Search

Intermittent rescue therapy may be used for seizure clusters, which are clinical emergencies that may persist ≥24 h and increase risk of status epilepticus, emergency room visits, and reduced quality of life for patients with epilepsy. Beyond effectiveness for aborting seizure clusters, no data exist on how intermittent rescue therapy may impact the long-term natural course of seizure clusters. This novel analysis explores SEIzure interVAL (SEIVAL; time between seizure clusters) in patients from a long-term safety study of diazepam nasal spray (Valtoco) to assess SEIVAL changes with intermittent rescue therapy across time.Patients were aged 6-65 years. Age- and weight-based doses of diazepam nasal spray were administered during a 12-month treatment period with an optional follow-up period. SEIVAL was evaluated in patients receiving two or more doses of diazepam nasal spray using 90-day periods.Of 163 treated patients, 151 had one or more SEIVALs. One hundred twenty had SEIVALs in Period 1 and one or more other periods. An increase in SEIVAL was noted from Period 1 compared with all subsequent periods (p ≤ .001). A consistent cohort (n = 76) had one or more SEIVALs in each of Periods 1-4 (360 days); mean SEIVALs increased significantly (p .01) from 12.2 days (Period 1) to 25.7 days (Period 4). Similar SEIVAL patterns occurred when repeat doses within a seizure cluster were eliminated and irrespective of age group, treatment duration, and change to concomitant medications. In adults, Quality of Life in Epilepsy scores were maintained with increased SEIVALs.Across 12 months, increases in SEIVAL were demonstrated in patients using diazepam nasal spray for seizure cluster treatment in a phase 3 safety study. Increased time between seizure clusters may reflect a previously unrecognized beneficial effect of intermittent rescue therapy. These results generate a range of biological and behavioral hypotheses and warrant exploration of the impact of intermittent rescue therapy.

To evaluate safety and tolerability of long-term treatment with diazepam nasal spray (Valtoco) for seizure clusters in patients aged six to 17 years.The study enrolled patients aged six to 65 years with frequent seizure clusters. Age- and weight-based doses of diazepam nasal spray were administered; second doses were permitted if needed. Safety assessments included treatment-emergent adverse events (TEAEs).Of 163 treated patients, 45 (27.6%) were aged six to 11 years and 33 (20.2%) were aged 12 to 17 years. Mean doses per month were 2.1 in the 6 to 11 subgroup and 2.4 in the 12 to 17 subgroup. Of 1634 seizure clusters in pediatric patients, 186 (11.4%) required a second dose of diazepam nasal spray within 24 hours of the first dose. Similar proportions of TEAEs and serious TEAEs were reported in 6 to 11 (91.1%, 40.0%) and 12 to 17 subgroups (81.8%, 30.3%), respectively. No serious TEAEs were considered treatment related, and no patients discontinued because of TEAEs. Treatment-related TEAEs were more frequent in the 12 to 17 subgroup; only epistaxis and somnolence occurred in two or more patients overall. TEAE rates were similar across subgroups that received concomitant clobazam (90.0%), received prior diazepam rectal gel (90.9%), and were administered less than two versus greater than or equal to two doses per month (87.2% for both) of diazepam nasal spray. Most survey respondents (88%) were satisfied or very satisfied with treatment.In this long-term safety analysis in pediatric patients with seizure clusters, repeated doses of diazepam nasal spray demonstrated a safety profile consistent across subgroups. These data support the dosing guidelines for diazepam nasal spray according to age and weight for pediatric patients.

An exploratory analysis from a long-term, phase 3, open-label, repeat-dose safety study of diazepam nasal spray for acute treatment of seizure clusters assessed the use of a second dose up to 24 hours after the initial dose and effectiveness in potentially reducing the number of seizures.Seizures and doses were recorded in diaries.Of 175 patients enrolled, 163 received ≥1 dose of diazepam nasal spray and were included in the safety population; those patients received a total of 4390 doses for a total of 3853 seizure clusters. Less than half of these patients used a second dose a least once during the study (79 patients [48.5%]), with a total of 485 second doses for seizure clusters (12.6% of all seizure clusters). Among these 79 patients, 33 (41.8%) used only one second dose during the study (range: 1-82). The proportion of seizure clusters treated with a second dose over time was consistently low across 24 h: 0-4 h, 152 (3.9%); 4-6 h, 72 (1.9%); 6-8 h, 39 (1.0%); 8-12 h, 55 (1.4%); 12-16 h, 42 (1.1%); 16-20 h, 42 (1.1%); 20-24 h, 83 (2.2%). Rates of treatment-emergent adverse events (TEAEs) and treatment-related TEAEs occurring within 1 day of a second dose were low (15.2% and 5.1%, respectively).Patients with epilepsy may experience seizure clusters lasting up to 24 hours, and little is known about the effectiveness of rescue therapies for that duration. The current labeling of the US Food and Drug Administration (FDA)-approved outpatient treatments for seizure clusters (rectal diazepam, intranasal midazolam, and diazepam nasal spray) allows for a second dose, if needed, for control. These findings support the safety profile of second doses, and the low use supports the effectiveness of diazepam nasal spray across 24 hours.

Background Previous studies of racial differences in Alzheimer disease (AD) presentation have not included Native Hawaiians and Pacific Islanders (NHPI). Objective To explore the presentation of AD and mild cognitive impairment (MCI) in NHPI. Method We conducted a retrospective review of patient records from Hawaii with a diagnosis of unspecified AD or MCI from September 2000 to September 2019. Variables of interest included age at diagnosis, gender, race, marital status, insurance, comorbidities, and scores on the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA). Results We reviewed the medical records of 598 patients, including 224 Asians, 202 Whites, 87 NHPI, and 85 Other. AD was more dominant than MCI across all of the groups, with the highest percentage in NHPI. Among the mean ages of diagnosis, NHPI were the youngest. Across all groups, a higher proportion of women than men had AD, with the highest female prevalence among NHPI. Hypertension, hyperlipidemia, and type II diabetes were highest among NHPI compared with the other groups. Of individuals with MMSE/MoCA scores, there were significant variations in scores by racial group. The mean MMSE/MoCA score was highest among Whites and lowest among NHPI. Conclusion Compared with other racial groups, NHPI have a higher proportion of AD than MCI at diagnosis, are diagnosed at a younger age, have a higher female prevalence, have more comorbidities that may contribute to AD/MCI onset, and present with lower MMSE scores.

Clinical trials for calcitonin gene-related peptide (CGRP) inhibitors excluded the concomitant use of onabotulinumtoxinA; thus, there is a lack of efficacy and safety data of the combined therapies. Our study aims to examine the effectiveness of CGRP inhibitors with onabotulinumtoxinA by evaluating migraine reductions in headache days and severity. Seventeen patients with chronic migraines were identified who had a partial or poor response to onabotulinumtoxinA, and were placed on dual therapy with a CGRP inhibitor. Patients’ initial headache days and severity ratings were compared to final values taken 1–6 months after adding the CGRP inhibitor to their treatment regime. Comparisons between headache days and severity ratings prior to and during dual treatment were performed utilizing the Kruskal–Wallis test. The significance was set at p

Clinical studies of rescue medications for seizure clusters are limited and are designed to satisfy regulatory requirements, which may not fully consider the needs of the diverse patient population that experiences seizure clusters or utilize rescue medication. The purpose of this narrative review is to examine the factors that contribute to, or may influence the quality of, seizure cluster research with a goal of improving clinical practice. We address five areas of unmet needs and provide advice for how they could enhance future trials of seizure cluster treatments. The topics addressed in this article are: (1) unaddressed end points to pursue in future studies, (2) roles for devices to enhance rescue medication clinical development programs, (3) tools to study seizure cluster prediction and prevention, (4) the value of other designs for seizure cluster studies, and (5) unique challenges of future trial paradigms for seizure clusters. By focusing on novel end points and technologies with value to patients, caregivers, and clinicians, data obtained from future studies can benefit the diverse patient population that experiences seizure clusters, providing more effective, appropriate care as well as alleviating demands on health care resources.

Objective Diazepam nasal spray (Valtoco), indicated for acute treatment of frequent seizure activity (seizure clusters) in patients with epilepsy ≥6 years of age, is designed to be a rapid, noninvasive, socially acceptable route of administration. This interim analysis evaluated the safety profile of diazepam nasal spray in patients with and without concomitant use of benzodiazepines, with use of a second dose for a seizure cluster as a proxy for effectiveness. Methods A long‐term, phase 3, open‐label safety study enrolled patients with epilepsy who had seizures despite a stable antiseizure medication regimen. Results Among 175 patients enrolled by October 31, 2019, a total of 158 were treated with diazepam nasal spray (aged 6–65 years; 53.8% female). Of those, 119 (75.3%) received concomitant benzodiazepines (60, chronic; 59, intermittent); 39 (24.7%) did not. Use of a second dose was similar in patients using chronic concomitant benzodiazepines (second dose in 11.1% [144/1299]) and those with no concomitant benzodiazepines (second dose in 10.3% [41/398]). Treatment emergent adverse events (TEAEs) occurred for 80.0% with chronic use of concomitant benzodiazepines and 61.5% without. Cardiorespiratory depression was not reported, and no serious TEAEs were treatment related. Study retention was high: 83.3% in the chronic benzodiazepine group and 76.9% in the no‐benzodiazepine group. Findings were similar in a sub‐analysis of patients who were (n = 44) or were not (n = 75) taking clobazam. Significance This analysis of patients from a long‐term study shows a similar safety profile of diazepam nasal spray in patients with and without concomitant benzodiazepines, and consistent with the established profile for diazepam. Use of a single dose of diazepam nasal spray and high study retention rates suggest the effectiveness of diazepam nasal spray in patients irrespective of chronic daily benzodiazepine use. Results were similar in the clobazam sub‐analysis. These results support the safety and effectiveness of diazepam nasal spray in patients with concomitant benzodiazepine use.

Seizure clusters must be treated quickly and effectively to prevent progression to prolonged seizures and status epilepticus. Rescue therapy for seizure clusters has focused on the use of benzodiazepines. Although intravenous benzodiazepine administration is the primary route in hospitals and emergency departments, seizure clusters typically occur in out‐of‐hospital settings, where a more portable product that can be easily administered by nonmedical caregivers is needed. Thus, other methods of administration have been examined, including rectal, intranasal, intramuscular, and buccal routes. Following US Food and Drug Administration (FDA) approval in 1997, rectal diazepam became the mainstay of out‐of‐hospital treatment for seizure clusters in the United States. However, social acceptability and consistent bioavailability present limitations. Intranasal formulations have potential advantages for rescue therapies, including ease of administration and faster onset of action. A midazolam nasal spray was approved by the FDA in 2019 for patients aged 12 years or older. In early 2020, the FDA approved a diazepam nasal spray for patients aged 6 years or older, which has a different formulation than the midazolam nasal product and enhances aspects of bioavailability. Benzodiazepines, including diazepam, present significant challenges in developing a suitable intranasal formulation. Diazepam nasal spray contains dodecyl maltoside (DDM) as an absorption enhancer and vitamin E to increase solubility in an easy‐to‐use portable device. In a Phase 1 study, absolute bioavailability of the diazepam nasal spray was 97% compared with intravenous diazepam. Subsequently, the nasal spray demonstrated less variability in bioavailability than rectal gel (percentage of geometric coefficient of variation of area under the curve = 42%–66% for diazepam nasal spray compared with 87%–172% for rectal gel). The diazepam nasal spray safety profile is consistent with that expected for rectal diazepam, with low rates of nasal discomfort (≤6%). To further improve the efficacy of rescue therapy, investigation of novel intranasal benzodiazepine formulations is underway.

OBJECTIVE: A survey was implemented for early assessment of pandemic-related practice processes and quality improvement (QI). BACKGROUND: In response to the public health measures in Hawaii to curtail the coronavirus 2019 pandemic, Hawaii Pacific Neuroscience (HPN) adapted their patient care to ensure continuity of neurological treatment. METHODS: The telephone survey was conducted on patients seen at HPN during the period of April 22, 2020-May 18, 2020 to address four areas related to patients' outpatient experience: delivery of care, general well-being, experience with telemedicine, and disease-specific questions. RESULTS: A total of 928 patients were contacted of which 429 (46.2%) patients responded and 367 (85.5%) agreed to participate. A total of 133 patients with migraine and 234 patients with other neurological conditions provided responses. Our migraine patients' survey responses suggest that their well-being was disproportionately negatively affected by the pandemic. Survey respondents with migraine were significantly more likely than their non-migraine peers to report worsening anxiety and sleep problems [62/132 (47.0%) vs. 78/234 (33.3%), χ2 = 6.64, p = 0.010, and 64/132 (48.5%) vs. 73/234 (31.2%), χ2 = 10.77, p = 0.001]; migraine patients also reported worsening of depression as a result of the pandemic more than patients with other diagnoses, though this was not statistically significant [44/132 (33.3%) vs. 57/234 (24.4%), χ2 = 3.40, p = 0.065]. In regard to access to healthcare, significantly more migraine patients reported running out of medications than those with other diagnoses [20/133 (15.0%) vs. 18/234 (7.7%), χ2 = 4.93, p = 0.026]. More avoided seeking medical help for new health problems because of the pandemic [30/133 (22.6%) vs. 30/234 (12.8%), χ2 = 5.88, p = 0.015]. Migraine patients were also significantly impacted economically by the pandemic; 43/132 (32.4%) of migraine patients reported losing their jobs as the result of the pandemic versus 34/234 (14.5%) of their peers (χ2 = 11.20, p

Patients with psychogenic non-epileptic seizures (PNES) experience significant morbidity and early mortality, secondary to delayed diagnosis. Better characterizing risk factors and exploring how PNES differentially affects sex and racial strata may facilitate earlier diagnosis.From a Hawai'i neuroscience institution, 101 PNES patients were investigated in relation to sociodemographic and medical comorbidities. Cases were compared to 202 sex-, age-, and race-matched controls-representing patients with neurological disorders (general controls)-, as well as 404 unmatched epilepsy controls.Relative to general controls, PNES patients had increased odds (p 0.05) of being: female, younger age, Native Hawaiian or other Pacific Islander (NHPI), suburban origin, from the lowest income quartile, Medicaid beneficiaries, homeless, current/former smoker, illicit drug users (marijuana, opioids/narcotics, polysubstance abuse), have anxiety, depression, post-traumatic stress disorder, bipolar disorder, traumatic history, World Health Organization obesity class 3, traumatic brain injury, epilepsy, and somatoform disorder. In relation to epilepsy controls, PNES patients exhibited increased odds of being: employed, having attention-deficit/hyperactivity disorder, asthma, migraines, and chronic pain. Relative to females, male PNES patients exhibited increased odds of military insurance, diabetes mellitus type 2, and hypertension. Relative to Whites, the NHPI and Asian PNES patients presented increased odds of asthma, migraines, chronic pain, gastroesophageal reflux disease, and thyroid disease. Per multivariable logistic regression, anxiety was the only consistent predictor of PNES across all sex and race strata.Predictors of PNES's vary amongst the strata of race and sex. Lower socioeconomic status, along with several psychiatric and medical comorbidities, could increase a clinician's suspicion for earlier medical workup and diagnosis of PNES.

The impact of seizure clusters and the use of intermittent rescue therapy for clusters on the quality of life (QoL) of patients with epilepsy has not been widely studied. The present analysis assessed QoL as a secondary endpoint among adult patients with seizure clusters enrolled in a long-term, phase 3, open-label safety study (NCT02721069) of diazepam nasal spray (Valtoco®). The QoL aspect of patients in this study has not been previously published.The 12-month safety study of diazepam nasal spray enrolled patients aged 6-65 years with seizure clusters. Adults aged ≥18 years completed the Quality of Life in Epilepsy (QOLIE)-31-P at baseline (day 0) and days 30, 150, 270, and 365. This instrument includes questions about patient health and daily activities with numeric values (1-100) assigned to responses; higher scores indicate better QoL. The QOLIE-31-P includes 7 subscales: Seizure Worry, Overall QoL, Emotional Well-Being, Energy/Fatigue, Cognitive Functioning, Medication Effects, and Social Functioning; an Overall Score is calculated as a weighted composite of the 7 subscales. Comparisons were made between subgroups of patients who had frequent (≥2) and infrequent (2) monthly dosing of diazepam nasal spray and those whose doses were administered by the patient or a care partner. This safety study was not powered to assess efficacy endpoints; descriptive statistics were calculated across time points. In addition, safety measures, including treatment-emergent adverse events, are reported.Seventy-two adults who responded to the QOLIE-31-P were included in the analyses. Mean QOLIE-31-P scores were stable or increased across time points. The mean total scores increased from day 0 to day 365 by 5.2 among patients providing data for ≥1 time point (follow-up group) and 2.2 among patients providing data at all time points (QOLIE all-assessments subgroup). Subscale means for Seizure Worry and Social Functioning showed the greatest numeric increase from baseline. Mean QOLIE-31-P scores were similar in all subgroups. The safety profile in the follow-up group was similar to that seen in all study adults.Adults with refractory epilepsy who were treated with diazepam nasal spray for seizure clusters maintained or improved QOLIE subscale scores across the 12-month study period. Seizure Worry and Social Functioning subscale scores increased over time, suggesting improvement in these domains for this population with intractable epilepsy. Changes among subscale results suggest differences in sensitivity to the use of an intermittent treatment. The potential to improve patient function with treatment for seizure clusters warrants further study.

INTRODUCTION Against the backdrop of the diverse minority-majority state of Hawaii, this study seeks to better characterize associations between idiopathic intracranial hypertension (IIH) with sociodemographic variables and medical comorbidities. METHODS A retrospective case-control study was conducted by utilizing 54 IIH patients and 216 age-, sex-, and race-matched controls, 216 unmatched controls, and 63 age-, sex-, and race-matched migraine patients. RESULTS Relative to controls, IIH were 25 years younger (p 40 kg/m2; OR: 6.10), recent weight gain (OR: 11.66), current smoker (OR: 2.48), hypertensive (OR: 3.08), and peripheral vascular disease (OR: 16.42). Odds of IIH were reduced (p

Objective Need for rescue therapy differs among patients with seizure clusters. Diazepam nasal spray is approved to treat seizure clusters in patients with epilepsy ≥6 years of age. This analysis used interim data from a phase 3 safety study to assess safety profile and effectiveness of diazepam nasal spray using average number of doses/month as a proxy measurement. Methods This phase 3, open‐label, repeat‐dose, safety study of diazepam nasal spray enrolled patients (6‐65 years) with epilepsy and need of benzodiazepine rescue. Patients were stratified by average number of doses/month (5, very‐high frequency). Safety was evaluated based on treatment‐emergent adverse events (TEAEs), assessed nasal irritation, and olfaction. The proportion of treatments given as a second dose was used as an exploratory proxy for effectiveness. Results Of 175 enrolled patients (data cutoff, October 31, 2019), 158 received ≥1 dose of diazepam nasal spray. Frequency of use was moderate in 43.7% of patients, high in 50.6% of patients, and very high in 5.7% of patients. Patients treated 3397 seizure episodes (moderate frequency, 14.2%; high frequency, 59.9%; very high frequency, 25.8%). Nasal discomfort was the most common treatment‐related TEAE in all groups. No notable changes in nasal irritation or olfaction were observed. Second doses represented only 2.5%, 7.5%, and 17.2% of all doses in the moderate‐, high‐, and very‐high‐frequency groups, respectively. Overall retention rate was 82.9%, without an observed relationship to frequency of use. Significance Frequency of dosing diazepam nasal spray had little impact on the safety/tolerability profile across a range of 5 doses/month. Effectiveness was suggested for all dosing frequencies by the high proportion of seizure clusters not treated with a second dose. These results support the utility, safety profile, and effectiveness of diazepam nasal spray across frequencies of seizure cluster burden.

Background Ideal rescue treatments for acute treatment of seizure clusters should be easy to administer, so it is important to assess user perceptions of these treatments. Diazepam nasal spray is designed to have a rapid, noninvasive, and socially acceptable route of administration. Patient and caregiver (including care partner) responses to surveys from a phase 3 safety study of diazepam nasal spray are reported. Methods The study enrolled patients aged 6–65 years with seizure clusters. Surveys distributed to patients and caregivers at study end, completion, or discontinuation collected data on comfort using diazepam nasal spray outside the home, timing of administration and return to their usual selves, and comfort of use compared with rectal diazepam. Safety was assessed. Results Of 175 patients enrolled at the October 31, 2019, interim cutoff, 158 received diazepam nasal spray. Sixty-seven (42.4%) patients and 84 (53.2%) caregivers responded to the surveys (including 35 matched pairs). Most patients (78.8%, 52/66) responded that they were very comfortable doing activities outside the home with diazepam nasal spray available; 59.4% of patients returned to their usual selves within an hour of administration. Twenty-seven (40.3%) of these patients reported self-administration, 48% doing so at the first sign of a seizure. Administration of diazepam nasal spray was rated extremely or very easy by 93.8% of caregivers. Safety profile was consistent with diazepam rectal gel; no patient discontinued owing to treatment-emergent adverse events. Nasal discomfort was typically mild and transient. Among patients who had used diazepam rectal gel, most were not at all comfortable using it outside the home (86.7%) or at home (64.5%) compared with diazepam nasal spray, whereas caregivers reported that diazepam rectal gel was not at all easy to use compared with diazepam nasal spray. Conclusions This survey from the phase 3 safety study of diazepam nasal spray shows that patients and caregivers were satisfied with, and more comfortable using, diazepam nasal spray than rectal diazepam in public. NCT02721069.

Hawaii is a multicultural state with many different ethnicities, including Native Hawaiians and other Pacific Islanders (NHOPI). This demographic has not been thoroughly studied, despite its significantly higher prevalence of stroke. This study aimed to characterize risk factors for ischemic stroke in NHOPI compared to other ethnicities.An Institutional Review Board (IRB) sanctioned retrospective chart review was conducted at a multi-site community neurology clinic from June 2017 through June 2019. Prospective patients were identified from the database using the International Classification of Diseases 10th Edition (ICD-10) codes for ischemic stroke. 326 patients (99 NHOPI, 116 Asian, 111 Caucasian) with a history of ischemic stroke met the inclusion criteria. Risk factors were determined based on the American Stroke Association guidelines; ethno-racial grouping was based on self-identification; and average household income levels were estimated based on patient zip codes US Census Bureau data. Continuous variable risk factors were analyzed using an analysis of variance (ANOVA) and post-hoc pairwise comparisons using Tukey-Kramer; a multivariate analysis was conducted.Compared to Asians and Caucasians, NHOPI patients were on average 11 years younger at the onset of stroke and more likely to be women. The NHOPI group also had the highest rates of diabetes and obesity. NHOPI average income was significantly lower compared to the Caucasian group. Hypertension and hyperlipidemia were found to be higher in the Asian population. Alcohol consumption was reported more frequently among Caucasian patients.These results better-characterized risk factors for ischemic stroke among NHOPI in Hawaii. The younger age of stroke onset in NHOPI patients is likely due to the higher burden of cardiovascular risk factors like obesity, smoking, and diabetes. Identifying such disparities in associated risk for NHOPI and other ethnicities can allow targeted stroke prevention and outpatient care in a multicultural setting.

Tolerance is a known consideration for maintenance use of benzodiazepines and other antiseizure drugs; however, clinical experience suggests that tolerance may not be anticipated with long-term intermittent use of benzodiazepines as rescue therapy. Diazepam nasal spray (Valtoco®) is a proprietary intranasal formulation approved for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients with epilepsy aged ≥6 years. Reported here are exploratory analyses investigating whether there was evidence of development of tolerance in an interim analysis of a long-term, phase 3, open-label safety study of diazepam nasal spray.Patients and care partners were trained to administer 5, 10, 15, or 20 mg of diazepam nasal spray (age- and weight-based dosing), with a second dose administered 4-12 hours later if needed. A series of analyses were performed to assess evidence of tolerance using 2 equal, adjacent time periods and data for each patient to compare the proportion of events for which second doses of diazepam nasal spray (as a proxy for effectiveness) were administered in period 1 compared with period 2.A total of 175 patients were enrolled at interim cutoff, and 158 were treated with diazepam nasal spray for 3370 seizure-cluster events. For 73.4% of patients, duration of exposure to diazepam nasal spray was ≥12 months. A total of 191 analyses were conducted; the proportion of analyses in which second doses in period 2 were lower than in period 1 was 72.8%. Only 5 analyses showed nominally statistically significant changes (P 0.05); this is fewer than expected by chance, and these differences were not directionally consistent. There was no safety signal with continued use.These analyses found no statistical evidence of tolerance with the use of diazepam nasal spray over time based on use of a second dose in an initial period of the study compared with a subsequent period for each patient. These results are in agreement with prior studies of benzodiazepine rescue therapy.

Objective To assess pharmacokinetics and safety of diazepam nasal spray (NRL‐1; VALTOCO®) in pediatric and adult patients with epilepsy in seizure and nonseizure states. Methods A single dose of diazepam nasal spray (5, 10, 15, or 20 mg based on weight) was administered during each of two conditions (ictal/peri‐ictal and interictal condition) to patients 6‐65 years old with partial or generalized epilepsy with motor seizures or seizures with clear alteration of awareness; a second dose was permitted if needed for persistent seizures. Dosing could be interictal or ictal/peri‐ictal first, with a washout of ≥14 days. Blood samples for pharmacokinetic analysis were taken at prespecified time points. Treatment‐emergent adverse events (TEAEs), sedation, nasal irritation, nasal mucosal pain, and olfactory changes were assessed. Results Of 57 patients in the study (mean age = 28.1 years [range = 6‐59], 54.4% female, 80.7% white), 49 were included in the primary pharmacokinetic analyses. Diazepam pharmacokinetic profiles were similar under both conditions, with approximately 2‐hour median time to mean (SD) maximum plasma concentrations of 164 (88) and 189 (110) ng/mL for ictal/peri‐ictal and interictal conditions, respectively; drug exposure during the first 6 hours postdosing was 532 (313) and 615 (368) h•ng/mL, respectively. Seventeen patients (29.8%) reported TEAEs, of whom eight (14%) had treatment‐related TEAEs, with those reported in ≥2 patients being dysgeusia (n = 3, 5.3%) and nasal discomfort (n = 2, 3.5%). One patient had serious TEAEs (recurrent seizures, metabolic encephalopathy), which were deemed unrelated to study treatment. No changes in respiratory rate were observed, nor were there clinically relevant changes in sedation, olfaction, nasal irritation, or acute nasal mucosal pain. Significance The epileptic conditions (ictal/peri‐ictal, interictal) had minimal impact on diazepam nasal spray pharmacokinetics in patients with epilepsy. Therefore, diazepam nasal spray can be administered ictally and interictally. Diazepam nasal spray safety was consistent with the profile of diazepam.

Purpose of review Disease-related treatment action plans for acute exacerbations providing information that may be helpful for self-management for patients and caregivers are commonly used for chronic conditions such as asthma and diabetes. However, among patients with epilepsy, a review of the literature suggested that the majority did not have an action plan in place for acute seizure treatment. Recent findings Currently, there is a lack of unified guidance on seizure action plans (SAPs) in the literature. In the authors’ opinion, available formats have limitations for practical use and may not be easily customizable to individual patients, and they are not often designed to provide simple-to-follow steps for rapid immediate steps to determine and initiate appropriate treatment of seizure emergencies. Our group reviewed current examples of SAPs and provided guidance on the development of acute seizure action plans (ASAPs) designed to facilitate rapid, appropriate acute care in the community and to be as useful as possible for a wide range of care partners, including those with limited experience. Summary This paper provides agreed upon expert opinion recommendations and considerations for goals, development process, types of content, and format for an ASAP.

Objective The study assesses the bioavailability of diazepam after intranasal administration (diazepam nasal spray) in healthy volunteers. Comparative agents were diazepam rectal gel, which served as the regulatory reference product; and oral diazepam, a product with decades of clinical use. Tolerability of diazepam nasal spray was also assessed. Methods This was a phase 1, open‐label, randomized, single‐dose, three‐treatment, three‐period, six‐sequence crossover study in 48 healthy adult subjects that consisted of a screening period, a baseline period, and an open‐label treatment period. Interperiod intervals were at least 28 days. Results Forty‐eight healthy volunteer subjects were enrolled, two of whom discontinued before receiving study medication. For all routes of administration, the onset of diazepam absorption was rapid, with measurable concentrations of drug present by the first sample time point. The t max (time to reach maximum plasma concentration) was similar for diazepam nasal spray and diazepam rectal gel, both of which were slower than oral diazepam in fasted individuals. Variability (as defined by % coefficient of variation of geometric mean) in peak plasma concentration and area under the curve0‐∞ was lowest with oral diazepam, followed by diazepam nasal spray, with diazepam rectal gel showing the greatest variability. Overall, 131 treatment‐emergent adverse events (TEAEs) were considered mild (42 subjects, 91.3%), four TEAEs were considered moderate (four subjects, 8.3%), and no TEAEs were considered severe. The most commonly reported TEAE was somnolence at 56.5% (26/46) during diazepam nasal spray treatment, 89.1% (41/46) with the rectal diazepam gel treatment, and 82.6% (38/46) with oral diazepam treatment. No nasal irritation was observed for the majority of the subjects at any time point after administration, with no score higher than 2 (“minor bleeding that stops within 1 minute”). Significance Diazepam nasal spray shows predicable pharmacokinetics and represents a potential novel therapeutic approach to control bouts of increased seizure activity (cluster seizures, acute repetitive seizures).

NRL‐1 is a novel intranasal formulation of diazepam that is being evaluated as rescue medication in patients with epilepsy who experience bouts of increased seizure activity despite stable regimens of antiepileptic drugs. This phase 1, open‐label, randomized, crossover study in healthy adult volunteers consisted of 3 single‐dose periods (5, 10, and 20 mg) followed by a 2‐dose period (2 × 10 mg) with a minimum 28‐day washout between treatments. Blood samples were taken at prespecified time points after intranasal dosing, and bioanalytic analysis of diazepam and nordiazepam was conducted using a validated liquid chromatography–tandem mass spectrometry method. Plasma pharmacokinetic parameters were summarized using descriptive statistics, and dose proportionality (peak concentration [Cmax] and area under the plasma concentration–time curve [AUC0‐∞]) was evaluated based on a power model within a 90%CI of 0.84 to 1.16. Comparisons were also conducted between single 10‐mg dose and multidose (2 × 10 mg) treatments. NRL‐1 administration resulted in rapid diazepam absorption (median time to peak concentration 1.4‐1.5 hours). Plasma concentration‐time profiles showed similar patterns of exposure that appeared to be dose dependent, with Cmax of 85.6, 133.6, and 235.3 ng/mL for the 5‐, 10‐, and 20‐mg doses, respectively, although the lower 90%CI for Cmax and AUC0‐∞ exceeded dose proportionality criteria. The coefficient of variation ranged from 59% to 67% for Cmax and 48% to 56% for AUC parameters. Dose‐normalized AUC0–∞ values were comparable between the 2 × 10‐mg and single 10‐mg doses. Treatment‐emergent adverse events were consistent with those expected for diazepam, with transient somnolence the most frequent adverse event (94.4%). These results support NRL‐1 as a potential therapy for managing seizure emergencies.

Purpose This exploratory study compared the semiology of psychogenic nonepileptic seizures (PNES) between a diverse group of patients in the state of Hawaii. This study may expand understanding of PNES across different ethnocultural and gender groups. Methods A retrospective chart review of patients admitted to our Epilepsy Monitoring Unit (EMU) over a 4-year period was performed to compare semiology in different ethnic groups and gender. Results A total of 139 patients were included in this study, 37% (n = 51) with PNES, 34% (n = 47) with epilepsy only, and 29% (n = 41) with other non-PNES, nonepilepsy diagnosis. The number of Asians with PNES were found to differ when compared with the patients with epilepsy and the patients with non-PNES, nonepilepsy diagnosis. A positive trend was found in the number of Native Hawaiians and Caucasians with PNES in comparison with patients with non-PNES, nonepilepsy diagnosis. In addition, three semiology of PNES in Native Hawaiians were found to differ in comparison with other ethnic groups with PNES: rhythmic motor, mixed semiology, and nonepileptic aura. There is a significant difference in all motor manifestation between males and females in Native Hawaiians. Between patients with PNES, patients with epilepsy, and patients with non-PNES, nonepilepsy diagnosis, significant correlation was found in psychiatric disorders including posttraumatic stress disorder (PTSD), anxiety, and any psychiatric disorder. Conclusion This cross-cultural study found significant differences in the expression of PNES across key ethnoracial groups for the Islands of Hawaii. These findings have implications to the diagnosis and treatment of PNES for Native Hawaiians and other Pacific Islanders in the United States.

Intranasal formulations are commonly used for drug delivery, and the literature has shown that seasonal allergies do not affect nasal administration of some agents. Diazepam nasal spray (Valtoco®) is a proprietary intranasal formulation with n-dodecyl-beta- d -maltoside (Intravail® A3) that is indicated for acute treatment of seizure clusters in patients with epilepsy aged 6 years and older. The analysis presented here is from an interim cutoff of a phase 3 open-label study evaluating the safety and tolerability of diazepam nasal spray. This analysis assessed whether seasonal allergies alter control of seizures with an intranasal formulation, using administration of a second dose as a surrogate efficacy endpoint. Of 158 evaluated patients with epilepsy having seizures despite a stable anti-seizure regimen, 62 patients had medical histories that included seasonal allergies or rhinitis. The results of this analysis show that seasonal allergies did not appear to influence use of a second dose; the groups of patients with and without a history of seasonal allergies both presented with low rates of seizure episodes for which a second dose was used, which suggests that there is not a major difference in pattern of use. Diazepam nasal spray demonstrated a similar safety and tolerability profile in patients with and without a history of seasonal allergies.

Diazepam rectal gel (RG) is currently the only approved rescue therapy for outpatient management of seizure clusters in the United States. There is an unmet medical need for an alternative rescue therapy for seizure clusters that is effective, and more convenient to administer with a socially acceptable method of delivery. An intranasal diazepam formulation has been developed, and this study evaluates the tolerability and bioavailability of diazepam nasal spray (NS) relative to an equivalent dose of diazepam-RG in healthy adults. Twenty-four healthy adults were enrolled in a phase 1, open-label, 3-period crossover study. Plasma diazepam and metabolite concentrations were measured by serial sampling. Dose proportionality for 5- and 20-mg intranasal doses and the bioavailability of 20mg diazepam-NS relative to 20mg diazepam-RG were assessed by maximum plasma concentration (Cmax) and systemic exposure parameters (AUC0-∞ and AUC0-24). The mean Cmax values for 20mg diazepam-NS and 20mg diazepam-RG were 378 ± 106 and 328 ± 152 ng/mL, achieved at 1.0 and 1.5h, respectively. Subjects administered intranasal and rectal gel formulations experienced nasal and rectal leakage, respectively. Diazepam absorption following intranasal administration was consistent but 3 subjects with diazepam-RG had low plasma drug levels at the earliest assessment of 5 min, due to poor retention, and were excluded from analysis. Excluding them, the treatment ratios (20mg diazepam-NS:20mg diazepam-RG) and 90% confidence intervals for diazepam Cmax and AUC0-24 were 0.98 (0.85-1.14) and 0.89 (0.80-0.98), respectively, suggesting that the bioavailability was comparable between the two formulations. Dose proportionality was observed between the lowest and highest dose-strengths of intranasal formulation. Both intranasal and rectal treatments were well tolerated with mild to moderate adverse events. Results suggest that a single-dose of 20mg diazepam-NS is tolerable and comparable in bioavailability to that of diazepam-RG. The intranasal formulation may provide caregivers and patients with a more socially acceptable and convenient alternative rescue therapy in the acute treatment of seizure clusters.

Summary Objective To determine the feasibility of administering a diazepam nasal spray formulation (diazepam-NS) to adults with epilepsy during a generalized tonic–clonic seizure or in the postictal period following a tonic–clonic or other seizure type, to assess pharmacokinetics and to assess tolerability. Methods An open-label study was conducted in patients admitted to the epilepsy monitoring unit. Eligible patients received a single dose of diazepam-NS approximating 0.2 mg/kg. Plasma diazepam concentrations were measured serially up to 12 h postdose, and maximum observed plasma concentration (Cmax); time to maximum concentration (Tmax); and the area under the plasma concentration–time curve for time zero to last sampling time (AUC0–12) were estimated and dose-normalized. Pharmacodynamic assessments included Kaplan-Meier analysis to determine the time-to-next seizure. Safety and tolerability were assessed. Results Of the 78 patients who consented, 30 had treatment and pharmacokinetic data. Ten patients were treated during a convulsive tonic–clonic seizure, seven within 5 min following the last clonic jerk, and 13 in the postictal period ≥5 min after a tonic–clonic or following other seizure-types. Diazepam median Tmax was 45 min. Dose-normalized mean Cmax and AUC0–12 values of diazepam were comparable among patients regardless of the timing of diazepam-NS administration in relation to seizure. Of those treated, 65% were seizure-free during the 12-h observation period and 35% had post-dose seizures. Treatment was well tolerated, with no unexpected safety findings: 74% had mild and 25% had moderate adverse events. Nasopharyngeal signs were resolved by 12 h postdose. Significance Diazepam can be delivered in effective therapeutic concentrations by a nasal spray device during the convulsive phase of tonic–clonic seizures or in the postictal periods following tonic–clonic or other seizure types.

Purpose The goal of this study was to evaluate the safety and tolerability of dalfampridine extended release (D-ER) in a pilot study of adults with cerebral palsy (CP) and limited ambulatory ability, and to explore drug effects on sensorimotor function. Methods An initial double-blind, single-dose crossover study was performed in 11 individuals randomized 1:1 to receive D-ER (10 mg) or placebo, followed by a 2-day washout period and the opposite treatment, with evaluation for safety and tolerability. A twice daily dosing, double-blind, placebo-controlled, crossover study was then performed. Participants were randomized in a 1:1 ratio to 1 of 2 sequences: 1 week of D-ER (10 mg BID) or placebo, followed by a 1-week washout and 1 week of the opposite treatment. Key inclusion criteria were age 18 to 70 years, body mass index 18.0 to 30.0 kg/m 2 , diagnosis of CP, and ability to perform all study procedures. Key exclusion criteria were severe CP, moderate or severe renal impairment, history of nonfebrile seizures, and prior dalfampridine use. Primary outcomes were safety profile and tolerability. Exploratory functional outcomes comprised changes in upper and lower extremity sensorimotor function (grip and pinch strength tests), manual dexterity (Box and Block Tests), and walking speed (Timed 25-Foot Walk). The most pronounced measured functional deficit in each individual was defined as the exploratory primary functional end point. Full crossover data were analyzed by using a mixed effects model. Findings Among the 24 total participants who were randomized to treatment and completed the twice daily dosing phase study, their mean age was 38.6 years (range, 20–62 years), 54% were women, and 83% had spastic CP. Adverse events were consistent with previous D-ER trials, most commonly headache (13% D-ER, 4% placebo), fatigue (13% D-ER, 0% placebo), insomnia (8% D-ER, 4% placebo), diarrhea (4% D-ER, 4% placebo), and nausea (4% D-ER, 4% placebo). The mixed model analysis of full crossover data identified no significant difference between D-ER and placebo in the primary functional analysis (the most pronounced deficit; P = 0.70) or in the secondary analyses (hand strength [ P = 0.48], manual dexterity [ P = 0.13], or walking speed [ P = 0.42]). Implications In this preliminary study of adults with CP, a BID dose of 10-mg D-ER was generally safe and well tolerated. The exploratory functional assessments for upper and lower sensorimotor deficits did not establish that the study population was markedly responsive to D-ER relative to placebo. These findings do not provide the proof-of-concept that would support further evaluation of D-ER as a potential intervention to improve function in adults with CP. ClinicalTrials.gov identifier: NCT01468350.

Objective: To evaluate the safety and tolerability of dalfampridine extended release (D-ER) in participants with chronic post-ischemic stroke deficits, and to assess for potential drug activity on sensorimotor function. Methods: Using a double-blind, placebo-controlled, crossover design, participants were randomized to placebo/ D-ER or D-ER/placebo sequences and given D-ER 10 mg or placebo twice daily. Key inclusion criteria were: ischemic stroke ≥ 6 months, Fugl-Meyer Assessment lower extremity motor score ≤ 28, ability to complete Timed 25-Foot Walk (T25FW). The primary outcome was safety and tolerability. The key exploratory measure was walking speed (T25FW). Other assessments were: Box and Block, and Grip and Pinch tests; Functional Independence Measure. Full-crossover data were analyzed using mixed-effects model. Results: A total of 83 participants were randomized: 70 completed and 13 discontinued the study. Adverse events were consistent with previous D-ER trials; no new safety signals were observed. Four participants experienced serious adverse events: 3 seizures (1 placebo, 2 D-ER), 1 was secondary to intentional overdose. Most common treatmentemergent adverse events were: dizziness, nausea, arthralgia and fatigue. Mixed-effects analysis showed an effect for D-ER vs placebo in improving walking speed (0.21 vs 0.10 ft/s; p = 0.027). Conclusions: D-ER was generally well tolerated in participants with chronic stroke deficits. Potential drug activity on lower extremity sensorimotor function, with an improvement in walking speed, was seen.

PurposeDalfampridine extended-release (ER) tablets 10 mg BID have been approved for use in improving walking in people with multiple sclerosis (MS). This subgroup analysis evaluated the effects of dalfampridine ER 5 and 10 mg BID on distance walked, as assessed using the 6-minute walk (6MW) test.MethodsThis analysis of data from a randomized, placebo-controlled, double-blind study (N = 430) included only the 153 patients with 6MW data available. Participants (aged 18–70 years) were randomly assigned in a 1:1:1 ratio to receive dalfampridine ER 5 or 10 mg or placebo, BID for 4 weeks. The 6MW was used for assessing walking distance at baseline and 2 weeks after the start of treatment at the 26 study sites that were able to perform this test. Participants were administered the 12-item MS Walking Scale (MSWS-12), a patient-reported measure of the impact of MS on walking. Post hoc outcomes included the percentages of patients who achieved an increase from baseline in 6MW distance of ≥20% and who achieved a minimal clinically important difference (MCID) from baseline in 6MW distance, defined as ≥+55 m. Changes from baseline in walking speed (MSWS-12) were compared, stratified by subgroup that achieved ≥20% versus

Summary: Clinical features of seizures occurring in a neurofibromatosis clinic population were examined in a retrospective study. Twenty-two individuals in a population of 359 persons with neurofibromatos 1 (NF1) had had one or more seizures. Age at first seizure ranged from 4 days to

Summary: We report 16 patients with infantile spasms in whom onset of the clusters of spasms appeared to be triggered by close temporal association with partial seizures. Common features included the presence of focal cerebral lesions in 12 infants (3 were classifiable as cryptogenic); all had partial seizures with EEG localization, clusters of bilateral spasms always preceded by partial seizures, and response to adrenocorticotropic hormone (ACTH) and traditional antiepileptic drugs (AEDs) generally was poor. Three had complete agenesis of the corpus callosum, which argues against interhemispheric callosal spread of focal discharges resulting in the generalized spasms. Surgical cortical resections were performed in 6 of the infants, with good outcomes. This group of patients supports a model in which the spasms, although probably generated at a subcortical level, are facilitated or possibly induced by focal discharges from cortical pathology. ReSUMe Les auteurs rapportent 16 observations de spasmes infantiles dans lesquelles le debut des series de spasmes semble avoir ete declenche par une association temporelle avec des crises partielles. Les traits communs incluent la presence de lesions cerebrales focales chez les 12 enfants, 3 avaient ete classes comme cryptogeniques. Tous avaient des crises partielles, localisees sur le plan EEG; des series de spasmes bilateraux etaient toujours precedees de crises partielles; la reponse au traitement par ACTH et par antiepileptiques classiques etait mauvaise. Trois presentaient une agenesie compMte du corps calleux, ce qui represente un argument contre l'extension inter-hemispherique par voie calleuse des decharges focales, dans la genese des spasmes generalises. Des resections corticales chirurgicales ont ete realisees chez 6 enfants, avec des evolutions favorables. Ce groupe de patients est en faveur d'un modele dans lequel les spasmes, bien qu'ils soient vraisemblablement generes a un niveau souscortical, sont facilites ou possiblement induits par des decharges focales liees a une pathologie corticale. RESUMEN Se presentan dieciseis pacientes con espasmos infantiles en los que el comienzo de los grupos de espasmos parecio ser precipitado por la associacion temporal a crisis parciales. Los datos comunes incluyeron la presencia de lesiones cerebrales focales en 12 ninos, tres habian sido clasificadas como criptogenicos; todos tenian ataques parciales con localizacion electroencefa- lografica; los grupos de espasmos bilaterales siempre se precedian de crisis parciales; generalmente se habia observado una respuesta pobre a la hormona adrenocorticotropica (ACTH) y a los antiepilepticos tradicionales. Tres tenian una agenesis completa del cuerpo calloso que habla en contra de una propagacion interhemisferica transcallosa de las descargas focales que conducen a espasmos generalizados. Las resecciones quirurgicas corticales se practicaron en seis de los ninos con buenos resultados. Este grupo de enfermos apoya el modelo en el que los espasmos, aunque probablemente se generan en niveles subcorticales, se facilitan o inducen por descagas focales originadas en patologia cortical.

Aspergillus infection involving the central nervous system are unusual, but should be included in the differential diagnosis in patients with the acquired immunodeficiency syndrome and neurologic signs and symptoms. Of the few reported AIDS cases with central nervous system aspergillosis, the majority have had focal brain abscesses. We report an atypical case that presented as a basal meningitis with pontine infarction secondary to invasive Aspergillus sinusitis.

To the Editor: The report of Lunardi et al.1 on the effectiveness of lamotrigine in trigeminal neuralgia was of interest, and complements other recent reports on the use of lamotrigine and gabapentin for chronic facial pain.2-4 We have used gabapentin successfully …

Many infants with cardiac anomalies undergo repair early in life. Both commonly used support techniques, deep hypothermic circulatory arrest (DHCA) and low-flow cardiopulmonary bypass (LFB), may be associated with adverse neurological outcomes, including seizures. In a single center study, 171 infants undergoing correction for D-transposition of the great arteries were randomized to one of these support techniques. Incidence and onset times of EEG seizures during continuous EEG-video monitoring in the first 48 h postoperatively and clinical seizures in the first postoperative week were compared. EEG seizures were characterized by time, duration, and localization of onset. Incidence of EEG seizures (20%) was more than 3 times that of clinical seizures (6%). Most infants with EEG seizures had multiple seizures beginning between 13 and 36 h postoperatively. Durations ranged from 6 s to 980 min. Onset of EEG seizures occurred most commonly in frontal and central regions. Factors associated with EEG seizures included randomization to DHCA, longer duration of circulatory arrest, and diagnosis of VSD. In this study EEG seizures were common following this type of cardiac surgery, illustrating the importance of EEG monitoring in detecting seizures. This data adds insight into mechanisms of seizures in infants undergoing cardiac surgery.

Hypothermic circulatory arrest is a widely used support technique during heart surgery in infants, but its effects on neurologic outcome have been controversial. An alternative method, low-flow cardiopulmonary bypass, maintains continuous cerebral circulation but may increase exposure to known pump-related sources of brain injury, such as embolism or inadequate cerebral perfusion.We compared the incidence of perioperative brain injury after deep hypothermia and support consisting predominantly of total circulatory arrest with the incidence after deep hypothermia and support consisting predominantly of low-flow cardiopulmonary bypass in a randomized, single-center trial. The criteria for eligibility included a diagnosis of transposition of the great arteries with an intact ventricular septum or a ventricular septal defect and a planned arterial-switch operation before the age of three months.Of 171 patients with D-transposition of the great arteries, 129 (66 of whom were assigned to circulatory arrest and 63 to low-flow bypass) had an intact ventricular septum, and 42 (21 assigned to circulatory arrest and 21 to low-flow bypass) had a ventricular septal defect. After adjustment for diagnosis, assignment to circulatory arrest as compared with low-flow bypass was associated with a higher risk of clinical seizures (odds ratio, 11.4; 95 percent confidence interval, 1.4 to 93.0), a tendency to a higher risk of ictal activity on continuous electroencephalographic (EEG) monitoring during the first 48 hours after surgery (odds ratio, 2.5; 95 percent confidence interval, 1.0 to 6.4), a longer recovery time to the first reappearance of EEG activity (only in the group with an intact ventricular septum, P0.001), and greater release of the brain isoenzyme of creatine kinase in the first 6 hours after surgery (P = 0.046). Analyses comparing durations of circulatory arrest produced results similar to those of analyses comparing treatments.In heart surgery in infants, a strategy consisting predominantly of circulatory arrest is associated with greater central nervous system perturbation in the early postoperative period than a strategy consisting predominantly of low-flow cardiopulmonary bypass. Assessment of the effect of these findings on later outcomes awaits follow-up of this cohort.

A newborn with bilateral uncal herniation secondary to acute bacterial meningitis is reported. The findings of previous neuropathologic studies of neonatal bacterial meningitis are reviewed and the factors most likely responsible for the relative rarity of herniation in this disease in newborns are discussed.

Topiramate treatment was associated with rapid improvement in 10 cluster headache patients. Cluster remission occurred in 1–3 weeks in 9 patients, and cluster period duration was reduced in all. The mechanism for this response may be related to gamma-aminobutyric acid (GABA) augmentation. However, further investigations are necessary to understand the significance of topiramate in treating cluster headache. The use of anticonvulsant medications in chronic pain management is not new. Anticonvulsants have several uses outside of the epilepsies, and there has been resurgence in their use for chronic pain. This particularly applies to such recently approved anticonvulsants as gabapentin, lamotrigine, and topiramate. Factors that contribute to this trend in anticonvulsant use include ease of use, favorable pharmacokinetic and side effect profiles, multiple potential mechanisms of action, and the intractable nature of chronic pain. Cluster headache is an uncommon, benign, primary headache disorder characterized by severe, short duration, unilateral, orbital-temporal pain; ipsilateral autonomic dysfunction; and chronobiological disturbances.1 Although treatment is usually successful, some patients have intractable pain. Valproate has shown efficacy in cluster headache, and a role for GABA augmentation has been suggested.2-4 Because topiramate appears to augment GABA,5-7 we hypothesized that it may be efficacious in cluster headache. We report the clinical findings in 10 cluster headache patients whose conditions improved when they took topiramate. Two patients had chronic cluster headache unremitting from onset (Patients 1 and 2), seven …

Kluver-Bucy syndrome is an uncommon constellation of behavioral abnormalities resulting from bilateral temporal lobe damage. The syndrome is rare in humans. In this paper we present a patient who developed the Kluver-Bucy syndrome following recovery from an intracerebral haemorrhage and transtentorial herniation.

We examined the clinical and pathological features of 26 patients who presented with a diagnosis of CNS toxoplasmosis. Patient data was analyzed with respect to demographics, clinical presentation, treatment course and pathology. Patients presented with a wide variety of signs and symptoms. All patients had positive serum antitoxoplasma IgG; ring enhancing lesion(s) were present on all but one brain CT scans. A series of guidelines in the management of CNS toxoplasmosis in AIDS patients are presented. Prior to biopsy, patients with positive serology and characteristic CT scans should receive two weeks of treatment. Biopsy is indicated in those cases with negative serology, atypical presentation, progressive clinical deterioration, or differential response of lesions to empiric therapy.