Matthew M. Troester

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.

Quality Measures for the Care of Adult Patients with Obstructive Sleep Apnea

ABSTRACT Obstructive sleep apnea (OSA) is a prevalent disorder associated with a multitude of adverse outcomes when left untreated. There is significant heterogeneity in the evaluation and management of OSA resulting in variation in cost and outcomes. Thus, the goal for developing these measures was to have a way to evaluate the outcomes and reliability of the processes involved with the standard care approaches used in the diagnosis and management of OSA. The OSA quality care measures presented here focus on both outcomes and processes. The AASM commissioned the Adult OSA Quality Measures Workgroup to develop quality care measures aimed at optimizing care for adult patients with OSA. These quality care measures developed by the Adult OSA Quality Measures Workgroup are an extension of the original Centers for Medicare & Medicaid Services (CMS) approved Physician Quality Reporting System (PQRS) measures group for OSA. The measures are based on the available scientific evidence, focus on public safety, and strive to improve quality of life and cardiovascular outcomes for individual OSA patients. The three outcomes that were selected were as follows: (1) improve disease detection and categorization; (2) improve quality of life; and (3) reduce cardiovascular risk. After selecting these relevant outcomes, a total of ten process measures were chosen that could be applied and assessed for the purpose of accomplishing these outcomes. In the future, the measures described in this document may be reported through the PQRS in addition to, or as a replacement for, the current OSA measures group. The overall objective for the development of these measures is that implementation of these quality measures will result in improved patient outcomes, reduce the public health burden of OSA, and provide a measurable standard for evaluating and managing OSA.

EEG and video-EEG seizure monitoring has limited utility in patients with hypothalamic hamartoma and epilepsy

Purpose:  Hypothalamic hamartomas (HHs) are a malformation of the ventral hypothalamus and tuber cinereum, associated with gelastic seizures and epilepsy. We sought to determine the spectrum of electroencephalography (EEG) abnormalities in a large cohort of HH patients.

Central Precocious Puberty due to Hypothalamic Hamartomas Correlates with Anatomic Features but Not with Expression of GnRH, TGFα, 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 α (TGFα), and GRM1A, which encodes the type 1 metabotropic glutamate receptor α 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), TGFα, 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, TGFα, 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.

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.

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.

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.

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.

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.

Electroclinical phenotypes and outcomes in TBC1D24 -related epilepsy

TBC1D24 is a newly recognized gene in which variations lead to variable clinical phenotypes including drug-resistant epilepsy. We report four patients with novel variants of TBC1D24 demonstrating drug-resistant focal epilepsy, developmental delays, and head growth deceleration. All patients had seizure semiologies consisting of prolonged, unilateral, focal clonic activity of the arm, leg or face, in addition to generalized clonic or myoclonic seizures. Ictal EEG characteristics included epilepsia partialis continua, epilepsy of infancy with migrating focal seizures, and other focal seizures with indiscrete interictal-ictal transitions. Two seemingly unrelated Navajo patients with identical variations experienced super-refractory status epilepticus at 9 months of age, with one achieving resolution with ketogenic diet therapy. Our series suggests that TBC1D24-related epilepsy can manifest with hypotonia, developmental delays, and a variety of focal-onset seizures prone to electroclinical dissociation.