Jacquelyn Bainbridge

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.

Report of the American Epilepsy Society and the Epilepsy Foundation Joint Task Force on Sudden Unexplained Death in Epilepsy

The American Epilepsy Society and the Epilepsy Foundation jointly convened a task force to assess the state of knowledge about sudden unexplained death in epilepsy (SUDEP). The task force had five charges: (1) develop a position statement describing if, when, what, and how SUDEP should be discussed with patients and their families and caregivers; (2) design methods by which the medical and lay communities become aware of the risk of SUDEP; (3) recommend research directions in SUDEP; (4) explore steps that organizations can take to perform large‐scale, prospective studies of SUDEP to identify risk factors; and (5) identify possible preventive strategies for SUDEP. Some of the major task force recommendations include convening a multidisciplinary workshop to refine current lines of investigation and to identify additional areas of research for mechanisms underlying SUDEP; performing a survey of patients and their families and caregivers to identify effective means of education that will enhance participation in SUDEP research; conducting a campaign aimed at patients, families, caregivers, coroners, and medical examiners that emphasizes the need for complete autopsy examinations for patients with suspected SUDEP; and securing infrastructure grants to fund a consortium of centers that will conduct prospective clinical and basic research studies to identify preventable risk factors and mechanisms underlying SUDEP. For now, the principal effort in preventing SUDEP should be prompt and optimal control of seizures, especially generalized convulsive seizures.

Challenges of Treatment Adherence in Older Patients with Parkinson’s Disease

Patient adherence to a medication regimen is critical to treatment outcome, quality of life and future healthcare costs. For elderly patients with Parkinson’s disease, obstacles to adherence can be particularly complex. Beyond age-related and economic factors, elderly patients with Parkinson’s disease often require complicated dosing or titration schedules and have multiple co-morbidities that necessitate administration of therapies from multiple drug classes. In addition, neuropsychiatric disturbances and cognitive impairment, which are often part of the disease process, can affect adherence, as can variable responses to antiparkinsonian agents as the disease progresses. Several recent studies in patients with Parkinson’s disease point to the need for establishing good adherence patterns early and maintaining these throughout the course of treatment. To achieve optimal adherence in elderly patients with Parkinson’s disease, a combination of pharmacological and non-pharmacological approaches appears to be the best strategy for success. Examples include a strong provider-patient relationship, educational intervention by phone or face-to-face contact, simplified dosing and administration schedules, management and understanding of medication adverse events, and the use of adherence aids such as pill boxes and hour-by-hour organizational charts. Research into new avenues that include improved drug monitoring, pharmacogenetics and neuroprotective regimens may give rise to better adherence in elderly patients with Parkinson’s disease in the future.

Restless Legs Syndrome Induced by Escitalopram : Case Report and Review of the Literature

Restless legs syndrome (RLS) is a sensorimotor disorder characterized by distressing sensations deep inside the limbs, typically occurring at bedtime or rest. These paresthesias involve an irresistible urge to move the limb, which provides temporary relief but at the expense of sleep and quality of life. The pathophysiology of RLS has been related to dopaminergic pathway dysfunction, thereby aligning it closely with depression from both pathophysiologic and treatment perspectives. Certain antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs) and serotonin‐norepinephrine reuptake inhibitors (SNRIs), may induce or exacerbate RLS. We describe the case of a 34‐year‐old woman with no history of RLS who came to the emergency department with acute decompensated heart failure. After 7 days of hospitalization, she was waitlisted to receive a heart transplant. Her mood became depressed, and she requested a psychiatric consultation; escitalopram 10 mg at bedtime was started. Within 2 days of starting therapy, she developed very severe (determined by a score based on an RLS symptom rating scale) RLS symptoms, warranting the discontinuation of escitalopram. Within 2 days of stopping therapy, her RLS symptoms improved considerably (rated as mild). One week later, the patient was rechallenged with a lower dose of escitalopram, and her very severe RLS symptoms reappeared. Within 2 days of stopping escitalopram, her RLS symptoms again improved, with complete resolution 1 week later. Using the Naranjo adverse drug reaction probability scale, which assesses the probability of a drug causing an adverse event, the patients score was 9, indicating a definite adverse drug reaction. Although published case reports have linked fluoxetine, sertraline, citalopram, paroxetine, and mirtazapine to RLS, this is the first report, to our knowledge, of escitalopram as a cause of RLS. Based on this case and additional data published with other SSRIs and SNRIs, we believe that escitalopram should be added to the list of agents that can induce RLS.

Topiramate in older patients with partial-onset seizures: A pilot double-blind, dose-comparison study

Purpose: Pharmacokinetics of antiepileptic drugs (AEDs) can be altered by age‐related changes in physiology, thereby altering clinical effects, especially tolerability, in older adults. We compared two dosages of topiramate (TPM) in a pilot study of patients ≥60 years of age with partial‐onset seizures.

Seizures associated with regadenoson: A case series

Introduction. In April of 2008, the Food and Drug Administration approved regadenoson, the first selective adenosine A2A receptor agonist, for resting stress-myocardial perfusion scans. Compared to other nonselective vasodilators, regadenoson offers a rapid onset yet short duration of action, a fixed-dose bolus, and a good safety and tolerability profile particular in patients with reactive airway disease. Increased patient exposure following release of the drug has noted other adverse events such as heart block (possible third degree), transient QTc prolongation, hypersensitivity reactions (e.g., angioedema, urticaria, and anaphylaxis), and seizures (particularly in patients with a history of seizure) through post-marketing surveillance. In April 2011, Astellas updated the regadenoson package insert to reflect these additional concerns; however, the package labeling provides little information to assist providers in mitigating or managing these adverse effects-particularly in regards to seizures. We report three cases of seizures associated with regadenoson administration in which we elucidate its potential epileptogenic mechanism and highlight clinical implications. Case Report. Case #1 The patient is a 48year-old white male who was referred for a treadmill stress test to evaluate his 4-month, intermittent, nonexertional chest pain. The patient had a past medical history of ulcerative colitis status post-total colectomy, seizure disorder, congenital venous malformation in his right cerebellar hemisphere, deep vein thrombosis, and arthritis with right hip replacement. The patient’s seizures were initially diagnosed at 5 years of age and believed to be related to his congenital venous malformation. These seizures manifested themselves with ‘‘fuzzy, tunnellike’’ vision with an inability to respond verbally and lasted 30-60 seconds. These symptoms were diagnosed as complex partial seizures that were controlled with carbamazepine and topiramate for several years. The patient had a drug allergy to sulfonamide antibiotics. On initial presentation, the patient had a blood pressure (BP) of 110/70 mm Hg and a heart rate (HR) of 73 beats per minute. His medications were carbamazepine 600 mg twice daily, topiramate 100 mg twice daily, and acetaminophen 325 mg every four hours as needed. All blood chemistries were within normal limits; however, his carbamazepine blood concentration was at the high end of normal at 11.6 mcg/ml (goal: 4-12.0 mcg/ ml). As per his wife, he was medically adherent and had been seizure-free for the past 4 months. Initially, the patient tolerated the procedure; however, 5 minutes after regadenoson 0.4 mg administration, he started to complain of left hand numbness. Thirty seconds later he had a blank stare on his face, became aphasic, and was unable to respond to verbal commands. The patient’s extremities became straight and rigid (tonic extension) with no clonic movement. His BP at the time was 120/80 mm Hg with a HR of 108 beats/minute, blood glucose of 108 g/dL, an oxygen saturation of 98% on room air, and an electrocardiogram (ECG) reflective of sinus tachycardia with no arrhythmia. Intranasal oxygen was applied and 1 mg intravenous (IV) lorazepam administered along with 75 mg IV aminophylline with no improvement. After 10 minutes, another 1 mg IV lorazepam was administered with no change in symptoms. The patient was immediately taken by stretcher to the emergency department (ED) where another 1 mg IV lorazepam was given. After 20 minutes, the patient slowly became interactive but remained postictal for 30 minutes. After 3 hours, he was able to complete his imaging study which was negative for myocardial ischemia, prior myocardial infarction, or left ventricular contractile dysfunction (ejection fraction, EF: 54%). No changes were made to From the Department of Clinical Pharmacy, School of Pharmacy, Division of Cardiology, Department of Medicine, School of Medicine, Department of Neurology, School of Medicine, Division of Nuclear Medicine, Department of Radiology, School of Medicine, University of Colorado, Aurora, CO. Funding sources: none. Reprint requests: Robert Lee Page II, Pharm.D., MSPH, FCCP, FAHA, BCPS, Department of Clinical Pharmacy, School of Pharmacy, University of Colorado, Anschutz Medical Campus, Mail Stop C238, 12850 E Montview Blvd, V20-4125, Aurora, CO 80045; Robert.page@ucdenver.edu. J Nucl Cardiol 2012;19:389–91. 1071-3581/

Caffeine and Progression of Parkinson Disease: A Deleterious Interaction With Creatine.

34.00 Copyright 2011 American Society of Nuclear Cardiology. doi:10.1007/s12350-011-9461-1

AES Position Statement on Generic Substitution of Antiepileptic Drugs

ObjectiveIncreased caffeine intake is associated with a lower risk of Parkinson disease (PD) and is neuroprotective in mouse models of PD. However, in a previous study, an exploratory analysis suggested that, in patients taking creatine, caffeine intake was associated with a faster rate of progression. In the current study, we investigated the association of caffeine with the rate of progression of PD and the interaction of this association with creatine intake. MethodsData were analyzed from a large phase 3 placebo-controlled clinical study of creatine as a potentially disease-modifying agent in PD. Subjects were recruited for this study from 45 movement disorders centers across the United States and Canada. A total of 1741 subjects with PD participated in the primary clinical study, and caffeine intake data were available for 1549 of these subjects. The association of caffeine intake with rate of progression of PD as measured by the change in the total Unified Parkinson Disease Rating Scale score and the interaction of this association with creatine intake were assessed. ResultsCaffeine intake was not associated with the rate of progression of PD in the main analysis, but higher caffeine intake was associated with significantly faster progression among subjects taking creatine. ConclusionsThis is the largest and longest study conducted to date that addresses the association of caffeine with the rate of progression of PD. These data indicate a potentially deleterious interaction between caffeine and creatine with respect to the rate of progression of PD.

Probable levetiracetam-associated depression in the elderly: Two case reports

Among the older antiepileptic drugs (AEDs), generic substitutes have been available for many years. Phenobarbital, synthesized in 1912, has long been available in generic form, and brand-name Luminal was discontinued in the United States decades ago. Phenytoin, developed in 1938, was prescribed for decades as extended-release Dilantin Kapseals (Pfizer, Inc., New York), but it has largely been replaced by generic extended-release products. After approval in the United States of carbamazepine in 1974 and valproic acid in 1978, the branded forms had many years of patent exclusivity, but generic alternatives later became available. Beginning in 1993 with felbamate, a series of approximately 20 new brand-name AEDs were approved by the U.S. Food and Drug Administration (FDA). Patent duration after FDA approval of these newer AEDs varied, but all approved before 2005 are now available as generics. Typically, generic drugs are less expensive than the branded original, which encourages, or may mandate, the substitution of generics for the brand product to reduce pharmaceutical costs. For any drug, bioavailability is defined as the rate and extent to which the active ingredient is absorbed from a drug product and becomes available at the site of action (1). In order for a generic AED to be approved by the FDA, manufacturers are required to show pharmaceutical equivalence and to demonstrate bioequivalence of the generic form to the original brand-name product. Pharmaceutical equivalence requires that the drug product contains the same active ingredient, dosage form and strength, and route of administration. However, it may differ in inactive ingredients (e.g., binders, excipients), manufacturing process, and physical appearance (1). Bioequivalence (BE) is achieved if the product exhibits no substantial difference in the rate and extent of drug absorption. BE is tested in single-dose pharmacokinetic generally involving 24 to 36 healthy subjects under both fed and fasting conditions (1). Statistically, the BE standard requires that the entire 90% confidence interval (CI) of the log-transformed ratios of the test/reference for the maximum plasma concentration (Cmax) and the area under the plasma concentration time curve (AUC) fall within the bounds of 80% to 125%. This is based on the judgment that a difference <20% between products would not result in a clinically-significant problem. Therefore, the test product is not significantly less than reference (T/R = 80%) and a reference product is not significantly less than test (T/R = 80%). As all data are expressed as T/R, this becomes 100/80 or 125%. In a recent analysis of 258 BE studies of AEDs the 80% to 125% BE rule resulted in <15% variability in AUC and Cmax in 99% and 89%, respectively (2).

Core elements of epilepsy diagnosis and management: expert consensus from the Leadership in Epilepsy, Advocacy, and Development (LEAD) faculty

BACKGROUND Compared with traditional antiepileptic drugs, levetiracetam has a unique mechanism of action and unique properties, including predominant renal excretion and lack of drug-drug interactions. In the elderly, depression associated with levetiracetam has not been reported. CASE SUMMARIES A 73-year-old black man (height, 172.7 cm; weight, 92.7 kg; body mass index [BMI], 31 kg/m(2)) with stage 4 kidney disease was taking levetiracetam 500 mg BID for partial complex seizures. After 5 months of taking medication, new-onset depression, evidenced by depressed mood, weight loss, fatigue, and appearing withdrawn, was noted in this patient. Levetiracetam was discontinued by order of the patients primary care physician. At a follow-up appointment 4 weeks later, the depressive symptoms had nearly resolved. The patients Naranjo Adverse Drug Reaction Probability Scale score was 6, indicating levetiracetam to be a probable cause of depression in this patient. In a second case, a 92-year-old white woman (height, 154.9 cm; weight, 54.5 kg; BMI, 22.7 kg/m(2)) with existing chronic kidney disease and new-onset partial seizure, likely due to a meningioma, was initiated on levetiracetam 500 mg once daily. Depressive symptoms (eg, anhedonia, hypersomnolence, decreased appetite) were noted within 5 weeks. Cessation led to improvement in mood and cognition within 8 days. Based on this patients Naranjo Adverse Drug Reaction Probability Scale score of 6, levetiracetam was a probable cause of depression in this patient. CONCLUSIONS Levetiracetam was a probable cause of depression in these 2 elderly patients. Cautious use and additional monitoring may be necessary when prescribing levetiracetam to elderly patients, especially when prescribing to those with a history of renal impairment.