Faculty Bibliography

Increased severity of problematic daytime behavior has been associated with poorer sleep quality in individuals with autism spectrum disorder. In this work, we investigate whether this relationship holds in a real-time setting, such that an individual's prior sleep can be used to predict their subsequent daytime behavior. We analyzed an extensive real-world dataset containing over 20,000 nightly sleep observations matched to subsequent challenging daytime behaviors (aggression, self-injury, tantrums, property destruction and a challenging behavior index) across 67 individuals with low-functioning autism living in two U.S. residential facilities. Using support vector machine classifiers, a statistically significant predictive relationship was found in 81% of individuals studied (P < 0.05). For all five behaviors examined, prediction accuracy increased up to approximately eight nights of prior sleep used to make the prediction, indicating that the behavioral effects of sleep may manifest on extended timescales. Accurate prediction was most strongly driven by sleep variability measures, highlighting the importance of regular sleep patterns. Our findings constitute an initial step towards the development of a real-time monitoring tool to pre-empt behavioral episodes and guide prophylactic treatment for individuals with autism. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Sleep disorders are a common sequel of sports-related concussion. Sleep-wake dysfunction can vary among patients, independent of cause or severity of concussive injury. The pathogenesis of postconcussive sleep disorder is unclear, but may be related to impaired signaling in neurons involved in normal sleep-wake control and circadian rhythm maintenance. Standardized methods of assessment for sleep disorders following concussion are important for diagnosis and management. Appropriate management is key because sleep dysfunction can have deleterious effects on concussion recovery. Management is patient-specific, based on sleep pathology and comorbid postconcussive symptomatology.

Despite sleep disturbance being a common complaint in individuals with autism, specific sleep phenotypes and their relationship to adaptive functioning have yet to be identified. This study used cluster analysis to find distinct sleep patterns and relate them to independent measures of adaptive functioning in individuals with autism. Approximately 50,000 nights of care-giver sleep/wake logs were collected on school-days for 106 individuals with low functioning autism (87 boys, 14.77 +/- 3.11 years) for 0.5-6 years (2.2 +/- 1.5 years) from two residential schools. Using hierarchical cluster analysis, performed on summary statistics of each individual across their recording duration, two clusters of individuals with clearly distinguishable sleep phenotypes were found. The groups were summarized as 'unstable' sleepers (cluster 1, n = 41) and 'stable' sleepers (cluster 2, n = 65), with the former exhibiting reduced sleep duration, earlier sleep offset, and less stability in sleep timing. The sleep clusters displayed significant differences in properties that were not used for clustering, such as intellectual functioning, communication, and socialization, demonstrating that sleep phenotypes are associated with symptom severity in individuals with autism. This study provides foundational evidence for profiling and targeting sleep as a standard part of therapeutic intervention in individuals with autism.

ABSTRACT: We report the case of a 50-year-old man with disabling recurrent hypersomnia with autonomic instability due to catatonia in the setting of atypical bipolar disorder. Treatment with valproic acid for bipolar disorder resulted in complete resolution of symptoms.

While sleep disturbance has been related to a number of negative health outcomes, few studies have examined the relationship between place of birth and sleep duration among individuals living in the US. Data for 416,152 adult participants in the 2000-2013 National Health Interview Survey (NHIS), who provided self-reported hours of sleep and place of birth were examined. Associations were explored between healthy sleep (7-8 h), referenced to unhealthy sleep (<7 or >8 h), and place of birth using multivariate logistic regression analysis. The mean age of the sample was 47.4 +/- 0.03 years; 56% were female. Of the respondents, 61.5% reported experiencing healthy sleep, 81.5% reported being born in the US and 18.5% were foreign-born adults. Descriptive statistics revealed that Indian Subcontinent-born respondents (71.7%) were more likely to report healthy sleep compared to US-born respondents (OR = 1.53, 95% CI = 1.37-1.71, p < 0.001), whereas African-born respondents (43.5%) were least likely to report healthy sleep (OR = 0.78, 95% CI = 0.70-0.87, p < 0.001). These findings suggest that place of birth should be considered in the assessment of risk factors for unhealthy sleep.

PURPOSE: Lennox-Gastaut syndrome (LGS), a rare, severe form of childhood-onset epilepsy, is difficult to control. Rufinamide is indicated for adjunctive treatment of seizures associated with LGS in adults and pediatric patients aged >/=1 year. In clinical practice, rufinamide dosing and titration may differ from the trial setting. Here, rufinamide clinical trial data are compared with real-world experience to provide insight into optimal dosing and titration strategies. METHODS: Rufinamide Phase III and open-label extension (OLE) studies were reviewed; effect of titration and dose on adverse events (AEs) and concomitant AED use were analyzed. Real-world studies of rufinamide in LGS were identified via PubMed search. Clinical data were extracted and compared. RESULTS: Results demonstrated that a rapid titration schedule (7 or 14 days) of rufinamide was tolerable for most patients and resulted in highly significant reductions in total and tonic-atonic seizures, with efficacy and tolerability sustained over 3 years. The most common AEs during the Phase III study - somnolence, vomiting, and pyrexia - occurred during the first 3 weeks of treatment, and a small subset of patients were unable to reach target dose in that time. Use of concomitant AEDs had no clinically significant effect on plasma concentrations of rufinamide. Data from real-world clinical studies are consistent with the Phase III and OLE study results. However, relative to those used in clinical trials, lower doses and slower titration schedules were commonly employed in real-world settings. CONCLUSIONS: A lower dose and slower titration schedule ("low and slow") may reduce incidence of AEs without compromising efficacy of rufinamide in LGS.

Objective: To compare the duration for which pediatric patients with refractory epilepsy who were started on these respective dietary treatments remained in treatment in this single-center cohort Background: The ketogenic diet (KD) is an effective treatment for refractory childhood epilepsy but its restrictiveness has limited widespread use. More recently, a modified Atkins diet (MAD) has been shown to similarly induce ketosis with fewer dietary and lifestyle restrictions. In practice, the benefits of both diets are limited by high discontinuation rates. Whether the less restrictive MAD is correlated with longer treatment adherence is unclear. Design/Methods: From 1/2010 - 6/2015, 148 children with refractory epilepsy were initiated on the classic KD (N=70) or MAD (N=78) in a non-randomized fashion as selected by their caretakers with support from the center's dietitians. Data was collected via retrospective chart review. We performed a Kaplan-Meier survival analysis comparing number of days maintained on the two diets, with further stratification by feeding mode and treatment response (as defined by >=50% reduction in seizure frequency). Results: Patients remained on the classic KD on average 638 +/-490 days, and MAD 348 +/-310 days (Mann-Whitney p<0.001). The mean age of children starting KD was 4 +/-3.9 vs. 8 +/-3.8 for MAD (Mann-Whitney p<0.001). Children assigned to MAD had a lower rate of delayed feeding skills (6.4% vs. 60.9% in KD group; Fisher's exact p <0.001). The 34 patients who were exclusively formula-fed stayed on the classic KD for 614 +/-562 days. When comparing only patients eating solid foods, adherence to KD was longer still (678 +/-411 days vs. 348 +/-310 days; logrank p<0.001. The trend remained when comparing only those with at least 50% treatment response, though sample sizes were small (logrank p=0.120). Conclusions: Further studies are needed to better understand the cause for earlier MAD discontinuation

Objective: To assess the utility and patterns of genetic testing in clinical practice in a single epilepsy center cohort. Background: The role of genetics in the etiology of many types of epilepsy has been long established, with approximately 40% of individuals with epilepsy having a genetic etiology (Pong et al., 2011). Genetic studies are often part of epilepsy work ups to confirm, rule out, or isolate suspected genetic causes of epilepsy. Design/Methods: Over two years (2014-2015), 253 Comprehensive and/or Infantile Epilepsy panels were completed by GeneDx for patients of the Comprehensive Epilepsy Center. Medical history and demographics were collected retrospectively using in house medical charts. Fifty-four reports were included in the analysis due to medical chart completeness. Results: The median age was 13.5(3,39), and 37% were female. Eight patients had positive results of clear pathogenicity (SCN1A(2), CLN5(2), TSC2, GABRG2, POLG, PCDH19), 16 negative and 30 of unclear significance. Parental studies were recommended in 7/8; while only five were completed. Single pathogenic mutations were identified in only two parental studies. Two patients were diagnosed with Dravet Syndrome, 2 neuronal-ceroid- lipofuscinosis, 1 Tuberous-sclerosis, 1 GEFS+, 1 Alpers-syndrome, and 1 female-with-dravet-like-syndrome. Of those with results of unclear significance, 60 mutations were considered likely pathogenic, 36 variants-of- unknown-significance, and 22 likely/reportable benign. 76.6% were recommended to have parental testing done, while only 52.2% did. Conclusions: With genetic testing in 44% of patients producing results of known significance, the yield for confirmatory or exclusionary purposes in this single epilepsy center cohort was high. Discrepancies between how often parental testing is recommended versus completed, suggests possible limitations and/or biases, which need to be explored. Further examination of the characteristics of patients with results of known significance are required to understand the full utility of genetic testing, including cost effectiveness