Faculty Bibliography

OBJECTIVE:Treatment options for seizure clusters are limited; the need for easy-to-administer treatments remains. The Staccato system delivers drug deep into the lung via inhalation. In this phase 2a study, we investigated the ability of three different doses of Staccato alprazolam to suppress the electroencephalographic (EEG) photoparoxysmal response (PPR) compared with placebo in participants with photosensitive seizures. METHODS:Adults (18-60 years) with a diagnosis and history of PPR on EEG with or without an epilepsy diagnosis were eligible to participate. Participants received Staccato alprazolam 0.5, 1.0, and 2.0 mg, and Staccato placebo (twice) in random order. Intermittent photic stimulation and clinical assessments were performed at one predose and seven postdose time points. The primary endpoint of the study was the change in standardized photosensitivity range (SPR) in participants receiving each dose of Staccato alprazolam. RESULTS:Fifteen participants with a prior epilepsy diagnosis were screened; five were enrolled, randomized, and completed the study. All participants were white females with a mean (SD) age of 27.2 (6.8) years. All doses of Staccato alprazolam reduced the SPR at 2 minutes; the effect was sustained through 4 hours for the 0.5-mg dose and 6 hours for the 1.0- and 2.0-mg doses. The magnitude and duration of sedation and sleepiness were dose-related. Four participants (80%) experienced ≥1 adverse event (AE); none was severe or serious. Cough, diarrhea, dysgeusia, oral dysesthesia, sedation, and somnolence were experienced by two participants (40%) each. SIGNIFICANCE/CONCLUSIONS:This proof-of-concept study demonstrated that Staccato alprazolam 0.5, 1.0, and 2.0 mg rapidly suppressed epileptiform activity in photosensitive participants with epilepsy. The AE profile of Staccato alprazolam was similar to what has been reported for alprazolam for other indications. The results support further development of Staccato alprazolam as a rescue medication for the acute treatment of seizures.

OBJECTIVE:receptors with minimal activity at α1-containing receptors, which are believed to mediate many of the adverse events associated with benzodiazepines, in the epilepsy photosensitivity model as a proof-of-principle of efficacy. METHODS:Seven participants with a photoparoxysmal response to intermittent photic stimulation (IPS) at baseline were randomized in a double-blind, 4-period cross-over study examining single doses of 17.5 and 52.5 mg PF-06372865, 2 mg lorazepam (active control), and placebo. Standardized photosensitivity ranges (SPRs) to IPS were recorded at screening, predose, and 1, 2, 4, and 6 hours postdose. The primary endpoint was the average least squares mean change in the SPR in the participant's most sensitive eye condition, across all time points. RESULTS:Both doses of PF-06372865 produced a marked and statistically significant mean reduction in SPR compared to placebo, which was similar in degree to lorazepam. There was complete suppression of SPR in 6/7 participants following PF-06372865 or lorazepam administration. PF-06372865 was safe and well-tolerated. CONCLUSION/CONCLUSIONS:PAM in humans. Further study of the antiepileptic properties of PF-06372865 is warranted. CLINICALTRIALSGOV IDENTIFIER/UNASSIGNED:NCT02564029. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class II evidence that for people with a stable photoparoxysmal response to intermittent photic stimulation, PF-06372865 reduces the SPR.

Although a memory systems view of the medial temporal lobe (MTL) has been widely influential in understanding how memory processes are implemented, a large body of work across humans and animals has converged on the idea that the MTL can support various other decisions, beyond those involving memory. Specifically, recent work suggests that perception of and memory for visual representations may interact in order to support ongoing cognition. However, given considerations involving lesion profiles in neuropsychological investigations and the correlational nature of fMRI, the precise nature of representations supported by the MTL are not well understood in humans. In the present investigation, three patients with highly specific lesions to MTL were administered a task that taxed perceptual and mnemonic judgments with highly similar face stimuli. A striking double dissociation was observed such that I.R., a patient with a cyst localized to right posterior PRc, displayed a significant impairment in perceptual discriminations, whereas patient A.N., an individual with a lesion in right posterior parahippocampal cortex and the tail of the right hippocampus, and S.D., an individual with bilateral hippocampal damage, did not display impaired performance on the perceptual task. A.N. and S.D. did, however, show impairments in memory performance, whereas patient I.R. did not. These results causally implicate right PRc in successful perceptual oddity judgments, however they suggest that representations supported by PRc are not necessary for correct mnemonic judgments, even in situations of high featural overlap.

Objective: Evaluate ability of inhaled alprazolam to rapidly suppress photosensitivity in a double blind placebo- controlled crossover proof of concept study. Background: Alprazolam formulated as an inhaled preparation (Staccato Alprazolam) could represent a rapidly effective rescue medication for epilepsy patients. Time to effect can be assessed in patients with photosensitive epilepsy, in whom epileptiform activity can be elicited at will. Design/Methods: Patients >= 18 y.o with photosensitive epilepsy at 3 sites were tested on a baseline day, and then received in randomized order either inhaled placebo (on 2 days) or .5, 1 or 2 mg inhaled alprazolam delivered using a hand-held Staccato device. Study days were separated by at least 1 week. Presence (and degree) of photosensitivity was measured predose, then at 2 min, 10 min, 30 min, 1, 2, 4 and 6 hours post-dose. Plasma concentration of study drug was measured at each time point. Sedation was assessed at each time point using the 100-mm linear visual analogue scale (VAS). Results: Five patients were enrolled and completed all treatment arms. All doses decreased the mean standardized photosensitivity range (SPR), with maximal or near-maximal effect occurring by 2 minutes post dose. Higher doses produced effects on SPR out to 4 hours. Sedation was dose related, but separated from SPR effects at later timepoints. Treatment was well tolerated with no serious adverse events. Conclusions: Results from this study suggest that inhaled alprazolam strongly suppresses epileptiform activity within 2 minutes. Duration of effect was dose related, as was sedation. This data supports the possibility that inhaled Alprazolam might have utility in stopping a seizure within 2 minutes of use

The antiepileptic drug (AED) perampanel is approved in >/=40 countries as adjunctive therapy for drug-resistant partial seizures in patients with epilepsy. This post hoc analysis of pooled data from three phase III, double-blind, randomized studies of perampanel examines between-gender differences in perampanel efficacy and safety. Of the 1,478 subjects in the pooled analysis (719 male, 759 female), 1,109 were included in the pharmacokinetic/pharmacodynamic analysis. Perampanel oral clearance was 17% lower in female than in male patients not receiving enzyme-inducing AEDs. Pooled efficacy analysis revealed that seizure frequency was reduced with perampanel treatment regardless of gender; a greater numerical reduction in seizure frequency and increased responder rates occurred in female participants at perampanel doses of 4, 8, and 12 mg. Tolerability was similar between groups, although common adverse events such as dizziness and headache occurred more frequently in female subjects. Modest elevations in perampanel exposure in female patients may result in meaningful between-gender differences in efficacy and safety; therefore, dosing should be individualized and clinical response monitored.

The present study examined the relationship between various sociocultural factors (e.g., acculturation, education), neurological variables (e.g., epilepsy duration and seizure frequency) and nonverbal neuropsychological (NP) test performance in a sample of 305 Latino/a and Non-Latino/a White adults with and without epilepsy. All participants completed nonverbal NP measures of visuospatial skills, memory, executive functioning, and psychomotor speed. An acculturation scale was administered to Spanish-speaking epilepsy patients and controls. Education was strongly correlated with performance on all but one of the nonverbal measures across the entire sample. Among Spanish-speaking Latino/a patients with epilepsy, level of acculturation to U.S. culture was associated with a measure of behavioral inflexibility (p < .05) and with a composite measure of nonverbal NP test performance (p < .05). Finally, the results of hierarchical regression models showed that sociocultural factors accounted for a greater proportion of variance in nonverbal NP test performance than did neurological factors. These results provide further evidence that sociocultural factors are strong predictors of NP test performance in clinical populations, even on nonverbal tests. Assessment of acculturation may be as critical as assessment of disease factors in interpreting cognitive performance in Latino/a individuals.

The Neuropsychological Screening Battery for Hispanics (NeSBHIS) was developed to address the growing need for linguistically appropriate Spanish-language assessment measures. Despite the potential benefits to clinical practice, no prior study has assessed its diagnostic validity in populations with epilepsy. One hundred and fifteen patients with confirmed epilepsy were evaluated via the NeSBHIS; these data were standardized according to age- and education-based norms. Performance decrements were observed in more than 40% of participants on measures of processing speed and naming. Deficits in verbal and visual recall were also exhibited by 29 and 26% of the sample, respectively. No significant differences in test performance emerged between patients with VEEG evidence of left (N=48) versus right (N=24) temporal lobe epilepsy. Although the NeSBHIS is sensitive to the cognitive impairments commonly observed in populations with epilepsy, there are limitations to its ability to identify lateralized neuropsychological impairment in patients with temporal lobe epilepsy

OBJECTIVE: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy. METHODS: Systematic review of relevant articles published between January 1985 and June 2007. RESULTS: It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine and possible compared to phenytoin or lamotrigine. Compared to untreated WWE, it is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. It is probable that antiepileptic drug (AED) polytherapy as compared to monotherapy regimens contributes to the development of MCMs and to reduced cognitive outcomes. For monotherapy, intrauterine exposure to VPA probably reduces cognitive outcomes. Further, monotherapy exposure to phenytoin or phenobarbital possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of <7. Recommendations: If possible, avoidance of valproate (VPA) and antiepileptic drug (AED) polytherapy during the first trimester of pregnancy should be considered to decrease the risk of major congenital malformations (Level B). If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered to prevent reduced cognitive outcomes (Level B). If possible, avoidance of phenytoin and phenobarbital during pregnancy may be considered to prevent reduced cognitive outcomes (Level C). Pregnancy risk stratification should reflect that the offspring of women with epilepsy taking AEDs are probably at increased risk for being small for gestational age (Level B) and possibly at increased risk of 1-minute Apgar scores of <7 (Level C)