The Utility of Early Brain MRI for Patients with Neurofibromatosis Type 1 and Optic Pathway Glioma: A Long-Term Follow-Up in a Tertiary Referral Hospital.

Screening studies have shown detection of optic pathway gliomas (OPGs) in 8 to 31% of children with neurofibromatosis type 1 (NF1). Many of those affected show prolonged indolent phases, but others develop vision disturbances even before diagnosis and treatment. We assessed the clinical presentation at diagnosis, location, natural progression, and risk factors for impaired vision of OPG. The clinical database of the NF1 multidisciplinary clinic of Schneider Children's Medical Center of Israel was reviewed for all patients diagnosed and followed with NF1 during 2007 to 2019. OPG was diagnosed by hyperintensity and thickening along the optic pathway on T2-weighted brain magnetic resonance imaging (MRI), with or without contrast enhancement. Of 257 children with NF1 who underwent MRI, 57 (22%) were diagnosed with OPG; 31 (54%) were females. Twenty-five (44%) had familial NF1. Fifteen (26%) who exhibited tumor progression and worsening in ophthalmic examinations required treatment. Post-chiasmatic glioma was a predictive factor for treatment (p < 0.05), whereas MRI done later and female gender were not significant. Four patients who eventually needed therapy had normal ophthalmic examinations at least 1 year prior to their first MRI. For 6 (40%) of the patients treated, vision continued to worsen. Our findings demonstrate that normal ophthalmic examinations do not always exclude OPG in children with NF1. Early brain MRI before age 36 months may detect OPG, lead to better follow-up and early treatment, and help improve vision outcome.

Evolution of EEG Findings in Pontocerebellar Hypoplasia Type 2A: Normal EEG in the First Few Months followed by Abnormal Tracing over the Years.

Pontocerebellar hypoplasia (PCH) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by cerebellar and pontine hypoplasia, progressive microcephaly, and developmental delay. Ten types of PCH have been described; PCH type 2A (PCH2A) due to a mutation in TSEN54 is the most frequent. Seizures have been reported in the large majority of patients. The probability of epilepsy developing increases with age, along with difficulties in differentiating seizures from dyskinetic movements. The aim of the present report was to describe the clinical symptoms and electroencephalogram (EEG) changes over time in three patients of Israeli Arab origin with PCH2A. All three, including two siblings and their first cousin, were homozygous for the TSEN54 p.A304S mutation. The patients demonstrated profound psychomotor retardation, severe spasticity and contractures, choreoathetoid movements, and seizures. The magnetic resonance imaging (MRI) scans and EEGs were reviewed by an experienced neuroradiologist and epileptologist, respectively. The MRI scans revealed a dragonfly-like cerebellar pattern in all patients. Despite the normal early EEG findings, all patients had characteristic features of epilepsy, with tonic seizures starting in the first days to months followed by focal to bilateral tonic-clonic seizures in early childhood which continued to adolescence. In conclusion, patients with PCH2A due to the missense mutation p.A304S in TSEN54 exhibit profound psychomotor delay, movement disorders, and intractable epilepsy. An evolution of EEG abnormalities and seizure semiology occurs over time. Similar to several other genetic epileptic encephalopathies, the normal early EEG tracing does not rule out the later occurrence of epilepsy.

Sensory processing patterns affect headache severity among adolescents with migraine.

OBJECTIVE: To evaluate the relationship between pain catastrophizing level, sensory processing patterns, and headache severity among adolescents with episodic migraine. BACKGROUND: Catastrophizing about pain is a critical variable in how we understand adjustment to pain and has a unique contribution in predicting pain intensity. Recent reports found that migraine is also related to enhanced sensory sensitivity. However, the relationship between pain severity, pain catastrophizing level and sensory sensitivity requires greater study especially among adolescents. METHODS: Participants were 92 adolescents aged 13-18 years, 40 with episodic migraine and 52 healthy controls. The migraine patients were prospectively recruited from outpatient pediatric neurology clinics. All participants completed the Adolescent/Adult Sensory Profile (AASP), and the Pain Catastrophizing Scale for children (PCS-ch). The migraine groups also completed the PedMIDAS, which measures Headache related disability. RESULTS: Adolescents with migraine had significantly lower tendency to seek sensory input than healthy controls. Elevated rumination and helplessness correlated with higher migraine pain severity. Tendency to avoid sensory input predicted the migraine related disability level. They also significantly higher pain catastrophizing level than healthy controls, as seen in enhanced rumination (p ≤ 0.001) and helplessness (p ≤ 0.05). CONCLUSIONS: Sensory processing difficulties are common among adolescents with episodic migraine. Sensory avoidance may be related to pain experience, and pain catastrophizing and disability level. TRIAL REGISTRATION: ISRCTN ISRCTN73824458. Registered 28 September 2014. retrospectively registered.

Handwriting in children with Attention Deficient Hyperactive Disorder: role of graphology.

BACKGROUND: Handwriting difficulties are common in children with attention deficient hyperactive disorder (ADHD). The aim of our study was to find distinctive characteristics of handwriting in children with ADHD by using graphology to analyze physical characteristics and patterns, and to evaluate whether graphological analysis is an effective ADHD diagnostic tool for clinicians. METHOD: The cohort included 49 children aged 13-18 years attending a tertiary neurology and epilepsy center in 2016-2017; 22 had a previous DSM-IV/V diagnosis of ADHD. The children were asked to write a 10-12-line story in Hebrew on a blank sheet of paper with a blue pen over a 20-min period. The samples were analyzed by a licensed graphologist blinded to the clinical details of the children against a predetermined handwriting profile of individuals with ADHD. Each ADHD characteristic identified in each sample was accorded 1 point, up to a total of 15 points. Patients with a graphology score of 9-15 were considered to have ADHD. RESULTS: There were 21 boys (43%) and 28 girls (57%) in the cohort; 15 boys (71.4%) and 7 girls (25%) had a DSM-IV/V diagnosis of ADHD. The mean graphology score was significantly higher in the children who had a DSM-IV/V diagnosis of ADHD than in the children who did not (9.61 + 3.49 vs. 5.79 + 4.01, p = 0.002, respectfully). Using a score of 9 as the cutoff, in the girls, graphology had a specificity of 80% (95% CI 59.2-92.8) and a of sensitivity 71.4% for predicting ADHD. Corresponding values in the boys were 75.0 and 76.2%. CONCLUSION: The handwriting of children with ADHD has specific characteristics. Graphology may serve as a clinically useful tool in the diagnosis of ADHD.

Polymicrogyria and myoclonic epilepsy in autosomal recessive cutis laxa type 2A.

Cutis laxa syndromes are rare inherited disorders of skin and connective tissue metabolism associated with variable systemic involvement. The main clinical manifestation is loose, wrinkled, redundant, inelastic skin, hypotonia, typical facies including short nose and down-slanting palpebral fissures, and varying degrees of developmental delay. The aim of this report is to describe two siblings diagnosed with a moderate form of ATP6V0A2-related cutis laxa with polymicrogyria (cobblestone-like brain dysgenesis). One of the patients has myoclonic epilepsy which may have contributed to his more severe clinical presentation. The literature on cutis laxa syndromes is reviewed.

Brain imaging findings and social/emotional problems in Israeli children with neurofibromatosis type 1.

UNLABELLED: A potential association between brain MRI findings and social/emotional difficulties in children with neurofibromatosis type 1 (NF1) was examined. Twenty-eight children with NF1 filled in the Strengths and Difficulties Questionnaire (SDQ), and possible associations between their responses and findings in their brain MRI were sought. T2 bright foci were identified in MRI scans of 24 patients (85 %). There were no associations between the presence of the bright foci in any specific brain region and any of the SDQ scores for the emotional/behavioral measures. Male patients had significantly abnormal SDQ scores and peer problems. Patients with abnormal SDQ scores were younger than those with normal SDQ scores (mean 13.2 years vs 14.3 years, respectively; p = 0.23). A comparison of the scores obtained in ours and in another group of 11 children with NF1 yielded a significant difference between the groups. CONCLUSION: We believe that the lack of correlation between the MRI findings and the social/emotional parameters of the SDQ is another demonstration of the marked clinical variability characteristic of NF1.

Expansion of the spectrum of TUBB4A-related disorders: a new phenotype associated with a novel mutation in the TUBB4A gene.

Mutations in the TUBB4A gene have been identified so far in two neurodegenerative disorders with extremely different clinical features and course: whispering dysphonia, also known as dystonia type 4 (DYT4), and hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). We describe a patient with slowly progressive spastic paraparesis, segmental dystonia, intellectual disability, behavioral problems, and evidence of permanent, incomplete myelination associated with progressive cerebellar atrophy. Whole exome sequencing revealed a novel E410K de novo heterozygous mutation in the TUBB4A gene. The clinical and radiological picture of our patient is different from the classic phenotype; thus, it expands the phenotypic variation of TUBB4A-gene-related disorders.

Prospective, Cross-Sectional Study Finds No Common Viruses in Cerebrospinal Fluid of Children with Pseudotumor Cerebri.

Pseudotumor cerebri (PTC) in children is a rare condition whose underlying cause remains largely unknown. No study has yet systematically examined viral infection as a cause of PTC. The current study aimed to characterize PTC in children and investigate the possible role of acute viral infection of the central nervous system in its pathogenesis. A prospective, cross-sectional study was conducted in three centers in Israel. Participants were 50 children aged 0.5-18 years, of whom 27 had a definitive diagnosis of pseudotumor cerebri (the study group) and 23 comprised a control. Data collected included clinical presentation, imaging, treatment, ophthalmic findings, and cerebrospinal fluid (CSF) analysis. Using the ALLPLEXTM meningitis panel, real-time polymerase chain reaction (PCR) was used to test for the presence of 12 common viruses. PTC patients (mean age 12 ± 4.3 years; 14 males, 13 females) had mean opening pressure of 41.9 ±10.2 mmH2O. All PTC patients had papilledema, and 25 (93%) had PTC symptoms. No viruses were found in the PTC group, while in the control group, one patient tested positive for Epstein-Barr virus and another for human herpesvirus type 6. Overall, in our study, PTC was not found to be associated with the presence of viruses in CSF.

High CCL2 Levels Detected in CSF of Patients with Pediatric Pseudotumor Cerebri Syndrome.

Pseudotumor cerebri (PTC) is a disorder characterized by increased intracranial pressure in the absence of a structural lesion or other identifiable cause. Cytokines, which are involved in the regulation of immune responses and inflammation, have been implicated in the pathogenesis of PTC. In a prospective, cross-sectional study at three centers in Israel, we analyzed cerebrospinal fluid (CSF) samples from 60 children aged 0.5-18 years, including 43 children with a definitive diagnosis of PTC and a control group of 17 children. Levels of IL-4, IL-10, IL-17, CCL2, CCL7, CCL8, CCL13, BDNF, and IFN-γ were measured using ELISA kits. Levels of CCL2 were significantly higher in the PTC group compared to the control group (p < 0.05), with no other significant differences in the measured cytokines between the two groups. The groups did not differ significantly in clinical presentation, imaging, treatment, or ophthalmic findings. Our findings provide preliminary evidence that CCL2 may be involved in the pathogenesis of PTC and may serve a potential target for therapy in PTC.

Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN.

BACKGROUND: This study reports on a hitherto undescribed autosomal recessive syndrome characterised by dysmorphic features and multiple congenital anomalies together with severe neurological impairment, chorea and seizures leading to early death, and the identification of a gene involved in the pathogenesis of the disease. METHODS: Homozygosity mapping was performed using Affymetrix Human Mapping 250k NspI arrays. Sequencing of all coding exons of the candidate genes was performed with primer sets designed using the Primer3 program. Fluorescence activated cell sorting was performed using conjugated antibody to CD59. Staining, acquisition and analysis were performed on a FACSCalibur flow cytometer. RESULTS: Using homozygosity mapping, the study mapped the disease locus to 18q21.32-18q22.1 and identified the disease-causing mutation, c.2126G→A (p.Arg709Gln), in PIGN, which encodes glycosylphosphatidylinositol (GPI) ethanolamine phosphate transferase 1, a protein involved in GPI-anchor biosynthesis. Arginine at the position 709 is a highly evolutionarily conserved residue located in the PigN domain. The expression of GPI linked protein CD59 on fibroblasts from patients as compared to that in a control individual showed a 10-fold reduction in expression, confirming the pathogenic consequences of the mutation on GPI dependent protein expression. CONCLUSIONS: The abundant expression of PIGN in various tissues is compatible with the diverse phenotypic features observed in the patients and with the involvement of multiple body systems. The presence of developmental delay, hypotonia, and epilepsy combined with multiple congenital anomalies, especially anorectal anomalies, should lead a clinician to suspect a GPI deficiency related disorder.

[Infantile spasms and modified hypsarrhythmia].

The West syndrome was described by the physician West in his own son in 1841 and is defined as a triad of myoclonic seizures called "infantile spasms", electrographic abnormalities called "hypsarrhythmia" and arrest of psychomotor development and mental retardation. These symptoms are so pathognomonic that the impression is that the syndrome is caused by a single mechanism, but actually there is heterogeneity of etiologies, different recommendations of treatment and prognosis. The West syndrome was established as an infantiLe epileptic syndrome (ILAE Task Force, 1989). Infantile spasm is the most common epileptic syndrome during infancy and entails 50% of all epilepsies between ages one month to one year. Its incidence is 1:3200-3500 live births. Despite its absolute definition, the variability of etiologies, clinical presentation and electrographic make it difficult to set rigid, clear treatment guidelines and research methodology. This review aims to present modified hypsarrhythmia, the etiologies and prognosis of symptomatic infantile spasms, and emphasize the importance of early recognition of modified hypsarrhythmia by surveillance of electroencephalograms.

Prognostic Parameters of Acute Transverse Myelitis in Children.

Acute transverse myelitis is a rare and disabling disorder. Data on the imaging features in children are sparse. The aim of this study was to describe the clinical and magnetic resonance imaging findings characteristic of pediatric idiopathic acute transverse myelitis and to identify those with prognostic value. The database of a tertiary pediatric medical center was retrospectively reviewed for patients aged less than 18 years who were diagnosed in 2002-2017 with acute transverse myelitis that was not associated with recurrence of a demyelinating autoimmune event. Data were collected on clinical, laboratory, and imaging findings and outcome. A total of 23 children (11 male, 12 female) met the study criteria. Mean age at disease onset was 10 years, and mean duration of follow-up was 6 years 10 months. Spinal cord and brain magnetic resonance imaging scans were performed on admission or shortly thereafter. The most common finding was cross-sectional involvement, in 16 patients (70%). The mean number of involved spinal segments was 8. The most frequently involved region was the thoracic spine, in 17 patients (74%). Clinical factors predicting good prognosis were cerebrospinal fluid pleocytosis, absence of tetraparesis, and prolonged time to nadir. In conclusion, most children with acute transverse myelitis appear to have a good outcome. Prompt diagnosis and treatment are important. Further research is needed in a larger sample to evaluate the predictive value of imaging features.

Sensory Processing Difficulties Correlate With Disease Severity and Quality of Life Among Children With Migraine.

Introduction: Headaches are common among children and about 80% of children reporting them. Migraine and tension type headaches are the most common primary headaches in children and the prevalence of migraine is about 8%. Accompanying sensory symptoms are common before, during and after migraine attacks. They may be a part of a wider symptom constellation called sensory processing disorder or difficulties (SPD). This includes both hyper or hypo sensitivity to sensations. However, the literature regarding sensory processing symptoms of children and youth with headaches as well as its interaction with child's emotional aspects and quality of life is scarce. Materials and Methods: One hundred and thirty-four children between the ages of 8 and 12 participated in this study. Fifty-four children (22 boys and 32 girls) with episodic migraine were prospectively recruited from pediatric neurological clinics during the years 2014-2017. The control group included 80 healthy children. Both groups completed a health and demographic questionnaire, headache assessment including Ped-MIDAS, Short Sensory Profile, State-Trait Anxiety Inventory (STAI) for children, and the Pediatric Quality of Life Inventory. Results: Children with migraine showed significantly higher prevalence of sensory processing difficulties and lower quality of life compared to healthy controls. Among children with migraine, sensory processing difficulties significantly correlated with lower quality of life. Headache-related disability and sensory processing difficulties predicted quality of life. Conclusion: The possible relationship between migraine and sensory processing disorder or difficulties stresses the need to screen for sensory processing difficulties among children with migraine and when found-refer to their impacts on children's daily function and quality of life.

Vertebral artery dissection and posterior stroke in a child.

Vertebral artery dissection is a relatively rare disease. Its symptoms and signs can be misleading, making the diagnosis, even with imaging assistance, difficult. We describe an 8-year-old boy in whom a brain tumor was suspected because of neurological signs and findings on computerized tomography of the brain. The differential diagnosis was broadened with further imaging evaluation. Magnetic resonance angiography demonstrated vertebral artery dissection, which was attributed to a trivial trauma the child had experienced 1 week before presentation. During the follow-up period, the child recovered, except for residual right hemianopsia.

Attention Deficit Hyperactivity Disorder in Neurofibromatosis Type 1: Evaluation with a Continuous Performance Test.

BACKGROUND AND PURPOSE: The objective of this study was to determine if the MOXO visual- and vocal-distractors-based continuous performance test distinguishes patients with attention deficit hyperactivity disorder (ADHD) and neurofibromatosis type 1 (NF1) from those without NF1. METHODS: Thirty-five patients (16 males; mean age 9.91 years) attending a multidisciplinary NF1 clinic completed the MOXO test. The findings were compared to 532 healthy age-matched standardized control subjects (285 males) without ADHD. RESULTS: The overall performance in the MOXO text was significantly worse in the NF1 group than in controls (p<0.01), but no group-specific pattern was identified. Impulsivity and hyperactivity were significantly more prominent in males than females (p<0.01). Compared to controls, the NF1 group exhibited significantly more failures to respond to target stimuli in the presence of visual distractors. CONCLUSIONS: MOXO scores are abnormal in patients with NF1, but the test cannot differentiate between NF1 with ADHD characteristics and ADHD. The test highlights sex differences in ADHD characteristics in NF1. Overreactivity to visual distractors may form part of the attention deficit in NF1.

Thick Corpus Callosum in Children.

BACKGROUND AND PURPOSE: A thick corpus callosum (TCC) can be associated with a very grave outcome in fetuses, but its clinical presentation in older children seems to be markedly different. METHODS: The corpus callosum (CC) was defined as thick based on observations and impressions. We reviewed cases of children who were diagnosed as TCC based on brain magnetic resonance imaging (MRI) studies. The pertinent clinical data of these children were collected, and their CCs were measured. RESULTS: Out of 2,552 brain MRI images, those of 37 children were initially considered as showing a TCC. Those initial imaging were reviewed by an experienced neuroradiologist, who confirmed the diagnosis in 34 children (1.3%): 13 had neurofibromatosis-1 (NF-1), 9 had epilepsy, 3 had macrocephaly capillary malformation (MCM) syndrome, 3 had autistic spectrum disorder, 1 had a Chiari-1 malformation, and 1 had increased head circumference. No specific neurologic disorder could be defined in seven children. The measured thickness of the CC in these children was comparable to those published in the literature for adults. CONCLUSIONS: A TCC is a rare brain malformation that can be found in neuropathologies with apparently diverse pathognomonic mechanisms, such as NF-1 and MCM. It is not necessarily associated with life-threatening conditions, instead being a relatively benign finding, different in nature from that reported in fetuses.

Congenital myasthenic syndrome in Israel: Genetic and clinical characterization.

The objective of the study was to evaluate the epidemiology of patients with congenital myasthenic syndrome (CMS) in Israel. Targeted mutation analysis was performed based on the clinical symptoms and electrophysiological findings for known CMS. Additional specific tests were performed in patients of Iranian and/or Iraqi Jewish origin. All medical records were reviewed and clinical data, genetic mutations and outcomes were recorded. Forty-five patients with genetic mutations in known CMS genes from 35 families were identified. Mutations in RAPSN were identified in 13 kinships in Israel. The most common mutation was c.-38A>G detected in 8 patients of Iranian and/or Iraqi Jewish origin. Four different recessive mutations in COLQ were identified in 11 kinships, 10 of which were of Muslim-Arab descent. Mutations in CHRNE were identified in 7 kinships. Less commonly detected mutations were in CHRND, CHAT, GFPT1 and DOK7. In conclusion, mutations in RAPSN and COLQ are the most common causes of CMS in our cohort. Specific mutations in COLQ, RAPSN, and CHRNE occur in specific ethnic populations and should be taken into account when the diagnosis of a CMS is suspected.

Development of Infants With Idiopathic External Hydrocephalus.

External hydrocephalus in an infant is a condition in which the rate of growth of head circumference exceeds the expectations of the Nellhouse curve together with increased size of the subarachnoid spaces. Developmental milestones of 20 infants (aged 0-16 months) with external hydrocephalus were studied by the Mullen Scales of Early Learning. The areas of development that were studied were visual reception, fine motor, expressive language, receptive language, and total Mullen score. There were no significant differences between the study group and the general population in all 5 scores. The only prominent feature of our external hydrocephalus patients was hypotonia (transient in 9 [45%] and persistent in 2 [10%]). Although the term external hydrocephalus describes a roentgenographic presentation, the term benign enlargement of subarachnoid space is preferred in infants similar to our group by better describing the benign nature of the phenomenon in appropriately selected infants.