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Background and ObjectivesZhu-Tokita-Takenouchi-Kim (ZTTK) syndrome (OMIM 617140) is a recently identified neurodevelopmental disorder caused by heterozygous loss-of-function (LoF) variants inSON. Because the SON protein functions as an RNA-splicing regulator, it has been shown that some clinical features of ZTTK syndrome can be attributed to abnormal RNA splicing. Several neurologic features have been observed in patients with ZTTK syndrome, including seizure/epilepsy and other EEG abnormalities. However, a relationship betweenSONLoF in ZTTK syndrome and hemiplegic migraine remains unknown.MethodsWe identified a patient with a pathogenic variant inSONwho shows typical clinical features of ZTTK syndrome and experienced recurrent episodes of hemiplegic migraine. To define clinical features, brain MRI and EEG during and after episodes of hemiplegic migraine were characterized. To identify molecular mechanisms for this clinical presentation, we investigated the impact of small interfering RNA (siRNA)-mediatedSONknockdown on mRNA expression of theCACNA1A,ATP1A2,SCN1A, andPRRT2genes, known to be associated with hemiplegic migraine, by quantitative RT-PCR. Pre-mRNA splicing ofPRRT2onSONknockdown was further examined by RT-PCR using primers targeting specific exons.ResultsRecurrent episodes of hemiplegic migraine in our patient typically followed modest closed head injuries, and recurrent seizures occurred during the most severe of these episodes. Transient hemispheric cortical interstitial edema and asymmetric EEG slowing were identified during episodes. Our siRNA experiments revealed thatSONknockdown significantly reducesPRRT2mRNA levels in U87MG and SH-SY5Y cell lines, although a reduction inCACNA1A,ATP1A2, andSCN1AmRNA expression was not observed. We further identified thatSONknockdown leads to failure in intron 2 removal fromPRRT2pre-mRNA, resulting in a premature termination codon that blocks the generation of functionally intact full-length PRRT2.DiscussionThis report identifies recurrent hemiplegic migraine as a novel clinical manifestation of ZTTK syndrome, further characterizes this clinical feature, and provides evidence for downregulation ofPRRT2caused bySONLoF as a mechanism causing hemiplegic migraine. Examination of theSONgene may be indicated in individuals with recurrent hemiplegic migraine.

To evaluate the long-term safety and efficacy of add-on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open-label extension (OLE) of the randomized, placebo-controlled phase 3 trial GWPCARE6 (NCT02544763). Results of an interim (February 2019 data cut) analysis are reported.Patients who completed the randomized trial enrolled to receive CBD (EpidiolexOf 201 patients who completed the randomized phase, 199 (99%) entered the OLE. Mean age was 13 years (range, 1-57). At the time of analysis, 5% of patients had completed treatment, 20% had withdrawn, and 75% were ongoing. One-year retention rate was 79%. Median treatment time was 267 days (range, 18-910) at a 27 mg/kg/day mean modal dose. Most patients (92%) had an adverse event (AE). Most common AEs were diarrhea (42%), seizure (22%), and decreased appetite (20%). AEs led to permanent discontinuation in 6% of patients. There was one death that was deemed treatment unrelated by the investigator. Elevated liver transaminases occurred in 17 patients (9%) patients; 12 were taking valproate. Median percentage reductions in seizure frequency (12-week windows across 48 weeks) were 54%-68%. Seizure responder rates (≥50%, ≥75%, 100% reduction) were 53%-61%, 29%-45%, and 6%-11% across 12-week windows for 48 weeks. Improvement on the S/CGIC scale was reported by 87% of patients/caregivers at 26 weeks.In patients with TSC, long-term add-on CBD treatment was well tolerated and sustainably reduced seizures through 48 weeks, with most patients/caregivers reporting global improvement.

Objective:The purpose of our study was to assess whether race/ethnicity was associated with seizure remission in pediatric epilepsy.Methods:This was a retrospective population-based cohort study of children who were evaluated for new-onset epilepsy in the clinic, emergency department, and/or hospital by a pediatric neurologist in an integrated health care delivery system. Children were between ages 6 months and 15 years at their initial presentation of epilepsy. The cohort, identified through an electronic database, was assembled over 6 years, with no less than 5 years of follow-up. All children were evaluated for race, ethnicity, insurance type, and socioeconomic background. Patient outcome was determined at the conclusion of the study period and categorized according to their epilepsy control as either drug resistant (pharmacoresistant and intractable) or drug responsive (controlled, probable remission, and terminal remission).Results:In the final cohort of 776 patients, 63% were drug responsive (control or seizure remission). After controlling for confounding socioeconomic and demographic factors, children of Hispanic ethnicity experienced reduced likelihood (hazard) of drug-responsive epilepsy (hazard ratio 0.6, P < .001), and had longer median time to remission (8 years; 95% CI 5.9-9.6 years) compared to white non-Hispanic patients (5.6 years; 95% CI 4.9-6.1 years). Among Hispanic patients, higher health care costs were associated with reduced likelihood of drug responsiveness.Significance:We found that Hispanic ethnicity is associated with a reduced likelihood of achieving seizure control and remission. This study suggests that factors associated with the race/ethnicity of patients contributes to their likelihood of achieving seizure freedom.

Objective To determine the diagnostic yield of a commercial epilepsy gene panel in adults with chronic epilepsy and accompanying intellectual disability, given that genetic evaluation is often overlooked in this group of patients. Methods This is a cross-sectional study analyzing the results of epilepsy gene panels including up to 185 genes in adult epilepsy patients with intellectual disability, according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition. Patients with acquired structural brain abnormalities or known chromosomal abnormalities were excluded. Results From approximately 600 patients seen from January 2017 to June 2018 at a single academic epilepsy center, 64 probands and two affected relatives (32 males, mean age = 31 years ± 10) were selected and clinically tested. Fourteen probands (14/64 = 22%; four males, mean age = 32 years ± 10) were found to have pathogenic or likely pathogenic variants in the following genes: SCN1A, GABRB3, UBE3A, KANSL1, SLC2A1, KCNQ2, SLC6A1, HNRNPU, STX1B, SCN2A, PURA, and CHD2. Six variants arose de novo, and the inheritance was not determined in eight. Nine probands (64%) had severe or profound intellectual disability, and five (35%) had autistic features. Eight patients (57%) had a diagnostic change from presumptive clinical diagnosis prior to genetic testing. Significance We were able to demonstrate that a commercial epilepsy gene panel can be an important resource in clinical practice, identifying the etiology in 22% of adults with epilepsy and intellectual disability. The diagnostic yield is similar to previously reported pediatric cohorts. Larger samples would be required to evaluate the more prevalent genotypes among adult epilepsy patients.

IntroductionComputational analysis of genome or exome sequences may improve inherited disease diagnosis, but is costly and time-consuming.MethodsWe describe the use of iobio, a web-based tool suite for intuitive, real-time genome diagnostic analyses.ResultsWe used iobio to identify the disease-causing variant in a patient with early infantile epileptic encephalopathy with prior nondiagnostic genetic testing.ConclusionsIobio tools can be used by clinicians to rapidly identify disease-causing variants from genomic patient sequencing data.

Innovative therapeutics are transforming care of children with previously untreatable neurological disorders. However, there are challenges in the use of new therapies: the medicine may not be effective in all patients, administration may not be tolerated, and matching therapy choice to patient is complex. Finally, costs are high, which imposes financial burdens on insurance companies, families, and the health-care system. Our objective was to address challenges for clinical implementation of the new therapeutics. We sought to develop a process that would be personalized for patient and disease, encourage appropriate use of a therapeutic agent while mitigating pressure on a clinician to prescribe the therapy in all instances, and assist third-party payers in approving therapeutic use based on safety and efficacy. We report our creation of a Neurology Therapeutics Committee for pediatric patients. We review the committee’s mechanisms, describe its use and report outcomes, and suggest the Neurology Therapeutics Committee’s broader applicability.

Early infantile epileptic encephalopathy (EIEE) is a devastating epilepsy syndrome with onset in the first months of life. Although mutations in more than 50 different genes are known to cause EIEE, current diagnostic yields with gene panel tests or whole-exome sequencing are below 60%. We applied whole-genome analysis (WGA) consisting of whole-genome sequencing and comprehensive variant discovery approaches to a cohort of 14 EIEE subjects for whom prior genetic tests had not yielded a diagnosis. We identified both de novo point and INDEL mutations and de novo structural rearrangements in known EIEE genes, as well as mutations in genes not previously associated with EIEE. The detection of a pathogenic or likely pathogenic mutation in all 14 subjects demonstrates the utility of WGA to reduce the time and costs of clinical diagnosis of EIEE. While exome sequencing may have detected 12 of the 14 causal mutations, 3 of the 12 patients received non-diagnostic exome panel tests prior to genome sequencing. Thus, given the continued decline of sequencing costs, our results support the use of WGA with comprehensive variant discovery as an efficient strategy for the clinical diagnosis of EIEE and other genetic conditions., Pediatric neurology: whole-genome analysis finds mutations causing severe newborn seizures Whole-genome sequencing combined with specialized bioinformatics can diagnose disease mutations in newborns with devastating seizures. Josh Bonkowsky, Gabor Marth, Aaron Quinlan, and colleagues from the University of Utah in Salt Lake City, USA, thoroughly detailed the genomic variation of 14 babies with early infantile epileptic encephalopathy (EIEE). EIEE is a severe pediatric neurodevelopmental disorder causing seizures and early death. In the 14 infants, who had previous testing that did not identify the cause, the research team found the genetic cause for all of the infants. Prior to this work, approaches for EIEE diagnosed only up to 60% of infants. With the cost of DNA sequencing continuing to fall, the authors suggest that whole-genome testing could be a cost-effective approach to diagnosing EIEE and other genetic conditions.

Objective We studied our collective open-label, compassionate use experience in using cannabidiol (CBD) to treat epilepsy in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes. Methods We included patients aged 1–30 years with severe childhood-onset epilepsy who received CBD for ≥10 weeks as part of multiple investigator-initiated expanded access or state access programs for a compassionate prospective interventional study: CDKL5 deficiency disorder (n = 20), Aicardi syndrome (n = 19), Dup15q syndrome (n = 8), and Doose syndrome (n = 8). These patients were treated at 11 institutions from January 2014 to December 2016. Results The percent change in median convulsive seizure frequency for all patients taking CBD in the efficacy group decreased from baseline [n = 46] to week 12 (51.4% [n = 35], interquartile range (IQR): 9–85%) and week 48 (59.1% [n = 27], IQR: 14–86%). There was a significant difference between the percent changes in monthly convulsive seizure frequency during baseline and week 12, χ2(2) = 22.9, p = 0.00001, with no difference in seizure percent change between weeks 12 and 48. Of the 55 patients in the safety group, 15 (27%) withdrew from extended observation by week 144: 4 due to adverse effects, 9 due to lack of efficacy, 1 withdrew consent, and 1 was lost to follow-up. Significance This open-label drug trial provides class III evidence for the long-term safety and efficacy of CBD administration in patients with treatment-resistant epilepsy (TRE) associated with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Adjuvant therapy with CBD showed similar safety and efficacy for these four syndromes as reported in a diverse population of TRE etiologies. This study extended analysis of the prior report from 12 weeks to 48 weeks of efficacy data and suggested that placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in these epileptic encephalopathies.

Item does not contain fulltext Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients.In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690.Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment.Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial.GW Pharmaceuticals.

Purpose: To report and compile the ophthalmological features critical to diagnosis of Vici syndrome, a rare congenital disorder characterized principally by agenesis of the corpus callosum, cataracts, cardiomyopathy, immune defects, and hypopigmentation. Methods: A child with Vici syndrome (OMIM 242840) is reported with emphasis on the ophthalmologic evaluation. Ophthalmologic assessments including fundus examination, visual evoked potentials (VEPs), and ocular coherence tomography are presented. These findings are compared with those identified in other published cases of children with Vici syndrome. Results: Ophthalmologic findings included bilateral nuclear and anterior polar cataracts, bilateral optic nerve atrophy, and mild fundus hypopigmentation. Evoked potentials recorded across the mid-occipital scalp demonstrated misrouting of optic pathways typical of albinism. Optical coherence tomography exhibited a poorly defined fovea demonstrating a lesser degree of foveal depression also consistent with ocular albinism. Review of reported children with Vici syndrome identifies bilateral cataracts, nystagmus, fundus hypopigmentation, visual impairment, and optic nerve hypoplasia as common ophthalmologic features. Conclusions: Ophthalmologic findings are critical to the diagnosis of Vici syndrome. Most common are bilateral cataracts and relative fundus hypopigmentation. VEPs can identify misrouting of optic pathways typical of ocular albinism, thereby establishing the diagnosis in challenging cases. [J Pediatr Ophthalmol Strabismus 2014;51(4):214–220.]

BACKGROUND:After licensure of the 7-valent pneumococcal conjugate vaccine (PCV7) in the United States in 2000, the incidence of pediatric pneumococcal meningitis decreased significantly. However, cases continue to occur. It is unknown whether meningitis due to PCV7 and non-PCV7 serotypes causes similar morbidity and mortality.METHODS:We performed a retrospective cohort study of laboratory-confirmed pneumococcal meningitis among Utah children from 1997 to 2010. We reviewed medical records and obtained clinical data during the acute illness and follow-up data on neurologic sequelae.RESULTS:Sixty-eight cases of meningitis were identified. PCV7 serotypes caused 64% of cases before and 25% of cases after licensure of PCV7 (P < .01). The age range was similar before and after PCV7 licensure (P = .5). The overall case fatality rate was 13% and was similar among cases caused by PCV7 and non-PCV7 serotypes (P = .7). Children with PCV7 serotypes were more likely to require mechanical ventilation (68% vs 34%; P < .01). Of all survivors, 63% had neurologic sequelae, and the proportion was similar after infection with PCV7 or non-PCV7 serotypes (P = .1). More than one-half (54%) of all children who developed pneumococcal meningitis in the PCV7 period were eligible for PCV7 and had not been immunized.CONCLUSIONS:Pneumococcal meningitis continues to be associated with high mortality and morbidity; death and neurologic sequelae are common with both PCV7 and non-PCV7 serotype meningitis. The substantial burden of this disease and continued cases among unimmunized children reinforce the need for more effective immunization strategies and continued surveillance in the era of PCV13.

Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 affected individuals. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies showed a severe block in autophagosomal clearance in muscle and fibroblasts from individuals with mutant EPG5, resulting in the accumulation of autophagic cargo in autophagosomes. These findings position Vici syndrome as a paradigm of human multisystem disorders associated with defective autophagy and suggest a fundamental role of the autophagy pathway in the immune system and the anatomical and functional formation of organs such as the brain and heart.

Pallister-Killian syndrome (PKS) is a congenital disorder attributed to supernumerary isochromosome 12p mosaicism. Craniofacial dysmorphism, learning impairment and seizures are considered cardinal features. However, little is known regarding the seizure and epilepsy patterns in PKS. To better define the prevalence and spectrum of seizures in PKS, we studied 51 patients (39 male, 12 female; median age 4 years and 9 months; age range 7 months to 31 years) with confirmed 12p tetrasomy. Using a parent-based structured questionnaire, we collected data regarding seizure onset, frequency, timing, semiology, and medication therapy. Patients were recruited through our practice, at PKS Kids family events, and via the PKS Kids website. Epilepsy occurred in 27 (53%) with 23 (85%) of those with seizures having seizure onset prior to 3.5 years of age. Mean age at seizure onset was 2 years and 4 months. The most common seizure types were myoclonic (15/27, 56%), generalized convulsions (13/27, 48%), and clustered tonic spasms (similar to infantile spasms; 8/27, 30%). Thirteen of 27 patients with seizures (48%) had more than one seizure type with 26 out of 27 (96%) ever having taken antiepileptic medications. Nineteen of 27 (70%) continued to have seizures and 17/27 (63%) remained on antiepileptic medication. The most commonly used medications were: levetiracetam (10/27, 37%), valproic acid (10/27, 37%), and topiramate (9/27, 33%) with levetiracetam felt to be "most helpful" by parents (6/27, 22%). Further exploration of seizure timing, in-depth analysis of EEG recordings, and collection of MRI data to rule out confounding factors is warranted.

Pallister–Killian syndrome (PKS) is a rare, sporadic genetic disorder caused by tetrasomy 12p mosaicism associated with a supernumerary isochromosome. Craniofacial dysmorphism, learning impairment and seizures are considered characteristic. However, little is known of the seizure and epilepsy patterns seen in PKS. To better define the occurrence and nature of epileptic and non-epileptic paroxysmal events in PKS, we describe our experience with 5 patients and compare their features with data from a larger cohort of PKS patients ascertained via a web-based parental questionnaire. Three of the 5 patients have had definite epileptic seizures, and one other has had paroxysmal events as yet not clarified. Four of the 5 have also had either non-epileptic paroxysmal events or episodes of uncertain nature. In those with epilepsy, all have had some period of relatively refractory seizures, all have required more than one antiepileptic drug, but none experienced status epilepticus. Only one of the patients with epilepsy (the oldest) has gone into remission. In two of the four with non-epileptic events, video-electroencephalographic monitoring has been valuable in clarifying the nature of the events. EEG characteristics include a slow dominant frequency as well as generalized and focal epileptiform features. Brain MRI findings can be normal but are variable. These specific findings correspond well to information reported by parents in a larger cohort of 51 individuals with PKS. Better understanding of the nature of epileptic and non-epileptic events in PKS will result from a more detailed analysis of objective data obtained from this larger cohort, and from deeper understanding of the molecular impact of 12p tetrasomy in selected cell lines.

Objectives: Leukodystrophies are diseases of the white matter for which data concerning clinical characteristics, incidence, disease burden, and description of outcomes are sparse. The purpose of our study was to determine the incidence and most common types of inherited leukodystrophies in a population, the mortality and time course of deaths, common neurologic features in patients, and health care costs associated with leukodystrophies. Methods: We conducted a retrospective, hospital- and clinic-based surveillance of inherited leukodystrophies among children younger than 18 years presenting to a regional children9s hospital. We enrolled children evaluated from January 1, 1999, through December 31, 2007; clinical information was obtained from medical records. We calculated incidence based on state birth rates. Results: A total of 122 children with an inherited leukodystrophy were identified; 542 patients were excluded. A total of 49% had epilepsy, 43% required a gastrostomy tube, and 32% had a history of developmental regression. Mortality was 34%; average age at death was 8.2 years. No final diagnosis was reported in 51% of patients. The most common diagnoses were metachromatic leukodystrophy (8.2%), Pelizaeus-Merzbacher disease (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (4.1%). Endocrine abnormalities and hypoplastic cerebellum were noted in significant portions of patients (15% and 14%). Average yearly per-patient medical costs were $22,579. Population incidence was 1 in 7,663 live births. Conclusions: Inherited leukodystrophies are associated with substantial morbidity and mortality in children. Overall population incidence is higher than generally appreciated (1 in 7,663 live births). Most leukodystrophies remain undiagnosed, but a logical algorithm based on prevalence could aid testing.

OBJECTIVES. Apparent life-threatening events in infants constitute a significant challenge for health care providers. Apparent life-threatening event evaluation and management are poorly defined, and outcomes have not been clearly determined. Our objectives were to characterize short- and long-term risks for death, child abuse, and abnormal neurological outcomes of infants after an apparent life-threatening event and to identify clinical features that are predictive of these outcomes.METHODS. We collected data from infants ages birth to 12 months of age who were hospitalized after an apparent life-threatening event during a 5-year time period. Patients were evaluated for subsequent death, child abuse, or adverse neurological outcome (chronic epilepsy or developmental delay).RESULTS. A total of 471 patients met inclusion criteria and were followed an average of 5.1 years. Two patients died after developing chronic epilepsy and severe developmental delay. Fifty-four (11%) patients were diagnosed as being a victim of child abuse, but only 2 were identified at initial presentation. There were 23 (4.9%) patients with adverse neurological outcomes, including 17 (3.6%) with chronic epilepsy and 14 (3.0%) with developmental delay. Of those who developed chronic epilepsy, 71% returned within 1 month of the initial apparent life-threatening event with a second event. Neurological evaluation at the time of the apparent life-threatening event had low yield for predicting those who would develop chronic epilepsy.CONCLUSIONS. Infants who suffer an apparent life-threatening event are at risk for subsequent child abuse and adverse neurological outcomes. Deaths were uncommon and only occurred in the setting of severe developmental delay and seizure disorders. Neurological evaluation during hospitalization for a first apparent life-threatening event is of low yield, but close follow-up is essential.

The local emergency medical services (EMS) council implemented a new pediatric treatment protocol using a Mucosal Atomization Device (MAD) to deliver intranasal (IN) midazolam for seizure activity.We sought to compare outcomes in seizing pediatric patients treated with IN midazolam using a MAD (IN-MAD midazolam) to those treated with rectal (PR) diazepam, 18 months before and after the implementation of the protocol.Of 857 seizure patients brought by EMS to our emergency department (ED), 124 patients (14%) had seizure activity in the presence of EMS and were eligible for inclusion in this study. Of the 124 patients eligible for this study, 67 patients (54%) received no medications in the prehospital setting, 39 patients (32%) were treated with IN-MAD midazolam, and 18 patients (15%) were treated with PR diazepam. Median seizure time noted by EMS was 19 minutes longer for PR diazepam (30 minutes) when compared with IN-MAD midazolam (11 minutes, P = 0.003). Patients treated with PR diazepam in the prehospital setting were significantly more likely to have a seizure in the ED (odds ratio [OR], 8.4; confidence interval [CI], 1.6-43.7), ED intubation (OR, 12.2; CI, 2.0-75.4), seizure medications in the ED to treat ongoing seizure activity (OR, 12.1; CI, 2.2-67.8), admission to the hospital (OR, 29.3; CI, 3.0-288.6), and admission to the pediatric intensive care unit (OR, 53.5; CI, 2.7-1046.8).The IN-MAD midazolam controlled seizures better than PR diazepam in the prehospital setting and resulted in fewer respiratory complications and fewer admissions.

Summary Background Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. Methods In this open-label trial, patients (aged 1–30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2–5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. Results Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death—a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30·0 (IQR 11·0–96·0) at baseline and 15·8 (5·6–57·6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36·5% (IQR 0–64·7). Interpretation Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. Funding GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.

Summary: Purpose: To use available evidence and expert consensus to develop performance indicators for the evaluation and management of pediatric epilepsy. Methods: We used a three-step process to develop the performance indicators. First, research findings were compiled into evidence tables focusing on different clinical issues. Second, an advisory panel of clinicians, educational and public health experts, and families of children with epilepsy reviewed the evidence. The advisory group used the evidence to draft a preliminary set of performance indicators for pediatric epilepsy management. Third, 13 internationally recognized experts in pediatric neurology or epilepsy rated the value of these indicators on a 5-point scale [1 (essential) to 5 (not necessary)] in a two-round Delphi process. Positive consensus was reached if ≥80% of experts gave an indicator a “1” rating and negative consensus if >80% gave an indicator a “5” rating. Indicators that achieved positive consensus during either round of the Delphi process constituted the final set of indicators. Results: Of the 68 draft performance indicators, the expert panel members achieved positive consensus on 30 performance indicators: eight indicators related to diagnostic strategies and seizure classification, nine related to antiepileptic drug use, six related to cognitive and behavioral issues, six related to quality of life, and three related to specialty referrals. Conclusions: We identified 30 potential indicators for evaluating the care provided to pediatric patients with epilepsy. The next step is to examine the relation of these performance indicators to clinical outcomes and health care utilization among pediatric patients with epilepsy.

Here we report an infant who had herpes simplex virus (HSV) encephalitis and sustained severe bilateral damage to the posterior frontal lobes, postcentral gyri, and the thalami despite intravenous acyclovir treatment. At 7 months of age, the patient developed infantile spasms and was treated with corticotropin injections. After 10 days of corticotropin treatment, she developed lethargy, fever, and opisthotonic posturing. Her cerebrospinal fluid again was positive for HSV DNA, indicating recurrent HSV encephalitis, and repeat MRI revealed new lesions of the right frontal, parietal, temporal, and occipital lobes. Immunosuppression by corticotropin may have led to the reactivation of the HSV encephalitis. Corticotropin should be relatively contraindicated for use when a patient has a history of HSV infection, or intravenous acyclovir should be administered concurrently.

The evidence base for the efficacy of the ketogenic diet was assessed among pediatric epileptic patients by application of a rigorous statistical meta-analysis. Nineteen studies from 392 abstracts met the inclusion criteria. The sample size was 1084 patients (mean age at initiation 5.78 ± 3.43 years). The pooled odds ratio, using a random effects model, of treatment success (> 50% seizure reduction) among patients staying on the diet relative to those discontinuing the diet was 2.25 (95% confidence interval = 1.69—2.98). The reasons for diet discontinuation included < 50% seizure reduction (47.0%), diet restrictiveness (16.4%), and incurrent illness or diet side effects (13.2%). The results indicate that children with generalized seizures and patients who respond with > 50% seizure reduction within 3 months tend to remain on the diet longer. Although no class I or II studies have been published regarding the efficacy of the ketogenic diet, this meta-analysis shows that current observational studies reporting on the therapeutic effect of the ketogenic diet contain valuable statistical data. Future observational studies should aim for long-term follow-up, patient dropout analysis, and improved seizure type characterization. ( J Child Neurol 2006;21:193—198; DOI 10.2310/7010.2006.00044).

Infant botulism causes acute bulbar dysfunction, weakness, and respiratory failure in infants living in endemic regions of the United States. Until Food and Drug Administration approval of botulism immune globulin (BIG) in October 2003, management of infant botulism had changed little since the 1970s. Currently, IV therapy with BIG is advised to shorten the duration and diminish the potential complications of the disorder. This review describes two decades of experience with infant botulism and provides a contemporary perspective on the role and benefit of BIG.

Concentrated hydrogen peroxide (H2O2) intoxication is relatively rare in children. Serious irreversible neurotoxicity generally results. The case of an 11-year-old boy who inadvertently drank a concentrated (35%) H2O2 solution is described. He exhibited signs of an acute encephalopathy with cortical visual impairment. Extensive cerebrocortical diffusion restriction with apparent gyral edema was evident at 3 days following ingestion, particularly in the parieto-occipital regions bilaterally. Spontaneous neurologic improvement quickly followed, and nearly full clinical resolution was evident 1 month later. The pattern of imaging abnormalities closely resembles that of reversible posterior leukoencephalopathy. Concentrated H2O2 neurotoxicity in children can exhibit unique patterns (a reversible posterior leukoencephalopathy) and a better than expected outcome. ( J Child Neurol 2003;18:805—808).

Central pontine and extrapontine myelinolysis are characterized by symmetric demyelination following rapid shifts in serum osmolality, although in extrapontine myelinolysis, demyelination is confined to the supratentorial compartment. We present a case of extrapontine myelinolysis in a 17-year-old female that occurred in the setting of diabetic ketoacidosis, cerebral edema, mannitol therapy, and meningitis. The rate of correction of this patient's glucose and electrolyte levels was within well-accepted limits. Extrapontine myelinolysis is rare in pediatric patients: there are only 12 reports of extrapontine myelinolysis in children under age 20 years and no pediatric cases of extrapontine myelinolysis or central pontine myelinolysis associated with diabetic ketoacidosis. We review the published cases of extrapontine myelinolysis and examine the underlying etiologies and electrolyte disturbances that characterize these cases. This case expands the list of conditions in which extrapontine myelinolysis occurs to include pediatric patients with complicated diabetic ketoacidosis, emphasizing the importance of sudden osmolar shifts in the genesis of this disorder. ( J Child Neurol 2003; 18: 144—147).

Management of pediatric epilepsy requires complex coordination of care. We hypothesized that an improved seizure management care plan would reduce health care utilization and improve outcomes. The authors conducted a cohort study with historical controls of 120 epilepsy patients before and after implementation of a “Seizure Action Plan.” The authors evaluated for differences in health care utilization including emergency department visits, hospitalizations, clinic visits, telephone calls, and the percentage of emergency department visits that resulted in hospitalization in patients who did or did not have a Seizure Action Plan. The authors found that there was no decrease in these measures of health care utilization, and in fact the number of follow-up clinic visits was increased in the group with Seizure Action Plans (4.2 vs 3.3, P = .006). However, the study was underpowered to detect smaller differences. This study suggests that pediatric epilepsy quality improvement measures may require alternative approaches to reduce health care utilization and improve outcomes.

Lesions in the splenium of the corpus callosum are a rare complication of a variety of clinical conditions including ischemia, trauma, acute disseminated encephalomyelitis, infection, electrolyte imbalances, seizures, and antiepileptic drugs. This report describes a child presenting with hemifield visual color anomia, headache, and papilledema, who was found to have a midline splenial lesion on diffusion-weighted magnetic resonance imaging (MRI). Lumbar puncture revealed elevated intracranial pressure. His symptoms and MRI findings resolved quickly following treatment of his increased intracranial pressure. This is the first report describing an association between intracranial hypertension and a lesion in the splenium of the corpus callosum.

This study examined central inhibitory function in children with Tourette syndrome (TS; N = 46) and normally developing controls (N = 22) matched on age, gender, and IQ. A negative priming task measured the ability to inhibit processing of irrelevant distractor stimuli presented on a visual display. Initial analyses indicated that participants with Tourette syndrome did not differ significantly in inhibitory function from controls. However, when the large Tourette syndrome sample was separated into subgroups, one without evidence of comorbidity (N = 23) and the other meeting research criteria for either AD/HD, OCD, or both (N = 23), it became evident that individuals with Tourette syndrome with comorbid conditions tended to perform less well than the control group, whereas those without comorbidity performed much like controls. Similarly, when the large Tourette syndrome sample was divided into two subgroups on the basis of severity of symptomatology (N = 23 in each), those with more numerous and severe symptoms of Tourette syndrome, AD/HD, and OCD performed significantly less well than both controls and Tourette syndrome subjects with fewer and less severe symptoms. This suggests that neuropsychological impairment occurs as a function of comorbidity and symptom severity in Tourette syndrome. It also suggests that categorical diagnoses alone may be less useful than dimensional methods for predicting cognitive impairment in individuals with Tourette syndrome.

RATIONALE AND OBJECTIVES Magnetic resonance (MR) imaging was used for the in vivo evaluation of bihemispheric hypoxic-ischemic (HI) injury in the neonatal rat. METHODS Seven-day-old rats underwent sham surgery (n = 7) or bilateral carotid artery ligation and hypoxia (30-45 min) (n = 8). T2-weighted imaging was used to study the temporal evolution of injury. Histopathology was used to correlate injury with MR signal changes. RESULTS T2-weighted images exhibited considerable anatomic detail (0.2 mm resolution in-plane). The cortex, dorsolateral striatum and thalamus were affected, while the hippocampus was spared. Magnetic resonance signal change was seen as early as 1.5 hrs post-HI (lesion extent, 27%-39%), and reached a maximum at 48 hrs (37%-49%). Magnetic resonance imaging estimation of injury at 72 hours after HI was compared with histopathology and correlated well (r = 0.98). CONCLUSIONS The study demonstrates the feasibility of magnetic resonance imaging for in vivo evaluation of neonatal brain injury and that vulnerability in the neonatal hippocampus is strikingly different than in adult HI models.

Recent developments in understanding the pathophysiology of disordered motor control in cerebral palsy are reviewed. In spastic cerebral palsy, evidence for abnormal segmental as well as supraspinal control of motor neuron output exists. Impaired Ia inhibition of antagonist muscles has been suggested but recently contested. Evidence also supports the role of decreased presynaptic inhibition of Ia afferents and decreased nonreciprocal Ib inhibition. Furthermore, early cerebral injury results in reorganization of supraspinal (corticospinal) inputs to motor neuron pools. In extrapyramidal cerebral palsy, injury of basal ganglia or thalamus has been demonstrated. A scheme for understanding the neurochemical circuitry of the extrapyramidal system is discussed. Animal models and certain specific human diseases provide examples of how this circuitry may be disturbed, thereby resulting in an imbalance between the direct and indirect striatal output systems and in impaired motor control. Future studies employing postmortem neurochemical analysis, functional magnetic resonance imaging, and positron emission tomographic scanning may foster progress in this area. (J Child Neurol 1996;11(Suppl 1):S5-S 12).

Neonatal hypoxic-ischemic (HI) brain injury in the rat alters dopamine receptors. To determine whether such changes are permanent, dopamine receptors and corresponding mRNA were examined at various time points after neonatal HI using receptor autoradiography and in situ hybridization. Rat pups underwent ligation of the left common carotid artery followed by hypoxic exposure (8.5% O2 for 3 h). Controls underwent sham surgery alone. Animals surviving for 2–80 days following HI were studied. Striatal D1 receptors (labeled by [3H]SCH 23390) were reduced as early as 2 days following HI, remained depressed for 21 days, but recovered to control levels by young adulthood (3 months of age). D2 receptors (labeled by [125I] iodosulpride) did not decline until 10 days after HI, and remained uniformly depressed throughout the caudate-putamen thereafter. Changes in D1 receptor mRNA transcripts closely paralleled alterations in receptors: early reductions in D1 mRNA signal recovered by young adulthood. D2 mRNA exhibited a unique temporal profile with an early decrease (2 days following HI), and prompt, persistent recovery. Dopamine receptors and transcripts are differentially affected by HI injury early in development. Whereas D1 receptor expression recovers from neonatal HI injury, D2 receptors remain permanently affected despite the presence of normal levels of D2 receptor transcripts. A persistent, post-transcriptional effect of HI on D2 receptor expression is suggested.

Objective Variability in the clinical phenotype of Tourette's disorder (TD) was assessed in a single large family, with a focus on the influence of bilineal transmission. Method Tics, obsessive-compulsive symptoms, and attention-deficit symptoms were evaluated through interview and standardized checklists for 175 descendants and 16 spouses who married into a single four-generation pedigree. Results Some form of tic disorder was diagnosed in 67% of descendants and 44% of married-in spouses. TD was found in 36% of descendants and in 31 % of married-in spouses. Impairment was minimal in most cases, but age at onset and location and number of tics were typical of TD described in clinic samples. Obsessive-compulsive symptoms were found in 38% of descendants and 62% of those with current TD, but obsessive-compulsive disorder was found in only four individuals. Attention-deficit hyperactivity disorder occurred in 25% of children. Multivariate analysis indicated that offspring of two parents with tic disorders manifested significantly more lifetime tics, more severe categories of tic disorders, and an earlier age at onset for TD compared with offspring of one or no affected parents. Conclusions TD in this family is most often a mild disorder but otherwise similar to published clinical cases. Increased morbidity is significantly associated with bilineality. The frequency and impact of bilineality raise questions about possible assortative mating, the prevalence of TD, and assumed mechanisms of transmission and etiology.

The L-type Ca2+ channel antagonist nitrendipine inhibits N- methyl - D - aspartate (NMDA)-activated Ca2+ flux into cerebellar granule cells, and [3H]dibenzocyclohepteneimine ([3H]MK 801) binding to mouse cerebral cortical and hippocampal membranes. To further study this interaction between nitrendipine and NMDA-activated channels, the effects of several L-channel active agents on [3H]MK 801 binding to mouse brain were investigated in an autoradiographic assay. Serial slide-mounted sagittal sections of mouse brain were labeled with [3H]MK 801 in the presence of varying concentration of L-channel active agents nitrendipine, nimodipine, nifedipine, Bay K 8644, and verapamil. Nitrendipine potently displaced 2 nM [3H]MK 801 binding to mouse brain sections (IC50 = 89.8 nM). Dose-dependent inhibition of [3H]MK 801 binding by nitrendipine was demonstrated in most brain regions examined. 10−5 M and 10−8 M concentrations of the other dihydropyridines studied, and verapamil, were without effect. The data supports a unique, direct interaction between nitrendipine and the NMDA-activated ion channel.

Core Concepts The neurological examination Neuroimaging Electrophysiology evaluation Cerebrospinal fluid Genetic evaluation Newborn screening and inborn errors of metabolism. A Problem-based Approach to Pediatric Neurological Disorders Disorders of development Disorders of behavior and cognition Disorders of hearing and language Disorders of head size and shape Disorders of cranial nerves Disorders of peripheral nerves Disorders of gait and balance Disorders of sleep Disorders of newborn Acute and focal deficits The dimorphic child Headaches Hypotonia/weakness Neurological infections Movement disorders Seizures and other paroxysmal disorders Neurological emergencies Legends Further reading Index

Considerable evidence indicates that dopamine (DA) may play a neurotoxic role in brain in certain pathologic circumstances. To investigate this issue, dopamine (1000 nmol/1 microliter) was directly injected into the striatum of anesthetized Sprague-Dawley rats. Control animals received equal-volume injections of gamma-aminobutyric acid (GABA) or NaCl at identical concentrations (diluted in distilled H2O, pH 7.0-7.7). Brains were removed 7 to 9 days later and frozen or fixed and sectioned for histologic and autoradiographic analysis. Dopamine injection resulted in a small-volume (3.3-mm3) lesion in comparison to control GABA and NaCl injections which produced only a needle track0.6 mm3 in volume (P0.01). Dose dependency of DA toxicity was demonstrated, with substantial parenchymal damage requiring an injection of 500 nmol/1 microliter. Within the lesion, marked neuronal loss, macrophage invasion, and capillary and glial proliferation were present. Acetylcholinesterase staining and D1 receptor binding were markedly reduced as well. [3H]RO5-4864 binding to peripheral benzodiazepine receptors (on astrocytes) was increased in the periphery of the lesion. The binding of 1-[3H]benzo[b]cyclohexylthiophenylpiperidine to dopamine uptake sites was also reduced, but over a wider striatal area in comparison to local parenchymal damage. Prior interruption of the dopaminergic nigrostriatal pathway (by injection of 6-hydroxydopamine) appeared to potentiate the toxicity of intrastriatal dopamine injection. The findings indicate that local injection of dopamine produces both post- and presynaptic damage to nigrostriatal structures, and support the contention that dopamine may act as a low-potency neurotoxin.

Objective To compare intranasal midazolam, using a Mucosal Atomization Device (IN-MMAD), with rectal diazepam (RD) for the home treatment of seizures in children with epilepsy. Design Prospective randomized study. Setting Patients' homes and a freestanding children's hospital that serves as a referral center for 5 states. Patients A total of 358 pediatric patients who visited a pediatric neurology clinic from July 2006 through September 2008 and were prescribed a home rescue medication for their next seizure. Intervention Caretakers were randomized to use either 0.2 mg/kg of IN-MMAD (maximum, 10 mg) or 0.3 to 0.5 mg/kg of RD (maximum, 20 mg) at home for their child's next seizure if it lasted more than 5 minutes. Outcome Measures The primary outcome measure was total seizure time after medication administration. Our secondary outcome measures were total seizure time, time to medication administration, respiratory complications, emergency medical service support, emergency department visits, hospitalizations, and caretakers' ease of administration and satisfaction with the medication. Results A total of 92 caretakers gave the study medication during a child's seizure (50 IN-MMAD, 42 RD). The median time from medication administration to seizure cessation for IN-MMAD was 1.3 minutes less than for RD (95% confidence interval, 0.0-3.5 minutes; P = .09). The median time to medication administration was 5.0 minutes for each group. No differences in complications were found between treatment groups. Caretakers were more satisfied with IN-MMAD and report that it was easier to give than RD. Conclusions There was no detectable difference in efficacy between IN-MMAD and RD as a rescue medication for terminating seizures at home in pediatric patients with epilepsy. Ease of administration and overall satisfaction was higher with IN-MMAD compared with RD. Trial Registration clinicaltrials.gov Identifier:NCT00326612

The calcium channel antagonists omega-agatoxin IIIA (omega-Aga-IIIA) and omega-conotoxin GVIA (omega-CgTx) were radioiodinated and used to locate binding sites in the rat brain by receptor autoradiography. While patterns of regional binding to sagittal sections of rat brain were generally similar for the 2 toxins, notable differences in the cerebellum and hippocampus were observed. Specific [125I]omega-Aga-IIIA binding was greatest in the granule cell layers of the cerebellum and of the dentate gyrus. In contrast, binding of [125I]omega-CgTx was most intense in the molecular layers of these structures. Less than one-third of [125I]omega-Aga-IIIA binding in rat brain slices was inhibited by pre-exposure to 250 nM omega-CgTx, while 40 nM omega-Aga-IIIA virtually eliminated the binding of [125I]omega-CgTx under the same conditions. The P-type calcium channel antagonist omega-Aga-IVA blocked only a small fraction of [125I]omega-Aga-IIIA and [125I]omega-CgTx binding. These autoradiographic data are consistent with membrane binding experiments and indicate that the combined use of agatoxins and conotoxins may be useful in the characterization of separate types of neuronal calcium channels.

A follow-up study of a large Utah family with significant linkage to chromosome 2q24 led us to identify a new febrile seizure (FS) gene, SCN9A encoding Nav1.7. In 21 affected members, we uncovered a potential mutation in a highly conserved amino acid, p.N641Y, in the large cytoplasmic loop between transmembrane domains I and II that was absent from 586 ethnically matched population control chromosomes. To establish a functional role for this mutation in seizure susceptibility, we introduced the orthologous mutation into the murine Scn9a ortholog using targeted homologous recombination. Compared to wild-type mice, homozygous Scn9aN641Y/N641Y knockin mice exhibit significantly reduced thresholds to electrically induced clonic and tonic-clonic seizures, and increased corneal kindling acquisition rates. Together, these data strongly support the SCN9A p.N641Y mutation as disease-causing in this family. To confirm the role of SCN9A in FS, we analyzed a collection of 92 unrelated FS patients and identified additional highly conserved Nav1.7 missense variants in 5% of the patients. After one of these children with FS later developed Dravet syndrome (severe myoclonic epilepsy of infancy), we sequenced the SCN1A gene, a gene known to be associated with Dravet syndrome, and identified a heterozygous frameshift mutation. Subsequent analysis of 109 Dravet syndrome patients yielded nine Nav1.7 missense variants (8% of the patients), all in highly conserved amino acids. Six of these Dravet syndrome patients with SCN9A missense variants also harbored either missense or splice site SCN1A mutations and three had no SCN1A mutations. This study provides evidence for a role of SCN9A in human epilepsies, both as a cause of FS and as a partner with SCN1A mutations.

The characteristics of seizures and epilepsy in infants who have had an apparent life-threatening event have been poorly defined. Our objective was to characterize in depth the cohort of patients with apparent life-threatening events who developed seizures. We collected data from infants hospitalized for an apparent life-threatening event, and evaluated patients for subsequent seizures or chronic epilepsy. Of 471 patients with an apparent life-threatening event, 25 (5.3%) had seizures and 17 (3.6%) developed chronic epilepsy. There was no increased risk for febrile seizures. Abnormal brain magnetic resonance imaging results and developmental delay were only found in those patients who developed chronic epilepsy. Of those who developed chronic epilepsy, 47% were diagnosed with seizures within 1 week of their apparent life-threatening event. The discharge diagnosis at the time of the apparent life-threatening event was poorly predictive of those who developed seizures. In most cases the cause of chronic epilepsy was unknown, although cortical dysplasias made up a significant percentage (12%).

To use available evidence and expert consensus to develop performance indicators for the evaluation and management of pediatric epilepsy.We used a three-step process to develop the performance indicators. First, research findings were compiled into evidence tables focusing on different clinical issues. Second, an advisory panel of clinicians, educational and public health experts, and families of children with epilepsy reviewed the evidence. The advisory group used the evidence to draft a preliminary set of performance indicators for pediatric epilepsy management. Third, 13 internationally recognized experts in pediatric neurology or epilepsy rated the value of these indicators on a 5-point scale [1 (essential) to 5 (not necessary)] in a two-round Delphi process. Positive consensus was reached ifor=80% of experts gave an indicator a "1" rating and negative consensus if80% gave an indicator a "5" rating. Indicators that achieved positive consensus during either round of the Delphi process constituted the final set of indicators.Of the 68 draft performance indicators, the expert panel members achieved positive consensus on 30 performance indicators: eight indicators related to diagnostic strategies and seizure classification, nine related to antiepileptic drug use, six related to cognitive and behavioral issues, six related to quality of life, and three related to specialty referrals.We identified 30 potential indicators for evaluating the care provided to pediatric patients with epilepsy. The next step is to examine the relation of these performance indicators to clinical outcomes and health care utilization among pediatric patients with epilepsy.

Iron deficiency anemia is a rare cause of cerebral sinovenous thrombosis in children. We report three cases of cerebral sinovenous thrombosis and iron deficiency anemia treated at Primary Children's Medical Center in Salt Lake City, Utah, between 1998 and 2001. The children were 9, 19, and 27 months old at the time of admission. Hemoglobin levels ranged from 6.6 to 7.0 g/dL, mean corpuscular volume levels from 45 to 56 fL, and platelet counts from 248,000 to 586,000/μL. Magnetic resonance imaging and magnetic resonance venography revealed thrombosis of the straight sinus and internal cerebral veins in all three children, with the addition of the vein of Galen, left transverse and sigmoid sinuses, and upper left internal jugular vein in one child. Recovery ranged from excellent to poor in 3 months to 3 years of follow-up. Four additional cases, ages 6 to 22 months, were found in the English-language literature. Evaluation for prothrombotic disorders was negative in all children, including the current cases. Treatments have included thrombectomy, corticosteroids, mannitol, heparin, low-molecular-weight heparin, warfarin, aspirin, blood transfusion, and iron supplementation, but there is no consensus regarding therapy, other than to correct the anemia and treat iron deficiency. Iron deficiency anemia, a preventable cause of cerebral sinovenous thrombosis, deserves consideration when cerebral sinovenous thrombosis is detected in young children. ( J Child Neurol 2004;19:526—531).

Tourette syndrome (TS), Sydenham chorea, and drug-induced dyskinesias are prototypical movement disorders affecting children. Underlying involvement of basal ganglia has been apparent for several decades, but new neuroimaging studies are adding detail to this mechanism. Genetic studies of TS and tardive dyskinesia may further reveal the underlying pathophysiology. Most provocative is the new conceptual model of poststreptococcal autoimmune neuropsychiatric disorder. Although unproven, substantial support for this model comes from immunologic, family, neuroimaging, and treatment studies.

Perinatal hypoxic-ischemic brain injury was induced in 7- to 8-day-old rats by ligating the left carotid artery with subsequent exposure to 9% oxygen atmosphere for 2.5 h. The animals were killed 7 days later and grouped according to the degree of brain injury sustained after hypoxia-ischemia. Total protein content measured in striatum ipsilateral to the ligation, and dissected from brains showing extensive damage, was reduced to 64% of contralateral tissue. The protein content was not altered in other groups including control animals exposed to air and in sham-operated animals exposed to hypoxic conditions. The concentration of (pg/mg protein) and total (pg/striatum) striatal dynorphin A-like immunoreactivity (DLI) from brains with extensive damage were increased to 481% and 285% of the contralateral side, respectively. Hypoxia-ischemia increased striatal neuropeptide Y-like immunoreactivity (NPYLI) concentration from brains with extensive damage to 157% of contralateral side, but when the results were expressed as total NPYLI content per striatum, NPYLI content in striatum with extensive damage remained unaltered. Substance P-like immunoreactivity (SPLI) concentration and total content per striatum from brains with extensive damage were reduced to 66% and 43% of the contralateral side, respectively. D1 and D2 receptor density in animals killed 10 days after injury was reduced by 24% and 22% of control, respectively, in striatum from brains with extensive damage. These results indicate complex changes in brain neuropeptides following neonatal hypoxia-ischemia. Damage in the substance P system could have functional effects on dopaminergic transmission while the increase in NPYLI and in DLI concentrations may respectively reflect the relative preservation from neuronal damage and possibly an increase in neuropeptide synthesis or decrease in release. The decrease in SPLI concentration and the increase DLI concentration induced by hypoxia-ischemia suggests that these peptides may be present in separate neurons.

An analogue of omega-conotoxin MVIIC, [125I]omega-MVIICnle, has been employed in an autoradiographic assay to define the distribution of binding sites in rat brain of this neuronal calcium channel antagonist. In comparison with N-type channels (labeled by [125I]omega conotoxin GVIA), omega-MVIICnle sites are much denser in cerebellum (molecular layer) than in forebrain. Binding in thalamus is also comparatively high for omega-MVIICnle. Under these conditions, [125I]omega-MVIICnle binding to rat brain sections is not displaceable by the N-channel antagonist, omega-conotoxin GVIA. The calcium channel blocker [125I]omega-conotoxin MVIICnle labels a unique set of binding sites in mammalian brain.