Faculty Bibliography

Focal cortical dysplasia (FCD) is the most common cause of pediatric epilepsy and the third most common cause in adults with treatment-resistant epilepsy. Surgical resection of the lesion is the most effective treatment to stop seizures. Technical advances in MRI have revolutionized the diagnosis of FCD, leading to high success rates for resective surgery. However, 45% of histologically confirmed FCD patients have normal MRIs (MRI-negative). Without a visible lesion, the success rate of surgery drops from 66% to 29%. In this work, we cast the problem of detecting potential FCD lesions using MRI scans of MRI-negative patients in an image segmentation framework based on hierarchical conditional random fields (HCRF). We use surface based morphometry to model the cortical surface as a two-dimensional surface which is then segmented at multiple scales to extract superpixels of different sizes. Each superpixel is assigned an outlier score by comparing it to a control population. The lesion is detected by fusing the outlier probabilities across multiple scales using a tree-structured HCRF. The proposed method achieves a higher detection rate, with superior recall and precision on a sample of twenty MRI-negative FCD patients as compared to a baseline across four morphological features and their combinations.

Malformations of cortical development are found at higher rates in autism spectrum disorder (ASD) than in healthy controls on postmortem neuropathological evaluation but are more variably observed on visual review of in-vivo MRI brain scans. This may be due to the visually elusive nature of many malformations on MRI. Here, we utilize a quantitative approach to determine whether a volumetric measure of heterotopic gray matter in the white matter is elevated in people with ASD, relative to typically developing controls (TDC). Data from a primary sample of 48 children/young adults with ASD and 48 age-, and gender-matched TDCs, selected from the Autism Brain Imaging Data Exchange (ABIDE) open-access database, were analyzed to compare groups on (1) blinded review of high-resolution T1-weighted research sequences; and (2) quantitative measurement of white matter hypointensity (WMH) volume calculated from the same T1-weighted scans. Groupwise WMH volume comparisons were repeated in an independent, multi-site sample (80 ASD/80 TDC), also selected from ABIDE. Visual review resulted in equivalent proportions of imaging abnormalities in the ASD and TDC group. However, quantitative analysis revealed elevated periventricular and deep subcortical WMH volumes in ASD. This finding was replicated in the independent, multi-site sample. Periventricular WMH volume was not associated with age but was associated with greater restricted repetitive behaviors on both parent-reported and clinician-rated assessment inventories. Thus, findings demonstrate that periventricular WMH volume is elevated in ASD and associated with a higher degree of repetitive behaviors and restricted interests. Although the etiology of focal WMH clusters is unknown, the absence of age effects suggests that they may reflect a static anomaly.

West Syndrome is characterized by infantile spasms, a hypsarrhythmic electroencephalogram (EEG) pattern, and a poor neurodevelopmental prognosis. First-line treatments include adrenocorticotrophic hormone (ACTH) and vigabatrin, but adverse effects often limit their use. CPP-115 is a high-affinity vigabatrin analogue developed to increase therapeutic potency and to limit retinal toxicity. Here, we present a child treated with CPP-115 through an investigational new drug protocol who experienced a marked reduction of seizures with no evidence of retinal dysfunction. Given the potential consequences of ongoing infantile spasms and the limitations of available treatments, further assessment of CPP-115 is warranted.

Introduction: The role of sleep in learning and memory has gained significant attention in cognitive neuroscience. We report our experience with a healthy subject population at a sleep research center. Methods: We recruited subjects for a daytime nap and overnight sleep study by advertising at an urban university over one year. Subjects were eligible if aged 18 to 35, English-speaking, and scored above 26 on the Montreal Cognitive Assessment (MOCA). They were excluded for any diagnosis of a neurologic or psychiatric disorder, including a sleep disorder (as identified by the insomnia symptom questionnaire, STOP-BANG, and Morningness-Eveningness scale); used psychoactive medications, alcohol or recreational drugs; or recent travel across time zones. Subjects participated in cognitive tasks and slept with simultaneous EEG-PSG, which was scored by a board-certified sleep neurologist. Results: We obtained 40 nap studies and 20 nighttime studies. Screening questionnaires identified eligible subjects with a low risk of insomnia (0.22 +/- 0.52), low r isk of sleep apnea (0.82 +/- 0.75), and inter mediate ci rcadian preferences (47.15 +/- 0.75). There was a wide var iance in sleep efficiency (0.68 +/- 0.29) and total sleep time (TST, 69.86 +/- 33.78 min) during naps; with less variance seen during nocturnal studies (SD 0.84 +/- 0.08; TST 454.13 +/- 45.0 min). Three (15%) nap subjects demonstrated excessive daytime REM. Two nap subjects (5%) and three (15%) nighttime subjects were diagnosed with OSA. One nap subject (2.5%) and two nighttime subjects (10%) were diagnosed with periodic limb movements of sleep (PLMS). Conclusion: Our experience with a healthy subject population suggests a wide variance in daytime sleep behavior and a notable prevalence of sleep disorders such as OSA, PLMS, and excessive daytime REM. These variables should be considered in planning and analysis of sleep and cognition studies

Reports an error in "Cannabidiol in patients with treatment-resistant epilepsy: An open-label interventional trial" by Orrin Devinsky, Eric Marsh, Daniel Friedman, Elizabeth Thiele, Linda Laux, Joseph Sullivan, Ian Miller, Robert Flamini, Angus Wilfong, Francis Filloux, Matthew Wong, Nicole Tilton, Patricia Bruno, Judith Bluvstein, Julie Hedlund, Rebecca Kamens, Jane Maclean, Srishti Nangia, Nilika Shah Singhal, Carey A. Wilson, Anup Patel and Maria Roberta Cilio (The Lancet Neurology, 2016[Mar], Vol 15[3], 270-278). The appendix of this Article has been resupplied to include the correct number of patients at each study site in supplementary table 1. This correction has been made to the online version as of March 7, 2016. (The following abstract of the original article appeared in record 2016-09081-023). Background: Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. Methods: In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. Results: Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n = 41 [25%]), decreased appetite (n = 31 [19%]), diarrhoea (n = 31 [19%]), fatigue (n = 21 [13%]), and convulsion (n = 18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n = 9 [6%]). The median monthly frequency of motor seizures was 30.0 (IQR 11.0-96.0) at baseline and 15.8 (5.6-57.6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36.5% (IQR 0-64.7). Interpretation: Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound.

Background: A combined PET/MR scanner with simultaneous acquisition allows direct correlations of PET data with MR-detected parameters on the same subject at the same time. This multi-modal analysis will facilitate the identification of an optimal biomarker. Here we report our study to compare dynamic SUV and cortical thickness between controls (HC) and epilepsy patients (Ep) using simultaneous PET/MR. Methods: Subjects (11 HC and 27 Ep) were imaged on a combined PET/MR scanner (Biograph muMR, Siemens). After FDG injection, dynamic PET scans and simultaneous MR imaging (including T1, T2 and other sequences) were acquired for ~90 minutes. Dixon sequence was acquired for attenuation correction. PET data were reconstructed using the e7tools provided by Siemens. Images were processed using Freesurfer, a fully automated image analysis tool. Over 100 masks (ROIs), including left and right, for cortical and subcortical regions were generated. Statistical analyses on mean SUV for entire study (SUVmean-all), meanSUV derived from the last three frames (SUVmean-late), and mean cortical thickness were compared between groups. Results: Based on Mann-Whitney U tests, SUVmean-late values showed significant differences between groups for most ROIs, while no difference was seen with SUVmean-all. Temporal-Mid-tempocci consistently showed significant difference when normalized SUV values were compared (p <0.01, by individual subject's mean cortical, white matter or global brain). Significant cortical thinning (Epi vs. HC) was detected bilaterally (left, right) within localized regions, such as precentral (p=0.017, 0.012) and superiorfrontal (p=0.016, 0.001). Binary logistic regression indicated that both SUVmean-late and cortical thickness were independent predictors for epilepsy. Conclusions: Our results suggest that simultaneous PET/ MR imaging provides a useful imaging tool to identify regional abnormality, and that SUVmean-late and cortical thickness are independent biomarkers for epilepsy

The current study examined whether negative illness perceptions help explain the link between depression and quality of life. Seventy patients with epilepsy completed standardized self-report questionnaires measuring depression, illness perception, and quality of life (QOL). Illness perception statistically mediated the relationship between depression and QOL (Indirect effect (CI; confidence interval) = -.72, lower limit = -1.7, upper limit = -.22, p < .05). Results held with and without adjusting for potential confounding variables (age, sex, ethnicity, income, and seizure frequency) and when operationalizing depression as a continuous variable that indexed severity of symptoms or as a dichotomous variable that indexed criteria consistent with a diagnosis of major depressive disorder. This study is the first to suggest that illness perceptions may be a useful target in screening and intervention approaches in order to improve QOL among low-income, racially/ethnically diverse patients with epilepsy.

Whole exome sequencing (WES) has been utilized with increasing frequency to identify mutations underlying rare diseases. Autism spectrum disorders (ASD) and intellectual disability (ID) are genetically heterogeneous, and novel genes for these disorders are rapidly being identified, making these disorders ideal candidates for WES. Here we report a 17-year-old girl with ASD, developmental delay, ID, seizures, Chiari I malformation, macrocephaly, and short stature. She was found by WES to have a de novo c.2028delT (P677LfsX19) mutation in the SET domain-containing protein 2 (SETD2) gene, predicted to be gene-damaging. This case offers evidence for the potential the role of SETD2 in ASD and ID and provides further detail about the phenotypic manifestations of mutations in SETD2.

Epilepsy is common in people with intellectual and developmental disabilities (IDD). In adulthood, patients with IDD and epilepsy (IDD-E) have neurologic, psychiatric, medical, and social challenges compounded by fragmented and limited care. With increasing neurologic disability, there is a higher frequency of epilepsy, especially symptomatic generalized and treatment-resistant epilepsies. The causes of IDD-E are increasingly recognized to be genetic based on chromosomal microarray analysis to identify copy number variants, gene panels (epilepsy, autism spectrum disorder, intellectual disability), and whole-exome sequencing. A specific genetic diagnosis may guide care by pointing to comorbid disorders and best therapy. Therapy to control seizures should be individualized, with drug selection based on seizure types, epilepsy syndrome, concomitant medications, and comorbid disorders. There are limited comparative antiepileptic drug data in the IDD-E population. Vagus nerve and responsive neural stimulation therapies and resective surgery should be considered. Among the many comorbid disorders that affect patients with IDD-E, psychiatric and sleep disorders are common but often unrecognized and typically not treated. Transition from holistic and coordinated pediatric to adult care is often a vulnerable period. Communication among adult health care providers is complex but essential to ensure best care when these patients are seen in outpatient, emergency room, and inpatient settings. We propose specific recommendations for minimum care standards for people with IDD-E.