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.

BACKGROUND:Migraine and epilepsy are comorbid conditions. While it is well known that epilepsy can have an impact on cognitive abilities, there is conflicting evidence in the literature on the relationship between migraine and cognitive function. The aim of this study was to assess whether migraine comorbidity in patients with newly diagnosed focal epilepsy is associated with cognitive dysfunction. METHODS:This is a post hoc analysis of data prospectively collected for the Human Epilepsy Project (HEP). There were 349 participants screened for migraine with the 13 questions used in the American Migraine Prevalence and Prevention (AMPP) study. Participants were also screened for depression using the Neurological Disorder Depression Inventory for Epilepsy (NDDI-E) and the Center for Epidemiologic Studies Depression Scale (CES-D) and for anxiety using the Generalized Anxiety Disorder-7 (GAD-7) scale. Cognitive performance was assessed with the Cogstate Brief Battery and Aldenkamp-Baker Neuropsychological Assessment Schedule (ABNAS). RESULTS:About a fifth (21.2%) of patients with a new diagnosis of focal epilepsy screened positive for migraine. There were more women and less participants employed full time among the participants with comorbid migraine. They reported slightly more depressive and anxious symptoms than the participants without migraine. Migraine comorbidity was associated with ABNAS memory score (median: 2, range: 0-12, Mann Whitney U p-value: 0.015). However, migraine comorbidity was not associated with Cogstate scores nor ABNAS total scores or other ABNAS domain scores. In linear regressions, depression and anxiety scores were associated with the ABNAS memory score. CONCLUSION/CONCLUSIONS:In this study, there was no association between migraine comorbidity and objective cognitive scores in patients with newly diagnosed focal epilepsy. The relationship between migraine comorbidity and subjective memory deficits seemed to be mediated by the higher prevalence of depression and anxiety symptoms in patients with epilepsy with comorbid migraine.

In the past two decades, there has been an increasing interest in the therapeutic potential of cannabinoids for neurological disorders such as epilepsy, multiple sclerosis, pain, and neurodegenerative diseases. Cannabis-based treatments for pain and spasticity in patients with multiple sclerosis have been approved in some countries. Randomised controlled trials of plant-derived cannabidiol for treatment of Lennox-Gastaut syndrome and Dravet syndrome, two severe childhood-onset epilepsies, provide evidence of anti-seizure effects. However, small clinical trials of cannabinoids in other neurological disorders such as Huntington's disease, attention deficit hyperactivity disorder, and dementia, have not found any effect. Despite positive results in these two severe epilepsy syndromes, further studies are needed to determine if the anti-seizure effects of cannabidiol extend to other forms of epilepsy, to overcome pharmacokinetic challenges with oral cannabinoids, and to uncover the exact mechanisms by which cannabidiol or other exogenous and endogenous cannabinoids exert their therapeutic effects.

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.

Over half a million women of childbearing age have epilepsy, many of which will require family planning care at some point in their reproductive years. Matters relating to contraception, pregnancy, fertility, and sexual functioning are all impacted to varying degrees by the use of antiepileptic drugs (AEDs) to treat epilepsy and require active management by a woman's neurologist. It is important that a woman's obstetrician/gynecologist (OBGYN) and internist are aware of the way in which their care may be related to her epilepsy care and how this can be successfully comanaged with her neurologist. This includes the impact AED therapies have on pregnancy, such as risk of teratogenicity, changes to AED clearance rates during pregnancy and postpartum, and risk of seizure worsening while pregnant; interactions of hormonal contraceptives and AEDs; side effects of AED treatment on hormonal systems and sexual functioning; and matters of fertility and infertility treatments. The current editorial discusses these relationships between AED choice, dose, and family planning matters for women with epilepsy in their childbearing years to support the collaboration of care between her neurologist, OBGYN, and internist.