ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability.

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.

Seizure characteristics in Pallister-Killian syndrome.

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.

Development, Implementation, and Use of a Neurology Therapeutics Committee.

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.

Disparities in Pediatric Epilepsy Remission Are Associated With Race and Ethnicity.

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.

Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy.

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.

Splenial corpus callosum lesion and hemifield visual color anomia associated with intracranial hypertension.

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.

Prehospital intranasal midazolam for the treatment of pediatric seizures.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: The IN-MAD midazolam controlled seizures better than PR diazepam in the prehospital setting and resulted in fewer respiratory complications and fewer admissions.

Rapid clinical diagnostic variant investigation of genomic patient sequencing data with iobio web tools.

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

Efficacy of the ketogenic diet as a treatment option for epilepsy: meta-analysis.

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.

Educational Intervention Improves Compliance With AAN Guidelines for Return Epilepsy Visits: A Quality Improvement Project.

In 2011, the American Academy of Neurology (AAN) released guidelines for return seizure visits detailing 8 points that should be addressed during such visits. These guidelines are designed to improve routine follow-up care for epilepsy patients. The authors performed a quality improvement project aimed at increasing compliance with these guidelines after educating providers about them. The authors performed a chart review before and after an intervention which included: education regarding the guidelines, providing materials to remind providers of the guidelines, and templates to facilitate compliance. The authors reviewed charts at 2 and 6 months after the intervention. Significant improvement in documentation of 4 of the 8 measures was observed after this educational intervention. This suggests that simple educational interventions may help providers change practice and can improve compliance with new guidelines while requiring minimal time and resources to implement.

Seizure Action Plans Do Not Reduce Health Care Utilization in Pediatric Epilepsy Patients.

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.

Cannabinoids for pediatric epilepsy? Up in smoke or real science?

Public interest in the use of "medical marijuana" for the treatment of childhood epilepsy has burgeoned in the last few years. This has occurred in parallel with a growing interest in "medical marijuana" in general. Physicians and pediatricians must balance their patients' desire for immediate access to these products with the tenets of evidence-based medicine. This review discusses the biochemistry of cannabis products (the phytocannabinoids) setting this in the context of the endogenous endocannabinoid system. The differing and potentially modulating effects of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are reviewed. The evidence-base supporting or not the use of cannabis products for the treatment of neurological disease and specifically epilepsy is explored. The potential for adverse effects and particularly of neurotoxicity is addressed. Finally, public health and sociocultural implications are touched upon. Specific recommendations for interested physicians are provided including advocacy for patients and for a change in the "scheduling" of cannabis in order to better foster much-needed high-quality scientific research in this important area.

Movement disorders in children and adolescents.

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.

Extrapontine myelinolysis in a pediatric case of diabetic ketoacidosis and cerebral edema.

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.

Hydrogen peroxide neurotoxicity in childhood: case report with unique magnetic resonance imaging features.

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.

Cerebral sinovenous thrombosis in children: another reason to treat iron deficiency anemia.

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/microL. 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.

Ophthalmologic features of Vici syndrome.

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.

Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy.

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.

Occurrence and clinical features of epileptic and non-epileptic paroxysmal events in five children with Pallister-Killian syndrome.

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.