse risk, challenging clinical management. The study aimed to identify predictors at MOGAD onset that are associated with a relapsing course. METHODS: Prospectively collected data from paediatric patients with MOGAD seen by the US Network of Paediatric MS Centres were leveraged. Univariable and adjusted multivariable models were used to predict recurrent disease. RESULTS: We identified 326 MOGAD cases (mean age at first event 8.9 years [SD 4.3], 57% female, 77% white and 74% non-Hispanic) and 46% relapsed during a mean follow-up of 3.9 years (SD 4.1). In the adjusted multivariable model, female sex (HR 1.66, 95% CI 1.17 to 2.36, p=0.004) and Hispanic/Latino ethnicity (HR 1.77, 95% CI 1.19 to 2.64, p=0.005) were associated with a higher risk of relapsing MOGAD. Maintenance treatment initiated before a second event with rituximab (HR 0.25, 95% CI 0.07 to 0.92, p=0.037) or intravenous immunoglobulin (IVIG) (HR 0.35, 95% CI 0.14 to 0.88, p=0.026) was associated with lower risk of a second event in multivariable analyses. Conversely, maintenance steroids were associated with a higher estimated relapse risk (HR 1.76, 95% CI 0.90 to 3.45, p=0.097). CONCLUSION: Sex and ethnicity are associated with relapsing MOGAD. Use of rituximab or IVIG therapy shortly after onset is associated with a lower risk of the second event. Preventive treatment after a first event could be considered for those with a higher relapse risk.

Nonverbal Cognitive Skills in Children With Aicardi Goutières Syndrome.

BACKGROUND AND OBJECTIVES: Aicardi Goutières syndrome (AGS) is type I interferonopathy characterized by severe neurologic impairment. Although many children with AGS demonstrate motor and expressive language deficits, the magnitude of receptive language impairment is uncharacterized. We sought to characterize cognitive function in AGS-affected children using assessment tools with reduced dependence on motor abilities and compare cognitive testing outcomes with overall severity and parental assessment of adaptive behavior. METHODS: We performed a cross-sectional study. Children were recruited as part of the Myelin Disorders Biorepository Project at the Children's Hospital of Philadelphia. We included individuals with a confirmed diagnosis of AGS. We administered the Leiter International Performance Scale, third edition (Leiter-3), and the Vineland Adaptive Behavior Scale, third edition (VABS-3), in the context of research encounters. Motor skills were categorized by AGS Severity Scale mobility levels. Descriptive statistics and Spearman's rank correlation were used to compare assessments. Mann-Whitney and Kruskal-Wallis tests with correction with Dunn's multiple comparison test were used to compare test performance between mobility groups. RESULTS: Cognitive and adaptive behavior performance was captured in 57 children. The mean age at encounters was 8.51 (SD 5.15) years. The median (IQR) Leiter-3 score was 51 (interquartile range [IQR] 60), with administration failure in 20 of 57 (35%) individuals. On the VABS-3, the Motor Domain (median 29, IQR 36.25) was more impacted than the Communication (median 50, IQR 52), Daily Living Skills (median 52, IQR 31), and Socialization (median 54, IQR 40) Domains (p < 0.0001). The AGS Scale correlated with VABS-3 (r = 0.86, p < 0.0001) and Leiter-3 (r = 0.87, p < 0.0001). There was correlation between VABS-3 Domains and Leiter-3 (r-range 0.83-0.97). Gross motor and fine motor categories, respectively, correlated with VABS-3 (H = 39.37, p < 0.0001; U = 63, p < 0.0001) and Leiter-3 (H = 40.43, p < 0.0001; U = 66, p < 0.0001). Within each gross motor and fine motor category of the AGS Scale, a subset of children scored within normal IQ range. DISCUSSION: Parental assessment of function by the VABS-3 correlated with directly assessed performance measures. Our data underscore the potential value of VABS-3 and Leiter-3 as tools to assess psychometric function in AGS. With a deeper understanding of our patients' abilities, we can better guide clinicians and families to provide appropriate support and personalized interventions to empower children with leukodystrophies to maximize their communication and educational potential.

Solitary Tumefactive Demyelinating Lesions in Children: Clinical and Magnetic Resonance Imaging Features, Pathologic Characteristics, and Outcomes.

BACKGROUND: Isolated tumefactive demyelinating lesions (≥2 cm) may be difficult to distinguish from contrast-enhancing brain tumors, central nervous system infections, and (rarely) tissue dysgenesis, which may all occur with increased signal on T2-weighted images. Establishing an accurate diagnosis is essential for management, and we delineate our single-center experience. METHODS: We performed a retrospective review of medical records, imaging, and biopsy specimens for patients under 18 years presenting with isolated tumefactive demyelination over a 10-year period. RESULTS: Ten children (eight female) met inclusion criteria, with a median age of 14.1 years. Lesions were most likely to involve the thalamus (six of 10), brainstem (five of 10), basal ganglia (four of 10), or corpus callosum (four of 10). Eighty percent had perilesional edema at presentation, and 60% had midline shift. Biopsies demonstrated demyelination with perivascular lymphocytic infiltration and axonal damage ranging from mild to severe. All patients were initially treated with high-dose corticosteroids, and eight of 10 required additional medical therapies such as intravenous immunoglobulin, plasmapheresis, cyclophosphamide, or rituximab. Increased intracranial pressure was managed aggressively with two of 10 patients requiring decompressive craniectomies. Clinical outcomes varied. CONCLUSIONS: Solitary tumefactive demyelinating lesions are rare, and aggressive management of inflammation and increased intracranial pressure is essential. Biopsy is helpful to evaluate for other diagnoses on the differential and maximize therapies. Treatment beyond initial therapy with corticosteroids is often required. Isolated tumefactive demyelinating lesions are uncommon; multicenter natural history studies are needed to better delineate differential diagnoses and optimal therapies.

A retrospective observational cohort study of the anesthetic management and outcomes of pediatric patients with Alexander disease undergoing lumbar puncture or magnetic resonance imaging.

BACKGROUND: Alexander disease is a rare, progressive leukodystrophy, which predisposes patients to complications under general anesthesia due to clinical manifestations including developmental delay, seizures, dysphagia, vomiting, and sleep apnea. However, study of anesthetic outcomes is limited. AIMS: Our aim was to describe patient characteristics, anesthetic techniques, and anesthesia-related complications for Alexander disease patients undergoing magnetic resonance imaging and/or lumbar puncture at a quaternary-care children's hospital. METHODS: We performed a retrospective review of anesthetic outcomes in patients with Alexander disease enrolled in a prospective observational study. Included patients had diagnosed Alexander disease and underwent magnetic resonance imaging and/or lumbar puncture at our institution. We excluded anesthetics for other procedures or at outside institutions. Collected data included patient characteristics, anesthetic techniques, medications, and complications under anesthesia and in the subsequent 24 h. We performed descriptive statistics as appropriate. RESULTS: Forty patients undergoing 64 procedures met inclusion criteria. Fifty-six procedures (87.5%) required general anesthesia or monitored anesthesia care (MAC) and eight (12.5%) did not. The general anesthesia/MAC group tended to be younger than nonanesthetized patients (median age 6 years [IQR 3.8; 9] vs. 14.5 years [IQR 12.8; 17.5]). In both groups, dysphagia (78.6% vs. 87.5%, respectively), seizures (62.5% vs. 25%), and recurrent vomiting (17.9% vs. 25%) were frequently reported preprocedure symptoms. Inhalational induction was common (N = 48; 85.7%), and two (3.6%) underwent rapid sequence induction. Serious complications were rare, with no aspiration or seizures. Hypotension resolving with ephedrine occurred in eight cases (14.3%). One patient each (1.8%) experienced postprocedure emergence agitation or vomiting. Fifty-three (94.6%) were ambulatory procedures. No inpatients required escalation in acuity of care. CONCLUSIONS: In this single-center study, patients with Alexander disease did not experience frequent or irreversible complications while undergoing general anesthesia/MAC. Co-morbid symptoms were not increased postanesthesia. Some patients may not require anesthesia to complete short procedures.

Brainstem Chipmunk Sign: A Diagnostic Imaging Clue across All Subtypes of Alexander Disease.

BACKGROUND AND PURPOSE: While classic brain MR imaging features of Alexander disease have been well-documented, lesional patterns can overlap with other leukodystrophies, especially in the early stages of the disease or in milder phenotypes. We aimed to assess the utility of a new neuroimaging sign to help increase the diagnostic specificity of Alexander disease. MATERIALS AND METHODS: A peculiar bilateral symmetric hyperintense signal on T2-weighted images affecting the medulla oblongata was identified in an index patient with type I Alexander disease. Subsequently, 5 observers performed a systematic MR imaging review for this pattern by examining 55 subjects with Alexander disease and 74 subjects with other leukodystrophies. Interobserver agreement was assessed by the κ index. Sensitivity, specificity, and receiver operating characteristic curves were determined. RESULTS: The identified pattern was present in 87% of subjects with Alexander disease and 14% of those without Alexander disease leukodystrophy (P < .001), 3 with vanishing white matter, 4 with adult polyglucosan body disease, and 3 others. It was found equally in both type I and type II Alexander disease (28/32, 88% versus 18/21, 86%; P = .851) and in subjects with unusual disease features (2/2). Sensitivity (87.3%; 95% CI, 76.0%-93.7%), specificity (86.5%; 95% CI, 76.9%-92.5%), and interobserver agreement (κ index = 0.82) were high. CONCLUSIONS: The identified pattern in the medulla oblongata, called the chipmunk sign due to its resemblance to the face of this rodent, is extremely common in subjects with Alexander disease and represents a diagnostic tool that can aid in early diagnosis, especially in subjects with otherwise atypical MR imaging findings and/or clinical features.

Gene-environment interactions: Epstein-Barr virus infection and risk of pediatric-onset multiple sclerosis.

BACKGROUND AND OBJECTIVE: Prior Epstein-Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS. METHODS: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mother's education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs). RESULTS: A total of 473 POMS cases and 702 controls contributed to the analyses. Anti-VCA seropositivity was significantly higher in POMS cases compared to controls (94.6% vs 60.7%, p < 0.001). There was evidence for additive interaction between childhood EBV infection and the presence of the HLA-DRB1*15 allele (RERI = 10.25, 95% confidence interval (CI) = 3.78 to 16.72; AP = 0.61, 95% CI = 0.47 to 0.75). There was evidence for multiplicative interaction (p < 0.05) between childhood EBV infection and the presence of DRB1*15 alleles (odds ratio (OR) = 3.43, 95% CI = 1.06 to 11.07). Among the pediatric MS variants also associated with EBV infection, we detected evidence for additive interaction (p = 0.02) between prior EBV infection and the presence of the GG genotype in risk variant (rs2255214) within CD86 (AP = 0.30, 95% CI = 0.03 to 0.58). CONCLUSION: We report evidence for interactions between childhood EBV infection and DRB1*15 and the GG genotype of CD86 POMS risk variant. Our results suggest an important role of antigen-presenting cells (APCs) in EBV-associated POMS risk.

Short-chain fatty acid producers in the gut are associated with pediatric multiple sclerosis onset.

OBJECTIVE: The relationship between multiple sclerosis and the gut microbiome has been supported by animal models in which commensal microbes are required for the development of experimental autoimmune encephalomyelitis. However, observational study findings in humans have only occasionally converged when comparing multiple sclerosis cases and controls which may in part reflect confounding by comorbidities and disease duration. The study of microbiome in pediatric-onset multiple sclerosis offers unique opportunities as it is closer to biological disease onset and minimizes confounding by comorbidities and environmental exposures. METHODS: A multicenter case-control study in which 35 pediatric-onset multiple sclerosis cases were 1:1 matched to healthy controls on age, sex, self-reported race, ethnicity, and recruiting site. Linear mixed effects models, weighted correlation network analyses, and PICRUSt2 were used to identify microbial co-occurrence networks and for predicting functional abundances based on marker gene sequences. RESULTS: Two microbial co-occurrence networks (one reaching significance after adjustment for multiple comparisons; q < 0.2) were identified, suggesting interdependent bacterial taxa that exhibited association with disease status. Both networks indicated a potentially protective effect of higher relative abundance of bacteria observed in these clusters. Functional predictions from the significant network suggested a contribution of short-chain fatty acid producers through anaerobic fermentation pathways in healthy controls. Consistent family-level findings from an independent Canadian-US study (19 case/control pairs) included Ruminococaccaeae and Lachnospiraceae (p < 0.05). Macronutrient intake was not significantly different between cases and controls, minimizing the potential for dietary confounding. INTERPRETATION: Our results suggest that short-chain fatty acid producers may be important contributors to multiple sclerosis onset.

Gene-environment interactions and risk of pediatric-onset multiple sclerosis associated with time spent outdoors.

BACKGROUND: Our previous study identified a significant association between lower time spent outdoors, as a proxy of sun exposure, and a higher risk of pediatric-onset multiple sclerosis (POMS). UV radiation modulates the expression of several genes, but it is unknown whether these genes modify the effect of sun exposure on POMS risk. METHODS: In an age- and sex-matched case-control study, we evaluated the additive and multiplicative interactions between time spent outdoors and genetic non-HLA risk variants for developing POMS within the metabolic pathways of UV radiation, including CD28(rs6435203), CD86(rs9282641), and NFkB1(rs7665090) and the top two HLA risk factors (presence of DRB1×15 and absence of A*02). RESULTS: In an adjusted model (332 POMS cases, 534 healthy controls), greater time compared to <30 min/day spent outdoors during the prior summer and higher UV radiation dose were associated with decreased odds of POMS (OR 0.66, 95% CI 0.56-0.78, p < 0.001; OR 0.78, 95 % CI 0.62-0.98, p = 0.04, respectively). No significant additive or multiplicative interactions were found between risk factors. CONCLUSIONS: The exploration of gene-environment interactions in the risk of developing MS can unravel the underlying mechanisms involved. Although we do not have evidence that our candidate genes contribute to interactions, other genes may.

Acquisition and Loss of Developmental Milestones and Time to Disease-Related Outcomes in Cerebral Alexander Disease.

Objective: To determine the ages at acquisition of developmental milestones, loss of motor function, and clinical symptoms in Alexander disease. Methods: Patients with confirmed cerebral Alexander disease were included. Data abstraction of developmental and disease-specific milestones was performed from medical records, physical exams, and questionnaires. Mixed effects logistic regression was used to determine if key clinical features were associated with milestone achievement, controlling for patient age. Results: 51 patients with cerebral/infantile Alexander disease were evaluated at a mean age of 10.96 years (range 2.29-31.08 years). Developmental milestones in Alexander disease were often achieved but delayed. Ambulation was achieved in 44 subjects (86%); 34 (67%) subjects walked independently (mean age 1.9 years, range 0.91-3.25 years) and an additional 10 (20%) subjects walked with assistance (mean age 3.9 years, range 1.8-8 years) but did not progress to independent ambulation. Developmental delay was the earliest and most prevalent symptom (N = 48 [94%], mean age 0.58 years), compared to an initial seizure (N = 41 [80%], mean age 2.80 years), and macrocephaly (N = 28 [55%], mean age 4.04 years), P < .0001 between these ages of onset. Loss of independent ambulation occurred in 11 of the 34 (32%) children who had acquired ambulation (range 3.41-15.10 years). Presence of seizures or macrocephaly did not predict the achievement or loss of ambulation. Conclusions: The clinical triad of developmental delay, seizures, and macrocephaly are not universally present in cerebral Alexander disease. Clinicians should have a high index of suspicion for Alexander disease in patients with mild delays and a first seizure.

Retinal hypoplasia and degeneration result in vision loss in Friedreich ataxia.

OBJECTIVE: Friedreich ataxia (FRDA) is an inherited condition caused by a GAA triplet repeat (GAA-TR) expansion in the FXN gene. Clinical features of FRDA include ataxia, cardiomyopathy, and in some, vision loss. In this study, we characterize features of vision loss in a large cohort of adults and children with FRDA. METHODS: Using optical coherence tomography (OCT), we measured peripapillary retinal nerve fiber layer (RNFL) thickness in 198 people with FRDA, and 77 controls. Sloan letter charts were used to determine visual acuity. RNFL thickness and visual acuity were compared to measures of disease severity obtained from the Friedreich Ataxia Clinical Outcomes Measures Study (FACOMS). RESULTS: The majority of patients, including children, had pathologically thin RNFLs (mean = 73 ± 13 µm in FRDA; 98 ± 9 µm in controls) and low-contrast vision deficits early in the disease course. Variability in RNFL thickness in FRDA (range: 36 to 107 µm) was best predicted by disease burden (GAA-TR length X disease duration). Significant deficits in high-contrast visual acuity were apparent in patients with an RNFL thickness of ≤68 µm. RNFL thickness decreased at a rate of -1.2 ± 1.4 µm/year and reached 68 µm at a disease burden of approximately 12,000 GAA years, equivalent to disease duration of 17 years for participants with 700 GAAs. INTERPRETATION: These data suggest that both hypoplasia and subsequent degeneration of the RNFL may be responsible for the optic nerve dysfunction in FRDA and support the development of a vision-directed treatment for selected patients early in the disease to prevent RNFL loss from reaching the critical threshold.

Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis.

BACKGROUND: Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown. OBJECTIVE: To test whether genes harboring rare variants associated with adult-onset MS risk (PRF1, PRKRA, NLRP8, and HDAC7) and 52 major histocompatibility complex (MHC) genes are associated with POMS. METHODS: We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method "SKAT-O," we tested the association between candidate genes and POMS risk. RESULTS: After correction for multiple comparisons, one adult-onset MS gene (PRF1, p = 2.70 × 10-3) and two MHC genes (BRD2, p = 5.89 × 10-5 and AGER, p = 7.96 × 10-5) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501. CONCLUSION: Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.

Gene-environment interactions increase the risk of paediatric-onset multiple sclerosis associated with household chemical exposures.

BACKGROUND: We previously reported an association between household chemical exposures and an increased risk of paediatric-onset multiple sclerosis. METHODS: Using a case-control paediatric multiple sclerosis study, gene-environment interaction between exposure to household chemicals and genotypes for risk of paediatric-onset multiple sclerosis was estimated.Genetic risk factors of interest included the two major HLA multiple sclerosis risk factors, the presence of DRB1*15 and the absence of A*02, and multiple sclerosis risk variants within the metabolic pathways of common household toxic chemicals, including IL-6 (rs2069852), BCL-2 (rs2187163) and NFKB1 (rs7665090). RESULTS: 490 paediatric-onset multiple sclerosis cases and 716 controls were included in the analyses. Exposures to insect repellent for ticks or mosquitos (OR 1.47, 95% CI 1.06 to 2.04, p=0.019), weed control products (OR 2.15, 95% CI 1.51 to 3.07, p<0.001) and plant/tree insect or disease control products (OR 3.25, 95% CI 1.92 to 5.49, p<0.001) were associated with increased odds of paediatric-onset multiple sclerosis. There was significant additive interaction between exposure to weed control products and NFKB1 SNP GG (attributable proportions (AP) 0.48, 95% CI 0.10 to 0.87), and exposure to plant or disease control products and absence of HLA-A*02 (AP 0.56; 95% CI 0.03 to 1.08). There was a multiplicative interaction between exposure to weed control products and NFKB1 SNP GG genotype (OR 2.30, 95% CI 1.00 to 5.30) but not for other exposures and risk variants. No interactions were found with IL-6 and BCL-2 SNP GG genotypes. CONCLUSIONS: The presence of gene-environment interactions with household toxins supports their possible causal role in paediatric-onset multiple sclerosis.

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.

Clinical Reasoning: A 12-Month-Old Male Child With Staring Episodes, Ataxia, and Right-sided Weakness.

Baylisascaris procyonis, or raccoon roundworm, is a rare cause of eosinophilic meningoencephalitis with historically poor clinical outcomes. Symptoms of neural larval migrans begin approximately 2-4 weeks after ingestion with fatigue, nausea, fever, and lethargy and then rapidly progress to weakness, incoordination, ataxia, seizures, altered mental status, and finally coma. Only 31 other cases of CNS Baylisascaris neural larval migrans have been reported, with more than 25% being lethal. Of the remaining cases, all but 3 were neurologically devastated largely because of delays in diagnosis and treatment. We present a case of an infant with Baylisascaris neural larval migrans manifested as right hemiparesis, ataxia, and cortical blindness. Eosinophilia was missed at an outside hospital due to misidentification of eosinophils as monocytes on automated cell differential. Repeated testing of serum and CSF revealed marked eosinophilia consistent with eosinophilic meningoencephalitis, and serum antibody testing through the Centers of Disease Control confirmed Baylisascaris infection. Notably, this child had a remarkably positive outcome with near complete recovery of neurologic function after treatment with albendazole and steroids. Although eosinophilic meningoencephalitis is rare, accounting for less than 3% of all lumbar punctures with pleocytosis, this case illustrates (1) the importance of early disease recognition and treatment to improve patient outcomes and (2) the fact that automated cell differentials may misidentify eosinophils as monocytes.

The Pediatric Optic Neuritis Prospective Outcomes Study: Two-Year Results.

PURPOSE: Pediatric optic neuritis (ON) is a rare disease that has not been well characterized. The Pediatric ON Prospective Outcomes Study (PON1) was the first prospective study to our knowledge aiming to evaluate visual acuity (VA) outcomes, including VA, recurrence risk, and final diagnosis 2 years after enrollment. DESIGN: Nonrandomized observational study at 23 pediatric ophthalmology or neuro-ophthalmology clinics in the United States and Canada. PARTICIPANTS: A total of 28 (64%) of 44 children initially enrolled in PON1 (age 3-<16 years) who completed their 2-year study visit. METHODS: Participants were treated at the investigator's discretion. MAIN OUTCOMES MEASURES: Age-normal monocular high-contrast VA (HCVA). Secondary outcomes included low-contrast VA (LCVA), neuroimaging findings, and final diagnoses. RESULTS: A total of 28 participants completed the 2-year outcome with a median enrollment age of 10.3 years (range, 5-15); 46% were female, and 68% had unilateral ON at presentation. Final 2-year diagnoses included isolated ON (n = 11, 39%), myelin oligodendrocyte glycoprotein-associated demyelination (n = 8, 29%), multiple sclerosis (MS) (n = 4,14%), neuromyelitis optica spectrum disease (NMOSD) (n = 3, 11%), and acute disseminated encephalomyelitis (n = 2, 7%). Two participants (7%; 95% confidence interval [CI], 1-24) had subsequent recurrent ON (plus 1 participant who did not complete the 2-year visit); all had MS. Two other participants (7%) had a new episode in their unaffected eye. Mean presenting HCVA was 0.81 logarithm of the minimum angle of resolution (logMAR) (∼20/125), improving to 0.14 logMAR (∼20/25-2) at 6 months, 0.12 logMAR (∼20/25-2) at 1 year, and 0.11 logMAR (20/25-1) at 2 years (95% CI, -0.08 to 0.3 [20/20+1-20/40-1]). Twenty-four participants (79%) had age-normal VA at 2 years (95% CI, 60-90); 21 participants (66%) had 20/20 vision or better. The 6 participants without age-normal VA had 2-year diagnoses of NMOSD (n = 2 participants, 3 eyes), MS (n = 2 participants, 2 eyes), and isolated ON (n = 2 participants, 3 eyes). Mean presenting LCVA was 1.45 logMAR (∼20/500-2), improving to 0.78 logMAR (∼20/125+2) at 6 months, 0.69 logMAR (∼20/100+1) at 1 year, and 0.68 logMAR (∼20/100+2) at 2 years (95% CI, 0.48-0.88 [20/50+1-20/150-1]). CONCLUSIONS: Despite poor VA at presentation, most children had marked improvement in VA by 6 months that was maintained over 2 years. Associated neurologic autoimmune diagnoses were common. Additional episodes of ON occurred in 5 (18%) of the participants (3 relapses and 2 new episodes).

Gene-environment interactions increase the risk of pediatric-onset multiple sclerosis associated with ozone pollution.

BACKGROUND: We previously reported a relationship between air pollutants and increased risk of pediatric-onset multiple sclerosis (POMS). Ozone is an air pollutant that may play a role in multiple sclerosis (MS) pathoetiology. CD86 is the only non-HLA gene associated with POMS for which expression on antigen-presenting cells (APCs) is changed in response to ozone exposure. OBJECTIVES: To examine the association between county-level ozone and POMS, and the interactions between ozone pollution, CD86, and HLA-DRB1*15, the strongest genetic variant associated with POMS. METHODS: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. County-level-modeled ozone data were acquired from the CDC's Environmental Tracking Network. Participants were assigned ozone values based on county of residence. Values were categorized into tertiles based on healthy controls. The association between ozone tertiles and having MS was assessed by logistic regression. Interactions between tertiles of ozone level and the GG genotype of the rs928264 (G/A) single nucleotide polymorphism (SNP) within CD86, and the presence of DRB1*15:01 (DRB1*15) on odds of POMS were evaluated. Models were adjusted for age, sex, genetic ancestry, and mother's education. Additive interaction was estimated using relative excess risk due to interaction (RERI) and attributable proportions (APs) of disease were calculated. RESULTS: A total of 334 POMS cases and 565 controls contributed to the analyses. County-level ozone was associated with increased odds of POMS (odds ratio 2.47, 95% confidence interval (CI): 1.69-3.59 and 1.95, 95% CI: 1.32-2.88 for the upper two tertiles, respectively, compared with the lowest tertile). There was a significant additive interaction between high ozone tertiles and presence of DRB1*15, with a RERI of 2.21 (95% CI: 0.83-3.59) and an AP of 0.56 (95% CI: 0.33-0.79). Additive interaction between high ozone tertiles and the CD86 GG genotype was present, with a RERI of 1.60 (95% CI: 0.14-3.06) and an AP of 0.37 (95% CI: 0.001-0.75) compared to the lowest ozone tertile. AP results indicated that approximately half of the POMS risk in subjects can be attributed to the possible interaction between higher county-level ozone carrying either DRB1*15 or the CD86 GG genotype. CONCLUSIONS: In addition to the association between high county-level ozone and POMS, we report evidence for additive interactions between higher county-level ozone and DRB1*15 and the CD86 GG genotype. Identifying gene-environment interactions may provide mechanistic insight of biological processes at play in MS susceptibility. Our work suggests a possible role of APCs for county-level ozone-induced POMS risk.

Semaphorin-Plexin Signaling: From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome.

BACKGROUND: Semaphorins and plexins are ligands and cell surface receptors that regulate multiple neurodevelopmental processes such as axonal growth and guidance. PLXNA3 is a plexin gene located on the X chromosome that encodes the most widely expressed plexin receptor in fetal brain, plexin-A3. Plexin-A3 knockout mice demonstrate its role in semaphorin signaling in vivo. The clinical manifestations of semaphorin/plexin neurodevelopmental disorders have been less widely explored. This study describes the neurological and neurodevelopmental phenotypes of boys with maternally inherited hemizygous PLXNA3 variants. METHODS: Data-sharing through GeneDx and GeneMatcher allowed identification of individuals with autism or intellectual disabilities (autism/ID) and hemizygous PLXNA3 variants in collaboration with their physicians and genetic counselors, who completed questionnaires about their patients. In silico analyses predicted pathogenicity for each PLXNA3 variant. RESULTS: We assessed 14 boys (mean age, 10.7 [range 2 to 25] years) with maternally inherited hemizygous PLXNA3 variants and autism/ID ranging from mild to severe. Other findings included fine motor dyspraxia (92%), attention-deficit/hyperactivity traits, and aggressive behaviors (63%). Six patients (43%) had seizures. Thirteen boys (93%) with PLXNA3 variants showed novel or very low allele frequencies and probable damaging/disease-causing pathogenicity in one or more predictors. We found a genotype-phenotype correlation between PLXNA3 cytoplasmic domain variants (exons 22 to 32) and more severe neurodevelopmental disorder phenotypes (P < 0.05). CONCLUSIONS: We report 14 boys with maternally inherited, hemizygous PLXNA3 variants and a range of neurodevelopmental disorders suggesting a novel X-linked intellectual disability syndrome. Greater understanding of PLXNA3 variant pathogenicity in humans will require additional clinical, computational, and experimental validation.

Association Between Time Spent Outdoors and Risk of Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: This study aims to determine the contributions of sun exposure and ultraviolet radiation (UVR) exposure to risk of pediatric-onset multiple sclerosis (MS). METHODS: Children with MS and controls recruited from multiple centers in the United States were matched on sex and age. Multivariable conditional logistic regression was used to investigate the association of time spent outdoors daily in summer, use of sun protection, and ambient summer UVR dose in the year before birth and the year before diagnosis with MS risk, with adjustment for sex, age, race, birth season, child's skin color, mother's education, tobacco smoke exposure, being overweight, and Epstein-Barr virus infection. RESULTS: Three hundred thirty-two children with MS (median disease duration 7.3 months) and 534 controls were included after matching on sex and age. In a fully adjusted model, compared to spending <30 minutes outdoors daily during the most recent summer, greater time spent outdoors was associated with a marked reduction in the odds of developing MS, with evidence of dose-response (30 minutes-1 hour: adjusted odds ratio [AOR] 0.48, 95% confidence interval [CI] 0.23-0.99, p = 0.05; 1-2 hours: AOR 0.19, 95% CI 0.09-0.40, p < 0.001). Higher summer ambient UVR dose was also protective for MS (AOR 0.76 per 1 kJ/m2, 95% CI 0.62-0.94, p = 0.01). DISCUSSION: If this is a causal association, spending more time in the sun during summer may be strongly protective against developing pediatric MS, as well as residing in a sunnier location.

Association Between Children With Life-Threatening Conditions and Their Parents' and Siblings' Mental and Physical Health.

Importance: Despite concerns regarding the potential deleterious physical and mental health outcomes among family members of a child with a life-threatening condition (LTC), few studies have examined empirical measures of health outcomes among these family members. Objectives: To examine whether mothers, fathers, sisters, and brothers of children with 1 of 4 types of pediatric LTCs have higher rates of health care encounters, diagnoses, and prescriptions compared with families of children without these conditions. Design, Setting, and Participants: This retrospective cohort study included US families with commercial insurance coverage from a single carrier. Children who had 1 of 4 LTCs (substantial prematurity, critical congenital heart disease, cancer, or a condition resulting in severe neurologic impairment) were identified by a diagnosis in their insurance claim data between July 1, 2015, and June 30, 2016. Each case child and their family was matched with up to 4 control children and their families based on the age of the case and control children. Data were analyzed between August 2020 and March 2021. Exposures: Having a child or sibling with substantial prematurity, critical congenital heart disease, cancer, or a condition resulting in severe and progressive neurologic impairment. Main Outcomes: Rates of occurrence of health care encounters, physical and mental health diagnoses, and physical and mental health medication prescriptions, identified from insurance claims data, were compared between case and control families using a multivariable negative binomial regression model. The statistical analysis adjusted for observed differences between case and control families and accounted for clustering at the family level. Results: The study included 25 528 children (6909 case children [27.1%] and 18 619 control children [72.9%]; median age, 6.0 years [IQR, 1-13 years]; 13 294 [52.1%] male), 43 357 parents (11 586 case parents [26.7%] and 31 771 control parents [73.3%]; mean [SD] age, 40.4 [8.1] years; 22 318 [51.5%] female), and 25 706 siblings (7664 case siblings [29.8%] and 18 042 control siblings [70.2%]; mean [SD] age, 12.1 [6.5] years; 13 114 [51.0%] male). Overall, case mothers had higher rates of the composite outcome of health care encounters, diagnoses, and prescriptions compared with control mothers (incident rate ratio [IRR], 1.61; 95% CI, 1.54-1.68), as did case fathers compared with control fathers (IRR, 1.55; 95% CI, 1.46-1.64). Sisters of children with LTCs had higher rates of the composite outcome compared with sisters of children without LTCs (IRR, 1.68; 95% CI, 1.55-1.82), as did brothers of children with LTCs compared with brothers of children without LTCs (IRR, 1.70; 95% CI, 1.56-1.85). Conclusions and Relevance: In this cohort study, mothers, fathers, sisters, and brothers who had a child or sibling with 1 of 4 types of LTCs had higher rates of health care encounters, diagnoses, and medication prescriptions compared with families who did not have a child with that condition. The findings suggest that family members of children with LTCs may experience poorer mental and physical health outcomes. Interventions for parents and siblings of children with LTCs that aim to safeguard their mental and physical well-being appear to be warranted.