Tolerability and efficacy of perampanel in children with refractory epilepsy.

AIM: There are few reports on the tolerability and efficacy of perampanel, a new antiepileptic drug with a novel mechanism of action, in children and adolescents. We aimed to describe our experience with perampanel add-on and mono-therapy in children with refractory epilepsy. METHOD: Computerized medical records of children treated with perampanel in the paediatric neurology clinic from December 2012 to October 2015 were reviewed. RESULTS: Twenty-four children treated with perampanel (15 females, 9 males) aged 1 year 6 months to 17 years (mean 10y, standard deviation [SD] 4y 5mo) were identified. Adverse events were more common in children aged 12 years or older (89%) compared to younger children (53%), and were mainly behavioural. Ten (42%) children had 50 per cent or higher seizure reduction, two (8%) children had 33 per cent seizure reduction, and seizures were less severe in one (4%) child. Perampanel was discontinued in 13 (54%) children mostly due to adverse events. The mean duration of follow-up in the remaining 11 children was 8.1 months (SD 5.2) (range 1.3-17mo). INTERPRETATION: Perampanel is associated with a relatively high rate of behavioural adverse events mostly in adolescents with refractory epilepsy.

[ANTI-N-METHYL-D-ASPARTATE (NMDA) ENCEPHALITIS: THE ISRAELI PEDIATRIC MULTI-CENTER EXPERIENCE].

INTRODUCTION: Anti-N-methyl-D-aspartate (NMDA) encephalitis is a disorder characterized by acute neuro-psychiatric symptoms, appearing mostly after a recent febrile disease, with a gradual progressive course, associated with laboratory or radiologic evidence of active inflammation. Many of the patients will present with a continuous neuro-cognitive disorder which could lead to major morbidity and even mortality. It was recently reported that this disorder can present at childhood as a primary disease or as a secondary complication of herpes simplex infection. Early diagnosis and treatment have significantly improved the patients' prognosis and prevented chronic complications. We will present six pediatric patients at ages 1-14 years, followed from 2011-2014 in Schneider Children's Medical Center and Assaf Harofeh Medical Center due to acute encephalitis, with a clinical course under suspicion for anti-NMDA encephalitis. The article will review the clinical and diagnostic dilemmas and suggested guidelines. Pediatricians should be aware of this new emerging syndrome.

[Neuro-psychiatric comorbidity among children and adolescents who suffer from epilepsy].

Epilepsy is quite a common disorder in the child and adolescent population, and it has been studied for many years. Recently, a better understanding has been achieved regarding the comorbidities in epilepsy, including: major depression, anxiety, learning disabilities, etc.. The comorbidities are extensive and affect many aspects in the life of the patient, and his family members, including: psychological development, learning abilities, independence, etc.. Several mechanisms take part in these comorbidities, starting in the cell and ending with a broadened psychological effect. A better understanding of these mechanisms may assist the physicians in diagnosing their patients and tailoring a wide-approach treatment plan, thereby improving the patient's clinical status and his quality of life (and that of his family). The objective of this article is to describe some of the common comorbidities that are present in epilepsy, and outline the multi-disciplinary approach in treating the epileptic child and his/her family.

Iron deficiency in children with attention deficit hyperactivity disorder.

BACKGROUND: Several studies have suggested that iron deficiency may be related to the pathophysiology of attention deficit hyperactivity disorder (ADHD) due to the role of iron in the production of dopamine and noradrenaline. OBJECTIVES: To evaluate the status of iron deficiency in ADHD children, using ferritin levels, a reliable measure of iron storage in body tissue, as an iron status marker, and to investigate a possible correlation between ferritin levels and the diagnosis of ADHD. METHODS: The study group included 113 newly referred ADHD children aged 5-15 years (mean age 8.8 +/- 2.7). RESULTS: Ferritin levels were below 20 ng/ml in 67 children (59%) and above 20 ng/ml in 46 (41%). There was a very low inverse statistical correlation between scores on Conners' Rating Scale and ferritin levels, probably without clinical significance. CONCLUSIONS: Our findings suggest that low iron stores may be related to ADHD pathophysiology; therefore, ferritin should be included in the overall evaluation of children with ADHD.

Effectiveness of motor learning coaching in children with cerebral palsy: a randomized controlled trial.

OBJECTIVE: To evaluate effectiveness of motor learning coaching on retention and transfer of gross motor function in children with cerebral palsy. DESIGN: Block randomized trial, matched for age and gross motor function. SETTING: Coordinated, multinational study (Israel, Jordan and Palestinian Authority) in schools and rehabilitation centers. SUBJECTS: 78 children with spastic cerebral palsy, gross motor functional levels II and III, aged 66 to 146 months. INTERVENTIONS: 1 hr/day, 3 days/week for 3 months treatment with motor learning coaching or neurodevelopmental treatment: two groups. MAIN MEASURES: Gross motor function Measure (GMFM-66), stair-climbing mechanical efficiency (ME) and parent questionnaire rating their child's mobility. Immediate treatment effects were assessed after 3 months and retention determined from follow-up measurements 6 months after treatment. RESULTS: GMFM-66, ME and parent questionnaires were obtained from 65, 31 and 64 subjects, respectively. Although both groups increased GMFM-66 score over 3 months, measurements 6 months later indicated retention was significantly superior by 2.7 in the motor learning coaching children of level-II. Similar retention trend was evident for ME, increasing 6 months after motor learning coaching by 1.1% and declining 0.3% after neurodevelopmental treatment. Mobility performance in the outdoors and community environment increased 13% from 3 to 9 months after motor learning coaching and decreased 12% after neurodevelopmental treatment. Minor group differences occurred in children of level-III. CONCLUSIONS: In higher functioning children with cerebral palsy, the motor learning coaching treatment resulted in significantly greater retention of gross motor function and transfer of mobility performance to unstructured environments than neurodevelopmental treatment.

Infantile encephalopathy due to vitamin deficiency in industrial countries.

INTRODUCTION: Severe avitaminosis causing life-threatening conditions in the infantile age group is extremely uncommon and has been reported in babies with malabsorption receiving prolonged inadequate vitamin supplements. CASE REPORTS: We report two infants who presented with neurological deterioration. Immediate work-up and treatment for infectious and inborn metabolic disorders were initiated and the diagnosis, made with a few days delay, was prolonged avitaminosis of thiamine (B1) and cobalamin (B12). B1 deficiency was suspected when further neurological deterioration was observed during administration of intravenous fluids containing glucose in an infant with high lactate levels in the cerebrospinal fluid. High transketolase activity that normalized after thiamine treatment and the findings in the MRI and MRS of the brain confirmed the suspected diagnosis. B12 deficiency was suspected in an infant of a strict vegetarian mother who presented with neurological deterioration and severe megaloblastic anemia. The diagnosis was confirmed when low serum levels of B12 and methylmalonic aciduria were detected and treatment with B12 resulted in normalization of urinary methymalonic acid. CONCLUSION: Avitaminosis, even in industrialized countries, should be considered in an atypical age group with no known risk factors. Early diagnosis and prompt treatment may accomplish a quick recovery with fewer sequelae.

Effect of a 24+ hour fast on breast milk composition.

In this preliminary prospective study, breast milk is sampled surrounding 4 religious fast days to determine the effect of a more than 24-hour fast on breast milk composition. The participants are 48 healthy women nursing healthy babies between 1 and 6 months of age. Samples are collected within 2 days before the fast (baseline), immediately after the fast, and 24 hours after fast completion. Samples are tested for sodium, calcium, phosphorus, triglycerides, total protein, and lactose. From baseline to immediately after fast, mean sodium, calcium, and protein levels increase (P = .013, P < .0001, and P < .0001, respectively) and mean phosphorus and lactose levels decrease (P < .0001 and P = .003, respectively). Mean triglycerides are unchanged. Twenty-four hours after fast, parameters are no longer significantly different from baseline except for elevated mean protein levels (P = .022) and lactose that is still reduced (P = .017). A fast of this nature is statistically associated with certain biochemical changes in breast milk.

Hemorrhagic shock and encephalopathy syndrome: clinical course and neurological outcome.

The syndrome of hemorrhagic shock and encephalopathy is associated with an acute onset of diarrhea, followed by shock, disseminated intravascular coagulopathy, multiorgan failure, and encephalopathy. The etiology of this syndrome is unknown, and despite intensive treatment, the outcome is often fatal or associated with severe neurological sequelae. Two infants aged 6 and 9 months were admitted with this syndrome within a 24-hour time interval. The authors hereby present the clinical course and a prospective evaluation of the neurological outcome. A review of the literature regarding this infrequent syndrome is presented.

Depletion of glutathione system enzymes of the liver and erythrocytes in a rat model of acute iron poisoning.

ABSTRACT The proposed mechanism of iron-induced hepatotoxicity is free radical formation. It was hypothesized that the glutathione system of the liver and erythrocytes will be affected by acute iron poisoning. Male Wistar rats, 6-8 weeks of age, were assigned to one of three groups. Group I received distilled water, group II received 400 mg/kg elemental iron, and group III received 750 mg/kg elemental iron. All groups were gavage fed. Iron concentration, glutathione, and glutathione system enzymes were then measured in the liver and erythrocytes. The hepatic level of reduced glutathione (GSH) was significantly lower in groups II (3.1 +/- 4.6 mumol/mg protein) and III (4.7 +/- 4.6 mumol/mg protein) in comparison with group I (11.5 +/- 6.2 mumol/mg protein) (p < 0.001). Hepatic levels of glutathione S-transferase (GST) were higher and glutathione peroxidase (GPX) levels were lower in group III compared to groups II and I (p < 0.001 and p < 0.001). Compared to group I, glutathione reductase (GR) was lower in groups II and III (p < 0.001). There was no correlation between GSH, oxidized glutathione (GSSG), GST, GR, and GPX levels in the erythrocytes and in the liver (p = 0.41, p = 0.48, p = 0.49, p = 0.53, p = 01.4, and p = 0.84, respectively). In conclusion, acute iron intoxication in rats is associated with depletion of reduced glutathione in the liver.

[Vagal nerve stimulation for refractory epilepsy in children].

Epileptic disease is defined as recurrent seizures not as a result of fever or acute cerebral insult. It is very common in all age groups. In the majority of cases, satisfactory control is being achieved, leading to normal life. However, in some cases, the disease is resistant to a variety of medications. In these cases, an attempt to decrease the number of epileptic episodes is done by trying other methods such as a ketogenic diet or neurosurgical interventions. Recently, a new modality of treatment with vagal nerve stimulation was introduced, particularly for cases resistant to medications and are not candidates for neurosurgical intervention.

Childhood-onset idiopathic intracranial hypertension: relation of sex and obesity.

The purpose of the present study was to perform a meta-analysis of all children with idiopathic intracranial hypertension reported since 1997 combined with our experience in order to investigate sex distribution and frequency of obesity among young children up 11 years of age vs adolescents at age 12-17 years. Overall, 244 children diagnosed with idiopathic intracranial hypertension were found suitable for the proposed meta-analysis: 132 (54%) were younger than 11 years of age; 72 (55%) were male and 60 (44%) were female. In contrast, of 112 older children (age 12-17 years), 79 (70%) were female. The association between age and obesity could be analyzed in 147 patients: only 19 (26%) out of 74 younger children up to age 11 years were reportedly obese, whereas 47 (64%) out of 73 older children were found obese. Differences in age at presentation, sex, and obesity were statistically significant (P < 0.01). Thus, a wide-scale meta-analysis of childhood-onset idiopathic intracranial hypertension revealed that the female/male ratio in children younger than age 11 years seems to be fairly equal, with a relatively low rate of obesity, contrasting to a majority of females in the group of adolescents at high risk to become obese.

Feasibility of sleep-deprived EEG in children.

BACKGROUND: Non-sedated EEG recording in children can be technically challenging, particularly when behavioral disorders are present. We aimed to assess the feasibility and the efficacy of non-sedated sleep-deprived EEG in children with behavioral disorders and in young children. METHODS: We retrospectively reviewed the EEG recordings and computerized medical records of all pediatric inpatients at least 2-month-old that had a sleep-deprived EEG during a 5-year period between 2009 and 2014. RESULTS: We present the data of 261 children, 142 (54%) boys, mean age 7.9 ± 4.9 years, 67 (26%) aged 0.5-4 years. Behavioral disorders were reported in 38 (15%) of the patients. Mean recording duration was 50.8 ± 12.5 min, and mean sleep duration- 31.8 ± 15.2 min. Thirty-seven (14%) patients slept less than 15 min during the EEG, including 19 (7%) patients with no sleep during the recording. Sleep duration and the presence of interictal epileptiform discharges did not significantly differ between children with/without behavioral disorders and in those younger/older than 4 years. Patients that did not fall asleep during the EEG did not differ from the others regarding presence of behavioral disorders or age. CONCLUSIONS: These results suggest that non-sedated sleep-deprived EEG is feasible in young children and in those with behavioral disorders. Further studies are needed in order to better characterize the etiologies of sleepless pediatric sleep-deprived EEG recordings.

The Role of Prematurity in Patients With Hemiplegic Cerebral Palsy.

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).

Bach flower remedies used for attention deficit hyperactivity disorder in children--a prospective double blind controlled study.

OBJECTIVE: To evaluate the effectiveness of Bach flower remedies in the treatment of children with attention deficit hyperactivity disorder (ADHD), in a double blind prospective controlled study. METHODS: Fourty Children with ADHD, aged 7-11 years, diagnosed according to the DSM criteria, were randomised to Bach flower remedies or placebo treatments for a period of 3 months. Children's performance was evaluated by the teacher before commencement of treatment and subsequently each month during the study period. RESULTS: Bach flower remedies have no statistically significant effect when compared to placebo in the treatment of children with ADHD. There was a significant correlation between treatment duration's and improvement of performance, with no difference between the treatment group compared to the placebo. CONCLUSIONS: There is no statistically significant difference between the effects of Bach flower remedies compared with placebo in the treatment of children with ADHD.

Severe refractory status epilepticus owing to presumed encephalitis.

The severe refractory type of status epilepticus is very rare in the pediatric population. Eight children with the severe refractory type of status epilepticus owing to presumed encephalitis are described. The age at the onset of status epilepticus of the eight study children ranged between 2.5 and 15 years. Seven of the eight children presented with fever several days prior to the onset of seizures. A comprehensive clinical and laboratory investigation failed to delineate a cause for their seizures. Burst suppression coma was induced by pentothal, midazolam, propofol, or ketamine in all of the children. The mean duration of anesthesia was 28 days (range 4-62 days), but the seizures persisted in spite of repeated burst suppression cycles in all of them. Two children died. Four of the surviving children continued to suffer from seizures, and cognitive sequelae were present throughout follow-up in four children. In summary, the severe refractory type of status epilepticus of the acute symptomatic type owing to relatively mild encephalitis carries a high mortality rate and poor morbidity in terms of seizures and cognition at follow-up.

Seizure occurrence during pediatric short-term EEG.

AIM: To identify the patients who are more likely to experience a seizure during short-term EEG recording. METHODS: We retrospectively reviewed the EEG recordings and medical records of 294 patients, who were admitted to the Pediatric Departments in Assaf Harofeh Medical Center, and referred for a short-term EEG during a 5-years period following a seizure. RESULTS: Fifteen (5.1%) patients had seizures during short-term EEG. The likelihood of seizure occurrence was increased by history of seizures (odds ratio 11.86, 95% confidence interval 2.54-55.37), abnormal neurological examination (odds ratio 3.33, 95% confidence interval 1.05-10.55), and the presence of interictal epileptiform discharges (odds ratio 10.07, 95% confidence interval 1.26-80.42). Treatment with antiepileptic drugs and mental retardation were significantly more common among patients with seizures. CONCLUSIONS: Children with a higher likelihood of a seizure during short-term EEG can be identified using data mainly obtained by history and neurological examination.

B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability.

Here we report inherited dysregulation of protein phosphatase activity as a cause of intellectual disability (ID). De novo missense mutations in 2 subunits of serine/threonine (Ser/Thr) protein phosphatase 2A (PP2A) were identified in 16 individuals with mild to severe ID, long-lasting hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and downslanting palpebral fissures. PP2A comprises catalytic (C), scaffolding (A), and regulatory (B) subunits that determine subcellular anchoring, substrate specificity, and physiological function. Ten patients had mutations within a highly conserved acidic loop of the PPP2R5D-encoded B56δ regulatory subunit, with the same E198K mutation present in 6 individuals. Five patients had mutations in the PPP2R1A-encoded scaffolding Aα subunit, with the same R182W mutation in 3 individuals. Some Aα cases presented with large ventricles, causing macrocephaly and hydrocephalus suspicion, and all cases exhibited partial or complete corpus callosum agenesis. Functional evaluation revealed that mutant A and B subunits were stable and uncoupled from phosphatase activity. Mutant B56δ was A and C binding-deficient, while mutant Aα subunits bound B56δ well but were unable to bind C or bound a catalytically impaired C, suggesting a dominant-negative effect where mutant subunits hinder dephosphorylation of B56δ-anchored substrates. Moreover, mutant subunit overexpression resulted in hyperphosphorylation of GSK3ß, a B56δ-regulated substrate. This effect was in line with clinical observations, supporting a correlation between the ID degree and biochemical disturbance.

Neurodevelopmental and behavioral abnormalities associated with deletion of chromosome 9p.

We report a child with craniosynostosis, partial absence of the corpus callosum, developmental delay, precocious puberty, and deletion of chromosome 9(p12p13,3). A review of the literature did not reveal any previous combination of the same kind. Craniosynostosis and partial absence of the corpus callosum, separately or in conjunction, may be part of the spectrum of malformations in the chromosome 9p deletion syndrome, and its presence, in combination with other known features, should prompt a search for this particular deletion as part of the differential diagnosis.