[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.

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.

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).

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.

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.

Efficacy and safety of felbamate in children with refractory epilepsy.

BACKGROUND: Despite the introduction of multiple new antiepileptic drugs in the past two decades, many patients with epilepsy continue to experience uncontrolled seizures or significant side effects. AIM: To present our experience with felbamate therapy in children with drug-resistant epilepsy. METHODS: We retrospectively reviewed the medical charts and video-EEG recordings of all patients receiving felbamate until May 2012. Efficacy was determined according to seizure frequency during the week prior to treatment initiation and the week after the maximal dosage of felbamate was reached. RESULTS: Fifty patients (34 boys) aged 4 months to 17 years (mean--5.5 years) were identified. Nearly third of the patients had Lennox-Gastaut syndrome. Mean epilepsy duration was 3.4 years (range--1 month to 13 years). The mean number of previous antiepileptic drugs was 7.5. The mean duration of follow-up was 1.1 years. Seizure frequency decreased by at least 50% in 29 (58%) patients. Side effects were reported in 22 (44%) patients, none of them included aplastic anemia or liver failure. In the responder group, the maximal dose of felbamate was lower and the patients were older compared to non-responders. CONCLUSIONS: Despite current recommendations, felbamate is initiated following multiple AEDs. Based on its efficacy and safety data, earlier initiation of felbamate is recommended in children with refractory epilepsy.

[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.

Lamotrigine serum concentration in children with epilepsy.

The correlation between lamotrigine serum concentration, efficacy, and toxicity in children is controversial. The database of the Clinical Pharmacology Laboratory at Assaf Harofeh Medical Center was retrospectively searched to identify lamotrigine serum concentrations in children aged 2-19 years with refractory epilepsy who received lamotrigine as monotherapy or polytherapy from 2007-2010. Data collected included age at epilepsy onset, additional antiepileptic drugs, lamotrigine dose, monthly seizure frequency before and after lamotrigine treatment, and side effects. Sixty blood samples were collected from 42 children aged 10.1 ± 4.9 years (range, 2-20 years). Seizure types included complex partial (n = 28), simple partial (n = 7), absence (n = 2), and generalized tonic-clonic (n = 23). Decreased seizure frequency was observed in 38 (63.3%) patients. No correlation with lamotrigine serum concentration was evident, but seizure frequency was significantly influenced by age and lamotrigine dose. Side effects were reported in 21 (35%) patients. Only diplopia was significantly correlated with lamotrigine serum concentration. Lamotrigine was more effective at lower doses and in older children. Lamotrigine serum concentration correlated significantly with diplopia, but not with other side effects or with clinical efficacy. Overall, lamotrigine is effective and safe in children with refractory epilepsy.

Remifentanil use in pediatric scoliosis surgery-an effective alternative to morphine (a retrospective study).

PURPOSE: The unique properties of remifentanil make it ideal for pediatric use despite a lack of wide randomized clinical trials and fear of adverse events due to its high potency. We aimed to consolidate preliminary conclusions regarding the efficacy of remifentanil use in pediatric scoliosis surgery. MATERIALS AND METHODS: The medical charts of children with idiopathic scoliosis who underwent primary spinal fusion between 1998 and 2007 at a large tertiary university-affiliated hospital were retrospectively reviewed and divided into two groups according to anesthetic regime (remifentanil vs. morphine). Demographic, surgery-related details and immediate postoperative course were recorded and compared. RESULTS: All 36 remifentanil children were extubated shortly after termination of surgery, compared to 2 of the 84 patients in the morphine group. The remaining patients in the morphine group were extubated hours after surgery [5.4 hours; standard deviation (SD) 1.7 hours]. Six remifentanil children were spared routine intensive care hospitalization (vs. 2 morphine children-significant difference). Shorter surgeries [5.6 hours (SD 1.82 hours) vs. 7.14 hours (SD 2.15 hours); p=0.0004] were logged for the remifentanil group. To achieve controlled hypotension during surgery, vasodilator agents were used in the morphine group only. A comparison of early postoperative major or minor complication rates (including neurological and pulmonary complications) between the two groups yielded no significant differences. CONCLUSION: Remifentanil use can shorten operating time and facilitate earlier spontaneous ventilation and extubation, with less of a need for intensive care hospitalization and no increase in significant complications.

Preliminary efficacy and safety of lacosamide in children with refractory epilepsy.

BACKGROUND: Despite the introduction of multiple new antiepileptic drugs (AEDs) in the past 20 years, about 30% of patients with epilepsy continue to experience uncontrolled seizures or significant side effects. AIMS: To present our experience with lacosamide therapy in children with drug-resistant epilepsy. METHODS: We retrospectively reviewed the medical charts of all patients receiving oral lacosamide until October 2010. Efficacy was determined according to seizure frequency during the week prior to treatment initiation and the week after the maximal dosage of lacosamide was attained. RESULTS: Seventeen patients (10 boys) aged 1.5-16 (mean - 8 ± 4.7) years were identified. Nine patients had epilepsy attributed to a structural cause, six patients had epilepsy of unknown cause, and two had Lennox-Gastaut syndrome. Mean epilepsy duration was 5.4 ± 3.3 years. The mean number of previous AEDs was 6.6 ± 2. Lacosamide was added to the baseline AEDs in13 patients. The mean duration of follow-up was 9.1 ± 4.4 months. Six (35%) patients had at least a 50%.seizure reduction (mean - 76%). Social, behavioral, and/or motor improvement were noted in seven (41%) patients. Lacosamide was discontinued in six (35%) patients because of inefficacy. Side effects were reported in 10 (59%) patients. CONCLUSIONS: Lacosamide seems to be effective and safe according to the data in our small cohort. Further prospective studies on lacosamide efficacy and safety in a large number of children are warranted.

Interictal encephalography can influence patient selection for methylprednisolone therapy in pediatric refractory epilepsy.

We describe our experience with intravenous methylprednisolone pulse therapy in older children with refractory epilepsy. Patients with refractory epilepsy, who were treated with steroids between 2005 and 2010, were retrospectively selected from the database of the pediatric epilepsy clinic at Assaf Harofeh Medical Center. Eight patients (5 boys) aged 1.1 to 9 years (5.2 ± 2.6) were identified. Intravenous methylprednisolone 30 mg/kg/d was given to all patients for 5 days in addition to a stable dosage of the regular antiepileptic drugs. Transient side effects were reported in 4 of the patients during pulse therapy. Significant clinical improvement was noted in 4 patients, accompanied by a significant reduction of the amplitude of the spike-slow wave discharges on the electroencephalogram (EEG). Children with refractory epilepsy, abnormal EEG background, and high-amplitude spike-slow wave discharges appear to be the best candidates for intravenous methylprednisolone pulse therapy.

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.

Advanced parental ages and low birth weight in autism spectrum disorders--rates and effect on functioning.

OBJECTIVES: (1) To assess the distribution of parental age and birth weight in a large cohort with autism spectrum disorder (ASD) and to compare them to Israeli national data. (2) To examine possible relationships between these risk factors and functioning. METHODS: The study included 529 participants diagnosed with ASD using standardized tests: the Autism Diagnosis Interview-Revised and the Autism Diagnosis Observation Schedule (ADOS). Medical, developmental and familial histories (gender, age, pregnancy and birth information, parental ages) were obtained. Autism severity was assessed using the new ADOS severity scale and adaptive skill using the Vineland Adaptive Behavior Scales. RESULTS: Advanced parental age was associated with ASD. In the older age range the percentages of mothers (35-44 y) and fathers (30-40 y) were significantly higher in the ASD cohort in comparison to the Israeli newborn data. The ASD cohort had significantly higher percentages of low birth weight (<2500 g) and very low birth weight (VLBW<1500 g) in comparison to the Israeli newborn data. Of these risk factors, only VLBW was associated with lower adaptive functioning. The group with VLBW had lower scores in daily living, socialization and motor skills in comparison to the >1500 g group. Autism severity was not associated with advanced parental age or VLBW. CONCLUSIONS: The shift in parental age distribution and birth weight in our ASD cohort suggests that the increase in ASD prevalence in recent years might be associated with novel prenatal insults. An adverse fetal course resulting in VLBW may represent a "second hit" phenomenon, causing a poorer outcome.

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.

Evidence-based review of bone strength in children and youth with cerebral palsy.

Children with cerebral palsy have various risk factors for compromised bone health. Evidence concerning their bone fragility is gathering; however, there is no consensus regarding risk factors, indications for evaluation, follow-up, or treatment. We performed an evidence-based review targeted to address the following questions concerning children with cerebral palsy: Is bone strength impaired and what are the risk factors? Are these children at increased risk for bone fractures? What are the relations between bone mineral density and fracture risk? What methods can be used for bone health assessment? How can bone strength be improved? Currently, the most acceptable method for evaluating bone status in children is dual-energy x-ray absorptiometry. Evidence demonstrates reduced bone mass in children with cerebral palsy; yet, no clear association with fractures. Preventive methods are suggested.