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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.

The objective of this study was to assess the prevalence of disordered eating behaviors (DEBs) in young individuals with idiopathic intracranial hypertension (IIH) and to identify predictors of DEBs in this population.Individuals with IIH aged eight to 25 years and their matched controls responded to a self-rating survey comprised of the Eating Attitude Test-26 for assessing the presence of DEBs and the Depression, Anxiety and Stress Scale.Fifty-three subjects with IIH and 106 healthy controls were included. DEBs were significantly more prevalent in individuals with IIH (P 0.001). Individuals with IIH and DEBs were more likely to have longer periods of treatment [odds ratio: 1.07, 95% CI: 1.02-1.41), P = 0.008] and to have lost a significant amount of weight during the course of treatment [odds ratio: 9.06 (95% CI: 1.30-62.9), P = 0.026]. Depression, anxiety, and stress were more prevalent in the IIH group than in the controls (P = 0.004) and were associated with DEBs in these individuals (P = 0.01).There is an increased prevalence of DEBs among young individuals with IIH, which persists even after disease resolution, and is associated with higher reported rates of depression, anxiety, and stress. Medical caregivers should have heightened awareness to DEBs in individuals with IIH with the aim of early identification and intervention.

OBJECTIVE: Perinatal intracranial hemorrhage (pICH) is a rare event that occurs during the fetal/neonatal period with potentially devastating neurological outcome. However, the etiology of pICH is frequently hard to depict. We investigated the role of rare genetic variations in unexplained cases of pICH. METHODS: We performed whole-exome sequencing (WES) in fetuses and term neonates with otherwise unexplained pICH, and their parents. Variant causality was determined according to the American College of Medical Genetics and Genomics (ACMG) criteria, consistency between suggested genes and phenotypes, and mode of inheritance. RESULTS: Twenty-six probands (25 families) were included in the study (9 with a prenatal diagnosis and 17 with a postnatal diagnosis). Intraventricular hemorrhage (IVH) was the most common type of hemorrhage (n = 16, 62%), followed by subpial (n = 4, 15%), subdural (n = 4, 15%), and parenchymal (n = 2, 8%) hemorrhage. Causative/likely causative variants were found in 4 subjects from 3 of the 25 families (12%) involving genes related to the brain microenvironment (COL4A1, COL4A2, and TREX-1). Additionally, potentially causative variants were detected in genes related to coagulation (GP1BA, F11, VWF, FGA, F7) (n = 4, 16%). A potential candidate gene for phenotypic expansion related to microtubular function (DNAH5) was identified in one case (4%). Fifty five percent of the variants were inherited from an asymptomatic parent. Overall, these findings showed a monogenic cause for pICH in 12% to 32% of the families. INTERPRETATION: Our findings reveal a clinically significant diagnostic yield of WES in apparently idiopathic pICH and support the use of WES in the evaluation of these cases. This article is protected by copyright. All rights reserved.

Aim To evaluate the long-term effectiveness of cannabidiol (CBD)-enriched oil for the treatment of refractory epilepsy and to assess the development of tolerance to its anti-seizure effect. Methods A prospective study of 92 consecutive patients (age 1–37 years, mean-11.8 years) with treatment resistant epilepsy who were treated with cannabis oil extract (CBD/tetrahydrocannabinol [THC] ratio of 20:1). Mean monthly seizure frequency was reported by the patients/their parents during monthly clinic visits. Tolerance was defined as either the need to increase the dose by ≥30% due to reduced treatment efficacy or as an increase of ≥30% in mean monthly seizure frequency in patients treated for at least 3 months with no change in other anti-seizure medications. Results Mean follow-up time was 19.8 ± 12.5 months (range 3–45). Mean CBD dose was 11.3 (4–38) mg/kg/day. Twenty-nine (31%) patients discontinued treatment due to lack of effect or adverse reactions, which were reported in 51% (47/87) of the patients. Overall responder rate (>50% seizures reduction) was 54%, whereas 8 patients (9%) became seizure-free. Eighty-four patients were included in the tolerance analysis. Tolerance was observed in 21 (25%) patients after a mean duration of 7.3 ± 5.4 months of CBD-enriched oil treatment. There was a negative correlation between epilepsy duration and tolerance development (p = 0.038). Conclusions We report for the first time the plausible appearance of tolerance to cannabidiol-enriched oil. This may limit treatment efficacy in the long-term clinical management of refractory epilepsy in both pediatric and adult population. Further studies are needed to investigate potential mechanisms.

Urea cycle disorders (UCDs), including OTC deficiency (OTCD), are life-threatening diseases with a broad clinical spectrum. Early diagnosis and initiation of treatment based on a newborn screening (NBS) test for OTCD with high specificity and sensitivity may contribute to reduction of the significant complications and high mortality. The efficacy of incorporating orotic acid determination into routine NBS was evaluated. Combined measurement of orotic acid and citrulline in archived dried blood spots from newborns with urea cycle disorders and normal controls was used to develop an algorithm for routine NBS for OTCD in Israel. Clinical information and genetic confirmation results were obtained from the follow-up care providers. About 1147986 newborns underwent routine NBS including orotic acid determination, 25 of whom were ultimately diagnosed with a UCD. Of 11 newborns with OTCD, orotate was elevated in seven but normal in two males with early-onset and two males with late-onset disease. Orotate was also elevated in archived dried blood spots of all seven retrospectively tested historical OTCD patients, only three of whom had originally been identified by NBS with low citrulline and elevated glutamine. Among the other UCDs emerge, three CPS1D cases and additional three retrospective CPS1D cases otherwise reported as a very rare condition. Combined levels of orotic acid and citrulline in routine NBS can enhance the detection of UCD, especially increasing the screening sensitivity for OTCD and differentiate it from CPS1D. Our data and the negligible extra cost for orotic acid determination might contribute to the discussion on screening for proximal UCDs in routine NBS.

Insulin-like growth factor-1 (IGF-1) is an anabolic hormone with myotrophic effects on muscle tissue. Patients with spinal muscular atrophy (SMA) sustain early-onset sarcopenia, which contributes to an increased prevalence of insulin resistance. Our aim was to determine the IGF-1 status in 5q-SMA patients and its association with insulin resistance. Real-life clinical and laboratory data of 34 patients (15 males; age 3 months-24 years) included: anthropometric measurements [weight, height/length, body mass index or weight-to-length ratio, delta-height standard deviation score (∆Ht SDS) as the difference between height/length SDS and mid-parental height (MPHt) SDS] and laboratory measurements [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and IGF-1]. HOMA-IR levels categorized patients as insulin-resistant [HOMA-IR ≥1.9 (n = 20)] or insulin-sensitive [HOMA-IR

The clinical applicability and yield of brain magnetic resonance imaging (MRI) in the setting of an inpatient pediatric department has not been investigated. The authors performed a retrospective chart review of nontraumatic/nonneurosurgical children who underwent brain MRI during their hospitalization in a general pediatric department over a 5-year period. Of the 331 children who underwent brain MRI, 148 (45%) had abnormal findings. High-risk headaches and focal seizures were significantly correlated with findings on brain MRI. Diagnostic and therapeutic yields were most significant in acute demyelinating events, acute cerebrovascular disorders, high-risk headaches when supported by neurologic and ophthalmologic findings, focal seizures with evidence of multifocal epileptic activity on an electroencephalogram and ophthalmic complaints when accompanied by cranial nerve palsy and optic nerve impairment. Since the contributions of a brain MRI in hospitalized children is pivotal in specific clinical situations, a judicious decision-making process should be done before its scheduling, in order to optimize clinical care.

The introduction of nusinersen, the first therapeutic modality for Spinal Muscular Atrophy (SMA) patients has raised hopes and led to construction of a multi-professional medical SMA service, including pediatric endocrinology. Our study aimed to provide a comprehensive description of the endocrine manifestations of SMA patients with variable degree of sarcopenia. Real-life clinical and laboratory data of 62 SMA patients (age range 3 months to 31 years, 24 type 1, 21 type 2, 17 type 3) were collected including: weight-status, self-reported information on puberty, current pubertal stage, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), basal gonadotropin and androgen levels. Precocious pubarche (mean age at onset 3.9 ± 2.8 years) was found in 24% (15/62) of the SMA cohort [45.9%(11/24) type 1 and 19%(4/21) type 2]. A higher HOMA-IR predicted precocious pubarche after adjustment for SMA type and age (OR=1.42; 95% CI, 1.05, 1.93, P = 0.025). Bilateral cryptorchidism was found in 60% of type 1 and 30% of type 2 boys; type 3 young adult males attained full puberty. Most of the young women had normal pubertal development and regular menses, regardless of degree of obesity. Our findings suggest that isolated precocious pubarche is associated with early-onset insulin resistance linked to severity of muscular atrophy.

Epilepsy is estimated to exist in approximately 40% of individuals with cerebral palsy; however, the specific features that make it drug resistant are not well defined. The main aim of this study was to determine the clinical risk factors that could predict drug-resistant epilepsy, in children with cerebral palsy. The study was performed via a retrospective chart review, analyzing clinical parameters of 118 children with cerebral palsy with either drug-resistant epilepsy or controlled epilepsy, between the years 2013 and 2018. We established a predictive model for drug-resistant epilepsy in children with cerebral palsy that is simple to apply in clinical settings and composed of the additive effect of a low Apgar score at 5 minutes, neonatal seizures, focal-onset epilepsy, and focal slowing on electroencephalogram (EEG; area under the receiver operating characteristic of 0.840). Early prediction of drug-resistant epilepsy may benefit to achieve better seizure control in children with cerebral palsy.

Several works have reported on the antiepileptic impact of cannabis-based preparations in patients with treatment-resistant epilepsy (TRE). However, current formulations suffer from low bioavailability and side effects. PTL-101, an oral formulation containing highly purified cannabidiol (CBD) embedded in seamless gelatin matrix beadlets was designed to enhance bioavailability and maintain a constant gastrointestinal transit time.This phase II, prospective study was open to pediatric patients with TRE on stable antiepileptic drugs' (AEDs) doses, who experienced ≥4 seizures within four weeks of enrolment and with a history of ≥4 AEDs failing to provide seizure control. Following a 4-week observation period, patients began a 2-week dose-titration phase (up to ≤25mg/kg or 450mg, the lower of the two), followed by a 10-week maintenance treatment period. Caregivers recorded seizure frequency, type, and severity and ranked their global impressions after 7 and 12weeks of treatment. Responders were those showing a ≥50% reduction from baseline monthly seizure frequency. Safety assessments monitored vital signs, adverse effects, physical and neurological exams, and laboratory tests.Sixteen patients (age: 9.1±3.4) enrolled in the study; 11 completed the full treatment program. The average maintenance dose was 13.6±4.2mg/kg. Patient adherence to treatment regimens was 96.3±9.9%. By the end of the treatment period, 81.9% and 73.4±24.6% (p0.05) reductions from baseline median seizure count and monthly seizure frequency, respectively, were recorded. Responders' rate was 56%; two patients became fully seizure-free. By study end, 8 (73%) caregivers reported an improved/very much improved condition, and 9 (82%) reported reduced/very much reduced seizure severity. Most commonly reported treatment-related adverse effects were sleep disturbance/insomnia, (4 (25.0%) patients), followed by somnolence, increased seizure frequency, and restlessness (3 patients each (18.8%)). None were serious or severe, and all resolved.PTL-101 was safe and tolerable for use and demonstrated a potent seizure-reducing effect among pediatric patients with TRE.

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.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.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.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.

Genetic alterations in COL4A2 are less common than those of COL4A1 and their fetal phenotype has not been described to date. We describe a three-generation family with an intragenic deletion in COL4A2 associated with a prenatal diagnosis of recurrent fetal intracerebral hemorrhage (ICH), and a myriad of cerebrovascular manifestations. Exome sequencing, co-segregation analysis, and imaging studies were conducted on eight family members including two fetuses with antenatal ICH. Histopathological evaluation was performed on the terminated fetuses. An intragenic heterozygous pathogenic in-frame deletion; COL4A2, c.4151_4168del, (p.Thr1384_Gly1389del) was identified in both fetuses, their father with hemiplegic cerebral palsy (CP), as well as other family members. Postmortem histopathological examination identified microscopic foci of heterotopias and polymicrogyria. The variant segregated in affected individuals demonstrating varying degrees of penetrance and a wide phenotypic spectrum including periventricular venous hemorrhagic infarction causing hemiplegic CP, polymicrogyria, leukoencephalopathy, and lacunar stroke. We present radiographic, pathological, and genetic evidence of prenatal ICH and show, for what we believe to be the first time, a human pathological proof of polymicrogyria and heterotopias in association with a COL4A2 disease-causing variant, while illustrating the variable phenotype and partial penetrance of this disease. We highlight the importance of genetic analysis in fetal ICH and hemiplegic CP.

Background The emergence of new treatments for spinal muscular atrophy (SMA) is revolutionary, especially for SMA type 1 (SMA1). Data on respiratory outcomes remain sparse and rely mostly on randomized clinical trials. We report our experience of Nusinersen-treated SMA1 patients in real-world settings. Methods Data from SMA1 patients treated with Nusinersen were prospectively collected between 1/2017 and 1/2020. Respiratory variables included the use of assisted ventilation, the use of mechanical insufflation-exsufflation (MIE), respiratory complications, and death or treatment cessation due to respiratory reasons. Results Twenty SMA1 patients were assessed before and after 2 years of Nusinersen treatment which was initiated at a median age of 13.5 months (range, 1-184). At baseline, 16 patients were using assisted ventilation, eight noninvasive and eight invasive. Twelve patients were using permanent ventilation and four partial ventilation. After 2 years of treatment, there was no change in respiratory support among ventilated patients. All four patients who were free from respiratory support at baseline required the initiation of assisted ventilation during the study period. All 20 patients used MIE after 2 years of treatment. Two patients died from acute respiratory failure and one sustained severe brain injury. Four patients had chronic and/or recurrent atelectasis. Conclusion Most of our patients were stable in their need for assisted ventilation and did not worsen as expected in SMA1, nor did they improve as might be hoped. Future studies are needed to determine if earlier treatment with Nusinersen might result in respiratory outcomes superior to those reported in this real-life study.

OBJECTIVEManagement of children with large temporal arachnoid cysts (TACs) remains controversial, with limited data available on their neurodevelopmental outcome. The aim of this study was to examine neurodevelopmental outcomes in children with large TACs.METHODSIn this medical center–based cohort study, 25 patients (19 males) who were diagnosed in childhood with large TACs (9 patients [36%] with a Galassi type II and 16 patients [64%] with a Galassi type III TAC) were examined. The mean ± SD age at assessment was 11.1 ± 5.6 years (range 2.7–22 years). Twelve patients (48%) had right-sided, 12 (48%) had left-sided, and 1 (4%) had bilateral cysts. Nine patients (36%) underwent surgery for the cyst. The siblings of 21 patients (84%) served as control participants. Neurodevelopmental function was assessed using the Adaptive Behavior Assessment System (ABAS), Vanderbilt Behavioral Rating Scale (VBRS), and Developmental Coordination Disorder Questionnaire (DCDQ), and quality of life was measured using the treatment-oriented screening questionnaire (TOSQ). The results of all instruments except for TOSQ were compared with those of the sibling control participants.RESULTSThe mean ± SD ABAS score of the patients was 93.3 ± 20.09 compared with 98.3 ± 18.04 of the sibling control participants (p = 0.251). Regarding the incidence of poor outcome (ABAS score < 80), there was a trend for more patients with TAC to have poor outcome than the sibling controls (p = 0.058). Patients who underwent surgery scored significantly worse with regard to the VBRS total score compared with those who did not (p = 0.020), but not on ABAS, DCD, or TOSQ. The mean score of the cognitive and psychological items on TOSQ was lower than that for the physical items (p < 0.001).CONCLUSIONSChildren with a large TAC performed similarly to their sibling control participants in neurodevelopmental function. However, a subgroup of those with cysts did have an increased risk for poor outcomes in general function. Neurodevelopmental assessment should be part of the management of all patients with TAC.

Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants (SNVs) in known epilepsy-associated genes to further validate CNVs using two different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and two deletions and two duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed two cases with pathogenic CNVs that one of the two CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with

Pseudotumor cerebri syndrome (PTCS) is a disorder defined by increased intracranial pressure in the absence of an intracranial space-occupying lesion. This retrospective study aimed to examine the outcomes in children with PTCS.Data was collected retrospectively from the charts of consecutive pediatric patients treated for PTCS at our hospital between 2000 and 2007 (60 patients; 36 females, 24 males).Forty-six patients (76.6%) responded well to acetazolamide therapy, with full resolution of symptoms, including papilledema (average treatment duration 1 year; range: 1 month-5 years). Of the 14 patients with no response to treatment, 9 (23.4%) required surgical intervention. Nonresponders tended to be younger at presentation (8.7 vs 11.5 years, P = 0.04). Twelve patients (26%) experienced relapse after acetazolamide was discontinued. The group that experienced relapse was significantly younger than the nonrelapsers (8.9 vs 12.1 years, P0.05).Younger age at presentation with PTCS was found to be a risk factor for treatment failure or relapse.

Background and Purpose: Postnatal progressive microcephaly, with seizures and brain atrophy (OMIM # 613668) is a rare disorder caused by a homozygous founder missense mutation c.1112T>C (p.L371P) in the MED17 gene on chromosome 11 that was identified in 2010 in Caucasus Jewish families. The present study aimed to delineate the phenotype and developmental outcomes in patients diagnosed with this mutation to date. Methods We conducted a medical charts review to collect the clinical, laboratory and neuroimaging findings in patients from several unrelated families of Caucasus-Jewish origin, who were diagnosed with the same homozygous c.1112T>C MED17 mutation. Results The study cohort, including the previously reported patients, comprised 10 males and 5 females from 11 families. All subjects had at birth a normal head circumference, which steeply declined to -6SD within a few months. None of the patients achieved developmental milestones. All patients had progressive spasticity and were wheelchair bound due to spastic quadriplegia. All of them eventually developed profound intellectual disability. Epilepsy of varied severity was present in all patients. Most patients required enteral feeding due to aspirations. Eight patients died before puberty (age range 2–13 years). Brain MRI showed marked cerebral atrophy and early prominent cerebellar atrophy (vermian > hemispheres) accompanied by pontine ventral flattening. Conclusions The founder c.1112T>C mutation in MED17 gene is expressed by a unique and homogeneous clinical phenotype with distinctive MRI findings. This mutation should be considered in patients of Caucasus-Jewish ancestry presenting with clinical features and a MRI pattern of progressive cerebral and cerebellar atrophy.

Hereditary spastic paraparesis (HSP) is a progressive neurodegenerative disorder, characterized by progressive lower limb weakness and spasticity. Multiple genes are associated with both the pure and complicated HSP types. Our study is aimed at seeking for novel genetic basis of HSP in a family with two affected siblings. Genetic analysis using whole exome sequencing was conducted in a family quartet with two female siblings, who presented with complicated HSP featuring slowly progressive paraparesis, mild-moderate intellectual disability, normal head circumference (HC), and normal magnetic resonance imaging (MRI). A homozygous pathogenic variant was identified in both siblings in the VPS53 gene (c.2084A>G: c.2084A>G, p.Gln695Arg). This gene acts as a component of the Golgi-associated retrograde protein (GARP) complex that is involved, among others, in intracellular cholesterol transport and sphingolipid homeostasis in lysosomes and was previously associated with progressive cerebello-cerebral atrophy (PCCA) type 2. This is the first description of the VPS53 gene as a cause of autosomal recessive complicated HSP. Lysosomal dysfunction as a result of impaired cholesterol trafficking can explain the neurodegenerative processes responsible for the HSP. Our finding expands the phenotype of VPS53-related disease and warrants the addition of VPS53 analysis to the genetic investigation in patients with autosomal recessive HSP. The exact role of GARP complex in neurodegenerative processes should be further elucidated.

We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a pivotal role in microtubule assembly in all cells. A total of seven mutations were found: five missense mutations, one nonsense, and one splice site mutation resulting in a frameshift. In vitro cell experiments revealed the impaired binding between most mutant TBCD proteins and ARL2, TBCE, and β-tubulin. The in vivo experiments using olfactory projection neurons in Drosophila melanogaster indicated that the TBCD mutations caused loss of function. The wide range of clinical severity seen in this neurodegenerative encephalopathy may result from the residual function of mutant TBCD proteins. Furthermore, the autopsied brain from one deceased individual showed characteristic neurodegenerative findings: cactus and somatic sprout formations in the residual Purkinje cells in the cerebellum, which are also seen in some diseases associated with mitochondrial impairment. Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of this neurodegenerative encephalopathy.

Objective: To assess the intracranial pressure in pediatric acute disseminated encephalomyelitis using spinal tap opening pressure on lumbar puncture, which is routinely performed as part of suspected acute disseminated encephalomyelitis workup. Compared to other cerebrospinal fluid parameters such as cell count, protein concentration, and presence of oligoclonal bands, cerebrospinal fluid opening pressure is infrequently recorded. Methods: A retrospective chart review of demographic, clinical, and laboratory data of children diagnosed with acute disseminated encephalomyelitis admitted to a tertiary referral hospital between 2005 and 2016. Results: Of the 36 children diagnosed with acute disseminated encephalomyelitis, 24 had the cerebrospinal fluid opening pressure documented in their records. The mean cerebrospinal fluid opening pressure was 27.6±12.6 cmH2O, range 9-55 cmH2O (95% confidence interval 21.9-33.6). Cerebrospinal fluid opening pressure in the acute disseminated encephalomyelitis group was statistically significantly higher ( P = .0013, 95% confidence interval 4.2-15.0) than the accepted upper limit in this age group (18 cmH2O). In 10 of 24 patients (42%), the opening pressure was above 28 cmH2O. Conclusions: Increased opening pressure was the most frequent cerebrospinal fluid abnormal finding in our cohort, which suggests a potential role of increased intracranial pressure in the acute disseminated encephalomyelitis pathophysiological disease mechanism. In certain cases, the opening pressure value could have monitoring and therapeutic implications, and therefore its measurement is highlighted by this study.

SNAP25 is a core component of the soluble N-ethylmaleimide-sensitive factor attachment receptor complex, which plays a critical role in synaptic vesicle exocytosis. To date, six de novo SNAP25 mutations have been reported in patients with neurological features including seizures, intellectual disability, severe speech delay, and cerebellar ataxia. Here, we analyzed an Israeli family with two affected siblings showing seizures and cerebellar dysfunction by whole-exome sequencing, and identified a novel missense SNAP25 mutation (c.176G > C, p.Arg59Pro) inherited from their unaffected father. Two SNAP25 isoforms are known, SNAP25a and SNAP25b, which each contain a different exon 5. The c.176G > C mutation found in this study was specific to SNAP25b, while five previously reported mutations were identified in exons common to both isoforms. Another was previously reported to be specific to SNAP25b. Comparing clinical features of reported patients with SNAP25 mutations, the current patients demonstrated apparently milder clinical features with normal intelligence, and no magnetic resonance imaging abnormality or facial dysmorphism. Our results expand the clinical spectrum of SNAP25 mutations.

Background In 2003, several hundred Israeli infants risked thiamine deficiency after being fed a soy-based formula deficient in thiamine. Approximately 20 patients were seriously affected, and three of them died. We report the clinical presentation of acute encephalopathy in 11 children and the long-term sequelae of eight children who initially survived. Patients In the acute phase, six had bulbar signs, five had ophthalmologic signs and two had phrenic neuropathy. Three of the five patients with cardiac involvement had cardiomyopathy and died in the acute phase. One patient presented with a complete atrioventricular block. Results In the long-term, one patient, who was in a chronic vegetative state, died after 6 years. Seven children exhibited mental retardation and motor abnormalities, six developed severe epilepsy, two early kyphoscoliosis, and one patient remained with a complete atrioventricular block. Conclusions Infants who survive severe infantile thiamine deficiency have serious residual motor and cognitive sequelae as well as epilepsy.

We investigated the long‐term implications of infantile thiamine (vitamin B1) deficiency on motor function in preschoolers who had been fed during the first 2 years of life with a faulty milk substitute. In this retrospective cohort study, 39 children aged 5–6 years who had been exposed to a thiamine‐deficient formula during infancy were compared with 30 age‐matched healthy children with unremarkable infant nutritional history. The motor function of the participants was evaluated with The Movement Assessment Battery for Children (M‐ABC) and the Zuk Assessment. Both evaluation tools revealed statistically significant differences between the exposed and unexposed groups for gross and fine motor development (p

CD59 deficiency is a common finding in RBCs and WBCs in patients with chronic hemolysis suffering from paroxysmal nocturnal hemoglobinuria in which the acquired mutation in the PIGA gene leads to membrane loss of glycosylphosphatidylinositol-anchored membrane proteins, including CD59. The objective of the present study was to elucidate the molecular basis of childhood familial chronic Coombs-negative hemolysis and relapsing polyneuropathy presenting as chronic inflammatory demyelinating polyradiculoneuropathy in infants of North-African Jewish origin from 4 unrelated families. A founder mutation was searched for using homozygosity mapping followed by exome sequencing. The expression of CD59, CD55, and CD14 was examined in blood cells by flow cytometry followed by Western blot of the CD59 protein. A homozygous missense mutation, p.Cys89Tyr in CD59, was identified in all patients. The mutation segregated with the disease in the families and had a carrier rate of 1:66 among Jewish subjects of North-African origin. The mutated protein was present in the patients' cells in reduced amounts and was undetectable on the membrane surface. Based on the results of the present study, we conclude that the Cys89Tyr mutation in CD59 is associated with a failure of proper localization of the CD59 protein in the cell surface. This mutation is manifested clinically in infancy by chronic hemolysis and relapsing peripheral demyelinating disease.

Background Members of two seemingly unrelated kindreds of Arab Moslem origin presented with pronounced early onset spastic paraparesis of upper and lower limbs, mild intellectual disability, kyphosis, pectus carinatum and hypertrichosis. Methods The authors performed neurological and developmental examinations on the affected individuals. The authors conducted whole genome linkage and haplotype analyses, followed by sequencing of candidate genes; RNA and protein expression studies; and finally proof of principle investigations on knockdown morpholino oligonucleotide injected zebrafish. Results The authors characterise a novel form of autosomal recessive complex hereditary spastic paraparesis (CHSP). MRI studies of brain and spinal cord were normal. Within a single significantly linked locus the authors ultimately identified a homozygous missense mutation c.1146A>T (p.K382N) in the vacuolar protein sorting 37A ( Vps37A ) gene, fully penetrant and segregating with the disease in both families. Mobility was significantly reduced in Vps37A knockdown morpholino oligonucleotide injected zebrafish, supporting the causal relationship between mutations in this gene and the phenotype described in the patients of this study. Conclusions The authors provide evidence for the involvement of Vps37A , a member of the endosomal sorting complex required for transport (ESCRT) system, in upper motor neuron disease. The ESCRT system has been shown to play a central role in intracellular trafficking, in the maturation of multivesicular bodies and the sorting of ubiquitinated membrane proteins into internal luminal vesicles. Further investigation of mechanisms by which dysfunction of this gene causes CHSP will contribute to the understanding of intracellular trafficking of vesicles by the ESCRT machinery and its relevance to CHSP.

Objective: To describe a novel pattern of magnetic resonance imaging (MRI) abnormalities as well as the associated clinical and laboratory findings. Design: The MRIs of more than 3000 patients with an unclassified leukoencephalopathy were systematically reviewed. Clinical and laboratory data were retrospectively collected. Setting: University hospital. Patients: Seven patients (3 male) shared similar MRI abnormalities and clinical features. Main Outcome Measures: Pattern of MRI abnormalities and clinical and laboratory findings. Results: The MRIs showed signal abnormalities of the deep cerebral white matter, corpus callosum, thalamus, basal ganglia, brainstem, and cerebellar white matter between the ages of 9 months and 2 years. On follow-up, abnormalities gradually improved. Clinical regression occurred in the second half-year of life with spasticity and loss of milestones. From the second year on, clinical improvement occurred. So far, no second episode of regression has happened. Lactate levels were elevated during clinical regression. Conclusion: These patients represent a single novel leukoencephalopathy, probably caused by a mitochondrial defect. Arch Neurol. 2012; 69(6): 718-722. Published online February 6, 2012. doi:10.1001/archneurol.2011.1048

The objectives of this study were to describe the nature of the attention deficits in children with Neurofibromatosis type 1 (NF1) in comparison with typically developing (TD) children, using the Virtual Classroom (VC), and to assess the utility of this instrument for detecting attention deficits. Twenty-nine NF1 children and 25 age-and gender-matched controls, aged 8-16, were assessed in a VC. Parents' ratings on the Conners' Parent Rating Scales-Revised: Long (CPRS-R:L) questionnaire were used to screen for Attention Deficit-Hyperactivity Disorder (ADHD). Significant differences were found between the NF1 and the control groups on the number of targets correctly identified (omission errors) and the number of commissions (commission errors) in the VC, with poorer performance by the NF1 children (p0.005). Significant correlations were obtained between the number of targets correctly identified, the number of commission errors, and the reaction time. Significant correlations were also found between the total correct hits and the cognitive problems/inattention scale, as well as two other indexes of the CPRS-R:L: the DSM-IV Symptoms Subscale and the ADHD Index. The VC results support the hypothesis that NF1 is marked by inattention and impulsivity and that participants with NF1 are more inattentive (omission errors) and impulsive (commission errors) than normal controls. The VC appears to be a sensitive and ecologically valid assessment tool for use in the diagnosis of attention deficits among children with NF1.

Pediatric brain tumors (PBTs) are the most common solid tumors and the leading cause of cancer-related morbidity and mortality in childhood. Previous studies have shown a significant delay between the onset of symptoms and the diagnosis of these tumors. Delayed diagnosis of PBTs may lead to acute situations and irreversible neurological damage. In this study, we looked for the incidence of delayed diagnosis of PBTs in Israel. We tried to find the reasons for these delays and the associated risk factors in order to provide a feedback to the system for improved education and earlier diagnosis.We analyzed the charts of 330 consecutive children aged 0-18 years diagnosed with brain tumors, between the years 1996 and 2004. In the cases where delay in diagnosis was suspected, further information was collected from a family interview.The average "time to diagnosis" was 7.7 months (SD ± 16.7). Symptomatic deterioration from the first symptom until diagnosis was found in about 50% of the cases. Unacceptable delay in diagnosis was found in 27% of the children. The major reason for delay was "delay in indicated imaging." Symptoms that were found to be associated with delayed diagnosis were torticollis, ataxia, and motor dysfunction. Interestingly, the examination by specialists such as ophthalmologists or neurologists was also associated with delayed diagnosis.There is an unacceptable rate of delay in the diagnostic process of PBTs in Israel. Greater awareness and familiarity with signs and symptoms associated with these tumors and lowering imaging threshold might minimize this phenomenon.

This study explored the effect of thiamine deficiency during early infancy on the development of syntax and lexical retrieval. We tested syntactic comprehension and production, lexical retrieval abilities and conceptual abilities of 59 children aged 5-7 years who had been fed during their first year of life with a thiamine-deficient milk substitute. We compared them to 35 age-matched control children who were fed with other milk sources. Experiment 1 tested the comprehension of relative clauses using a sentence-picture-matching task. Experiment 2 tested the production of relative clauses using a preference elicitation task. Experiment 3 tested the repetition of various syntactic structures with various types of syntactic movement and embedding. Experiment 4 tested picture naming and Experiment 5 tested lexical substitutions in a sentence repetition task. Experiments 6 and 7 tested the children's conceptual abilities using a picture association task and a picture absurdity description task. The results indicated a very high rate of syntactic and lexical retrieval deficits in the group of children who were exposed to thiamine deficiency in early infancy: 57 of the 59 thiamine-deficient children examined had language impairment, compared with three of the 35 controls (9%). Importantly, unlike the impairment this group sustained in their language abilities, the conceptual abilities of most of the children were intact (only six children, 10%, were conceptually impaired). These findings indicate that thiamine deficiency in infancy causes severe and long-lasting language disorders and that nutrition may be one of the causes for language impairment.

Influenza is associated with a variety of neurologic complications. Although the epidemiologic and clinical characteristics of influenza A H1N1 were reviewed in depth, only brief descriptions of neurologic complications exist. We describe the neurologic complications of children hospitalized with influenza A H1N1 infection. We undertook a retrospective study of all hospitalized children with laboratory-confirmed influenza A H1N1 infection accompanied by neurologic complications during a 4-month winter period. Their demographics and clinical characteristics of neurologic presentations were reviewed. Fourteen of 74 children (19%) with laboratory-confirmed influenza A H1N1 infection presented with neurologic complications. Eleven (11/14, 79%) were previously healthy, and three exhibited chronic conditions. Ten (10/14, 71%) presented with seizures: six were febrile, and four were nonfebrile. Other complications included transverse myelitis, myositis, expressive aphasia, and syncope. Only the child with transverse myelitis required a course of rehabilitation. Neurologic complications associated with influenza A H1N1 in our patients were relatively mild. Seizures (febrile or nonfebrile) were the most common. However, the possibility of influenza A H1N1 infection should be borne in mind when diagnosing children with neurologic signs during the influenza A H1N1 season.

The objective of this study was to analyze the process and product of handwriting among children with Neurofibromatosis Type 1 (NF1) in comparison to those of Typically Developing (TD) children. Children with NF1 are at risk for some cognitive deficits, a wide range of deficits in perceptual skills and, motor and visual-motor integration skills which may interfere with handwriting competency, which is an essential ingredient for success at school. Participants were 30 NF1 children and 30 age and gender matched TD children, between the ages 8 and 16.08. The handwriting performance of children with NF1 was evaluated with the Beery–Buktenica Developmental Test of Visual-Motor Integration (VMI), for copying text and free style writing tasks, using: (1) Computerized Penmanship Evaluation Tool (ComPET) to assess mechanical aspects of the writing process. (2) The Hebrew Handwriting Evaluation (HHE) to examine product legibility. (3) The Six-Trait Writing Model to judge the quality of the written product. Significant differences between the NF1 children and the control group were found in the process and product measures. Significant correlations were found between the VMI, the ComPET, the HHE and the Six-Trait Writing Model variables for both groups. We suggest a possible relationship between executive dysfunction and poor performance in handwriting.

Limited information is available on the use of botulinum toxin type A injections for children with hereditary spastic paraplegia. This report includes 12 children with hereditary spastic paraplegia (mean age 4.8 ± 2.5 years) who underwent 1 to 6 sessions of botulinum toxin A injections to the hamstrings, adductors and gastrocnemius muscles. Patients showed both improved muscle tone (mean 1.9 ± 0.5 vs 1.18 ± 0.33, P < .001, Ashworth Scale) and motor function (75.3 ± 11.9 vs 77.7 ± 11, P < .001, Gross Motor Function Measure). The effect lasted for a mean of 6.6 ± 3.6 months. During the study period (mean 2.8 ± 1.8 years), the preinjection Gross Motor Function Measure increased (69.2 ± 14.7 vs 78.3 ± 13.5, P = .005), whereas the Ashworth Scale remained stable, suggesting a prolonged effect of botulinum toxin A on motor function. The authors conclude that botulinum toxin A injections to lower limbs of pediatric patients with hereditary spastic paraplegia result in prolonged functional improvement despite the progressive nature of the disease.

The aim of this study was to investigate the language development of 20 children who had been exposed to thiamine (vitamin B1) deficiency in infancy due to feeding with soy-based formula that was accidentally deficient of thiamine. In this case–control study, 20 children (12 males, eight females; mean age 31.8mo [SD 4.1], range 24–39mo) who were fed thiamine-deficient formula in infancy were compared with 20 children (12 males, eight females; mean age 32.2mo [SD 3.9], range 25–39mo) fed with other milk sources and matched for age, sex, and maternal education. Receptive and expressive language development was assessed with the Preschool Language Scale, 3rd edition. Other assessments included mental development (Bayley Scales of Infant Development, 2nd edition), evaluation for autistic spectrum disorders, and neurological examination. Motor development was compared by age at independent walking. The study and control groups differed significantly in the expressive communication (p

Epileptic negative myoclonus is an uncommon seizure type characterized by a sudden, brief loss of muscle tone that may lead to falling. It has been associated largely with benign childhood epilepsy with centrotemporal spikes (rolandic epilepsy), although it may also be a feature of other epileptic syndromes. In patients with rolandic epilepsy, epileptic negative myoclonus usually appears during the course of the disease, well after a diagnosis of the epilepsy has been established. Described here are five patients with rolandic epilepsy in which the presenting seizure was falls due to epileptic negative myoclonus. Because developmental delay or neurocognitive problems were present in three of the children, it is possible that epileptic negative myoclonus may be misinterpreted as clumsiness-related falls in some children who actually have undiagnosed rolandic epilepsy.

Objective:To report the follow-up findings of 7 children with severe epilepsy as a result of thiamine deficiency in infancy caused by a defective soy-based formula.Methods:The medical records of 7 children aged 5-6 years with thiamine deficiency in infancy who developed epilepsy were reviewed and their clinical data, EEG tracings, and neuroimaging results were recorded. The clinical course and present outcome of these children, now 5 years after exposure to thiamine deficiency, are described.Results:All infants displayed seizures upon presentation, either tonic, myoclonic, or focal. Six infants had an EEG recording at this stage and all showed slow background. Five of them had no epileptic activity and only 1 displayed focal activity. Following a seizure-free period of 1-9 months, the seizures recurred, and all 7 children displayed either myoclonic or complex partial seizures. Multifocal or generalized spike wave complexes were recorded on the EEGs of all 7 patients, and the tracings of 3 children evolved into hypsarrhythmia. The seizures were refractory to most antiepileptic drugs, and 4 children remain with uncontrolled seizures. All children have mental retardation and motor disabilities as well as symptoms of brainstem dysfunction.Conclusions:Our findings indicate that severe infantile thiamine deficiency may result in epilepsy.

The brain has a remarkable capacity for reorganization following injury, especially during the first years of life. Knowledge of structural reorganization and its consequences following perinatal injury is sparse. Here we studied changes in brain tissue volume, morphology, perfusion, and integrity in children with hemiplegia compared to typically developing children, using MRI. Children with hemiplegia demonstrated reduced total cerebral volume, with increased cerebrospinal fluid (CSF) and reduced total white matter volumes, with no differences in total gray matter volume, compared to typically developing children. An increase in cortical thickness at the hemisphere contralateral to the lesion (CLH) was detected in motor and language areas, which may reflect compensation for the gray matter loss in the lesion area or retention of ipsilateral pathways. In addition, reduced cortical thickness, perfusion, and surface area were detected in limbic areas. Increased CSF volume and precentral cortical thickness and reduced white matter volume were correlated with worse motor performance. Brain reorganization of the gray matter within the CLH, while not necessarily indicating better outcome, is suggested as a response to neuronal deficits following injury early in life. Guy’s and St Thomas’ Charity and the Marnie Kimelman Trust

Background. Motor-learning interventions may improve hand function in children with unilateral cerebral palsy (UCP) but with inconsistent outcomes across participants. Objective. To examine if pre-intervention brain imaging predicts benefit from bimanual intervention. Method. Twenty children with UCP with Manual Ability Classification System levels I to III, aged 7-16 years, participated in an intensive bimanual intervention. Assessments included the Assisting Hand Assessment (AHA), Jebsen Taylor Test of Hand Function (JTTHF) and Children’s Hand Experience Questionnaire (CHEQ) at baseline (T1), completion (T2) and 8-10 weeks post-intervention (T3). Imaging at baseline included conventional structural (radiological score), functional (fMRI) and diffusion tensor imaging (DTI). Results. Improvements were seen across assessments; AHA ( P = 0.04), JTTHF ( P < .001) and CHEQ ( P < 0.001). Radiological score significantly correlated with improvement at T2; AHA ( r = .475) and CHEQ ( r = .632), but negatively with improvement on unimanual measures at T3 (JTTFH r = −.514). fMRI showed negative correlations between contralesional brain activation when moving the affected hand and AHA improvements (T2: r = −.562, T3: r = −0.479). Fractional Anisotropy in the affected posterior limb of the internal capsule correlated negatively with increased bimanual use on CHEQ at T2 ( r = −547) and AHA at T3 ( r = −.656). Conclusions. Children with greater structural, functional and connective brain damage showed enhanced responses to bimanual intervention. Baseline imaging may identify parameters predicting response to intervention in children with UCP.

Three recessive mutations in the sodium leak channel, nonselective (NALCN) have been reported to cause intellectual disability and hypotonia. In addition, 14 de novo heterozygous mutations have been identified in 15 patients with arthrogryposis and neurodevelopmental impairment. Here, we report three patients with neurodevelopmental disease and hypotonia, harboring one recurrent (p.R1181Q) and two novel mutations (p.L312V and p.V1020F) occurring de novo in NALCN. Mutation p.L312 is located in the pore forming S6 region of domain I and p.V1020F in the S5 region of domain III. Mutation p.R1181Q is in a linker region. Mapping these three mutations to a model of NALCN showed p.Leu312 and p.Val1020 positioned in the hydrophobic core of the pore modules, indicating these two mutations may affect the gating function of NALCN. Although p.R1181Q is unlikely to affect the ion channel structure, previous studies have shown that an analogous mutation in Caenorhabditis elegans produced a phenotype with a coiling locomotion, suggesting that p.R1181Q could also affect NALCN function. Our three patients showed profound intellectual disability and growth delay, facial dysmorphologies and hypotonia. The present data support previous work suggesting heterozygous NALCN mutations lead to syndromic neurodevelopmental impairment.

A multicenter retrospective study was conducted to investigate the perinatal factors, imaging findings and clinical characteristics of hemiplegic cerebral palsy with a particular focus on children born prematurely. Our cohort included 135 patients of whom 42% were born prematurely; 16% were extreme premature infants who were born at 30 weeks or earlier. Nineteen (14%) were twins. Right hemiplegia was slightly more common and accounted for 59% of the patients. Imaging findings of intraventricular hemorrhage and periventricular leukomalacia were more prevalent in premature children whereas stroke, porencephaly, cerebral hemorrhage and cerebral atrophy were more evenly distributed in both term-born and prematurely-born children ( p < 0.01). The overall prevalence of epilepsy in the cohort was 26% with no differences in full-term compared to prematurely-born children. Regardless of the gestational birth age, intellectual deficits were more common in the presence of comorbidity of both hemiplegia and epilepsy ( p < 0.05).

Background Leukodystrophies are genetic white matter disorders affecting the formation or maintenance of myelin. Among the recently discovered genetic defects associated with leukodystrophies, several genes converge on a common mechanism involving protein transcription/translation and ER stress response. Methods The genetic basis of a novel congenital leukodystrophy, associated with early onset spastic paraparesis, acquired microcephaly and optic atrophy was studied in six patients from three unrelated Ashkenazi-Jewish families. To this end we used homozygosity mapping, exome analysis, western blot (Hikeshi, HSF1-pS326 and b-actin) in patient fibroblasts, indirect immunofluorescence (HSP70 and HSF1) in patient fibroblasts undergoing heat shock stress, nuclear injection of plasmids expressing Hikeshi or EGFP in patient fibroblasts, in situ hybridization and Immunoblot analysis of Hikeshi in newborn and adult mouse brain. Results All the patients were homozygous for a missense mutation, p.Val54Leu, in C11ORF73 encoding HSP70 nuclear transporter protein, Hikeshi. The mutation segregated with the disease in the families and was carried by 1:200 Ashkenazi-Jewish individuals. The mutation was associated with undetectable level of Hikeshi in the patients' fibroblasts and with lack of nuclear HSP70 during heat shock stress, a phenomenon which was reversed upon the introduction of normal human Hikeshi to the patients cells. Hikeshi was found to be expressed in central white matter of mouse brain. Conclusions These data underscore the importance of Hikeshi for HSP70 relocation into the nucleus. It is likely that in the absence of Hikeshi, HSP70 cannot attenuate the multiple heat shock induced nuclear phenotypes, leaving the cells unprotected during heat shock stress. We speculate that the sudden death of three of the six patients following a short febrile illness and the life-threatening myo-pericarditis in the fourth are the result of excess extra-nuclear HSP70 level which initiates cytokine release or provide target for natural killer cells. Alternatively, nuclear HSP70 might play an active role in stressed cells protection.

The objective was to report our positive experience of using dexamethasone to treat 13 patients with symptomatic slit ventricle syndrome (SVS).Thirteen SVS patients who received dexamethasone during acute episodes were studied. The etiology for hydrocephalus was prematurity and intraventricular hemorrhage in 9 patients and neonatal meningitis, chorioamnionitis, Dandy-Walker variant, and congenital in 1 case each. The shunt was inserted at 1.8+/-1.0 months of age and SVS was diagnosed at 4.9+/-3.2 years of age.All patients reported relief and shorter duration of symptoms with dexamethasone. Surgical intervention was decided upon and carried out within 11+/-8 months of SVS diagnosis in 9 out of 13 patients. The other 4 are being monitored and continue to receive dexamethasone when needed.Dexamethasone appears to be a useful treatment in acutely increased intracranial pressure caused by SVS. It can provide temporary relief during the decision-making process of whether and when to perform surgery.

Objective. Between October and November 2003, several infants with encephalopathy were hospitalized in pediatric intensive care units in Israel. Two died of cardiomyopathy. Analysis of the accumulated data showed that all had been fed the same brand of soy-based formula (Remedia Super Soya 1), specifically manufactured for the Israeli market. The source was identified on November 6, 2003, when a 5.5-month-old infant was admitted to Sourasky Medical Center with upbeat nystagmus, ophthalmoplegia, and vomiting. Wernicke's encephalopathy was suspected, and treatment with supplementary thiamine was started. His condition improved within hours. Detailed history revealed that the infant was being fed the same formula, raising suspicions that it was deficient in thiamine. The formula was tested by the Israeli public health authorities, and the thiamine level was found to be undetectable ( Methods. After the index case, an additional 8 infants were identified in our centers by medical history, physical examination, and laboratory testing. The group consisted of 6 male and 3 female infants aged 2 to 12 months. All were assessed with the erythrocyte transketolase activity assay, wherein the extent of thiamine deficiency is expressed in percentage stimulation compared with baseline (thiamine pyrophosphate effect [TPPE]). Normal values range from 0% to 15%; a value of 15% to 25% indicates thiamine deficiency, and >25% indicates severe deficiency. Blood lactate levels (normal: 0.5–2 mmol/L) were measured in 6 infants, cerebrospinal fluid lactate in 2 (normal: 0.5–2 mmol/L), and blood pyruvate in 4 (normal: 0.03–0.08 mmol/L). The diagnostic criteria for thiamine deficiency were abnormal transketolase activity and/or unexplained lactic acidosis. Treatment consisted of intramuscular thiamine 50 mg/day for 14 days combined with a switch to another infant formula. Results. Early symptoms were nonspecific and included mainly vomiting (n = 8), lethargy (n = 7), irritability (n = 5), abdominal distension (n = 4), diarrhea (n = 4), respiratory symptoms (n = 4), developmental delay (n = 3), and failure to thrive (n = 2). Infection was found in all cases. Six infants were admitted with fever. One patient had clinical dysentery and group C Salmonella sepsis; the others had mild infection: acute gastroenteritis (n = 2); upper respiratory infection (n = 2); and bronchopneumonia, acute bronchitis, and viral infection (n = 1 each). Two infants were treated with antibiotics. Three infants had neurologic symptoms of ophthalmoplegia with bilateral abduction deficit with or without upbeat nystagmus. All 3 had blood lactic acidosis, and 2 had high cerebrospinal fluid lactate levels. Patient 1, our index case, was hospitalized for upbeat nystagmus and ophthalmoplegia, in addition to daily vomiting episodes since 4 months of age and weight loss of 0.5 kg. Findings on brain computed tomography were normal. Blood lactate levels were high, and TPPE was 37.8%. Brain magnetic resonance imaging (MRI) revealed no abnormalities. Patient 2, who presented at 5 months with lethargy, vomiting, grunting, and abdominal tenderness, was found to have intussusception on abdominal ultrasound and underwent 2 attempts at reduction with air enema several hours apart. However, the lethargy failed to resolve and ophthalmoplegia appeared the next day, leading to suspicions of Wernicke's encephalopathy. Laboratory tests showed severe thiamine deficiency (TPPE 31.2%). In patients 1 and 2, treatment led to complete resolution of symptoms. The third infant, a 5-month-old girl, was admitted on October 10, 2003, well before the outbreak was recognized, with vomiting, fever, and ophthalmoplegia. Her condition deteriorated to seizures, apnea, and coma. Brain MRI showed a bilateral symmetrical hyperintense signal in the basal ganglia, mamillary bodies, and periaqueductal gray matter. Suspecting a metabolic disease, vitamins were added to the intravenous solution, including thiamine 250 mg twice a day. Clinical improvement was noted 1 day later. TPPE assay performed after treatment with thiamine was started was still abnormal (17.6%). Her formula was substituted after 4 weeks, after the announcement about the thiamine deficiency. Although the MRI findings improved 5 weeks later, the infant had sequelae of ophthalmoplegia and motor abnormalities and is currently receiving physiotherapy. All 3 patients with neurologic manifestations were fed exclusively with the soy-based formula for 2 to 3.5 months, whereas the others had received solid food supplements. Longer administration of the formula (ie, chronic thiamine deficiency) was associated with failure to thrive. For example, one 12-month-old girl who received the defective formula for 8 months presented with refusal to eat, vomiting, failure to thrive (75th to 15%) were noted in 8 infants, 3 male and 5 female, all >1 year old, who were receiving solid food supplements. Although their parents failed to notice any symptoms, irritability, lethargy, vomiting, anorexia, failure to thrive, and developmental delay were documented by the examining physicians. None had signs of neurologic involvement. Treatment consisted of oral thiamine supplements for 2 weeks. Conclusions. Clinician awareness of the possibility of thiamine deficiency even in well-nourished infants is important for early recognition and prevention of irreversible brain damage. Therapy with large doses of thiamine should be initiated at the earliest suspicion of vitamin depletion, even before laboratory evidence is available and before neurologic or cardiologic symptoms appear.

Intrauterine growth retardation plays a significant role in neurodevelopmental outcome. The assessment of general movements during the first 20 weeks is a new method for early detection of brain dysfunction. General movements in 31 infants with asymmetric intrauterine growth retardation and their appropriate for gestational age—matched controls were examined. General movements were scored as normal or abnormal by sequential videotape recordings in the writhing (term to 2 weeks), early fidgety (9—11 weeks), and late fidgety (14—16 weeks) periods. Scores were compared between the groups and correlated with neurodevelopmental outcome at 2 years. The incidence of normal general movements was lower in the intrauterine growth retarded infants than in the controls ( P < .001). Significant correlations were found between general movement quality and neurodevelopmental scores in the intrauterine growth retarded group. The fidgety movements were the most sensitive and specific for prediction of neurologic outcome. The general movement assessment can, therefore, serve as an additional tool for examining the neurologic status of the preterm and term intrauterine growth retarded infant. ( J Child Neurol 2004;19:14—18).

Neuroplasticity studies examining children with hemiparesis (CH) have focused predominantly on unilateral interventions. CH also have bimanual coordination impairments with bimanual interventions showing benefits. We explored neuroplasticity following hand-arm bimanual intensive therapy (HABIT) of 60 hours in twelve CH (6 females, mean age 11 ± 3.6 y). Serial behavioral evaluations and MR imaging including diffusion tensor (DTI) and functional (fMRI) imaging were performed before, immediately after, and at 6-week follow-up. Manual skills were assessed repeatedly with the Assisting Hand Assessment, Children’s Hand Experience Questionnaire, and Jebsen-Taylor Test of Hand Function. Beta values, indicating the level of activation, and lateralization index (LI), indicating the pattern of brain activation, were computed from fMRI. White matter integrity of major fibers was assessed using DTI. 11/12 children showed improvement after intervention in at least one measure, with 8/12 improving on two or more tests. Changes were retained in 6/8 children at follow-up. Beta activation in the affected hemisphere increased at follow-up, and LI increased both after intervention and at follow-up. Correlations between LI and motor function emerged after intervention. Increased white matter integrity was detected in the corpus callosum and corticospinal tract after intervention in about half of the participants. Results provide first evidence for neuroplasticity changes following bimanual intervention in CH. This project was funded by grants from Guy’s and St Thomas’ Charity, Marnie Kimelman Trust and ILAN, the Israeli Association for Disabled children. Beit Issie Shapiro funded and provided the camp venue. D. Green was supported by a grant from the Department of Immigration and Absorption during 2010-2011.

The purpose of this study was to characterize the sleep patterns of children with intrauterine growth retardation, known to be at risk for neurodevelopmental disorders, and seek a possible correlation with behavior, concentration, and attention problems. The sleep patterns of 26 children with intrauterine growth retardation aged 4 to 7 years were compared with those of 47 control children using activity monitors (actigraphs). In addition, data were collected from the parents regarding sleep habits, behavior, concentration, and attention. Children with intrauterine growth retardation aged 4 to 7 years were found to have a tendency toward poorer quality of sleep than their matched controls. This inclination was statistically significant only for one sleep measure, the true sleep time. A tendency toward increased fragmentation of sleep, prolonged waking, and decreased sleep efficiency, although not statistically significant in this study, was demonstrated. Our results showed that 58% of the children with intrauterine growth retardation, compared with 40% of the children in the control group, could be defined as “poor sleepers” (sleep efficiency lower than 90% or three or more waking episodes per night). This disturbed sleep profile is probably an integral part of the neurodevelopmental profile typical of these at-risk children. No significant correlations were found between sleep quality and behavior, concentration, and attention problems. ( J Child Neurol 2002;17:872—876).

In a community-based study of 4,309 children with neurodevelopmental disabilities who were referred to the Institute for Child Development, Tel Aviv, Israel, 62 (1.4%) had macrocephaly (head circumference above the ninety-eighth percentile for age), of whom 42 (1%) had macrocephaly not associated with hydrocephalus. With the exception of neonatal respiratory distress the incidence of perinatal complications was not different from that in other children referred to the Institute for Child Development. In children with developmental disabilities, macrocephaly was a significant risk factor for febrile seizures (odds ratio = 3.1, P < 0.001) and epilepsy (odds ratio = 7.7, P < 0.001), but not for mental retardation (odds ratio = 1.1, P = 0.78) or cerebral palsy (odds ratio = 1.3, P = 0.67). Children with macrocephaly had a high rate of comorbid diagnosis. We conclude that in children with developmental disabilities the presence of macrocephaly even when not associated with hydrocephalus is associated with an increased risk of seizures.

The aim of this study was to determine the features of pseudotumor cerebri or idiopathic intracranial hypertension in prepubertal and pubertal children. We retrospectively reviewed patient charts of those 16 years and younger, diagnosed with pseudotumor cerebri/idiopathic intracranial hypertension. Our study group consisted of 27 patients; the mean age was 10.9 years, and there was a male-to-female ratio of 13 to 14. In the prepubertal group ( n = 13), the male-to-female ratio was 8 to 5; in the pubertal group, ( n = 14), the ratio was 5 to 9. Overweight or obesity was found in 16 (59%) patients. Outcome was favorable except for one who remained symptomatic. Pseudotumor cerebri/idiopathic intracranial hypertension in children is rare. Its characteristics differ from adults. We found the prepubertal group to be a distinct group since pseudotumor cerebri/idiopathic intracranial hypertension did not occur predominantly in females and was not associated with obesity. ( J Child Neurol 2002;17:745—748).

We sought markers for predicting a favorable outcome of botulinum toxin A injected to the lower-extremity muscles of 26 children with hemiplegic or diplegic cerebral palsy. Clinical assessment preceding and 1 month following injection included gross motor function measure, a modified Ashworth scale, and evaluation of range of motion of knee extension and ankle dorsiflexion. Response to treatment was classified based on a parent questionnaire. The 19 children (73%) considered by their parents as being good responders were compared to the 7 (27%) considered as being poor responders. In the good responders, the preinjection Ashworth scale (spasticity) was significantly higher (P < .05) and gross motor function measure scores (function) were lower (P < .05). Sixty-eight percent of the good responders were nonindependent walkers compared to 14% of the poor responders (P < .05). There were no differences in age, type of cerebral palsy, and dose of injection. An Ashworth scale indicating increased muscle tone, lower gross motor function measure scores, and nonindependent ambulatory status were predictive for a favorable response to botulinum toxin A injections and can guide patient selection and expectations of treatment outcome. (J Child Neurol 2002;17:272-277).

The present study aimed to compare the executive function (EF) of children with neurofibromatosis type 1 (NF1) to those of typically developing children and to investigate whether those abilities could predict the child's academic success in terms of academic skills and enablers. Twenty-nine children with NF1 and 27 age-and-gender-matched controls (aged 8-16 years) were examined with two tests to measure EF in an ecologically valid manner: the Behavioural Assessment of the Dysexecutive Syndrome in Children (BADS-C) and the parent questionnaire for the Behavior Rating Inventory of Executive Function (BRIEF). In order to evaluate academic success we used the Academic Competence Evaluation Scales (ACES). The performance of the NF1 group was significantly lower on the Water and Key search subtest of the BADS-C and on four scales of the BRIEF: initiate; working memory; plan/organise and organisation of materials. Significant correlations and predictive models via regression analysis were generated for: BADS-C, BRIEF and ACES scores. Based on these findings, children with NF1 have executive dysfunction that partially accounts for their difficulties in academic achievements.

BACKGROUND AND PURPOSE: Brain MR imaging is recommended in children with cerebral palsy. Descriptions of MR imaging findings lack uniformity, due to the absence of a validated quantitative approach. We developed a quantitative scoring method for brain injury based on anatomic MR imaging and examined the reliability and validity in correlation to motor function in children with hemiplegia. MATERIALS AND METHODS: Twenty-seven children with hemiplegia underwent MR imaging (T1, T2-weighted sequences, DTI) and motor assessment (Manual Ability Classification System, Gross Motor Functional Classification System, Assisting Hand Assessment, Jebsen Taylor Test of Hand Function, and Children's Hand Experience Questionnaire). A scoring system devised in our center was applied to all scans. Radiologic score covered 4 domains: number of affected lobes, volume and type of white matter injury, extent of gray matter damage, and major white matter tract injury. Inter- and intrarater reliability was evaluated and the relationship between radiologic score and motor assessments determined. RESULTS: Mean total radiologic score was 11.3 ± 4.5 (range 4–18). Good inter- (ρ = 0.909, P < .001) and intrarater (ρ = 0.926, P = < .001) reliability was demonstrated. Radiologic score correlated significantly with manual ability classification systems (ρ = 0.708, P < .001), and with motor assessments (assisting hand assessment [ρ = −0.753, P < .001]; Jebsen Taylor test of hand function [ρ = 0. 766, P < .001]; children's hand experience questionnaire [ρ = −0. 716, P < .001]), as well as with DTI parameters. CONCLUSIONS: We present a novel MR imaging–based scoring system that demonstrated high inter- and intrarater reliability and significant associations with manual ability classification systems and motor evaluations. This score provides a standardized radiologic assessment of brain injury extent in hemiplegic patients with predominantly unilateral injury, allowing comparison between groups, and providing an additional tool for counseling families.