Sleep in Children with Congenital Malformations of the Central Nervous System.

PURPOSE OF REVIEW: Congenital malformations of the central nervous system may be seen in isolation or in association with syndromes that have multiorgan involvement. Among the potential health challenges these children may face, sleep concerns are frequent and may include chronic insomnia, sleep-related breathing disorders, and circadian rhythm disorders. RECENT FINDINGS: In this review, we describe recent research into sleep disorders affecting children with congenital malformations of the CNS including visual impairment, septo-optic dysplasia, agenesis of the corpus callosum, Aicardi syndrome, Chiari malformation, spina bifida, achondroplasia, Joubert syndrome, fetal alcohol spectrum disorders, and congenital Zika syndrome. In many cases, the sleep disturbance can be directly related to observed anatomical differences in the brain (such as in apnea due to Chiari malformation), but in most syndromes, a complete understanding of the underlying pathophysiology connecting the malformation with sleep problem is still being elucidated. Our review provides a synthesis of available evidence for clinicians who treat this patient population, in whom appropriate diagnosis and management of sleep problems may improve the quality of life for both patient and caregiver.

Utility and safety of prolonged video-EEG monitoring in a tertiary pediatric epilepsy monitoring unit.

Prolonged video-EEG (vEEG) monitoring helps characterize paroxysmal events and epilepsy. There is limited literature in pediatrics describing the safety and utility of vEEG. We retrospectively reviewed 454 pediatric epilepsy monitoring unit admissions over two years. Final event diagnoses, duration of seizures, and medical complications were analyzed. Two hundred twenty admissions (48.4%) captured epileptic seizures, 150 (33.0%) captured nonepileptic events, and 84 (18.5%) failed to capture any events. Medical complications were seen in 4 patients (1.8%) with no long-term complications. Seventeen episodes of status epilepticus occurred in 13 patients. This constituted 2.9% of all admissions and 5.9% of admissions with epileptic seizures. The median duration of status was 26 min, and three patients required transfer to the pediatric intensive care unit. Video-EEG monitoring had a high yield in capturing events and differentiating epileptic from nonepileptic events. Our pediatric patients experienced greater risk of status epilepticus but lesser risk of injury.

Resting-state functional MRI connectivity impact on epilepsy surgery plan and surgical candidacy: prospective clinical work.

OBJECTIVE: The authors' goal was to prospectively quantify the impact of resting-state functional MRI (rs-fMRI) on pediatric epilepsy surgery planning. METHODS: Fifty-one consecutive patients (3 months to 20 years old) with intractable epilepsy underwent rs-fMRI for presurgical evaluation. The team reviewed the following available diagnostic data: video-electroencephalography (n = 51), structural MRI (n = 51), FDG-PET (n = 42), magnetoencephalography (n = 5), and neuropsychological testing (n = 51) results to formulate an initial surgery plan blinded to the rs-fMRI findings. Subsequent to this discussion, the connectivity results were revealed and final recommendations were established. Changes between pre- and post-rs-fMRI treatment plans were determined, and changes in surgery recommendation were compared using McNemar's test. RESULTS: Resting-state fMRI was successfully performed in 50 (98%) of 51 cases and changed the seizure onset zone localization in 44 (88%) of 50 patients. The connectivity results prompted 6 additional studies, eliminated the ordering of 11 further diagnostic studies, and changed the intracranial monitoring plan in 10 cases. The connectivity results significantly altered surgery planning with the addition of 13 surgeries, but it did not eliminate planned surgeries (p = 0.003). Among the 38 epilepsy surgeries performed, the final surgical approach changed due to rs-fMRI findings in 22 cases (58%), including 8 (28%) of 29 in which extraoperative direct electrical stimulation mapping was averted. CONCLUSIONS: This study demonstrates the impact of rs-fMRI connectivity results on the decision-making for pediatric epilepsy surgery by providing new information about the location of eloquent cortex and the seizure onset zone. Additionally, connectivity results may increase the proportion of patients considered eligible for surgery while optimizing the need for further testing.

A novel mutation of the ARX gene in a male with nonsyndromic mental retardation.

ARX (Aristaless-related homeobox gene) is located at Xp22. It contains 5 exons and encodes a 562-amino acid protein. The protein contains 4 polyalanine tracts, 3 of which are encoded in exon 2 and 1 in exon 4. Mutations in the ARX gene have been found in X-linked infantile spasms syndrome, Partington syndrome (mental retardation with dystonic movements of the hands), X-linked lissencephaly with abnormal genitalia, X-linked myoclonus epilepsy with spasticity and intellectual disability, and in nonsyndromic X-linked mental retardation. The most common mutation in ARX (seen in X-linked infantile spasms syndrome, Partington syndrome, and X-linked mental retardation) is a 24-bp duplication in exon 2 resulting in expansion of a polyalanine tract. Truncating mutations (deletions, frameshift, non-sense) have been found in X-linked lissencephaly with abnormal genitalia, as well as homeodomain missense mutations in X-linked myoclonus epilepsy with spasticity and intellectual disability. The authors report a novel 24-bp in-frame deletion within exon 2 of the ARX gene in a male child with X-linked mental retardation and review the spectrum of ARX mutations. This mutation results in a contraction of the second polyalanine repeat.

Consensus Statement of the American Academy of Sleep Medicine on the Recommended Amount of Sleep for Healthy Children: Methodology and Discussion.

ABSTRACT: Members of the American Academy of Sleep Medicine developed consensus recommendations for the amount of sleep needed to promote optimal health in children and adolescents using a modified RAND Appropriateness Method. After review of 864 published articles, the following sleep durations are recommended: Infants 4 months to 12 months should sleep 12 to 16 hours per 24 hours (including naps) on a regular basis to promote optimal health. Children 1 to 2 years of age should sleep 11 to 14 hours per 24 hours (including naps) on a regular basis to promote optimal health. Children 3 to 5 years of age should sleep 10 to 13 hours per 24 hours (including naps) on a regular basis to promote optimal health. Children 6 to 12 years of age should sleep 9 to 12 hours per 24 hours on a regular basis to promote optimal health. Teenagers 13 to 18 years of age should sleep 8 to 10 hours per 24 hours on a regular basis to promote optimal health. Sleeping the number of recommended hours on a regular basis is associated with better health outcomes including: improved attention, behavior, learning, memory, emotional regulation, quality of life, and mental and physical health. Regularly sleeping fewer than the number of recommended hours is associated with attention, behavior, and learning problems. Insufficient sleep also increases the risk of accidents, injuries, hypertension, obesity, diabetes, and depression. Insufficient sleep in teenagers is associated with increased risk of self-harm, suicidal thoughts, and suicide attempts. COMMENTARY: A commentary on this article apears in this issue on page 1439.

Recommended Amount of Sleep for Pediatric Populations: A Consensus Statement of the American Academy of Sleep Medicine.

ABSTRACT: Sleep is essential for optimal health in children and adolescents. Members of the American Academy of Sleep Medicine developed consensus recommendations for the amount of sleep needed to promote optimal health in children and adolescents using a modified RAND Appropriateness Method. The recommendations are summarized here. A manuscript detailing the conference proceedings and the evidence supporting these recommendations will be published in the Journal of Clinical Sleep Medicine.

TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features.

OBJECTIVE: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. METHODS: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). RESULTS: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. CONCLUSIONS: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.

Pediatric Sleep Pharmacology: A Primer.

"What will you give my child to help him sleep?" is a common question parents ask and some health care providers abhor hearing. Entire families may suffer when one member does not sleep well. Poor sleep may complicate the management of other comorbid conditions. Health care providers may have received only limited education on sleep disorders and are frequently forced to choose between treatment options that are poorly studied in children. Fortunately, when addressed correctly, many children with chronic sleep disorders may improve their sleep and daytime behavior in a relatively short time. This review provides a framework to help understand the causes of poor sleep in children and the potential pharmacologic options.

Quality measures for the care of pediatric patients with obstructive sleep apnea.

ABSTRACT: The Board of Directors of the American Academy of Sleep Medicine (AASM) commissioned a Task Force to develop quality measures as part of its strategic plan to promote high quality patient-centered care. Among many potential dimensions of quality, the AASM requested Workgroups to develop outcome and process measures to aid in evaluating the quality of care of five common sleep disorders: insomnia, obstructive sleep apnea in adults, obstructive sleep apnea in children, restless legs syndrome, and narcolepsy. This paper describes the rationale, background, general methods development, and considerations in implementation of these quality measures in obstructive sleep apnea (OSA) in children. This document describes measurement methods for five desirable process measures: assessment of symptoms and risk factors of OSA, initiation of an evidence-based action plan, objective evaluation of high-risk children with OSA by obtaining a polysomnogram (PSG), reassessment of signs and symptoms of OSA within 12 months, and documentation of objective assessment of positive airway pressure adherence. When these five process measures are met, clinicians should be able to achieve the two defined outcomes: improve detection of childhood OSA and reduce signs and symptoms of OSA after initiation of a management plan. The AASM recommends the use of these measures as part of quality improvement programs that will enhance the ability to improve care for patients with childhood OSA.

Lennox-Gastaut syndrome symptomatic to hypothalamic hamartoma: evolution and long-term outcome following surgery.

BACKGROUND: Lennox-Gastaut syndrome is a catastrophic childhood cryptogenic or symptomatic epilepsy. Hypothalamic hamartomas cause refractory epilepsy often consistent with Lennox-Gastaut syndrome. METHODS: Children with Lennox-Gastaut syndrome were defined by a triad of multiple generalized seizure types, slow spike-and-wave on EEG, and mental retardation. RESULTS: Twenty-one of 159 hypothalamic hamartoma patients (14%) met the diagnostic criteria of Lennox-Gastaut syndrome. The median age of patients at epilepsy onset was 0.9 years (range, birth to 9 years). Six of the 21 patients (28%) had preceding infantile spasms. All patients underwent different surgical approaches, including endoscopic, transcallosal, orbitozygomatic resections, and radiosurgery treatment. Five of the 21 (24%) were seizure free with an additional 9 (42%) having at least >90% seizure reduction. Only 1 patient was not effectively treated (<50% seizure reduction). Eighty-eight percent of parents reported improvement in behavioral functioning. Shorter duration of epilepsy prior to surgery was a significant predictor of surgical outcome. CONCLUSIONS: Patients with Lennox-Gastaut syndrome symptomatic to hypothalamic hamartomas have better postsurgical outcome due to other etiologies compared with cryptogenic and symptomatic Lennox-Gastaut syndrome patients. However, compared with overall hypothalamic hamartomas postsurgical outcomes, this cohort was less favorable. Earlier surgery may lead to better outcomes.

Dissolving oral clonazepam wafers in the acute treatment of prolonged seizures.

Klonopin (clonazepam; Genentech Inc, South San Francisco, California) oral wafers are benzodiazepines with anticonvulsive and anxiolytic properties. Our institution has been prescribing clonazepam wafers for acute treatment of prolonged seizures for years. Patients' size determined dosing at 0.25, 0.5, 1, or 2 mg wafers. We proceeded to obtain evidence for efficacy. Hospital Institutional Review Board approval was obtained for anonymous patient survey. All children who had been prescribed clonazepam wafers over a 6-year period at our institution were mailed detailed questionnaires. Three hundred eighty-one questionnaires were mailed with 88 replies but only 56 with meaningful data. Average age was 12.1 years. There were 31 males. Efficacy was defined as stopping seizure within 10 minutes, >50% of the time. Thirty-eight of the 56 (68%) patients met this criterion. From these 38 patients, 19 (50%) had seizures stop within 1 minute. Overall results were comparable to Diastat (rectal diazepam; Valeant Pharmaceuticals International, Aliso Viejo, California). Clonazepam wafers are an effective acute therapy for prolonged seizures.

Central precocious puberty due to hypothalamic hamartomas correlates with anatomic features but not with expression of GnRH, TGFalpha, or KISS1.

BACKGROUND/AIMS: Hypothalamic hamartomas are the most common identifiable cause of central precocious puberty (CPP). Hamartoma characteristics proposed to be associated with CPP include specific anatomic features and expression of molecules such as gonadotropin-releasing hormone (GnRH), transforming growth factor alpha (TGFalpha), and GRM1A, which encodes the type 1 metabotropic glutamate receptor alpha isoform. We sought to determine whether hamartomas that cause CPP could be distinguished by anatomic features, expression of these molecules, or expression of KISS1, whose products signal through the receptor GPR54 to stimulate GnRH release. METHODS: Clinical records and radiologic images were reviewed for 18 patients who underwent hamartoma resection for intractable seizures; 7 had precocious puberty. Resected tissue was examined for expression of GnRH, GnRH receptor (GnRHR), TGFalpha, KISS1, GPR54, and GRM1A. RESULTS: Hypothalamic hamartomas associated with CPP were more likely to contact the infundibulum or tuber cinereum and were larger than hamartomas not associated with CPP. GnRH, TGFalpha, and GnRHR were expressed by all hamartomas studied. Expression of KISS1, GPR54, and GRM1A did not differ significantly between hamartomas associated and not associated with CPP. CONCLUSION: Anatomic features rather than expression patterns of candidate molecules distinguish hypothalamic hamartomas that are associated with CPP from those that are not.