Purpose The aim of this review was to systematically examine safety and efficacy outcomes, as well as patient/caregiver satisfaction, from clinical studies in pediatric and adult patients treated with benzodiazepines (BZDs) through various administration routes in response to seizure emergencies. Methods A literature search was conducted to identify articles describing the use of various routes of administration (RoAs) of BZDs for the treatment of seizure emergencies through April 21, 2015, using Embase™ and PubMed®. Eligible studies included (a) randomized controlled trials or (b) controlled nonrandomized clinical trials, either retrospective or prospective. Outcome assessments reviewed were 1) time to administration, 2) time to seizure termination, 3) rate of treatment failure, 4) prevention of seizure recurrence, 5) patient and caregiver treatment satisfaction, 6) adverse events related to BDZ treatment or RoA, and 7) respiratory adverse events. Results Seventy-five studies evaluated safety and efficacy using individual or comparator BDZs of various RoAs for treating seizure emergencies in all-aged patients with epilepsy. Buccal, intranasal (IN), or intramuscular (IM) BZDs were often more rapidly administered compared with rectal and intravenous (IV) formulations. Time to seizure termination, seizure recurrence rates, and adverse events were generally similar among RoAs, whereas nonrectal RoAs resulted in greater patient and caregiver satisfaction compared with rectal RoA. Significance Results of this systematic literature review suggest that nonrectal and non-IV BZD formulations provide equal or improved efficacy and safety outcomes compared with rectal and IV formulations for the treatment of seizure emergencies.

CONTEXT: The optimal pharmacologic treatment for early convulsive status epilepticus is unclear. OBJECTIVE: To analyze efficacy, tolerability and safety data for anticonvulsant treatment of children and adults with convulsive status epilepticus and use this analysis to develop an evidence-based treatment algorithm. DATA SOURCES: Structured literature review using MEDLINE, Embase, Current Contents, and Cochrane library supplemented with article reference lists. STUDY SELECTION: Randomized controlled trials of anticonvulsant treatment for seizures lasting longer than 5 minutes. DATA EXTRACTION: Individual studies were rated using predefined criteria and these results were used to form recommendations, conclusions, and an evidence-based treatment algorithm. RESULTS: A total of 38 randomized controlled trials were identified, rated and contributed to the assessment. Only four trials were considered to have class I evidence of efficacy. Two studies were rated as class II and the remaining 32 were judged to have class III evidence. In adults with convulsive status epilepticus, intramuscular midazolam, intravenous lorazepam, intravenous diazepam and intravenous phenobarbital are established as efficacious as initial therapy (Level A). Intramuscular midazolam has superior effectiveness compared to intravenous lorazepam in adults with convulsive status epilepticus without established intravenous access (Level A). In children, intravenous lorazepam and intravenous diazepam are established as efficacious at stopping seizures lasting at least 5 minutes (Level A) while rectal diazepam, intramuscular midazolam, intranasal midazolam, and buccal midazolam are probably effective (Level B). No significant difference in effectiveness has been demonstrated between intravenous lorazepam and intravenous diazepam in adults or children with convulsive status epilepticus (Level A). Respiratory and cardiac symptoms are the most commonly encountered treatment-emergent adverse events associated with intravenous anticonvulsant drug administration in adults with convulsive status epilepticus (Level A). The rate of respiratory depression in patients with convulsive status epilepticus treated with benzodiazepines is lower than in patients with convulsive status epilepticus treated with placebo indicating that respiratory problems are an important consequence of untreated convulsive status epilepticus (Level A). When both are available, fosphenytoin is preferred over phenytoin based on tolerability but phenytoin is an acceptable alternative (Level A). In adults, compared to the first therapy, the second therapy is less effective while the third therapy is substantially less effective (Level A). In children, the second therapy appears less effective and there are no data about third therapy efficacy (Level C). The evidence was synthesized into a treatment algorithm. CONCLUSIONS: Despite the paucity of well-designed randomized controlled trials, practical conclusions and an integrated treatment algorithm for the treatment of convulsive status epilepticus across the age spectrum (infants through adults) can be constructed. Multicenter, multinational efforts are needed to design, conduct and analyze additional randomized controlled trials that can answer the many outstanding clinically relevant questions identified in this guideline.

April 23, 2015April 6, 2015Free AccessThe Sabril® Registry After 5 Years: Patient Characteristics and Vision Loss (P7.006)Robert Sergott, Rod Foroozan, John Pellock, Edward Faught, W. Donald Shields, Gregory Krauss, Adam Ziemann, Deborah Lee, Yekaterina Dribinsky, Sarah Torri, and Jouko IsojarviAuthors Info & AffiliationsApril 6, 2015 issue84 (14_supplement)https://doi.org/10.1212/WNL.84.14_supplement.P7.006 Letters to the Editor

April 20, 2015April 6, 2015Free AccessInvestigations of USL255, Qudexy™ XR (Topiramate) Extended-Release Capsules, Sprinkled onto Soft Food or Delivered via Enteral Feeding Tubes (P1.248)Mary Holmay, Annie Clark, Bob Anders, and John PellockAuthors Info & AffiliationsApril 6, 2015 issue84 (14_supplement)https://doi.org/10.1212/WNL.84.14_supplement.P1.248 Letters to the Editor

SummaryObjectiveTo evaluate the safety, tolerability, and pharmacokinetics (PK) of pregabalin as adjunctive therapy in children with refractory partial seizures.MethodsThis was a phase 1, randomized, placebo‐controlled, parallel‐group, escalating‐dose, multiple‐dose study comprising a 7‐day, double‐blind treatment period and a single‐blind, single dose of pregabalin administered to all children on day 8. Children in four age cohorts (1–23 months, 2–6, 7–11, and 12–16 years) received one of four doses of pregabalin (2.5, 5, 10, or 15 mg/kg/day) or placebo. Safety and tolerability were assessed throughout the study. Steady‐state and single‐dose PK parameters on day 8 were analyzed using standard noncompartmental procedures.ResultsSixty‐five children received at least one dose of treatment. Four pregabalin‐treated children discontinued treatment, three of whom received 15 mg/kg/day. Two children experienced serious adverse events, one of whom received pregabalin 15 mg/kg/day. During double‐blind treatment, the most common adverse events reported in the pregabalin‐treated population were somnolence (27.1%) and dizziness (12.5%). Steady‐state pregabalin peak and total exposure in each age cohort appeared to increase linearly with dose. Apparent oral clearance (CL/F) was directly related to creatinine clearance, consistent with adults. CL/F normalized for body weight was 43% higher in patients weighing <30 kg. Steady‐state and single‐dose PK were consistent.SignificancePregabalin at doses up to 10 mg/kg/day in children aged 1 month to 16 years, and at doses up to 15 mg/kg/day in those aged <6 years, demonstrated acceptable safety and tolerability. For children weighing <30 kg, a dose increase of 40% (mg/kg dosing) is required to achieve comparable exposure with adults or children weighing ≥30 kg. These data will inform dose selection in phase 3 trials of the efficacy and safety of adjunctive pregabalin in children with refractory partial seizures.

OBJECTIVE: Review literature describing benzodiazepine administration for treatment of seizure emergencies by routes other than those FDA approved. BACKGROUND: Benzodiazepines are considered effective rescue therapies for seizure emergencies. Current FDA-approved routes of administration (intravenous and rectal) can be associated with administration challenges, and several alternative routes have been reported. Here we present a review of published data on safety, efficacy, and tolerability of benzodiazepines administered by various routes for treatment of seizure emergencies. DESIGN/METHODS: Systemic review of Scopus, using “English language,” “human subject,” and “article” filters. Search terms: Acute Seizures; Acute Repetitive Seizures; Prolonged Seizure; Seizure Clusters; Seizure Emergency; Seizure + Out of Hospital; Status Epilepticus + individual benzodiazepines (clobazam, clonazepam, diazepam, lorazepam, midazolam). Studies using benzodiazepines for maintenance therapy, as second-line treatment, or in combination with other antiepileptic drugs were excluded. RESULTS: In total, 100 unique citations were identified. Of these, 61 were in children, 28 were in adults, and 11 in children and adults. Intranasal, buccal, and intramuscular benzodiazepines were faster to administer to pediatric subjects than IV and rectal. Time from benzodiazepine administration to termination of seizure activity was generally rapid with no significant difference between routes of administration (IV, 1.0-5.0 minutes (min); rectal, 1.3-15.0 min; buccal, 2.8-10.0 min; IM, .25-7.8 min; IN, 2.3-15.0 min). In some studies, caregivers found buccal and intranasal methods more acceptable than rectal administration. Respiratory adverse events (persistent O 2 saturation <92% or <12 breaths/min) were more frequently found with IV administration versus other routes (IV: 0-20.6%; rectal, 0-6.0%; buccal/oral, 0-5.0%; IM, 0-12.0%; IN, 2.0% [reported only in one study]). CONCLUSION: Emerging benzodiazepine administration methods appear to offer a rapid and convenient alternative to IV or rectal routes. The literature supports that these methods are safe and effective alternative routes of benzodiazepine administration for rapid treatment of seizures in children and adults. Disclosure: Dr. Haut has received personal compensation for activities with Upsher Smith, Acorda, and Impax. Dr. Seinfeld has nothing to disclose. Dr. Pellock has received personal compensation for activities with the National Institutes of Health, Acorda Therapeutics, Catalyst, Eisai Inc., GlaxoSmithKline Inc., King Pharmaceuticals, Marinus Pharmaceuticals, Medscape, Neuropace, Lundbeck Research USA Inc., Pfizer Inc., Questcor Pharmaceuticals Inc., Sepracor Inc., UCB Pharma, Upsher-Smith Laboratories, Inc., and Valeant Pharmaceuticals Inc. Dr. Pellock has received research support from the National Institutes of Health, Center for Disease Control, Eisai Inc., Lundbeck Research USA Inc., Marinus Pharamceuticals, Pfizer Inc., Questcor Pharmaceuticals, UCB Pharma, and Upsher-Smith Laboratories, Inc.

OBJECTIVE: To provide analyses of Sabril Registry data for the 4-year period Aug. 21, 2009-Aug. 27, 2013. BACKGROUND: To manage risk of vision loss with vigabatrin (VGB), the FDA and Lundbeck require an ongoing patient registry. DESIGN/METHODS: Registry participation is mandatory for all US VGB prescribers and patients. 1 Ophthalmologic assessments are required at baseline, every 3 months during therapy, and 3-6 months post-discontinuation. Two independent expert neuro-ophthalmologists (masked to patients’ identities) evaluated voluntarily submitted, detailed vision test findings. RESULTS: As of Aug. 27, 2013, 5,487 patients were enrolled: 3,436 with infantile spasms (IS), 1,696 with refractory complex partial seizures (rCPS), and 343 with other diagnoses. Median duration of VGB treatment in the registry was 9.9 months. 3,242/5,487 (59%) had discontinued VGB after enrolling, and 15/3,242 (0.5%) discontinued because of reported visual field deficits. Twelve patients continuing on therapy met predefined criteria for vision loss (11 for visual acuity changes; one for perimetry changes). A separate data subset from 928 patients with cumulative, detailed vision results (voluntarily submitted) was reviewed. 23% of those tests showed clinically significant existing pathology assessed as unrelated to VGB, regardless of prior VGB exposure before registry entry. Most common pre-existing deficits included visual field loss, optic disc pallor, or abnormal electrophysiology, reflecting effects of underlying conditions and prior therapies. 24 patients (2.6% of 928) were found to have a vision effect possibly or probably related to VGB. CONCLUSIONS: The Sabril Registry continues to detect afferent visual system abnormalities at baseline for >20% of those with IS, rCPS, or other conditions. Median exposure is approaching 1 year. 15/3,242 (0.5%) patients have discontinued because of reported visual field deficits, and 24/928 (2.6%) of those with voluntarily submitted vision results had a vision deficit possibly or probably related to VGB. 1 Pellock JM, et al. Epilepsy Behav . 2011;22:710−7. Study Supported by: Lundbeck LLC. Disclosure: Dr. Sergott has received personal compensation for activities with Pfizer Inc., Serono Inc., Centocor, and Lundbeck. Dr. Sergott has received personal compensation in an editorial capacity for Current Opinion in Neuro-Opthamology. Dr. Foroozan has received personal compensation for activities with Lundbeck Research USA, Inc. Dr. Pellock has received personal compensation for activities with the National Institutes of Health, Acorda Therapeutics, Catalyst, Eisai Inc., GlaxoSmithKline Inc., King Pharmaceuticals, Marinus Pharmaceuticals, Medscape, Neuropace, Lundbeck Research USA Inc., Pfizer Inc., Questcor Pharmaceuticals Inc., Sepracor Inc., UCB Pharma, Upsher-Smith Laboratories, Inc., and Valeant Pharmaceuticals Inc. Dr. Pellock has received research support from the National Institutes of Health, Center for Disease Control, Eisai Inc., Lundbeck Research USA Inc., Marinus Pharamceuticals, Pfizer Inc., Questcor Pharmaceuticals, UCB Pharma, and Upsher-Smith Laboratories, Inc. Dr. Faught has received personal compensation for activities with Supernus, UCB Pharma, and Vertex as a member of Scientific Advisory Boards, and Eisa Inc., Lundbeck Research USA, Inc. as a member of Data Monitoring Boards. Dr. Faught has received research support from Cyberonics Inc. and GlaxoSmithKline Inc. Dr. Shields has received personal compensation for activities with Novartis. Dr. Burkhart has received personal compensation for activities with Lundbeck Research USA, Inc. Dr. Prabhakaran has received personal compensation for activities with Lundbeck Research USA, Inc. as an employee. Dr. Torri has received personal compensation for activities with Lundbeck Research USA, Inc. as an employee. Dr. Lee has received personal compensation for activities with Lundbeck Research USA, Inc. and the Foundation for Peripheral Neuropathy. Dr. Lee holds stock and/or stock options in Baxter, which sponsored research in which Dr. Lee was involved as an investigator. Dr. Isojarvi has received personal compensation for activities with Lundbeck.

Objective: Analyze pre-hospital and emergency department (ED) recognition of febrile seizures and treatment of febrile status epilepticus (FSE). Background Seizure recognition and prompt treatment is important. Design/Methods: 200 subjects were children 1 month to 5 years who are part of a prospective, multicenter study of consequences of FSE, defined as a febrile seizure or series of seizures lasting >30 minutes. FSE was classified by 3 independent central raters, and based exclusively on clinical features. The emergency medical service (EMS) and ED management, including seizure recognition, medication administration and respiratory support, were reviewed. Results: 46 subjects (23%) did not activate EMS. 154 subjects were transported by EMS, 12 (8%) were not seizing when EMS arrived and 24 (16%) did not have documentation of the patient9s clinical condition. 118 subjects were actively seizing on EMS arrival, 81% (96 subjects) were recognized by EMS. During EMS transport, 9 subjects (6%) were not actively seizing. EMS recognized seizure during transport in 83 patients (54%). Anti-epileptic medications (AED) were given by family/EMS in 73 subjects (37%). 19 of the 154 patients (12%) were given respiratory support by EMS. 167 subjects (84%) were actively seizing on ED arrival. ED recognized the seizure in 163 subjects (98%). 91 of 200 subjects (46%) were given respiratory support by the ED. 150 subjects (75%) required an AED to terminate seizure. Mean time from seizure onset to first AED was 55 minutes (3 minutes to 465 minutes). Conclusions: Febrile status epilepticus is a neurological emergency requiring prompt recognition and treatment. The majority of children with prolonged febrile seizures required abortive medications to terminate their seizures, which were very prolonged. Although the majority of seizures are recognized, there is a considerable delay in administration of first AED. Supported by: Grant NS 43209 (PI: S Shinnar MD PhD) from NINDS. Disclosure: Dr. Seinfeld has nothing to disclose. Dr. Pellock has received personal compensation for activities with NIH/NINDS, Eisai, GSK, King Pharmaceuticals, KV Pharmaceuticals, Marinus Pharmaceuticals, Neuropace, Ortho McNeil Johnson&Johnson, Lundbeck, Pfizer, Questcor, Sepracor, UCB Pharmaceuticals, and Valeant as an advisory board member, consultant, or lecturer. Dr. Pellock has received research support from NIH/NINDS, Eisai, GSK, Lundbeck, Pfizer, Questcor, UCB Pharmaceuticals, and Valeant. Dr. Shinnar has received personal compensation for activities with Design Write, Eisai, Inc., King Pharmaceuticals, Questcor Pharmaceuticals, Valeant Pharmaceuticals, and UCB Pharma. Dr. Shinnar has received research support from Questcor Pharmaceuticals. Dr. Hesdorffer has nothing to disclose. Dr. Shinnar has nothing to disclose. Dr. O9Hara has received personal compensation for activities with Cyberonics and Questcor as a speaker and/or serving on an advisory board. Dr. Nordli has received personal compensation in an editorial capacity for UpToDate. Dr. Nordli has received research support from NIH/NINDS. Dr. Frank has nothing to disclose. Dr. Gallentine has nothing to disclose. Dr. Moshe has received personal compensation for activities with Eisai and GlaxoSmithKline. Dr. Moshe has received personal compensation in an editorial capacity for Neurobiology of Disease, Epileptic Disorders, and Brain and Development and Physiological Research. Dr. Moshe has received research support from NIH and the Heffer Family Foundation. Dr. Deng has nothing to disclose. Dr. Sun has nothing to disclose.

Background and Objective: Acute repetitive seizures (ARS) are a debilitating part of episodic seizure activity that can sometimes progress to status epilepticus. Currently approved treatment that can be administered by non-medical personnel to patients with ARS is a diazepam rectal gel. While effective, rectal administration can be difficult, inconvenient and objectionable. A diazepam autoinjector has been developed to deliver diazepam via an intramuscular (IM) injection. This study evaluated the dose proportionality of the diazepam autoinjector and the consequent diazepam bioavailability relative to an equivalent dose of diazepam administered rectally as a commercial gel.

OBJECTIVE:In prior studies of febrile seizures (FSs), prolonged FSs were defined, absent empirical evidence, as lasting 10 or 15 minutes or more. We assessed the distribution of FS duration in a cohort with first FSs, and the association between FS duration and baseline characteristics of the children.METHODS:We calculated the observed cumulative probability, S(t), that a FS would last at least t minutes, S(t) = exp(-t/τ). Data were also fit using a model obtained as the sum of 2 exponential distributions (S[t] = αexp[-t/τ(1) ] + [1 - α]exp[-t/τ(2) ]). After assessing the best fit, the cutoff defining long FS was determined. Logistic regression was used to examine associations between long FSs and baseline characteristics, behavior, and development.RESULTS:In 158 children with a first FS, median duration was 4.0 minutes. Duration of FS was best fit by a 2-component mixture exponential model. Using this model, we identified 1 population that accounts for 82.3% of FSs and has a mean duration of 3.8 minutes (short FS) and a second population that accounts for 17.7% of FSs and has a mean duration of 39.8 minutes (long FS). Long FSs were significantly associated with developmental delay (p = 0.010) and delays and younger age at first FS (p = 0.048).INTERPRETATION:Like the distribution of afebrile seizure duration in children, the distribution of first FS duration is best modeled by assuming 2 populations. Developmental delay and younger age are associated with prolonged FSs. Our data lend further support to defining 10 minutes as the upper limit for a simple FS.

Objective The purpose of this study was to survey the impact of epilepsy and its treatment on the quality of life, development, and opportunities for children/teenagers with the condition. Methods We asked three groups—children/teenagers, parents and caregivers, and health care professionals—to complete specifically designed questionnaires containing clinical and demographic information and perceptions of the impact of epilepsy and its treatment on aspects of daily living, including education and leisure. For health care professionals, the survey included questions on area of speciality and volume of children with epilepsy seen in their clinic. Questionnaires were translated into the local written language in each participating country. Prepaid envelopes were provided for return of completed questionnaires. Responses were analyzed by an independent data analysis company. Results Two hundred twelve young people with epilepsy and 507 parents or carers of children/teenagers from 16 different countries completed the questionnaire. The majority of children were over the age of 12 (74%) and attended mainstream schools (64%). Approximately two-thirds (65%) of the children/teenagers who responded reported that their seizures caused them to lose, on average, 7 school days per year. More than one-third of the children/teenagers who responded to the survey (36%) have kept their epilepsy a secret from other people at some time for fear of being treated differently and a belief that people should not know (47%). The majority (87%) of respondents were taking epilepsy medications. More than a third of the children/teenagers who responded had experienced side effects in some form or another, with weight change (49%), headaches (46%), dizziness (41%), and shaking (33%) most commonly reported. More than one-third of the children/teenagers expected the condition to hinder their lives in the future, with impact on employment opportunities (73%), traveling and exploring (37%), and education (36%) most commonly reported. Conclusions This survey documents some of the real-life consequences of childhood epilepsy and highlights important challenges and issues faced by children/teenagers with epilepsy and their families. Although there are a number of limitations to this study relating to sample selection, ensuring that children are as free from seizures as possible and minimizing the side effects of treatment must be the primary goal of epilepsy management, but considering the wider implications of epilepsy and treatment is also important.

First of all, Dr. Iinuma is to be congratulated for studying this population of patients. Patients with mental disabilities represent one of the largest populations in pediatric epilepsy. However, researchers generally tend to either not address this population as a special group, or to avoid such studies because of the behavior difficulties and other challenges. The differences in the frequency of monotherapy in this study illustrate the difficulty in treating these patients. While monotherapy was used in 60% of the normally intelligent patients in this study, only 12% of those with intellectual disabilities were treated with single agents. The mean number of antiepileptic drugs (AEDs) was 1.6 for the first group versus 2.94 for the disabled group. Regardless of the seizure type, better overall control was attainable in the normally intelligent versus the intellectually disabled persons. The incidence of adverse events was interesting, with 21% of the normal group experiencing side effects, 28% of the disabled, and 24% overall. Usually, adverse events are reported in the mentally disabled population at about 20–40%. This is due to the excess of behavioral abnormalities seen with so many of our current drugs. Zonisamide appears to be an effective AED in both normal and intellectually deficient children. No special adverse effects were worsened in the intellectually challenged group. Overall, we need more double-blind, placebo-controlled, or comparative studies to determine which patients will respond most favorably to treatment. This study examined the responses of normal versus intellectually disabled children. We also need to better define the adverse effects profile of infants versus older children. For example, will a 5-year-old or 3-year-old mentally disabled child respond the same way as a 20-year-old mentally disabled individual? We currently do not know the answer. For these special population groups, we also need to better define very specific abnormalities, such as behavior abnormalities, anorexia, weight loss, and hypohidrosis in particular. We need a strategy to handle these adverse effects. Will we reduce the drug? Discontinue the drug? There must be an available answer when the drug is being used in children. US development must progress quickly to make zonisamide available to children, the mentally retarded population, and those with myoclonic syndromes of various types including progressive myoclonic epilepsy. However, we must be syndrome-specific in our recommendations. While the experience may be very good in a particular type of myoclonic syndrome, it may not be as beneficial in some of the other syndromes. The once- or twice-a-day dosing is also an advantage. The 25 mg preparation is acceptable and would be welcomed, especially if it were available as a divisible or chewable tablet. In conclusion, despite the introduction in the US of felbamate, lamotrigine, topiramate, gabapentin, levetiracetam and oxcarbazepine patients with progressive encephalopathic epilepsy still require additional agents. The data presented in this paper and others, certainly suggest that zonisamide may play an active role in meeting that need.

PURPOSE:To assess the psychometric properties of the Quality of Life in Epilepsy Inventory-89 (QOLIE-89) administered via telephone and to compare these properties with data gathered through self-administration. METHODS:A study of 139 patients with epilepsy was undertaken at three clinical sites in the United States. Patients participated in both telephone interview (T) and self-administration (S). Order effect was controlled through randomization (T-S and S-T). Twenty-eight S-T subjects participated in an assessment of the 2-week reproducibility of telephone interviews. RESULTS:Internal consistency and test-retest reliability levels of the QOLIE-89 overall score were very high across method of administration (T = 0.98; S = 0.98; ICC of T = 0.96). Scores were significantly related to mood (Profile of Mood States, r = -0.76, for both methods, p<0.001) and two indicators of epilepsy severity (seizure frequency in the past month, T: r = 0.52, p<0.0001; S: r = 0.54, p<0.0001; days since last seizure, T: r = 0.28, p<0.001; S: r = 0.25, p<0.01), with no significant differences in coefficients by method of administration. Performance of the measure was consistent for patients with unimpaired and impaired memory, using the Rivermead Behavioural Memory Test, and across level of education. CONCLUSIONS:Results of this study indicate telephone interview is a viable option for evaluating HRQL in persons with epilepsy and support the reliability and validity of the QOLIE-89 regardless of method of administration.