Autoimmune encephalitis in Israeli children - A retrospective nationwide study.

Immune-mediated or autoimmune encephalitis (AE) is a relatively new, rare and elusive form of encephalitis in children. We retrospectively collected seropositive children (0-18 years old) with well characterized antibodies through 3 reference laboratories in Israel. Clinical symptoms, MRI and EEG findings and treatment courses were described. A total of 16 patients were included in the study, with 10 females. Anti NMDA encephalitis was most common followed by anti HU and anti mGLuR1. Psychiatric symptoms, abnormal movements, seizures and behavioral changes were the most common presentation. Pathological MRI and EEG findings were described in 37% and 56% of children, respectively. Treatment with corticosteroids, Intravenous immunoglobulins (IVIG) was first line in most children. Following inadequate response children were treated with plasmapheresis and/or rituximab. Two patients relapsed following both first and second line protocols. In terms of long term prognosis, 9 children (56%) had one or more residual behavioral, psychiatric or neurologic findings. Three children required hospitalization for rehabilitation. AE remains a rare diagnosis with variable presenting symptoms, requiring a high index of suspicion. Consensus recommended treatment is generally effective in the pediatric population. Female gender was associated with a higher chance of severe disease. Larger cohorts would be needed to identify prognostic factors in the pediatric population.

Validation of the 2023 international diagnostic criteria for MOGAD in a pediatric cohort.

OBJECTIVE: To validate the recently published diagnostic criteria for Myelin Oligodendrocyte Glycoprotein-antibody associated disease (MOGAD) in real-world cohort of children with acquired demyelinating syndromes. METHODS: Patients <18yrs presenting with demyelinating disease to Pediatric neuroimmunology clinics at two Israeli tertiary centers who had MOG antibodies (MOG-Abs) tested between 01/07/2017 and 15/08/2023 were included. Diagnostic criteria for MOGAD were applied and sensitivity and specificities were calculated. RESULTS: MOG-Abs were detected in 28/63 (44 %). Median age at onset for all patients was 11.4 yrs (range 1.1-17.6 yrs) and 41 (65 %) were female. Of the patients testing negative, ADEM was the most common diagnosis (n = 11) followed by MS (n = 8). No patients without MOG-Abs were diagnosed with MOGAD. All patients with a clinical diagnosis of MOGAD had positive MOG-Abs and fulfilled the 2023 international diagnostic criteria for MOGAD. Sensitivity, specificity, positive predictive value, and negative predictive value were 100 %. We found no difference between younger (<10yrs old) and older (>10 yrs old) children in the number of supportive criteria fulfilled at onset (median 2 vs. 2.5, p = 0.4) The number of supporting features was higher in patients with relapsing (n = 5) vs. monophasic (n = 23) disease course at onset (median 3 vs. 2, p = 0.03) and at final follow-up (median 5 vs. 2, p = 0.004). CONCLUSION: Recent MOGAD diagnostic criteria had excellent performance in this pediatric cohort but did not add to the diagnostic accuracy of the antibody test alone.

Utility of genetic testing in children with leukodystrophy.

BACKGROUND: Leukodystrophies are monogenic disorders primarily affecting the white matter. We aimed to evaluate the utility of genetic testing and time-to-diagnosis in a retrospective cohort of children with suspected leukodystrophy. METHODS: Medical records of patients who attended the leukodystrophy clinic at the Dana-Dwek Children's Hospital between June 2019 and December 2021 were retrieved. Clinical, molecular, and neuroimaging data were reviewed, and the diagnostic yield was compared across genetic tests. RESULTS: Sixty-seven patients (Female/Male ratio 35/32) were included. Median age at symptom onset was 9 months (interquartile range (IQR) 3-18 months), and median length of follow-up was 4.75 years (IQR 3-8.5). Time from symptom onset to a confirmed genetic diagnosis was 15months (IQR 11-30). Pathogenic variants were identified in 60/67 (89.6%) patients; classic leukodystrophy (55/67, 82.1%), leukodystrophy mimics (5/67, 7.5%). Seven patients (10.4%) remained undiagnosed. Exome sequencing showed the highest diagnostic yield (34/41, 82.9%), followed by single-gene sequencing (13/24, 54%), targeted panels (3/9, 33.3%) and chromosomal microarray (2/25, 8%). Familial pathogenic variant testing confirmed the diagnosis in 7/7 patients. A comparison between patients who presented before (n = 31) and after (n = 21) next-generation sequencing (NGS) became clinically available in Israel revealed that the time-to-diagnosis was shorter in the latter group with a median of 12months (IQR 3.5-18.5) vs. a median of 19 months (IQR 13-51) (p = 0.005). CONCLUSIONS: NGS carries the highest diagnostic yield in children with suspected leukodystrophy. Access to advanced sequencing technologies accelerates speed to diagnosis, which is increasingly crucial as targeted treatments become available.

Sleep Disturbances in Adolescents With Idiopathic Intracranial Hypertension.

BACKGROUND: We aimed to assess the presence of sleep disturbances in adolescents with idiopathic intracranial hypertension (IIH) and to determine whether demographic, anthropometric, and clinical factors are associated with disrupted sleep. METHODS: Sleep disturbances and patterns were evaluated in a cohort of adolescents (aged 12 to 18 years) with ongoing IIH and compared with a healthy age- and sex-matched control group. All participants responded to three self-rating questionnaires: the School Sleep Habits Survey (SSHS), the Pediatric Sleep Questionnaire (PSQ), and the Depression, Anxiety, and Stress Scale. The study group's demographic, clinical, laboratory, and radiological data were documented, and their association with sleep patterns was examined. RESULTS: Thirty-three adolescents with ongoing IIH and 71 healthy controls were included. There was a significantly higher prevalence of sleep disturbances in the IIH group compared with the controls (SSHS, P < 0.001 and PSQ, P < 0.001), as well as of their independent subscales: sleep-related breathing disorders (P = 0.006), daytime sleepiness (P = 0.04), sleep/wake disruptions (P < 0.001), and sleep-related depressive tendencies (P < 0.001). According to subgroup analyses, these differences were also present between the normal-weight adolescents but not between the overweight IIH and control adolescents. No differences were found in the demographic, anthropometric, and IIH disease-related clinical measures between individuals with IIH with disrupted and normal sleep patterns. CONCLUSIONS: Sleep disturbances are common among adolescents with ongoing IIH, irrespective of their weight and disease-related characteristics. Screening adolescents with IIH for sleep disturbances is recommended as part of their multidisciplinary management.

Radiologically isolated aquaporin-4 antibody neuromyelitis optica spectrum disorder.

Aquaporin-4 antibody (AQP4-Ab) Neuromyelitis Optica Spectrum Disorder (NMOSD) is a rare neuroinflammatory syndrome presenting predominantly with optic neuritis and transverse myelitis. We report a case of radiologically isolated longitudinally extensive optic neuritis in an asymptomatic 12-year-old female with positive serum AQP4-Ab, with resolution of imaging changes after immune therapy. By contrast to patients with radiologically isolated syndrome, of which some will never convert to multiple sclerosis, the pathogenicity of AQP4-Ab in the context of sub-clinical disease, supported treatment in our patient. Given the severe morbidity in AQP4-Ab NMOSD, prognostic biomarkers for disease severity are required to guide optimal therapy for patients.

Neurodevelopmental outcome of children born with an isolated atretic cephalocele.

PURPOSE: The existing data on the neurodevelopmental outcome of children born with an isolated atretic cephalocele (IAC) are scant. We aimed to expand upon these data by describing our experience with affected children, as well as assist parents and clinicians in deciding how to proceed when an IAC is diagnosed prenatally. METHODS: A follow-up study was conducted on nine children who were born with an IAC. Evaluations were performed by pediatric neurologists and child development specialists. Developmental outcomes were based on a global development evaluation that assessed gross and fine motor skills, receptive and expressive language levels, activities of daily living, communication skills, and social domains. Adaptive skills were estimated by the Adaptive Behavior Assessment System, Second Edition. RESULTS: None of the nine children (median age 4 years and 6 months) had abnormal findings on neurological examination. Six children had age-appropriate developmental milestones, two had a mild motor delay, and one had mild expressive language delay (catchup was achieved by all of the latter three by ~ 3.5 years of age). The mean general adaptive composite score was 105 ± 11.7 (normal = 100). None of the children had behavioral, social, or communication problems. CONCLUSIONS: Children diagnosed with an IAC with/without a falcine sinus and devoid of coexisting intracranial abnormalities seem to have a normal neurodevelopmental outcome. Continuation of pregnancy may be recommended when an IAC is detected prenatally, and reassurance if detected postnatally.

Medical treatment of tuberous sclerosis-related epilepsy.

Epilepsy is one of the most frequent CNS manifestations of tuberous sclerosis, and for most patients, it is the major debilitating factor. In up to 70% of the cases, the epilepsy is refractory and usually associated with significant behavioral as well as developmental consequences. Therefore, controlling seizures is one of the biggest medical and surgical challenges. Understanding the cellular mechanism involved in the disease empowered targeted research aimed toward early intervention in the epileptogenicity process. In this review, we present an update on the pharmacological treatments in tuberous sclerosis-related epilepsy.

The role of ICP monitoring in paediatric IIH.

INTRODUCTION: Diagnosis of idiopathic intracranial hypertension (IIH) in children is an extrapolation of the guidelines suggested for adult population. Lumbar puncture (LP) plays a crucial role in the diagnosis. The diagnosis of IIH at times is solely dependent on the interpretation of the opening pressure (OP). Unfortunately, LP-OP can vary due circumstantial parameters and therefore may be an unreliable form of intracranial pressure (ICP) measurement. Confirming the diagnosis based (as suggested by guidelines) on LP-OP in a doubtful clinical situation would be inappropriate. The aim of our study was to analyse the reliability of LP-OP and importance of ICP monitoring in situations where diagnosis of IIH was questionable. METHODS: Retrospective review of all children with diagnosis of IIH over a 10-year period was conducted. Children who underwent ICP monitoring (ICPM) were selected. We considered 2 LP-OP values-last LP (lLP) and the mean LP (mLP) for analysis. ICPM and LP-OP were compared. Follow-up till last clinic visit was also considered for long-term outcome. RESULTS: Eleven children (male 3; female 8) were included in the study. Mean delay between LP and ICPM was 112.8 days (17-257 days). There was lack of correlation between LP-OP and ICP in 9 children. ICP monitoring refuted the diagnosis of IIH in 80% of children and prevented exposure to unnecessary medical and surgical intervention. There was 1complication with ICPM. In 90% of children, there was no progression of symptoms following a decision based on ICP monitoring on long-term follow-up (mean, 36.5 months). CONCLUSION: When the diagnosis of IIH is in doubt, LP may be unreliable and formal ICP monitoring is advised.

Seasonality of birth month of children with celiac disease differs from that in the general population and between sexes and is linked to family history and environmental factors.

BACKGROUND: Patients with autoimmune diseases, such as type 1 diabetes mellitus, atopic dermatitis, autoimmune thyroid diseases, and multiple sclerosis have a different seasonality of month of birth (MOB) from the general population. This study was undertaken to determine the seasonality of MOB in children with celiac disease (CD), an autoimmune-mediated enteropathy. PATIENTS AND METHODS: The medical records of 431 children with CD (239 girls, 192 boys) were included in the study; 138 girls and 81 boys were under the age of 24 months. Data were analyzed by the cosinor method, which, in addition to statistical significance, provides parameters of rhythms. Statistical differences between groups were also analyzed by the chi test. RESULTS: Patients with CD showed different patterns from that in the general population, which peaks in September. Boys and girls with CD were found to have a different seasonality of MOB (P < 0.02). Girls whose CD was diagnosed before age 24 months (peak July-August) had a different seasonality of MOB from those whose CD was diagnosed after age 24 months (no rhythm; P < 0.005) and showed a different seasonality from boys whose CD was diagnosed above 24 months (peak July; P < 0.02). In addition, we found a different seasonality of MOB in children with a family history of CD compared with those with no family history (P < 0.001). CONCLUSIONS: Girls with the diagnosis of CD and patients of both sexes with a family history of CD have a different pattern of seasonality of birth from the general population. This is suggestive of a perinatal virus infection as a plausible candidate for the primary trigger.