Intracerebral electrographic activity following a single dose of diazepam nasal spray: A pilot study.

OBJECTIVE: Rescue benzodiazepine medication can be used to treat seizure clusters, which are intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient's usual seizure pattern. The NeuroPace RNS® System is a device that detects abnormal electrographic activity through intracranial electrodes and administers electrical stimulation to control seizures. Reductions in electrographic activity over days to weeks have been associated with the longer-term efficacy of daily antiseizure medications (ASMs). In this pilot study, electrographic activity over hours to days was examined to assess the impact of a single dose of a proven rescue therapy (diazepam nasal spray) with a rapid onset of action. METHODS: Adult volunteers (>18 years old) with clinically indicated RNS (stable settings and ASM usage) received a weight-based dose of diazepam nasal spray in the absence of a clinical seizure. Descriptive statistics for a number of detections and a sum of durations of detections at 10-min, hourly, and 24-h intervals during the 7-day (predose) baseline period were calculated. Post-dose detections at each time interval were compared with the respective baseline-detection intervals using a 1 SD threshold. The number of long episodes that occurred after dosing also were compared with the baseline. RESULTS: Five participants were enrolled, and four completed the study; the excluded participant had recurrent seizures during the study. There were no consistent changes (difference >1 SD) in detections between post-dose and mean baseline values. Although variability was high (1 SD was often near or exceeded the mean), three participants showed possible trends for reductions in one or more electrographic variables following treatment. SIGNIFICANCE: RNS-assessed electrographic detections and durations were not shown to be sensitive measures of short-term effects associated with a single dose of rescue medication in this small group of participants. The variability of detections may have masked a measurable drug effect. PLAIN LANGUAGE SUMMARY: Rescue drugs are used to treat seizure clusters. Responsive neurostimulation (RNS) devices detect and record epilepsy brain waves and then send a pulse to help stop seizures. This pilot study looked at whether one dose of a rescue treatment changes brain activity detected by RNS. There was a very wide range of detections, which made it difficult to see if or how the drug changed brain activity. New studies should look at other types of brain activity, multiple doses, and larger patient groups.

Physiologic and cortical response to acute psychosocial stress in left temporal lobe epilepsy - a pilot cross-sectional fMRI study.

Stress is commonly reported as a seizure precipitant in individuals with poorly controlled seizures including temporal lobe epilepsy. The aim of the study was to assess the neural and physiologic correlates of psychosocial stress response during functional magnetic resonance imaging (fMRI) and their relationship with seizure occurrence in patients with left temporal lobe epilepsy (LTLE). We enrolled 23 patients with LTLE and 23 age- and sex-matched healthy controls (HCs); all underwent fMRI with control math task (CMT) and stress math task (SMT) and pre-/post-fMRI salivary cortisol analysis (acute stress reactivity calculated as % reduction from post-stress to recovery baseline; dCORT). The Beck Depression Inventory-II (BDI-II) and Perceived Stress Scale (PSS-10) were administered. T-tests of performance and cortisol variables were performed. Processing and single-subject modeling of fMRI response to CMT positive feedback and SMT negative feedback, group comparisons, and whole-brain correlation of seizure occurrence and fMRI response in patients with poorly controlled LTLE were performed. Patients with LTLE and healthy controls were similar in demographics, math performance, heart rate, and PSS-10 scores (all p>0.05). Patients with LTLE exhibited greater dCORT (p=0.048) and lower BDI-II scores (p=0.016) compared with HCs. Patients with poorly controlled LTLE showed a positive association between seizure frequency and dCORT (r=0.73, p=0.016). Functional MRI activation to feedback was similar between groups, including midfrontal, temporal, parietal, and occipital regions. Regression analyses revealed no group differences to positive feedback, but, compared with HCs, patients with LTLE showed decreased activation to negative feedback in the left cerebellum/middle occipital/fusiform gyri, left hippocampus/parahippocampus, bilateral medial frontal/cingulate/superior frontal gyri, right postcentral gyrus/inferior parietal lobule, and right insula/postcentral gyrus (p<0.05, corrected). Patients with poorly controlled LTLE showed negative association between seizure frequency and activation in the bilateral subgenual anterior cingulate (p<0.05, corrected). This study is the first to characterize the cortical and physiologic responses to acute psychosocial stress and to show a significant relationship between seizure control in LTLE and both the hypothalamic-pituitary-adrenal axis and fMRI signal reactivity to acute psychosocial stress. These findings extend our understanding of the complex interplay between stress, physiologic stress markers, and seizures/epilepsy.

Functional MRI of facial emotion processing in left temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) may negatively affect the ability to recognize emotions. This study aimed to determine the cortical correlates of facial emotion processing (happy, sad, fearful, and neutral) in patients with well-characterized left TLE (LTLE) and to examine the effect of seizure control on emotion processing. We enrolled 34 consecutive patients with LTLE and 30 matched healthy control (HC) subjects. Participants underwent functional MRI (fMRI) with an event-related facial emotion recognition task. The seizures of seventeen patients were controlled (no seizure in at least 3months; LTLE-sz), and 17 continued to experience frequent seizures (LTLE+sz). Mood was assessed with the Beck Depression Inventory (BDI) and the Profile of Mood States (POMS). There were no differences in demographic characteristics and measures of mood between HC subjects and patients with LTLE. In patients with LTLE, fMRI showed decreased blood oxygenation level dependent (BOLD) signal in the hippocampus/parahippocampus and cerebellum in processing of happy faces and increased BOLD signal in occipital regions in response to fearful faces. Comparison of groups with LTLE+sz and LTLE-sz showed worse BDI and POMS scores in LTLE+sz (all p<0.05) except for POMS tension/anxiety (p=0.067). Functional MRI revealed increased BOLD signal in patients with LTLE+sz in the left precuneus and left parahippocampus for "fearful" faces and in the left periarcheocortex for "neutral" faces. There was a correlation between the fMRI and Total Mood Disturbance in the left precuneus in LTLE-sz (p=0.019) and in LTLE+sz (p=0.018). Overall, LTLE appears to have a relatively minor effect on the cortical underpinnings of facial emotion processing, while the effect of seizure state (controlled vs. not controlled) is more pronounced, indicating a significant relationship between seizure control and emotion processing.

Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study.

PURPOSE: To examine patterns of use, efficacy, and safety of intravenous ketamine for the treatment of refractory status epilepticus (RSE). METHODS: Multicenter retrospective review of medical records and electroencephalography (EEG) reports in 10 academic medical centers in North America and Europe, including 58 subjects, representing 60 episodes of RSE that were identified between 1999 and 2012. Seven episodes occurred after anoxic brain injury. KEY FINDINGS: Permanent control of RSE was achieved in 57% (34 of 60) of episodes. Ketamine was felt to have contributed to permanent control ("possible" or "likely" responses) in 32% (19 of 60) including seven (12%) in which ketamine was the last drug added (likely responses). Four of the seven likely responses, but none of the 12 possible ones, occurred in patients with postanoxic brain injury. No likely responses were observed when infusion rates were lower than 0.9 mg/kg/h, when ketamine was introduced at least 8 days after SE onset, or after failure of seven or more drugs. Ketamine was discontinued due to possible adverse events in five patients. Complications were mostly attributed to concurrent drugs, especially other anesthetics. Mortality rate was 43% (26 of 60), but was lower when SE was controlled within 24 h of ketamine initiation (16% vs. 56%, p = 0.0047). SIGNIFICANCE: Ketamine appears to be a relatively effective and safe drug for the treatment of RSE. This retrospective series provides preliminary data on effective dose and appropriate time of intervention to aid in the design of a prospective trial to further define the role of ketamine in the treatment of RSE.