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.

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.

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.

Early-onset childhood absence epilepsy: is it a distinct entity?

Childhood absence epilepsy (CAE) typically starts between four and seven years of age. Onset before three years is rare and has not been previously reported from North America. We retrospectively reviewed the electroencephalography laboratory database and paediatric neurology clinic records (from January 2000 to June 2009) at our institution in order to identify patients with absence seizures beginning before age three. Information was collected for age, gender, neurodevelopment, antiepileptic drugs (AEDs) used, seizure control, follow-up, and side effects. Of 12 patients identified, mean age at onset was 20.5 months (range: 11 months to two years; follow-up: six months to 11 years). Seven of 12 patients had normal neurodevelopment and five had speech delay. Four patients were seizure-free without AEDs, three were seizure-free with a single AED, and five still had seizures with multiple AEDs. Three patients had recurrences after medication withdrawal. Other previously published series have identified better seizure control than that reported here, however, 16% of the 130 patients so far documented are reported to have poorly controlled epilepsy, indicating that early-onset CAE is not a homogeneous condition. The debate as to whether early-onset CAE is a distinct epilepsy syndrome therefore continues. We believe that early-onset CAE may be a distinct epilepsy syndrome, with some features that overlap with those of typical CAE, as well as unique distinguishing features. Large prospective multicentric studies would be necessary to definitely resolve this matter.

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.

Significance of interictal occipital epileptiform discharges in children.

OBJECTIVE: Interictal occipital epileptiform abnormalities have not been well characterized. The objective of this pilot study was to assess their significance in children. METHODS: A search was performed on the EEG database for the keywords "occipital", "spike", "sharp wave" and "epileptiform". Patients were divided into two groups based on the absence of all (group 1) or presence of any (group 2) of the following criteria: mental retardation, cerebral palsy, neurological deficits, abnormal MRI and/or intractable epilepsy. Special attention was given to the spike/sharp wave amplitude/duration and background slowing. RESULTS: A total of 44 children (eight months to 15 years) were studied. Groups 1 and 2 were each composed of 22 children. Background slowing was more frequent in group 2 (10/22, 45%) compared to group 1 (1/22, 4.5%; p = 0.002). In group 2, 8/22 (36%) had spikes or sharp waves with amplitudes below 50 microV or above 150 microV with a positive predictive value of 89%, and a negative predictive value of 39%. Only 1/22 (4.5%) in group 1 had epileptiform activity outside of the 50-150 microV range. CONCLUSIONS: The presence of very high or low-amplitude occipital epileptiform abnormalities or background slowing may be indicative of encephalopathy.

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.

Correlates of periodic limb movements of sleep in the pediatric population.

Periodic limb movements of sleep are clinically underdiagnosed in children. Polysomnography is the most accurate diagnostic test. There is a paucity of information regarding polysomnography findings in children. We evaluated the prevalence and correlates of pediatric periodic limb movements detected by polysomnography. Periodic limb movements of sleep were identified in 77 of 982 polysomnograms, with a prevalence of 7.8% and male predominance (47 boys; 30 girls). Mean age was 9.4 +/- 4.2 years (1-19 years) (body mass index, 24.1 +/- 12.3). Mean sleep time was 395.4 +/- 73.4 minutes, of which rapid eye movement sleep constituted 16.6% +/- 6.7%, and slow-wave sleep, 22% +/- 10%. Sleep efficiency was 93.8 +/- 9.83, periodic limb movement index, 9.78 +/-7.9; periodic limb movement arousal, 4.5 +/- 8.4; arousal index, 27.8 +/- 12.4; and peak end-tidal CO(2), 48.9 +/- 10.5 mm Hg. Associated diagnoses included obstructive sleep apnea in 36 (46.8%), attention deficit hyperactivity disorder in 10 (13%), migraine in 7 (9.1%), seizures in 7 (9.1%), autism spectrum disorders in 5 (6.5%), and narcolepsy in 7 (9.1%). Serum ferritin was decreased (mean, 26.1 mug/L) in 29 (96.6%). Prospective studies may clarify the significance of incidental pediatric periodic limb movements in sleep detected on polysomnograms.

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.

Perinatal stroke and the risk of developing childhood epilepsy.

OBJECTIVES: To describe the prevalence of epilepsy after 6 months of age in children with perinatal stroke and examine whether perinatal data predict epilepsy onset and resolution. STUDY DESIGN: A retrospective review of 64 children with perinatal stroke. In children with at least 6 months of follow-up data, Kaplan-Meier curves, univariate log-rank tests, and Cox proportional hazards models were used to examine predictors of time to development of seizures, and time to resolution of seizures in children with epilepsy. The association of risk factors with the presence of epilepsy at any time after 6 months of age was examined using Fisher's exact test. RESULTS: Forty-one of the 61 children with at least 6 months of follow-up data (67%) had epilepsy between 6 months of age and last follow-up, but in 13 of 41, seizures eventually resolved and anticonvulsants were discontinued. Infarct on prenatal ultrasonography (P = .0065) and family history of epilepsy (P = .0093) were significantly associated with time to development of seizures after 6 months of age in the univariate analysis. No assessed variables were associated with time to resolution of epilepsy or with the presence of epilepsy after 6 months of age. CONCLUSIONS: Childhood epilepsy is frequent after perinatal stroke. Evidence of infarction on prenatal ultrasonography and a family history of epilepsy predict earlier onset of active seizures.

Carotid dissection and stroke after tonsillectomy and adenoidectomy.

Carotid dissection and cerebral infarction are extremely rare complications of tonsillectomy and adenoidectomy. We describe a 12-year-old boy who presented with a right internal carotid dissection and right middle cerebral artery infarction, associated with tonsillectomy and adenoidectomy. We discuss the risk factors that may predispose patients to these complications.

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.

Cerebral sinovenous thrombosis in the neonate.

BACKGROUND: There are few studies on neonatal cerebral sinovenous thrombosis (SVT). OBJECTIVES: To describe the presentations, treatments, and outcomes of neonatal SVT and to assess infarction as a predictor of outcome. DESIGN: Retrospective chart study. SETTING: A tertiary pediatric hospital in Indianapolis, Ind. Patients Forty-two children with neonatal SVT identified using International Classification of Diseases, Ninth Revision code searches from 1986 through June 2005 and review of neurology clinic records. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Cognitive impairment, motor impairment, and epilepsy at last clinic visit. RESULTS: Gestational or delivery complications or risk factors and comorbid conditions such as dehydration, sepsis, and cardiac defects were common (gestational/delivery factors in 82% [31 of 38 with available maternal data]; comorbid conditions in 62% [26 of the 42]). Twenty-four (57%) presented with seizures. Twenty-five (60%) had infarcts, which were hemorrhagic in 22. Only 27 (64%) of 42 received prothrombotic evaluations; none had persistent deficiencies of protein C, protein S, or antithrombin III. Three (7%) received heparin sodium. All other children received only supportive care. One child died. Outcome data were available for 29 (71%) of the 41 survivors; of these, 23 (79%) had impairment(s). Two were known to be in early intervention, and no further information was available. Of the remaining 27, 16 (59%) had cognitive impairment, 18 (67%) had cerebral palsy, and 11 (41%) had epilepsy. Infarction was associated with the presence of later impairment (P = .03). CONCLUSIONS: The presentation of neonatal SVT is often nonspecific, the diagnosis can be difficult to make, treatment beyond supportive care is rarely used, and outcomes can be severe. Further work is needed to develop standardized guidelines for the evaluation and treatment of neonatal SVT.

Chiari in the family: inheritance of the Chiari I malformation.

This report presents three families with Chiari malformation type I that became symptomatic during childhood: a mother and son; a set of monozygotic twins; and two half-siblings and their two maternal cousins. These children presented with various symptoms, including headache, stiff neck, and swallowing difficulty. A review of the relevant literature is presented, with an emphasis on familial examples and proposed inheritance. Less common presentations of Chiari malformation type I are discussed, as well as the possible pathogenesis of Chiari malformation type I and associated syringomyelia.

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 9-year-old boy with a history of large perinatal stroke, infantile spasms, and high academic achievement.

The prognosis for intellectual development in children with symptomatic infantile spasms is usually poor. We report a 9-year-old boy with a history of a large, presumed perinatal, left middle cerebral artery infarct discovered when he developed infantile spasms at 6 months of age. The infantile spasms responded to treatment with adrenocorticotropic hormone. He attained cognitive milestones at normal times, requiring only speech therapy for dysarthric speech. At 9 years of age, he has seizures and a severe right hemiparesis but is an articulate honor roll student in advanced English classes. The development of infantile spasms after large-branch middle cerebral artery stroke does not always predict future mental retardation.