Risk of Developing Seizures in Children With Abnormal EEG Findings During Polysomnography.

BACKGROUND: Polysomnography (PSG) utilizes abbreviated electroencephalogram (EEG) to stage sleep. The aim of this study was to determine whether epileptiform abnormalities on this limited EEG coverage correlated with abnormalities on routine EEG (rEEG) and an increased risk for seizures in children without a prior diagnosis of epilepsy. METHODS: A six-year retrospective chart review was performed assessing children with abnormalities on EEG during PSG. Children who underwent subsequent rEEG were included; children with a prior diagnosis of seizures were excluded. The main outcome measures were rEEG results and subsequent diagnosis of epilepsy. RESULTS: A total of 67 children met inclusion criteria. Average age was six years, and 43 (64%) were male. rEEG was normal in 16 (24%). Epileptiform abnormalities were focal in 36 (54%), generalized in eight (12%), and mixed in five (8%). An additional two (3%) had slow background rhythm without epileptiform discharges. Thirty-one patients had neurology clinic follow-up with an average duration of 31 months (range 4 to 65 months). Of these, nine (29%) developed seizures, including all three with generalized epileptiform discharges, four of 19 (21%) with focal epileptiform discharges, and two of five (40%) with mixed epileptiform discharges or background slowing. None of the four patients with a normal rEEG had seizures. Eight of the nine patients with seizures were treated with antiepileptic drugs. CONCLUSIONS: Children with no history of seizures found to have abnormal EEG during PSG are likely to have an abnormal rEEG. Additionally, they have an increased risk for developing seizures.

A Case Report of Myelopathy Following Heroin Overdose in a Child.

Neurologic complications secondary to heroin abuse in the adult population have been widely described in the literature. With the recent opioid epidemic and increasing rates of heroin abuse in adolescents, pediatricians are now encountering the diagnostic and management challenge of similar complications in children. We report a case of a 16-year-old girl who presented with complete paraplegia after a heroin overdose. Spinal magnetic resonance imaging showed diffuse thoracic spinal cord abnormalities. She rapidly recovered after high dose intravenous corticosteroids and, upon hospital discharge 2 weeks later, required minimal assistance with ambulation. This case represents the youngest patient reported with the rare complication of myelopathy associated with heroin use.

Safety and Efficacy of Brivaracetam in Pediatric Refractory Epilepsy: A Single-Center Clinical Experience.

Brivaracetam is a new antiepileptic drug with limited data in children. The objective of this study was to assess the efficacy/tolerability of brivaracetam. This is a retrospective chart review of children/adolescents with refractory epilepsy treated with brivaracetam from 2016 to 2018. The primary outcome was seizure reduction (decrease in seizure frequency >50%). Twenty-three patients were identified. Mean age at initiation was 12.5 years. Fourteen were females. Epilepsy was focal in 11, generalized in 6, and mixed in 3. Average dose was 3.9 mg/kg/d. The mean duration of treatment was 8.2 months. Eight had greater than 50% decrease in seizure frequency, of which 7 had focal epilepsy, and 1 had Lennox-Gastaut/mixed epilepsy. Two had drowsiness and 3 behavioral complaints. One experienced tingling and dizziness. Our retrospective review suggests that brivaracetam is an effective therapy for refractory focal epilepsy in children older than 4 years of age.

Tremors: Essential Tremor and Beyond.

Tremor is a fairly common movement disorder presenting to an outpatient pediatric neurology practice. Tremors can be primary or secondary to underlying neurologic or systemic diseases. When assessing a child with tremor, it is paramount to evaluate the phenomenology of the tremor, determine the presence or absence of other neurologic signs and symptoms, and the possible modifying influence of medications. Proper classification is essential for specific diagnosis and prompt adequate management. Treatment considerations should take into account objective assessment of tremor severity and the degree of disability or impairment experienced by the child. Overall effectiveness of pharmacologic treatments of tremor is unfortunately disappointing. In this article we review the clinical examination, classification, and diagnosis of tremor. The pathophysiology of the different forms of tremor is outlined, and treatment options are discussed.

A case report of hypersomnia in tetrasomy X improved with medical therapy.

Tetrasomy X is a rare chromosomal anomaly in which sleep disorders have not been previously reported. We report on one patient with tetrasomy X and hypersomnia successfully treated with psychostimulant therapy. Sleep disorders are rarely reported in chromosomal anomalies. Clinicians should screen patients for sleep disorders and manage them appropriately.

Cost-Effectiveness of Evaluation of Children With Epilepsy in the Emergency Department: Need for Investment in Patient Education.

We aimed to study cost-effectiveness of seizure evaluation of children with epilepsy in the emergency department (ED). We reviewed epilepsy patients seen at our ED for 1 year. Age, laboratory and neuroimaging results, treatment, disposition, and usefulness of the visit (need for hospitalization, clinical improvement) were analyzed. We identified 330 patients, aged 23 days-21 years, 190 (57.5%) had blood tests, 45 (13.6%) urinalysis, 2 (0.6%) cerebrospinal fluid testing, and 44 neuroimaging studies (13.3%). Tests' positive yield were 41%, 11%, 0%, and 4.5%, respectively. One-third of patients (n = 122) were treated with antiepileptic drugs. Other treatments were administered to 44 (13.3%). One hundred eighteen patients (35.7%) were admitted to our hospital, 208 (63%) discharged to home. Two hundred eight visits were useful (63%). One-third of visits did not provide useful patient care. Their visits were expensive and not very cost-effective. Investment in patient education could decrease unnecessary ED visits.

PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature.

BACKGROUND: De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. OBJECTIVES: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. METHODS: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes. RESULTS: We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. CONCLUSION: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.

Neurological Complications of Respiratory Disease.

The respiratory and central nervous systems are intimately connected. Ventilatory control is strictly regulated by central mechanisms in a complex process that involves central and peripheral chemoreceptors, baroreceptors, the cardiovascular system, and specific areas of the brain responsible for autonomic control. Disorders of the lung and respiratory system can interfere with these mechanisms and temporarily or permanently disrupt this complex network resulting in mild to severe neurological sequelae. This article explores the wide variety of neurological problems resulting from respiratory dysfunction, with emphasis on its pathophysiology, clinical features, prognosis, and long-term outcome.

Neurological Complications of Cardiac Disease.

This article focuses on the complex interactions between the cardiovascular and neurologic systems. Initially, we focus on neurological complications in children with congenital heart disease both secondary to the underlying cardiac disease and complications of interventions. We later discuss diagnosis and management of common syncope syndromes with emphasis on vasovagal syncope. We also review the diagnosis, classification, and management of children and adolescents with postural orthostatic tachycardia syndrome. Lastly, we discuss long QT syndrome and sudden unexpected death in epilepsy (SUDEP), reviewing advances in genetics and current knowledge of pathophysiology of these conditions. This article attempts to provide an overview of these disorders with focus on pathophysiology, advances in molecular genetics, and current medical interventions.

Neurological Complications of Endocrine Disease.

The endocrine system is a complex group of organs and glands that relates to multiple other organs and systems in the body with the ultimate goal of maintaining homeostasis. This complex network functions through hormones excreted by several glands and released in the blood, targeting different body tissues and modulating their function. Any primary disorders affecting the endocrine glands and altering the amount of hormones synthesized and released will lead to disruption in the functions of multiple organs. The central nervous system of a developing child is particularly sensitive to endocrine disorders. A variety of neurological manifestations have been described as features of several endocrine diseases in childhood. Their knowledge may contribute to an early diagnosis of a particular endocrine condition, especially when more typical features are not present yet. In this article, we discuss specific neurological manifestations found in various endocrine disorders in children.

Efficacy and Tolerability of Lacosamide in the Treatment of Children With Refractory Generalized Epilepsy.

Lacosamide is FDA-approved in patients 17 years or older with partial-onset epilepsy. We evaluated the efficacy and tolerability of lacosamide in children with refractory generalized epilepsy. We retrospectively reviewed records of 21 children with refractory generalized epilepsy treated with lacosamide in our institution from 2009-2013 divided into 2 subgroups- I, Lennox-Gastaut Syndrome, and II, other generalized epilepsies. Efficacy was defined as seizure freedom or ≥50% seizure reduction. Descriptive data analysis including seizure freedom was compared using c(2) analysis. There were eleven females and ten males with a mean age, of 11.9 years. Five patients became seizure free, nine had ≥50% seizure reduction, and seven had no response. Group I: seven had ≥50% improvement, one did not respond. Group II: five became seizure free, two had ≥50% improvement, five had no response. Lacosamide is effective and well tolerated in children with refractory generalized epilepsy particularly patients with Lennox-Gastaut Syndrome.

A novel 2q37 microdeletion containing human neural progenitors genes including STK25 results in severe developmental delay, epilepsy, and microcephaly.

2q37 microdeletion syndrome is a rare syndrome characterized by neurodevelopmental delay, bone, cardiovascular, and neurological alterations. This syndrome is typically associated with loss of genetic material of approximately 100 genes in the 2q37 band. However, the genes associated with neurodevelopmental phenotype in this syndrome are still unknown. We identified a deleted region of 496 kb by whole genome array CGH in a patient who fulfilled criteria for 2q37 microdeletion syndrome with developmental delay, microcephaly, hypoplasia of the corpus callosum, hand wringing, toe walking, and seizures. The deleted segment contains genes that are highly expressed in the developing human cortical plate and the subventricular zone (SVZ) in vivo and human neural progenitors in vitro, including SEPT2, THAP4, ATG4B, PPP1R7, and STK25. Network analysis revealed that STK25 was the most interacting gene associated with neural development in this deletion. Our report narrows the likely causative genomic region for microcephaly and neurodevelopmental delay in 2q37 microdeletion syndrome to a small genomic region enriched with neural progenitor genes that may represent an important locus for the development of the human cortex and corpus callosum.

EEG Duration: The Long and the Short of It.

Current American Clinical Neurophysiology Society guidelines require a minimum of 20 minutes of artifact-free EEG recording; however, the optimum duration for routine EEGs is not established. Our hypothesis was that an EEG recording of 40 minutes' duration would yield more information than a 20-minute EEG in capturing epileptiform abnormalities and in obtaining sleep. We retrospectively studied 150 consecutive EEGs of 40 minutes' duration performed at St Christopher's Hospital for Children. Although the majority (89%) of interictal EEG abnormalities can be identified within the first 20 minutes of a routine EEG, extending the time of a routine EEG increases the yield significantly by identifying an additional 11% of abnormal studies (P = .0001), precluding the need for further long-term monitoring in these patients. Forty-three percent of interictal epileptiform abnormalities were found during sleep. We recommend that routine EEGs be performed for 40 minutes, whenever possible, to improve yield in a cost-effective manner.

Generalized epilepsies: immunologic and inflammatory mechanisms.

This article focuses on the inflammatory processes in patients with generalized epilepsies. We specifically review the data regarding West, Lennox-Gastaut, and Landau-Kleffner syndromes as they have generalized clinical or electroencephalogram features. There is substantial evidence for a pathogenic implication of immune mechanisms in these epilepsies. Animal models and abnormalities in both cellular and humoral immunity support this hypothesis. They also appear to be particularly responsive to immunomodulatory therapies, which has raised the speculation that an unbalanced immune system may play an important role in the pathophysiology of these epileptic syndromes. In this article, we discuss clinical and experimental data that support the potential implication of immune mediated inflammation and immune response in the mechanism of these entities.

Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis.

A 7-year-old child presented with atypical absence epilepsy. He also had autism and severe cognitive deficit. As part of his diagnostic workup, a chromosomal microarray analysis was performed, which showed novel biallelic deletions in the neurexin 1 gene (NRXN1). His fraternal twin sister, who also had autism and cognitive impairment, was subsequently found to have the same biallelic deletions. Deletions included a 272-282kb loss at band 2p16.3 in one allele and a smaller 135-174-kb loss on the second allele. Neurexin 1 (NRXN1) is a cell adhesion protein, forming a synaptic complex with neuroligin. This signals a pathway that is critical for activity-dependent synaptic transmission. Mutations in this gene have been associated with autism and neurodevelopmental delay. Although there are many reports of heterozygous mutations with variable expressivity, only 3 cases with biallelic NRXN1 mutations have been previously reported, all of which have a more severe phenotype. We report 2 siblings with biallelic deletions, both of which affect the promoter region and exons 1-5 in the α-NRXN1 isoform, which has a role in the Ca(2+)-dependent release of neurotransmitters in the central nervous system. Our cases expand the phenotype of biallelic α NRXN 1 mutations and emphasize the important role of NRXN1 in autism and intellectual disability. Chromosomal microarray analysis should be the clinical standard in all specialties for first-tier genetic testing in autistic spectrum disorders.

Attention deficit hyperactivity disorder and sleep disordered breathing in pediatric populations: a meta-analysis.

A relationship between attention deficit hyperactivity disorder (ADHD) and sleep disordered breathing (SDB) in children and adolescents has been suggested by some authors. Yet, this topic remains highly controversial in the literature. A meta-analysis was conducted in order to examine the extent of relationship between SDB and ADHD symptoms in pediatric populations and whether there are differences in ADHD symptoms pre- versus post-adenotonsillectomy in pediatric populations. PubMed/Medline, PsychInfo and Cochrane databases were searched using the key words "attention deficit hyperactivity disorder" or "ADHD" and "obstructive sleep apnea" or "OSA" or "sleep disordered breathing" (SDB) or "SDB". English language publications through September 2012 were surveyed. Meta-analysis was conducted to assess the relationship between SDB and ADHD symptoms in the first part of the study, and the extent of change in ADHD symptoms before and after adenotonsillectomy in the second part. Eighteen studies satisfied the inclusion criteria for the first part of the study. This represented 1113 children in the clinical group (874 diagnosed with SDB who were examined for ADHD symptoms; 239 diagnosed with ADHD who were examined for SDB) and 1405 in the control-group. Findings indicate that there is a medium relationship between ADHD symptoms and SDB (Hedges' g = 0.57, 95% confidence interval: 0.36-0.78; p = 0.000001). A high apnea hypopnea index (AHI) cutoff was associated with lower effect sizes, while child age, gender and body mass index did not moderate the relationship between SDB and ADHD. Study quality was associated with larger effect sizes. In the second part of the study, twelve studies were identified assessing pre- versus post-surgery ADHD symptoms. Hedges' g was 0.43 (95% confidence interval = 0.30-0.55; p < 0.001; N = 529) suggesting a medium effect, as adenotonsillectomy was associated with decreased ADHD symptoms at 2-13 months post-surgery. The findings of this meta-analysis suggest that ADHD symptoms are related to SDB and improve after adenotonsillectomy. Therefore, patients with ADHD symptomatology should receive SDB screening. Treatment of comorbid SDB should be considered before medicating the ADHD symptoms if present.

Efficacy of lacosamide as adjunctive therapy in children with refractory epilepsy.

Lacosamide is a US Food and Drug Administration (FDA)-approved antiepileptic drug for patients 17 years or older with partial epilepsy. There are sparse data on children. The objective of our study was to evaluate its efficacy/safety in children with refractory epilepsy. Forty children (mean age 14.3 years) were treated with lacosamide at our institution (adjunctive therapy in 36, monotherapy in 4). Fifteen patients had symptomatic focal epilepsy, 2 had cryptogenic focal epilepsy, 20 had symptomatic generalized epilepsy, and 3 had cryptogenic generalized epilepsy. Two had juvenile myoclonic epilepsy and 5 had Lennox-Gastaut syndrome. Forty-two percent had at least >50% reduction in seizure frequency, and 6 became seizure free. Average dose was 7 mg/kg/d and average follow-up was 9.2 months. Responders had a 76.5% mean decrease in seizures. Fifteen children experienced an adverse reaction and 7 discontinued lacosamide (4: Ineffective, I: insurance denial, 1: tremor, 1: behavior). Lacosamide is effective and well-tolerated in children with refractory epilepsy.

Deep brain stimulation of the globus pallidus suppresses post-traumatic dystonic tremor.

Dystonic tremor is an unusual movement disorder that is highly disabling and difficult to treat medically. We describe an 18-year-old patient with dystonic tremor whose medical treatment failed, and was considered for surgery. The patient had a long-standing dystonic tremor and was recommended for globus pallidus (GP) deep brain stimulation. At 2 year follow-up, we observed substantial tremor suppression and best clinical effect with contact three, which, radiographically, is located in the internal globus pallidus/external globus pallidus transition area. The stimulation was more rostral than expected. We conclude that the GP is a potentially useful therapeutic target for dystonic tremor.

Mitochondrial dysfunction in demyelinating diseases.

Dysfunction of the mitochondrial (mt) system is thought to play an important role in the mechanism of progression of various neurodegenerative disorders, including demyelinating disorders. They are characterized by neuroinflammation, ultimately leading to neurodegeneration. Mitochondria (mt) dysfunction is closely related to the mechanism of neuroinflammation, causing increased production of reactive oxygen species, which is detrimental to neurons and glia. Vice versa, neuroinflammation is increasingly recognized to produce mt failure, which then contributes to further neuronal injury and degeneration. Multiple sclerosis and X-linked adrenoleukodystrophy are examples of neurodemyelinating diseases that despite having a diverse etiology have in common a progressive course and significant neuroinflammation and neurodegeneration, leading to severe neurologic disability. The scientific community has become increasingly interested in how mt dysfunction relates to neuroinflammation and demyelination and what role it may play in the natural history of progressive demyelinating diseases. Research studies investigating how mt failure contributes to the progression of these conditions are emerging. A better understanding of the role of oxidative stress in progressive inflammatory demyelinating diseases might generate new potential neuroprotective therapeutic approaches for these devastating neurologic conditions.