Jennifer DeWolfe

Hyperammonemia following intravenous valproate loading

BACKGROUND Valproic acid (VPA) has been associated with hyperammonemia with and without encephalopathy. We report the frequent but transient nature of hyperammonemia following intravenous (IV) administration of loading doses of VPA. METHODS Forty participants received a VPA loading dose (20 or 30 mg/kg) at 6 or 10mg/kg/min. All participants were monitored for signs of systemic and local intolerance. Serum VPA level, ammonia, complete blood count, bilirubin, transaminases, pancreatic enzymes, and level of consciousness were obtained at baseline, 1 and 24h after administration. Changes in ammonia levels were assessed using repeated-measures ANOVA. RESULTS Asymptomatic hyperammonemia occurred in 30 of 40 participants at 1h post-VPA infusion. Majority of the participants (66%) demonstrated decreasing ammonia concentrations at 24h post-infusion. Multivariable repeated-measures analysis indicates the lack of influence of VPA dose (p=0.8), VPA levels (p>0.24, all time points), infusion rate (p=0.41) and gender (0.68) on ammonia levels across time. Age (p=0.015), time since dosing (p=0.017) and co-therapy with enzyme-inducing antiepileptic drugs (p=0.035) were significant predictors of changes in ammonia levels. CONCLUSIONS Hyperammonemia is a frequent but transient finding following intravenous administration of loading doses of VPA. Hyperammonemia was not associated with alteration in consciousness or hepatic transaminases.

Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study

The objective of this study was to characterize the changes in adverse events, seizure severity, and frequency in response to a pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex®) in a large, prospective, single-center, open-label study. We initiated CBD in 72 children and 60 adults with treatment-resistant epilepsy (TRE) at 5 mg/kg/day and titrated it up to a maximum dosage of 50 mg/kg/day. At each visit, we monitored treatment adverse events with the adverse events profile (AEP), seizure severity using the Chalfont Seizure Severity Scale (CSSS), and seizure frequency (SF) using seizure calendars. We analyzed data for the enrollment and visits at 12, 24, and 48 weeks. We recorded AEP, CSSS, and SF at each follow-up visit for the weeks preceding the visit (seizures were averaged over 2-week periods). Of the 139 study participants in this ongoing study, at the time of analysis, 132 had 12-week, 88 had 24-week, and 61 had 48-week data. Study retention was 77% at one year. There were no significant differences between participants who contributed all 4 data points and those who contributed 2 or 3 data points in baseline demographic and AEP/SF/CSSS measures. For all participants, AEP decreased between CBD initiation and the 12-week visit (40.8 vs. 33.2; p < 0.0001) with stable AEP scores thereafter (all p ≥ 0.14). Chalfont Seizure Severity Scale scores were 80.7 at baseline, decreasing to 39.2 at 12 weeks (p < 0.0001) and stable CSSS thereafter (all p ≥ 0.19). Bi-weekly SF decreased from a mean of 144.4 at entry to 52.2 at 12 weeks (p = 0.01) and remained stable thereafter (all p ≥ 0.65). Analyses of the pediatric and adult subgroups revealed similar patterns. Most patients were treated with dosages of CBD between 20 and 30 mg/kg/day. For the first time, this prospective, open-label safety study of CBD in TRE provides evidence for significant improvements in AEP, CSSS, and SF at 12 weeks that are sustained over the 48-week duration of treatment.

Facial emotion processing in patients with seizure disorders

Studies of emotion processing are needed to better understand the pathophysiology of psychogenic nonepileptic seizures (PNES). We examined the differences in facial emotion processing between 12 patients with PNES, 12 patients with temporal lobe epilepsy (TLE), and 24 matched healthy controls (HCs) using fMRI with emotional faces task (EFT) (happy/sad/fearful/neutral) and resting state connectivity. Compared with TLE, patients with PNES exhibited increased fMRI response to happy, neutral, and fearful faces in visual, temporal, and/or parietal regions and decreased fMRI response to sad faces in the putamen bilaterally. Regions showing significant differences between PNES and TLE were used as functional seed regions of interest (ROIs), in addition to amygdala structural seed ROIs for resting state functional connectivity analyses. Whole brain analyses showed that compared with TLE and HCs, patients with PNES exhibited increased functional connectivity of the functional seed ROIs to several brain regions, particularly to cerebellar, visual, motor, and frontotemporal regions. Connectograms showed increased functional connections between left parahippocampal gyrus/uncus ROIs and right temporal ROIs in PNES compared with both the TLE and HC groups. Resting state functional connectivity of the left and right amygdala to various brain regions including emotion regulation and motor control circuits was increased in PNES when compared with those with TLE. This study provides preliminary evidence that patients with PNES exhibit altered facial emotion processing compared with patients with TLE and HCs and increased amygdala functional connectivity compared with TLE. These findings identify potential key differences in facial emotion processing reflective of neurophysiologic markers of neural circuitry alterations that can be used to generate further hypotheses for developing studies that examine the contributions of emotion processing to the development and maintenance of PNES.

Personalities of patients with nonepileptic psychogenic status.

The purposes of this study were to determine whether personalities of patients with nonepileptic psychogenic status (NEPS) are different from those of patients with typical intermittent psychogenic nonepileptic seizures (iPNES) using the Personality Assessment Inventory (PAI) and to compare their PAI profiles with the population norms. We hypothesized that patients with NEPS have more psychopathology compared with patients with iPNES and that, as a group, patients with PNES (iPNES+NEPS) would have more psychopathology compared with healthy individuals. We first compared the PAI profiles of patients with iPNES and NEPS and then the profiles of patients with NEPS, iPNES, and PNES with population norms in order to assess which PAI specific scales differed between groups in order to better characterize the psychopathology of PNES. All patients admitted for diagnostic evaluation to the epilepsy monitoring unit (EMU) were prospectively approached for participation. All patient/family interviews were conducted by an epileptologist, and the diagnosis of iPNES or NEPS was confirmed in all cases through video/EEG and/or family interview. The population norms for PAI were obtained from the manual. Of the 224 approached patients, 130 completed the PAI, and included 43 iPNES and 11 with NEPS. There were no significant differences between the two groups in regard to demographic or PAI profiles. Comparison with population norms revealed the presence of abnormal personality profiles on all scales in patients with iPNES, NEPS, or PNES. We conclude that while the occurrence of NEPS is relatively common in patients with PNES, the demographic characteristics and personality profiles of patients with NEPS are not different from those of patients with iPNES. We also confirmed the presence of significant psychopathology in the group with PNES when compared with population norms.

Chronic ambulatory electrocorticography findings preceding sudden death in epilepsy

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature mortality in patients with refractory epilepsy, but the underlying mechanisms and the predictors of patient risk remain an active area of research.1,2 At present, risk assessment is based on disease severity accrued over the preceding years, but how the risk changes with therapy and disease progression have been poorly understood.3 To establish the pathophysiology of SUDEP, studies have capitalized on experimental models4 and rare terminal events recorded in the epilepsy monitoring unit.5 In these settings, the seizures are either induced or precipitated by weaning off medications and hence the electrophysiologic changes should be validated with spontaneous seizures recorded over longer time scale. Here we report progressive electrophysiologic changes in ambulatory electrocorticography preceding sudden death in a 38-year-old, right-handed woman who had intractable bitemporal epilepsy.

Effects of Subthalamic Nucleus Deep Brain Stimulation on Objective Sleep Outcomes in Parkinson's Disease

Sleep dysfunction is a common and disabling nonmotor symptom in Parkinsons disease (PD). DBS of the STN improves motor symptoms and subjective sleep in PD, but alternative stimulation parameters to optimize sleep have not been explored. We hypothesized that low‐frequency STN DBS would improve objective sleep more than conventional settings.

Sleep, Circadian Rhythms, and Epilepsy

Purpose of reviewThere is a known interrelationship between sleep and epilepsy. This review highlights the recent findings regarding interactions between sleep and circadian rhythms and the manifestations of epilepsy and surgical treatments for refractory epilepsy.Recent findingsCLOCK gene expression may be reduced within the epileptogenic focus in patients with refractory epilepsy. Interictal epileptiform discharges during NREM and especially REM sleep may lateralize to the epileptogenic hemisphere. Intracranial video EEG monitoring and EEG from implanted responsive neurostimulator devices confirm scalp video EEG findings of a nocturnal peak for interictal epileptiform discharges. Successful epilepsy surgery may improve sleep macrostructure and quality.SummarySleep outcomes in people with epilepsy undergoing epilepsy surgery and neurostimulator implantation may provide innovative understandings into the associations between sleep and epilepsy. These associations may then provide novel therapeutic options targeting sleep and circadian pathways to improve seizure control and improve the quality of life for patients with this debilitating disorder.

Sleep Disorders in Epilepsy: Current Trends and Future Perspectives

Purpose of ReviewSleep complaints are common in people with epilepsy (PWE). We aim to highlight the updated evidence regarding comorbid sleep disorders and epilepsy and the impact of epilepsy and its treatments on sleep.Recent FindingsUp to two thirds of PWE report sleep disturbances which may signal presence of a comorbid sleep disorder, including insomnia, arousal parasomnias, excessive daytime sleepiness, obstructive sleep apnea, or restless legs syndrome. Uncontrolled seizures contribute to poor sleep quality, while presence of epilepsy (with or without seizures) and antiepileptic drugs is associated with changes in sleep architecture. Chronic intracranial EEG monitoring with implanted devices reveals a nocturnal peak for interictal epileptiform activity. Epilepsy surgery outcomes suggest better seizure control may improve sleep architecture and quality.SummaryScreening for and treating sleep disorders may lead to improved seizure control and quality of life in PWE. Epilepsy surgery and implanted devices to treat refractory epilepsy provide new insights into the relationship between sleep and epilepsy.

Non-neurologic Causes of Nonconvulsive Status Epilepticus/Nonconvulsive Seizures

Nonconvulsive status epilepticus (NCSE) is an underdiagnosed condition due to its minimal or inconspicuous clinical presentation. With increasing use of continuous electroencephalogram (EEG), NCSE has been diagnosed more frequently in critically ill patients. In 2012, the Neurocritical Care Society defined NCSE as seizure activity on EEG that is continuous or recurrent without return to baseline between seizures for 5 or more minutes that is not associated with convulsive activity. In acutely ill patients, NCSE often follows convulsive status epilepticus and presents with severely impaired mental status with or without subtle motor movements as well as other positive or negative signs [1]. (See Chap. 5 for further NCSE classification). Nonconvulsive seizures (NCS)/NCSE have been reported in 8–21 % of critically ill patient populations [2–4]. Delayed diagnosis and treatment of NCSE may lead to increased mortality which has been reported to be as high as 52 % in critically ill patients [2, 5].