Brian K. Alldredge

De novo mutations in epileptic encephalopathies

Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox–Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10−3). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10−10 and P = 7.8 × 10−12, respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10−8), as has been reported previously for autism spectrum disorders.

Guidelines for the Evaluation and Management of Status Epilepticus

Status epilepticus (SE) treatment strategies vary substantially from one institution to another due to the lack of data to support one treatment over another. To provide guidance for the acute treatment of SE in critically ill patients, the Neurocritical Care Society organized a writing committee to evaluate the literature and develop an evidence-based and expert consensus practice guideline. Literature searches were conducted using PubMed and studies meeting the criteria established by the writing committee were evaluated. Recommendations were developed based on the literature using standardized assessment methods from the American Heart Association and Grading of Recommendations Assessment, Development, and Evaluation systems, as well as expert opinion when sufficient data were lacking.

Status epilepticus at an urban public hospital in the 1980s

We retrospectively reviewed the clinical course of adult patients treated for generalized status epilepticus (SE) at the San Francisco General Hospital (SFGH) from 1980 to 1989. The review was designed to determine whether the etiologies of SE at our hospital have changed over the last two decades, and to investigate the relationships between etiology, response to anticonvulsant therapy, and short-term clinical outcome. Of 154 patients reviewed, the four leading etiologies for SE were anticonvulsant drug withdrawal (39), alcohol-related (39), drug toxicity (14), and CNS infection (12). This pattern was essentially unchanged from observations made at SFGH in the 1970s. Sixty percent of all patients responded to first-line drug treatment (usually phenytoin 2 diazepam), and the remainder required an additional agent (usually phenobarbital) for control of SE. The best response to anticonvulsants occurred in patients with SE related to tumor, anticonvulsant drug withdrawal, or refractory epilepsy, and the poor responders had anoxia, drug toxicity, CNS infection, or other metabolic abnormalities. Seventy-six percent of the patients had good outcomes. Of the 22 patients who died, SE was a likely cause of death in only two (ie, 1.3% of the entire study group). Metabolic abnormalities, stroke, and anoxia were associated with particularly poor outcomes compared with other etiologies. These observations show that the etiologies of SE have remained similar over two successive decades, and that the etiology of SE may help predict both the initial response to drug therapy and the short-term outcome.

Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society

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.

Seizures associated with recreational drug abuse

We retrospectively identified 49 cases of recreational drug-induced seizures in 47 patients seen at the San Francisco General Hospital between 1975 and 1987. Most patients experienced a single generalized tonic-clonic seizure associated with acute drug intoxication, but 7 patients had multiple seizures and 2 patients developed status epilepticus. The recreational drugs implicated were cocaine (32 cases), amphetamine (11), heroin (7), and phencyclidine (4). A combination of drugs was responsible in 11 cases. Seizures occurred independent of the route of administration, and occurred in both first-time and chronic abusers. Ten patients (21%) reported having had prior seizures, all with a close temporal association with drug abuse. Other than 1 patient who developed prolonged status epilepticus that caused a fixed neurologic deficit, most patients had no obvious short-term neurologic sequelae.

Effect of prehospital treatment on the outcome of status epilepticus in children.

Diazepam is administered to children in status epilepticus by paramedics in many Emergency Medical Services systems throughout the United States despite the lack of clear evidence that this therapy is safe and effective when employed in the prehospital environment. We reviewed the clinical course of 45 episodes of generalized convulsive status epilepticus (SE) in 38 children to determine the effect of prehospital diazepam therapy (given rectally or intravenously) on the clinical course of SE and subsequent patient management. Nineteen SE episodes were treated with prehospital diazepam therapy--9 episodes with rectal diazepam (mean dose: 0.6 mg/kg) and 10 episodes with intravenous diazepam (mean dose: 0.2 mg/kg). Prehospital diazepam therapy was associated with SE of shorter duration (32 min vs 60 min; P = .007) and a reduced likelihood of recurrent seizures in the emergency department (58% vs 85%; P = .045). There were no significant differences between rectal and intravenous diazepam therapy with regard to SE duration, intubation, or recurrent seizures in the emergency department. These data suggest that prehospital administration of diazepam may shorten the duration of SE in children and simplify the subsequent management of these patients in the emergency department.

AHRQ'S Hospital Survey on Patient Safety Culture: Psychometric Analyses

Objective: This project analyzed the psychometric properties of the Agency for Healthcare Research and Quality Hospital Survey on Patient Safety Culture (HSOPSC) including factor structure, interitem reliability and intraclass correlations, usefulness for assessment, predictive validity, and sensitivity. Methods: The survey was administered to 454 health care staff in 3 hospitals before and after a series of multidisciplinary interventions designed to improve safety culture. Respondents (before, 434; after, 368) included nurses, physicians, pharmacists, and other hospital staff members. Results: Factor analysis partially confirmed the validity of the HSOPSC subscales. Interitem consistency reliability was above 0.7 for 5 subscales; the staffing subscale had the lowest reliability coefficients. The intraclass correlation coefficients, agreement among the members of each unit, were within recommended ranges. The pattern of high and low scores across the subscales of the HSOPSC in the study hospitals were similar to the sample of Pacific region hospitals reported by the Agency for Healthcare Research and Quality and corresponded to the proportion of items in each subscale that are worded negatively (reverse scored). Most of the unit and hospital dimensions were correlated with the Safety Grade outcome measure in the tool. Conclusion: Overall, the tool was shown to have moderate-to-strong validity and reliability, with the exception of the staffing subscale. The usefulness in assessing areas of strength and weakness for hospitals or units among the culture subscales is questionable. The culture subscales were shown to correlate with the perceived outcomes, but further study is needed to determine true predictive validity.

Placebo-controlled trial of intravenous diphenylhydantoin for short-term treatment of alcohol withdrawal seizures

PURPOSE Despite conflicting experimental and clinical evidence, diphenylhydantoin continues to be used for the treatment of alcohol withdrawal seizures in emergency departments and alcohol detoxification centers. Our goal was to evaluate the effectiveness of intravenous diphenylhydantoin for prevention of alcohol withdrawal seizures in high-risk patients using a prospective, randomized, double-blind, placebo-controlled study design. PATIENTS AND METHODS Ninety alcoholic patients, enrolled within six hours of the initial alcohol-related seizure in a withdrawal episode, were randomly assigned to treatment with intravenous diphenylhydantoin (1,000 mg) or placebo. Seventy-one patients had a history of seizures during prior alcohol withdrawal episodes. Patients with a history of seizures unrelated to alcohol withdrawal were excluded. Drugs known to affect the seizure threshold or demonstrating cross-tolerance with alcohol were withheld. For each patient, the study endpoint was either (1) seizure recurrence or (2) a minimum 12-hour seizure-free observation period after completion of the study drug infusion. RESULTS During the postinfusion observation period, six of 45 diphenylhydantoin-treated patients and six of 45 placebo-treated patients experienced at least one recurrent seizure. Equivalent diphenylhydantoin serum levels were measured in patients with and without subsequent seizures. There was no statistically significant difference between the response rates for the two treatments (p greater than 0.05). The 95% confidence interval for the difference in response probabilities was -14.0%, 14%. CONCLUSION When administered to non-epileptic patients within six hours of the onset of alcohol withdrawal seizures, intravenous diphenylhydantoin failed to show a significant benefit over placebo in the prevention of subsequent seizures. We suggest that the well-documented risks of intravenous diphenylhydantoin therapy outweigh the potential benefit in the short-term treatment of alcohol withdrawal seizures.

Status Epilepticus Related to Alcohol Abuse

We reviewed the case records of 249 adult patients with generalized convulsive status epilepticus (SE) examined at San Francisco General Hospital between 1977 and 1989 and identified 27 patients (10.8%) in whom alcohol abuse was the only identifiable precipitating cause of SE. In 12 patients (44% of the study group), SE was the first presentation of alcohol‐related seizures. Seizures with focal features were observed in 11 patients (40.1%), but there was little correlation with localized computed tomography (CT) or EEG abnormalities. SE was controlled with phenytoin (PHT), with or without a benzodiazepine (BZD), in 18 patients (66.7%). Twentytwo patients (81.5%) were discharged with no new neurologic deficits, but time to recovery of baseline mental status was prolonged (>12 h) in 24 patients. With regard to alcohol abuse history, study patients did not differ from a comparison group with isolated alcohol withdrawal seizures. The results indicate that alcohol abuse is a common cause of SE and that SE may be the first presentation of alcohol‐related seizures. Furthermore, the outcome of patients with alcohol‐related SE compares favorably with that of patients with SE due to other causes, but recovery of these patients may be complicated by a prolonged postictal state.

Treatment of Status Epilepticus: An International Survey of Experts

BackgroundAs part of the development of the Neurocritical Care Society (NCS) Status Epilepticus (SE) Guidelines, the NCS SE Writing Committee conducted an international survey of SE experts.MethodsThe survey consisted of three patient vignettes (case 1, an adult; case 2, an adolescent; case 3, a child) and questions regarding treatment. The questions for each case focused on initial and sequential therapy as well as when to use continuous intravenous (cIV) therapy and for what duration. Responses were obtained from 60/120 (50%) of those surveyed.ResultsThis survey reveals that there is expert consensus for using intravenous lorazepam for the emergent (first-line) therapy of SE in children and adults. For urgent (second-line) therapy, the most common agents chosen were phenytoin/fosphenytoin, valproate sodium, and levetiracetam; these choices varied by the patient age in the case scenarios. Physicians who care for adult patients chose cIV therapy for RSE, especially midazolam and propofol, rather than a standard AED sooner than those who care for children; and in children, there is a reluctance to choose propofol. Pentobarbital was chosen later in the therapy for all ages.ConclusionThere is close agreement between the recently published NCS guideline for SE and this survey of experts in the treatment of SE.