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Background: Preliminary studies have shown that electrical source imaging (ESI) has numerous advantages for the pre-surgical evaluation of epileptic patients. However, the role of ESI for children with non-lesional drug resistance in focal epilepsy has been poorly characterized. Objectives: This study aimed to investigate this issue according to interictal epileptiform discharges (IEDs) and constraints in developing countries. Methods: The present study used long-term video electroencephalography (EEG) monitoring (LTM) data that were recorded using the standard 19 scalp electrodes (10 - 20 system) and 3 tesla T1 image data. Accordingly, first, IEDs were clustered and then assessed by an epileptologist. Afterward, some operations were conducted that included EEG inverse problem solving with three known methods, namely brain electrical source analysis (BESA) with the individual head model, cortical classical LORETA analysis recursively analysis (CLARA) with the individual head model, and BESA with the age template head model. Seven children were processed in this project. Results: In most cases (n = 5, 71%), the seizure onset zone (SOZ) was the same in the LTM report and the present proposed methodology. Moreover, this study succeeded in localizing the region of the predicted SOZ. Conclusions: According to limitations in a developing country, for the configuration of multi-modal studies (e.g., 3T magnetic resonance imaging, LTM, and ESI) with a specific and valuable protocol, this investigation defined a pilot study with a 7 data sample for the first step. These findings, based on the small sample size, suggest that ESI based on combining ensemble methods improves information for children with focal drug-resistant epilepsy. It is hoped that future studies with large sample sizes show the role of ESI in developing countries more than before.

Previously known as severe myoclonic epilepsy of infancy, Dravet syndrome is characterized by febrile or afebrile prolonged hemiconvulsive seizures or generalized status epilepticus in an infant with previously normal development. Immediate management of status epilepticus is critical in these patients. Early control of status epilepticus prevents further brain damage; however, there is no consensus regarding the management of status epilepticus in children with Dravet syndrome, as many conventional antiseizure medications that are recommended in the management of status epilepticus worsen the seizures in these patients. A 2.5-year-old girl child patient was referred due to status epilepticus which was refractory to antiseizure medications. Sodium valproate, nitrazepam, ketogenic diet, intravenous phenytoin, and midazolam continuous infusion were administered. After controlling status epilepticus, the probable diagnosis of Dravet syndrome was proposed and confirmed by a mutation in SCN1A. As previously stated in numerous case reports, phenytoin worsens seizures in patients with Dravet syndrome. Therefore, it seems logical that in every infant with status epilepticus and probable Dravet syndrome, the practicing physician considers administering intravenous valproate or even midazolam continuous infusion instead of intravenous phenytoin.

Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is now increasingly identified from all countries over the world, possibly rendering it one of the most common autosomal recessive ataxias. Here, we selected patients harboring SACS variants, the causative gene for ARSACS, in a large cohort of 137 patients with early-onset ataxia recruited from May 2019 to May 2021 and were referred to the ataxia clinic. Genetic studies were performed for 111 out of 137 patients (81%) which led to a diagnostic rate of 72.9% (81 out of 111 cases). Ten patients with the molecular diagnosis of ARSACS were identified. We investigated the phenotypic and imaging spectra of all confirmed patients with ARSACS. We also estimated the frequency of ARSACS in this cohort and described their clinical and genetic findings including seven novel variants as well as novel neuroimaging findings. While the classic clinical triad of ARSACS is progressive cerebellar ataxia, spasticity, and sensorimotor polyneuropathy, it is not a constant feature in all patients. Sensorimotor axonal-demyelinating neuropathy was detected in all of our patients, but spasticity and extensor plantar reflex were absent in 50% (5/10). In all patients, brain magnetic resonance imaging (MRI) showed symmetric linear hypointensities in the pons (pontine stripes) and anterior superior cerebellar atrophy as well as a hyperintense rim around the thalami (thalamic rim). Although infratentorial arachnoid cyst has been reported in ARSACS earlier, we report anterior temporal arachnoid cyst in two patients for the first time, indicating that arachnoid cyst may be an associated imaging feature of ARSACS. We also extended molecular spectrum of ARSACS by presenting 8 pathogenic and one variant of unknown significance (VUS) sequence variants, which 7 of them have not been reported previously. MetaDome server confirmed that the identified VUS variant was in the intolerant regions of sacsin protein encoded by SACS.

Mutations in the dystrophin gene could cause Duchenne muscular dystrophy (DMD), which is the most common muscular disorder in pediatrics. Considering the growing evidence on appropriateness of gene therapies for DMD, precise genetic diagnosis seems essential. Hence, we conducted a study to determine mutational patterns in Iranian children with DMD. To detect all probable large mutations in the dystrophin gene, 314 DMD patients were evaluated using the multiplex ligation-dependent probe amplification (MLPA). Subjects who were MLPA-negative underwent the next generation sequencing (NGS) to identify potential point mutations. MLPA detected deletions (79.93%) and duplications (5.41%) along the dystrophin gene of 268 patients. Distribution of large mutations was heterogeneous and followed hotspot pattern throughout the gene. From 46 patients who were MLPA-negative, 43 exhibited point mutations including nonsense in 7.64%, frameshifts in 4.77%, splicing in 0.96%, and missense variations in 0.32% of participants. Most of the point mutations were located between exons 19 and 40. In three patients (1%), no mutation was found using either MLPA or NGS. Two subjects had novel nonsense mutations (L1675X and E1199X) in their dystrophin gene, which were considered as the possible reason for elimination of major domains of the gene. The results of this study provided invaluable information regarding the distribution of various large and small mutations in Iranian individuals with DMD. Besides, the novel nonsense mutations L1675X and E1199X were identified within the highly conserved residues, leading to elimination of significant domains of the dystrophin gene.

Background Few migraine preventive agents have been assessed in a pediatric population. We evaluated the safety and efficacy of cinnarizine and sodium valproate for migraine prophylaxis in children and adolescents. Methods We carried out a randomized double-blind placebo-controlled trial in the Children’s Medical Center and Sina hospital, Tehran, Iran. Eligible participants were randomly assigned in 1:1:1 ratio via interactive web response system to receive either cinnarizine, sodium valproate, or placebo. The primary endpoints were the mean change in frequency and intensity of migraine attacks from baseline to the last 4 weeks of trial. The secondary endpoint was the efficacy of each drug in the prevention of migraine. The drug was considered effective if it decreased migraine frequency by more than 50% in the double-blind phase compared with the baseline. Safety endpoint was adverse effects that were reported by children or their parents. Results A total of 158 children participated. The frequency of migraine attacks significantly reduced compared to baseline in cinnarizine (difference: −8.0; 95% confidence interval (CI): −9.3 to −6.6), sodium valproate (difference: −8.3; 95% confidence interval: −9.3 to −7.2), and placebo (difference: −4.4; 95% confidence interval: −5.4 to −3.4) arms. The decrease was statistically greater in cinnarizine (difference: −3.6; 95% confidence interval: −5.5 to −1.6) and sodium valproate (difference: −3.9; 95% confidence interval: −5.8 to −1.9) arms, compared to placebo group. Children in all groups had significant reduction in intensity of episodes compared to baseline (cinnarizine: −4.6; 95% confidence interval: −5.2 to −4.0; sodium valproate: −4.0; 95% confidence interval: −4.8 to −3.3; placebo: −2.6; 95% confidence interval: −3.4 to −1.8). The decrease was statistically greater in cinnarizine (difference: −2.0; 95% confidence interval: −3.2 to −0.8) and sodium valproate (difference: −1.5; 95% confidence interval: −2.7 to −0.3) arms, compared to the placebo group. Seventy-one percent of individuals in the cinnarizine group, 66% of cases in the sodium valproate group, and 42% of people in the placebo arm reported more than 50% reduction in episodes at the end of the trial. The odds ratio for >50% responder rate was 3.5 (98.3% confidence interval: 1.3 to 9.3) for cinnarizine versus placebo and 2.7 (98.3% confidence interval: 1.0 to 6.9) for sodium valproate versus placebo. Nine individuals reported adverse effects (three in cinnarizine, five in sodium valproate, and one in the placebo group) and one case in the sodium valproate group discontinued the therapy due to severe sedation. Conclusion Cinnarizine and sodium valproate could be useful in migraine prophylaxis in children and adolescents. Trial registration: IRCT201206306907N4.

Aims Child growth is one of the important health indicators in pediatric care. Few studies focused on the impact of prenatal exposure to gestational diabetes mellitus (GDM) on growth trajectories particular in early years of childhood. The aim of this study was identifying growth pattern of GDM exposed offspring's, comparison with new WHO child growth standards. Methods and materials In a population-based Longitudinal study 438 infants exposed to gestational diabetes in utero, aged 0–24 months, born between 2014 and 2016 with at least 9 visits in first 2 years of life were enrolled. Twenty health centers of Ahvaz city (Capital of Khuzestan province, located in south western of Iran) and two referral centers for neonatal hypothyroidism involved the study. Results Of 438 GDM exposed infants, 54.6% were boys. Incidence of low birth weight and macrosomia were 4.6% and 8.7% respectively. Results 4.6% had birth weight less than 2500gr and 8.7% was rate of macrosomia. Boys had higher weight and BMI than girls. Peak of BMI was 17.8 (±2.07) at 6 months after Gender was significant factor in predicted of BMI growth trajectories in GDM exposed children (p = 0.001). BMI in GDM exposed infants, in first 2 years of life was higher than WHO growth standards 2006 (P Conclusion Medians of BMI in GDM exposed infants in all measures was higher than WHO reference data 2006 (P

NTNG2 encodes netrin-G2, a membrane-anchored protein implicated in the molecular organization of neuronal circuitry and synaptic organization and diversification in vertebrates. In this study, through a combination of exome sequencing and autozygosity mapping, we have identified 16 individuals (from seven unrelated families) with ultra-rare homozygous missense variants in NTNG2; these individuals present with shared features of a neurodevelopmental disorder consisting of global developmental delay, severe to profound intellectual disability, muscle weakness and abnormal tone, autistic features, behavioral abnormalities, and variable dysmorphisms. The variants disrupt highly conserved residues across the protein. Functional experiments, including in silico analysis of the protein structure, in vitro assessment of cell surface expression, and in vitro knockdown, revealed potential mechanisms of pathogenicity of the variants, including loss of protein function and decreased neurite outgrowth. Our data indicate that appropriate expression of NTNG2 plays an important role in neurotypical development.

Summary BCAS3 microtubule-associated cell migration factor (BCAS3) is a large, highly conserved cytoskeletal protein previously proposed to be critical in angiogenesis and implicated in human embryogenesis and tumorigenesis. Here, we established BCAS3 loss-of-function variants as causative for a neurodevelopmental disorder. We report 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. The human phenotype is less severe compared with the Bcas3 knockout mouse model and cannot be explained by angiogenic defects alone. Consistent with being loss-of-function alleles, we observed absence of BCAS3 in probands’ primary fibroblasts. By comparing the transcriptomic and proteomic data based on probands’ fibroblasts with those of the knockout mouse model, we identified similar dysregulated pathways resulting from over-representation analysis, while the dysregulation of some proposed key interactors could not be confirmed. Together with the results from a tissue-specific Drosophila loss-of-function model, we demonstrate a vital role for BCAS3 in neural tissue development.

Background Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in the pediatric population. The manifestations of this disease include progressive muscle weakness, gait dysfunction, and motor impairment, leading to a loss of ambulation by the age of 13 years. Molecular diagnosis is the standard diagnostic tool for DMD. This study aimed to investigate disease progression and genetic patterns in Iranian ambulant boys and to find the correlation between genotypes and motor function phenotypes. Methods This study was performed on 152 DMD patients. Clinical history, including the disease phenotype, steroid therapy, and the North Star Ambulatory Assessment (NSAA) score, was taken for all the patients. Molecular diagnoses were confirmed by multiplex ligation-dependent probe amplification and next-generation sequencing tests. Results A total of 152 Iranian DMD patients were examined in this study. The mean age at the time of disease onset was 4.04 ± 2.00 years, and the mean age at diagnosis was 5.05 ± 2.08 years. The mean age of ambulation loss was 10.9 years. Contracture was reported in 38.9% of cases. In terms of age, the mean total NSAA score showed a peak at 4 years of age, with a mean NSAA score of 24. Annual changes in the NSAA score were determined for all cases, based on the mutation type and exon site. Deletion mutation was found in 79.1% of cases, duplication in 6.8%, nonsense in 12.8%, and splice site in 1.4%. The most common single exon deletion was exon 44 (5.3%), and the most common multiexon deletions were attributed to exons 45–50 and exons 45–52 (4.6%). The results did not indicate any correlation between the mutation type and age at the time of disease onset, loss of ambulation age, and wheelchair dependence; however, a significant association was found between contracture and mutation type. The results showed a significant difference in the NSAA score between the deletion and nonsense groups at the age of 3 years (P = 0.04). No significant correlation was found between the phenotype and exon site. Overall, 91.1% of the study population had a history of corticosteroid use, and 54.1% showed compliance with rehabilitation therapy. Conclusion This study demonstrated the phenotypes and mutational features of Iranian DMD boys and provided information regarding the natural motor history of the disease, disease progression, diagnosis, and status of DMD management in Iran. The present findings can promote the development of clinical trials and future advanced molecular therapies in Iran.

Childhood leukodystrophies are a fast-growing field of pediatric neurology practice. Epidemiologic studies on the incidence of these disorders in children show different results. This is the first report of childhood leukodystrophies incidence from Iran. The enrolled patients were recruited from the neurometabolic bioregistry system that was organized in 2010 in the Children’s Medical Center, Tehran, Iran. Herein is reported the incidence rate of leukodystrophies in those patients who were residents of 2 big popular provinces near Iran’s capital city Tehran, with an average child population of 2 988 800 children. Ninety cases of leukodystrophies from Tehran and Alborz provinces who were registered between 2010 and 2016 in the bioregistry system were enrolled in this study. The annual incidence of inherited white matter disorders was 3.01/100 000, the highest number compared with those found in other studies using similar methods throughout the world. One of the main cause of this higher incidence could be the higher number of consanguineous marriages in Iran.

Highlights • Corpus callosum plays the important role in bilateral synchronous expression of focal discharges of ESES. • Sparing dominant hemisphere form continuous spike and slow waves during sleep accounts for normal cognitive scores. • Early detection and treatment of ESES have a great impact on cognitive and language scores and final prognosis.

ObjectiveTo characterize clinically and molecularly an early-onset, variably progressive neurodegenerative disorder characterized by a cerebellar syndrome with severe ataxia, gaze palsy, dyskinesia, dystonia, and cognitive decline affecting 11 individuals from 3 consanguineous families.MethodsWe used whole-exome sequencing (WES) (families 1 and 2) and a combined approach based on homozygosity mapping and WES (family 3). We performed in vitro studies to explore the effect of the nontruncating SQSTM1 mutation on protein function and the effect of impaired SQSTM1 function on autophagy. We analyzed the consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in vivo using zebrafish as a model.ResultsWe identified 3 homozygous inactivating variants, including a splice site substitution (c.301+2T>A) causing aberrant transcript processing and accelerated degradation of a resulting protein lacking exon 2, as well as 2 truncating changes (c.875_876insT and c.934_936delinsTGA). We show that loss of SQSTM1 causes impaired production of ubiquitin-positive protein aggregates in response to misfolded protein stress and decelerated autophagic flux. The consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in zebrafish documented a variable but reproducible phenotype characterized by cerebellum anomalies ranging from depletion of axonal connections to complete atrophy. We provide a detailed clinical characterization of the disorder; the natural history is reported for 2 siblings who have been followed up for >20 years.ConclusionsThis study offers an accurate clinical characterization of this recently recognized neurodegenerative disorder caused by biallelic inactivating mutations in SQSTM1 and links this phenotype to defective selective autophagy.

We conducted a study to evaluate the quality of life in boys with Duchenne muscular dystrophy aged 8-18 years, compared with that in matched healthy controls. A total of 85 boys with Duchenne muscular dystrophy aged 8-18 years and 136 age, sex and living place matched healthy controls were included in this study. Patients and one of their parents separately completed the 27-item Persian version of KIDSCREEN questionnaire (child and adolescent version and parent version). From the children's perspective, the quality of life in patients was found to be lower in two subclasses: "physical activities and health" (p 0.001) and "friends" (p = 0.005). Parental estimation of their sick child's quality of life was significantly lower than children's own assessment in two subclasses: "physical activities and health" (p 0.001) and "general mood and feelings" (p 0.001). Our results indicate that boys with Duchenne muscular dystrophy have quite a satisfactory quality of life. A happier and more hopeful life can be promoted through increasing social support and improving the parental knowledge regarding their child's more positive life perspective.

More than 25 % of children with epilepsy develop refractory seizures unresponsive to both old and new generation anticonvulsants. Since such seizures have a serious negative impact on the quality of life, other treatment options are considered. The ketogenic diet is a well-known treatment for managing refractory seizures, although its mechanism of action is unknown. Studies have shown that this diet is as good as, or better than, any of the newer medications in reducing seizure frequency. However, concerns about adverse effects have been raised. We conducted an open label trial to show the effects of this diet on serum lipid profile. Thirty-three children with refractory epilepsy were treated with the ketogenic diet and were followed for 6 months. Their serum lipid profile was assessed at baseline, and at 3 and 6 months after initiating the diet. Seizure frequency was reduced in 63 % of children (no seizures in 2/33 and reduced >50 % in 19/33). However, after 6 months of administering the diet, median triglyceride was significantly increased (from 84 to 180 mg/dl, P

Biallelic mutations of the alsin Rho guanine nucleotide exchange factor (ALS2) gene cause a group of overlapping autosomal recessive neurodegenerative disorders including infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (JALS/ALS2), caused by retrograde degeneration of the upper motor neurons of the pyramidal tracts. Here, we describe 11 individuals with IAHSP, aged 2-48 years, with IAHSP from three unrelated consanguineous Iranian families carrying the homozygous c.1640+1G>A founder mutation in ALS2. Three affected siblings from one family exhibit generalized dystonia which has not been previously described in families with IAHSP and has only been reported in three unrelated consanguineous families with JALS/ALS2. We report the oldest individuals with IAHSP to date and provide evidence that these patients survive well into their late 40s with preserved cognition and normal eye movements. Our study delineates the phenotypic spectrum of IAHSP and ALS2-related disorders and provides valuable insights into the natural disease course.

OBJECTIVE: To characterize clinically and molecularly an early-onset, variably progressive neurodegenerative disorder characterized by a cerebellar syndrome with severe ataxia, gaze palsy, dyskinesia, dystonia, and cognitive decline affecting 11 individuals from 3 consanguineous families. METHODS: We used whole-exome sequencing (WES) (families 1 and 2) and a combined approach based on homozygosity mapping and WES (family 3). We performed in vitro studies to explore the effect of the nontruncating SQSTM1 mutation on protein function and the effect of impaired SQSTM1 function on autophagy. We analyzed the consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in vivo using zebrafish as a model. RESULTS: We identified 3 homozygous inactivating variants, including a splice site substitution (c.301+2T>A) causing aberrant transcript processing and accelerated degradation of a resulting protein lacking exon 2, as well as 2 truncating changes (c.875_876insT and c.934_936delinsTGA). We show that loss of SQSTM1 causes impaired production of ubiquitin-positive protein aggregates in response to misfolded protein stress and decelerated autophagic flux. The consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in zebrafish documented a variable but reproducible phenotype characterized by cerebellum anomalies ranging from depletion of axonal connections to complete atrophy. We provide a detailed clinical characterization of the disorder; the natural history is reported for 2 siblings who have been followed up for >20 years. CONCLUSIONS: This study offers an accurate clinical characterization of this recently recognized neurodegenerative disorder caused by biallelic inactivating mutations in SQSTM1 and links this phenotype to defective selective autophagy.

The common diagnosis of loss of consciousness and clonic movements in children is seizure or epilepsy, but in a number of patients these symptoms could also be due to syncope. Over interpreted electroencephalography is misleading in a number of patients; therefore, in addition to a detailed and thorough history, a reliable test is needed to differentiate between these conditions. The aim of the study was to evaluate the utility of the head upright tilt test to differentiate between seizure-like events and syncope in children. A chart review descriptive study was conducted in a tertiary medical center in Ahvaz, Iran. We selected sixteen children (nine boys and seven girls) with convulsions of any type who were first diagnosed as epileptic based on the event description by their parents or caregivers to undergo the head upright tilt test. The main findings were the reproduction of previously presyncopal or syncopal symptoms in the tilted position. Fourteen children showed positive results after conducting the head upright tilt test, and their heart rates were significantly decreased compared to baseline at the onset of the syncopal or presyncopal manifestations. Systolic and diastolic blood pressures were significantly reduced in patients with positive results. In three children who initially had negative head upright tilt tests, intravenous isoproterenol was administered, and all three showed presyncopal and syncopal symptoms. The results indicate that the head upright tilt test could differentiate presyncopal and syncopal events in children who present with seizure-like movements but their history has clues for conclusive syncope.

Congenital muscular dystrophies display a wide phenotypic and genetic heterogeneity. The combination of clinical, biochemical, and molecular genetic findings must be considered to obtain the precise diagnosis and provide appropriate genetic counselling. Here we report five individuals from four families presenting with variable clinical features including muscular dystrophy with a reduction in dystroglycan glycosylation, short stature, intellectual disability, and cataracts, overlapping both the dystroglycanopathies and Marinesco-Sjogren syndrome. Whole-exome sequencing revealed homozygous missense and compound heterozygous mutations in INPP5K in the affected members of each family. INPP5K encodes the inositol polyphosphate-5-phosphatase K, also known as SKIP (skeletal muscle and kidney enriched inositol phosphatase), which is highly expressed in the brain and muscle. INPP5K localizes to both the endoplasmic reticulum and to actin ruffles in the cytoplasm. It has been shown to regulate myoblast differentiation and has also been implicated in protein processing through its interaction with the ER chaperone HSPA5/BiP. We show that morpholino-mediated inpp5k loss of function in the zebrafish results in shortened body axis, microphthalmia with disorganized lens, microcephaly, reduced touch-evoked motility, and highly disorganized myofibers. Altogether these data demonstrate that mutations in INPP5K cause a congenital muscular dystrophy syndrome with short stature, cataracts, and intellectual disability.

In spite of the high occurrence of migraine headaches in school-age children, there are currently no approved and widely accepted pharmacologic agents for migraine prophylaxis in children. Our previous open-label study in children revealed the efficacy of cinnarizine, a calcium channel blocker, in migraine prophylaxis. A placebo-controlled trial was conducted to demonstrate the efficacy and safety of cinnarizine in the prophylaxis of migraine in children.A double-blind, placebo-controlled, parallel-group study conducted in a tertiary medical center in Tehran, Iran.Children (5-17 years) who experienced migraines with and without aura, as defined on the basis of 2004 International Headache Society criteria, were recruited into the study. Children were excluded if they had complicated migraine, epilepsy, or a history of use of migraine prophylactic agents. Each participant was randomly assigned to receive cinnarizine (a single 1.5 mg/kg/day dose in children weighing less than 30 kg and a single 50 mg dose in children weighing more than 30 kg, administered at bedtime) or placebo. The frequency, severity, and duration of headaches over the trial period were assessed and adverse effects were monitored.A total of 68 children (34 in each group) with migraine were enrolled and 62 participants completed the study. After 3 months of taking cinnarizine or placebo, children in both groups experienced significantly reduced frequency, severity, and duration of headaches compared with baseline measurements (P0.001). However, compared with 31.3% of children in the placebo group, 60% of children in the cinnarizine group reported more than 50% reduction in monthly headache frequency (P = 0.023), suggesting that cinnarizine was significantly more effective than placebo in reducing the frequency of headaches. No serious adverse effects of the medications were observed in the treated children, including no abnormal weight gain or extrapyramidal signs.Our results indicate that the use of cinnarizine at doses administered in this study is effective and safe for prophylaxis of migraine headaches in children.

More than 25% of seizures in children are refractory to anti-seizure medications and need other modalities to control. Recently, herbal agents with anticonvulsive effects on seizure models in animals have received significant attention, but studies that show their impact on seizures in children are scarce. In a randomized, double-blind placebo-controlled cross-over design, we tried to demonstrate the efficacy of a mixture of Nigella sativa and Thymus vulgaris extracts (Epistop) on seizures in a group of children with refractory epilepsies. Twenty-two children with refractory epilepsies were randomly assigned into two sequences to receive Epistop or placebo in a cross-over design. Neither Epistop nor placebo had effects on the seizure frequency and duration over the study period. Only four children experienced clinically substantial seizure frequency (more than 50%) reduction after Epistop administration. These results indicate that a mixture of Nigella sativa and Thymus vulgaris extracts does not affect the seizure frequency and duration in children with refractory seizures. However, a minority of highly selected children with refractory seizures might benefit from the effects of a mixture of these agents’ extracts.

To evaluate the efficacy, safety, and tolerability of a classic 4:1 ketogenic diet using a formula-based powder in infants and children with refractory seizures who are reluctant to eat homemade foods. We conducted an open label trial and administered a ketogenic diet using formula-based power (Ketocal®). Twenty-seven infants and children aged between 12 months and 5 years were enrolled who had refractory seizures and were reluctant to eat homemade foods. Of 27 children, 5 were lost to follow-up and 22 were remained at the end of the study. After 4 months, the median frequency of seizures per week was reduced >50% in 68.2% of patients, while 9/22 children (40.9%) showed a 50-90% reduction in seizure frequency per week, and 6/22 children (27.3%) showed more than 90% reduction in seizure frequency per week. Over the study course, 6/22 (27%) children who continued to receive the diet developed constipation, one child developed gastroesophageal reflux, and one child developed hypercholesterolemia. None of these children discontinued the diet because of the complications. Thirteen children and their parents (59%) reported that the diet was palatable and tolerable enough. The ketogenic diet using a formula-based powder (Ketocal®) is effective, safe, and tolerable in infants and children with refractory seizures who are reluctant to eat homemade foods according to the rules of the ketogenic diet.

Objective: To determine effects of implementing a practice period of modified constraint-induced movement therapy in a virtual environment on upper limb function in children with spastic hemiparetic cerebral palsy. Methods: In a single-blinded, randomised, controlled trial, 32 participants (18 female, 14 male) received 18 hours training in 3 different groups (virtual reality, modified constraint-induced movement therapy, and a combination group). The fourth group was a control group. Training sessions occurred every other day, 3 times per week for 4-week. Each session lasted for 1.5 hours. Assessment sessions were conducted before, after, and 3-month after treatment period using pediatric motor activity log and the speed and dexterity subtest of the bruininks-oseretsky test of motor proficiency. Data analysis was conducted by ANOVA with repeated measures using SPSS 16.0 with alpha levels set at P< 0.05. Results: Significantly higher gains were observed in the combination therapy group for the amount of limb use (mean change, 2.72), quality of movement (mean change, 2.79), and speed and dexterity (mean change, 1.74) at post-test. These gains were maintained at the 3-month follow-up assessment. Conclusions: Modified constraint-induced movement therapy in a virtual environment could be a promising rehabilitation procedure to enhance the benefits of both virtual reality and constraint-induced therapy techniques.

Status epilepticus and acute prolonged seizures are the most commonly occurring neurological emergencies in children. Such events have high morbidity and mortality rates along with poor long-term outcomes, depending on their duration and causes. Therefore, such seizures warrant urgent treatment using appropriate doses of anticonvulsants. Benzodiazepines, phenobarbital, and phenytoin are the most commonly used anticonvulsants for controlling status epilepticus and acute prolonged seizures. However, these medications have several well-known adverse effects. Previous studies on both adults and children have shown the efficacy and safety of rapid infusion of valproate in controlling status epilepticus. However, few well-designed randomised trials have been carried out in children, and there remains a paucity of data regarding intravenous sodium valproate use in children. Therefore, our aim was to compare the efficacy and safety of rapid loading of valproate with those of intravenous phenobarbital in children with status epilepticus and acute prolonged seizures. Sixty children (30 in each group) with convulsive status epilepticus and acute prolonged seizures were enrolled and randomly assigned to receive either valproate or phenobarbital. The main outcome variable was termination of all convulsive activity within 20 min of starting anticonvulsant infusion. Intravenous rapid loading of valproate was successful in seizure termination in (27/30, 90%) of patients compared to phenobarbital (23/30, 77%) (p = 0.189). Clinically significant adverse effects occurred in 74% patients of the phenobarbital group and 24% patients of the valproate group (p

Background: Neuroblastoma is the most common extracranial malignant solid tumor in children under 5 years, and it is characterized by wide clinical and biological heterogeneity. N-myc oncogene amplification is considered to be one of the most important prognostic factors used to evaluate survival in these patients. Objectives: The aim of our study was to determine amplification of the N-myc oncogene using real-time quantitative polymerase chain reaction (PCR) and to show the influence of N-myc amplified tumors on the overall survival rate. Patients and Methods: This study is an analytical historical cohort study of forty children with neuroblastoma admitted to the Shafa Hospital, Iran from 1999 to 2010. Paraffined blocks of tumoral tissue were analyzed for N-myc amplification by a PCR. The degree of N-myc amplification was derived from the ratio of the N-myc oncogene and the single copy reference gene, NAGK. In the statistical analysis, a Kaplan-Meier survival analysis was used. Results: We found a variable degree of N-myc amplification, from 3 to 2 200, in 32 of the 40 neuroblastomas (80%). NMYC amplification was seen more frequently in patients older than 2.5 years (71.9%), stage 4 (65.6%) and female (53.1%). Median survival time in the males was significantly longer than in the females (P = 0.03). The overall median survival for N-myc amplified tumor patients was 20 months, and 30 months for the non amplified tumors. Conclusions: The N-myc amplified tumors may increase the probability of more aggressive behavior and rapid tumor progression, especially in advanced stages of neuroblastoma. This study confirmed the importance of obtaining correct measurements of oncogene amplification in the early evaluation of neuroblastomas in order to target more aggressive therapies in patients with a higher risk of cancer progression.

Migraine headaches are common in children. Early diagnosis and appropriate interventions are mandatory to prevent decades of suffering and diminished quality of life. There is need for data regarding the efficacy and safety of prophylactic agents in children with migraine; therefore, we designed a randomized clinical trial to compare the efficacy and safety of cinnarizine with that of a well-known prophylactic agent (propranolol) in the prophylaxis of pediatric migraine headache. A total of 120 patients aged between 6 and 17 years were recruited and 113 patients succeeded in completing all phases of the trial. Of them, 57 patients were given cinnarizine, and propranolol was administered in 56 patients. Reduction in headache frequency was the main response to treatment. Cinnarizine reduced the baseline headache frequency by more than 50% in 74.6% of patients and the mean headache frequency per month was reduced from 11.851 ± 0.739 (mean ± SEM) to 3.358 ± 0.739 (mean ± SEM) attacks per month (P

The aim of this study was to evaluate the efficacy and safety of intramuscular midazolam in controlling convulsive status epilepticus in children, by comparing it with rectal diazepam.In this randomized trial, 100 children (50 in each group) with convulsive status epilepticus aged 1 month to 16 years were enrolled and randomly assigned into two groups to receive either 0.3 mg/kg intramuscular midazolam or 0.5 mg/kg rectal diazepam. Main outcome measure was stopping of all motor activity after drug administration. Another measures were times between patient's arrival to emergency department till drug administration, between drug administration to seizure cessation, and between patient's arrival to seizure cessation.Both medication were effective for seizure control and no significant difference was found between successful treatments after administering the medication (P = 0.061). In the midazolam group, in 96% (48/50) of cases treatment was successful and in the diazepam group, in 94% (47/50) of cases treatment was successful. Time from arrival to administering the medication was significantly shorter in midazolam group (P = 0.017). The majority of seizures in midazolam group were stopped in less than 66 s (median) compared to 130 s (median) for diazepam group, (P 0.001). No serious adverse effects were seen in both groups.IM midazolam is not superior but may be at least as effective as rectal diazepam for controlling of status epilepticus in children. Midazolam via IM route could be one of the choices in children with convulsive status seizures who have difficult IV access.

Dear Editor, Febrile convulsions are the most common convulsive seizures in infants and preschool children (1, 2). Such events, have great impact on the parents and are a leading cause of parental anxiety and family disruption (3). Pathophysiology of febrile convulsions has not been known.2 Genetics and environment have been implicated in their generation (4). Trace elements have been hypothesised to involve in the pathophysiology of febrile convulsions. Recent studies have shown lower post ictal serum zinc levels in children with febrile convulsions (5). Considering the importance of febrile convulsions in our province (south west of Iran) and the theorised implication of hypozincemia in their occurrence, we carried out a case-control study to determine post ictal serum zinc level in a group of children with simple febrile convulsions comparing by those of a control group of febrile children with the same age. To be enrolled children had to be between 6 months and 5 years old and had to meet the diagnostic criteria of simple febrile convulsions according to the International League against Epilepsy definition (6). Excluded were those who received zinc supplements. The control group was comprised of children less than 5 years who were seen in the outpatient clinic or emergency department because of a febrile illness other than central nervous system infection. Informed consent was obtained from the parents of all children before enrolment into the study. Blood samples (2 ml) were drawn by venipuncture from the antecubital vein using a disposal plastic syringe with a 23 gauge needle in the morning between 8:00 and 10:00 am. All children with febrile convulsions were at least 24 hours seizure-free from the sampling time. Blood samples were centrifuged at 1500 RPM for 10 min, and the serum was stored at -86oC until the time of analysis. Serum zinc concentration was measured by the graphite furnace flame atomic absorption spectrophotometry (AAS; SpectrAA 220, GTA 110, Varian, Australia) technique. Serum zinc concentration was reported as microgr/dl. Statistical analysis was performed using SPSS version 16.0 statistical software (SPSS, Inc, Chicago, IL). Categorical variables were analysed using the χ2 test. Continuous variables were analysed using independent sample t-test, or Mann-Whitney Rank Sum test when appropriate. A P 0.05). In both groups the most frequent cause of fever was otitis media and other upper respiratory tract infections. No significant difference was found between two groups in terms of aetiology of fever. In the patients’ group, serum zinc level (median; 70 microgr/dl) was significantly lower than the control group (median; 90 microgr/dl) (P < 0.001) (Figure 1). Figure 1. Serum Zinc Level Was Significantly Lower in Children With Febrile Convulsion (40) Than Children With Fever (40) (P < 0.001) In both groups, no relation was found between serum zinc level and age. In both groups, no relation was found between serum zinc level and aetiology of fever. Our results indicate that low or reduced postictal serum zinc level in children with febrile convulsion is a reproducible finding in different geographical regions of the world. Moreover, no relation was found between aetiology of fever and serum zinc level. Recently, hypozincemia and reduced levels of CSF zinc have been reported in children who had febrile convulsions (5). However, exact role of the zinc in the pathogenesis of febrile convulsions is still unknown. Previous studies have been proposed a theory about induction of febrile convulsions with a reduced level of serum zinc level. Based on this theory, hypozincemia activates the NMDA receptor, one of the glutamate families of receptors, which may play an important role in inducting epileptic discharge.5 Moreover, zinc has a regulatory effect on glutamic acid decarboxylase and this enzyme is the core in the synthesis of GABA. Decreased function of the mentioned enzyme has been hypothesized in hypozincemia. Therefore, hypozincemia could lead to reduced levels of GABA in the brain and finally seizure threshold could be reduced in conditions with hypozincemia. The major limit of this study was that we only measured serum zinc level during a febrile illness; therefore we could not compare the serum zinc level of our participants during illness and healthy states. Few studies with the same methods were conducted in different countries to measure the serum zinc level in children with febrile convulsions. In all of these studies, results were shown that children with simple febrile convulsions had serum zinc levels lower than that of febrile children with the same age (7, 8). In conclusion, a considerable body of evidence now exists that shows hypozincemia in children with febrile convulsions during an episode of seizure. We think it is valuable to design large prospective trials to assess the serum zinc level in children at risk for the occurrence of febrile convulsions during healthy states and before a seizure occurrence.

A Prolonged convulsive seizure is the most common neurological medical emergency with poor outcome. An ideal anticonvulsant should be easy-to-use, effective, and safe, and it should also have a long-lasting effect. Benzodiazepines, give via the intravenous or rectal route have generally been used as first-line drugs. In small children, IV access can be difficult and time consuming. Midazolam is a potent anticonvulsant and is rapidly absorbed from the rectal, nasal, and buccal mucosa. Our aim was to evaluate the efficacy and usability of buccal midazolam in controlling seizures in children with acute prolonged seizures, by comparing it with rectal diazepam. Ninety-eight patients were enrolled, with 49 patients in each treatment group. In the buccal midazolam group, 42 (88%) patients were controlled in less than 4 min of drug administration, and all of the patients were controlled within 5 min of drug administration. In the rectal diazepam group, 24 (49%) patients were controlled in less than 4 min and 40 (82%) patients were controlled within 5 min of drug administration. The time for drug administration and drug effect was significantly less with buccal midazolam than with rectal diazepam (p value0.001). In the buccal midazolam group, 46 (94%) parents were satisfied with their child's treatment and route of drug administration while in the rectal diazepam group, 7 (14%) parents were satisfied. Buccal midazolam was significantly more acceptable than rectal diazepam (p value0.001). In conclusion, buccal midazolam may be as effective as rectal diazepam but more convenient to use in the controlling acute prolonged seizures in children, especially in situations in which there is a difficulty in gaining IV access, for example, in infants.

Aim: We aimed to determine the relative frequency of febrile convulsion in children with major thalassemia to theorize that higher serum iron levels could reduce the incidence of febrile convulsion. Background: Febrile convulsion is the most common type of seizure in childhood that its causes are not fully understood. However, some risk factors have been cited such as the serum iron level. Materials and methods: Three hundred and fifty-nine children aged more than 5 years with major thalassemia who were receiving blood were enrolled as the case group. The control group consisted of 357 children without thalassemia aged 4–7 years (151 boys, 206 girls) who were referred to healthcare centers for routine health monitoring. Included data were the history of febrile convulsion, age of onset and type and the frequency of convulsions. Results: Children in control group significantly experienced more febrile convulsions than thalassemic children [4/359 (1.1%) in the thalassemic children and 14/357 (3.9%) in the control group had experienced febrile convulsions ( P = 0.017)]. Conclusion: The frequency of febrile convulsion in children with major thalassemia is less than that of normal children. Children with thalassemia major may have higher serum levels of iron and such high serum iron levels might have a protective role in the children who have a vulnerability for febrile convulsions.