Focal to bilateral tonic-clonic seizures predict pharmacoresistance in focal cortical dysplasia-related epilepsy.

OBJECTIVE: Focal cortical dysplasia (FCD) is the most common etiology of surgically-remediable epilepsy in children. Eighty-seven percent of patients with FCD develop epilepsy (75% is pharmacoresistant epilepsy [PRE]). Focal to bilateral tonic-clonic (FTBTC) seizures are associated with worse surgical outcomes. We hypothesized that children with FCD-related epilepsy with FTBTC seizures are more likely to develop PRE due to lesion interaction with restricted cortical neural networks. METHODS: Patients were selected retrospectively from radiology and surgical databases from Children's National Hospital. INCLUSION CRITERIA: 3T magnetic resonance imaging (MRI)-confirmed FCD from January 2011 to January 2020; ages 0 days to 22 years at MRI; and 18 months of documented follow-up. FCD dominant network (Yeo 7-network parcellation) was determined. Association of FTBTC seizures with epilepsy severity, surgical outcome, and dominant network was tested. Binomial regression was used to evaluate predictors (FTBTC seizures, age at seizure onset, pathology, hemisphere, lobe) of pharmacoresistance and Engel outcome. Regression was used to evaluate predictors (age at seizure onset, pathology, lobe, percentage default mode network [DMN] overlap) of FTBTC seizures. RESULTS: One hundred seventeen patients had a median age at seizure onset of 3.00 years (interquartile range [IQR] .42-5.59 years). Eighty-three patients had PRE (71%); 34 had pharmacosensitive epilepsy (PSE) (29%). Twenty patients (17%) had FTBTC seizures. Seventy-three patients underwent epilepsy surgery. Multivariate regression showed that FTBTC seizures are associated with an increased risk of PRE (odds ratio [OR] 6.41, 95% confidence interval [CI] 1.21-33.98, p = .02). FCD hemisphere/lobe was not associated with PRE. Percentage DMN overlap predicts FTBTC seizures. Seventy-two percent (n = 52) overall and 53% (n = 9) of patients with FTBTC seizures achieved Engel class I outcome. SIGNIFICANCE: In a heterogeneous population of surgical and non-operated patients with FCD-related epilepsy, the presence of FTBTC seizures is associated with a tremendous risk of PRE. This finding is a recognizable marker to help neurologists identify those children with FCD-related epilepsy at high risk of PRE and can flag patients for earlier consideration of potentially curative surgery. The FCD-dominant network also contributes to FTBTC seizure clinical expression.

SCN3A-Related Neurodevelopmental Disorder: A Spectrum of Epilepsy and Brain Malformation.

OBJECTIVE: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder. METHODS: Patients were ascertained via an international collaborative network. We compared sodium channels containing wild-type versus variant Nav1.3 subunits coexpressed with ß1 and ß2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293T cells). RESULTS: Of 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20, 75%). Many, but not all (15/19, 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4 to 6 of domains II to IV. Most pathogenic missense variants tested (10/11, 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function. INTERPRETATION: Our study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in >75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis. ANN NEUROL 2020;88:348-362.

Validation of the structure-function correlation report from the heidelberg edge perimeter and spectral-domain optical coherence tomography.

PURPOSE: To compare the diagnostic assessment of glaucoma specialists with an automated structure-function correlation report combining visual field (VF) and spectral-domain optical coherence tomography (SD-OCT) imagining in subjects with glaucoma. METHODS: This prospective, cross-sectional study was conducted at Wills Eye Hospital, Philadelphia, PA, USA. Subjects with glaucoma received ophthalmic examination, VF testing, and SD-OCT imaging. An automated report was generated describing structure-function correlations between the two structural elements [retinal nerve fiber layer (RNFL) and Bruch's membrane opening-minimum rim width (MRW)] and VF sectors. Three glaucoma specialists masked to the automated report and to each other identified clinically significant structure-function correlations between the VF and SD-OCT reports. Raw agreement and chance-corrected agreement (kappa statistics) between the automated report and the clinical assessments were compared. RESULTS: A total of 53 eyes from 45 subjects with glaucoma were included in this study. The overall agreement between the automated report and clinical assessment comparing MRW and VF was good at 74.8% with a kappa of 0.62 (95% CI 0.55-0.69). Agreements for the six different MRW sections were moderate to good with kappa values ranging from 0.54 to 0.69. For mean RNFL thickness and VF comparisons, agreement between the automated report and clinical assessment was 75.4% with a kappa of 0.62 (95% CI 0.54-0.70). For different RNFL sectors, kappa values ranged from 0.47 (moderate agreement) to 0.80 (good agreement). CONCLUSIONS: This study suggests that the automated structure-function report combining results from the SD-OCT and the HEP may assist in the evaluation and management of glaucoma.

Abnormal downward gaze and cold caloric examination due to propofol: a case study.

BACKGROUND: An adolescent girl had isolated abnormal downward gaze and oculovestibular (cold caloric) testing during propofol administration, prompting concern for brainstem abnormality. PATIENT: An otherwise healthy 16-year-old girl presented after an intentional hanging. Brainstem reflexes were normal except that both eyes exhibited tonic downward gaze on initial examination. After propofol was suspended for 30 minutes in order to evaluate her level of responsiveness, her eyes normalized to midposition from tonic downward gaze. With reinitiation of propofol, the eyes returned to the former downward position. C-collar stabilization prohibited the usual oculocephalic (doll's eyes) evaluation. Right-sided cold water instillation resulted in right eye exodeviation to the right with minimal medial movement of the left eye to the right. After left-sided cold water instillation, the left eye deviated downward with minimal medial deviation of the right eye. She was extubated and off sedatives within 48 hours of admission, and normal ocular motility returned. CONCLUSION: This patient exhibited abnormal ocular motility and cold caloric response with single-agent propofol exposure. The remainder of her cranial nerve examination was normal, and her normal imaging studies and prompt resolution led us to suspect a propofol effect. Physicians should be aware of the pharmacologic alterations of ocular motility and cold caloric testing when propofol is administered.

Abdominal migraine: an under-diagnosed cause of recurrent abdominal pain in children.

OBJECTIVE: Our objective was to demonstrate that, despite recognition by both the gastroenterology and headache communities, abdominal migraine (AM) is an under-diagnosed cause of chronic, recurrent, abdominal pain in childhood in the USA. BACKGROUND: Chronic, recurrent abdominal pain occurs in 9-15% of all children and adolescents. After exclusion of anatomic, infectious, inflammatory, or other metabolic causes, "functional abdominal pain" is the most common diagnosis of chronic, idiopathic, abdominal pain in childhood. Functional abdominal pain is typically categorized into one, or a combination of, the following 4 groups: functional dyspepsia, irritable bowel syndrome, AM, or functional abdominal pain syndrome. International Classification of Headache Disorders--(ICHD-2) defines AM as an idiopathic disorder characterized by attacks of midline, moderate to severe abdominal pain lasting 1-72 hours with vasomotor symptoms, nausea and vomiting, and included AM among the "periodic syndromes of childhood that are precursors for migraine." Rome III Gastroenterology criteria (2006) separately established diagnostic criteria and confirmed AM as a well-defined cause of recurrent abdominal pain. METHODS: Following institutional review board approval, a retrospective chart review was conducted on patients referred to an academic pediatric gastroenterology practice with the clinical complaint of recurrent abdominal pain. ICHD-2 criteria were applied to identify the subset of children fulfilling criteria for AM. Demographics, diagnostic evaluation, treatment regimen and outcomes were collected. RESULTS: From an initial cohort of 600 children (ages 1-21 years; 59% females) with recurrent abdominal pain, 142 (24%) were excluded on the basis of their ultimate diagnosis. Of the 458 patients meeting inclusion criteria, 1824 total patient office visits were reviewed. Three hundred eighty-eight (84.6%) did not meet criteria for AM, 20 (4.4%) met ICHD-2 formal criteria for AM and another 50 (11%) had documentation lacking at least 1 criterion, but were otherwise consistent with AM (probable AM). During the observation period, no children seen in this gastroenterology practice had received a diagnosis of AM. CONCLUSION: Among children with chronic, idiopathic, recurrent abdominal pain, AM represents about 4-15%. Given the spectrum of treatment modalities now available for pediatric migraine, increased awareness of cardinal features of AM by pediatricians and pediatric gastroenterologists may result in improved diagnostic accuracy and early institution of both acute and preventative migraine-specific treatments.