David M. Treiman

A comparison of four treatments for generalized convulsive status epilepticus

BACKGROUND AND METHODS Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyses were performed with data on only the 518 patients with verified generalized convulsive status epilepticus as well as with data on all 570 patients who were enrolled. RESULTS Three hundred eighty-four patients had a verified diagnosis of overt generalized convulsive status epilepticus. In this group, lorazepam was successful in 64.9 percent of those assigned to receive it, phenobarbital in 58.2 percent, diazepam plus phenytoin in 55.8 percent, and phenytoin in 43.6 percent (P=0.02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (P=0.002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7 to 24.2 percent). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (P=0.12) or among those with subtle status epilepticus (P=0.91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days. CONCLUSIONS As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use.

Comparison of Carbamazepine, Phenobarbital, Phenytoin, and Primidone in Partial and Secondarily Generalized Tonic–Clonic Seizures

We conducted a 10-center, double-blind trial to compare the efficacy and toxicity of four antiepileptic drugs in the treatment of partial and secondarily generalized tonic-clonic seizures in 622 adults. Patients were randomly assigned to treatment with carbamazepine, phenobarbital, phenytoin, or primidone and were followed for two years or until the drug failed to control seizures or caused unacceptable side effects. Overall treatment success was highest with carbamazepine or phenytoin, intermediate with phenobarbital, and lowest with primidone (P less than 0.002). Differences in failure rates of the drugs were explained primarily by the fact that primidone caused more intolerable acute toxic effects, such as nausea, vomiting, dizziness, and sedation. Decreased libido and impotence were more common in patients given primidone. Phenytoin caused more dysmorphic effects and hypersensitivity. Control of tonic-clonic seizures did not differ significantly with the various drugs. Carbamazepine provided complete control of partial seizures more often than primidone or phenobarbital (P less than 0.03). Overall, carbamazepine and phenytoin are recommended drugs of first choice for single-drug therapy of adults with partial or generalized tonic-clonic seizures or with both.

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.

GABAergic Mechanisms in Epilepsy

Summary: γ‐Aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tone that counterbalances neuronal excitation. When this balance is perturbed, seizures may ensue. GABA is formed within GABAergic axon terminals and released into the synapse, where it acts at one of two types of receptor: GABAA, which controls chloride entry into the cell, and GABAB, which increases potassium conductance, decreases calcium entry, and inhibits the presynaptic release of other transmitters. GABAA‐receptor binding influences the early portion of the GABA‐mediated inhibitory postsynaptic potential, whereas GABAB binding influences the late portion. GABA is rapidly removed by uptake into both glia and presynaptic nerve terminals and then catabolized by GABA transaminase. Experimental and clinical study evidence indicates that GABA has an important role in the mechanism and treatment of epilepsy: (a) Abnormalities of GABAergic function have been observed in genetic and acquired animal models of epilepsy; (b) Reductions of GABA‐mediated inhibition, activity of glutamate decarboxylase, binding to GABAA and benzodiazepine sites, GABA in cerebrospinal fluid and brain tissue, and GABA detected during microdialysis studies have been reported in studies of human epileptic brain tissue; (c) GABA agonists suppress seizures, and GABA antagonists produce seizures; (d) Drugs that inhibit GABA synthesis cause seizures; and (e) Benzodiazepines and barbiturates work by enhancing GABA‐mediated inhibition. Finally, drugs that increase synaptic GABA are potent anticonvulsants. Two recently developed antiepileptic drugs (AEDs), vigabatrin (VGB) and tiagabine (TGB), are examples of such agents. However, their mechanisms of action are quite different (VGB is an irreversible suicide inhibitor of GABA transaminase, whereas TGB blocks GABA reuptake into neurons and glia), which may account for observed differences in drug side‐effect profile.

Electroclinical Features of Status Epilepticus

Summary: Status epilepticus (SE) is a condition wherein epileptic seizure discharges are sufficiently prolonged or repetitive so as to produce persistent alterations in neurologic function and in the underlying physiologic and neurochemical activities of the brain. Thus, the definition of SE now includes any disorder in which there is sustained and prolonged excitation of neurons. Electroencephalographic (EEG) patterns associated with specific types of SE are important components in their classification. Like epileptic seizures, SE can be divided into partial onset SE and primarily generalized SE. Partial onset SE includes secondarily generalized convulsive SE (GCSE), complex partial SE (CPSE), simple partial SE (SPSE), and the syndromes of epilepsia partialis continua (EPC) and rolandic SE (RSE). Primarily generalized SE includes primarily GCSE, absence SE, atypical absence SE, generalized myoclonic SE, generalized clonic SE, generalized tonic SE, atonic SE, and the syndromes of electrical SE of sleep (ESES) and minor epileptic SE of Brett. SE is a dynamic disorder. Behavioral and electrical manifestations change over time if seizure activity is allowed to persist without successful treatment. A progression from overt to subtle convulsive activity occurs in secondarily GCSE and there is also a progression of predictable EEG changes in prolonged GCSE. CPSE begins as discrete complex partial seizures but also progresses behaviorally and electrically through a sequence similar to that observed in GCSE. Progressive behavioral and electrical changes have not been reported in primarily generalized forms of SE. EEG is an important tool for verifying successful treatment of SE if the patient does not immediately recover neurologic function. EEG recordings also contribute substantially to understanding the mechanisms of, and development of better treatments for, human SE through their use in the study of experimental SE in the laboratory.

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.

A method of quantification for the evaluation of antiepileptic drug therapy

The design of clinical trials of antiepileptic drugs should include explicit methods for numeric quantification of seizures and side effects. Rating scales were developed to assess frequency and severity of seizures (partial and generalized tonic-clonic), systemic toxicity, and neurotoxicity. These scales are combined to form a single composite rating that reflects the overall effect of the drug on the patient. The rating system can be adapted to compare efficacy and toxicity of any antiepileptic drugs, for any types of seizures.

CONTROL OF SYNCHRONIZATION OF BRAIN DYNAMICS LEADS TO CONTROL OF EPILEPTIC SEIZURES IN RODENTS

We have designed and implemented an automated, just-in-time stimulation, seizure control method using a seizure prediction method from nonlinear dynamics coupled with deep brain stimulation in the centromedial thalamic nuclei in epileptic rats. A comparison to periodic stimulation, with identical stimulation parameters, was also performed. The two schemes were compared in terms of their efficacy in control of seizures, as well as their effect on synchronization of brain dynamics. The automated just-in-time (JIT) stimulation showed reduction of seizure frequency and duration in 5 of the 6 rats, with significant reduction of seizure frequency (>50%) in 33% of the rats. This constituted a significant improvement over the efficacy of the periodic control scheme in the same animals. Actually, periodic stimulation showed an increase of seizure frequency in 50% of the rats, reduction of seizure frequency in 3 rats and significant reduction in 1 rat. Importantly, successful seizure control was highly correlated with desynchronization of brain dynamics. This study provides initial evidence for the use of closed-loop feedback control systems in epileptic seizures combining methods from seizure prediction and deep brain stimulation.

Treatment of convulsive status epilepticus.

Status epilepticus (SE) is a medical and neurological emergency requiring prompt and aggressive treatment, particularly for elderly individuals in whom comorbid conditions may increase the severity of consequences in SE. Generalized convulsive status epilepticus (GCSE) is the most common and life-threatening type of SE. It may be overt or subtle in its presentation. Most cases are overt, but as the duration of GCSE increases, its presentation may become more subtle. Progressive electroencephalographic changes also occur during GCSE. A predictable sequence of five electroencephalographic patterns has been identified: (1) discrete seizures with interictal slowing, (2) merging seizures with waxing and waning ictal discharges, (3) continuous ictal sharp or spike-wave discharges, (4) continuous ictal discharges with episodes of generalized flattening, and (5) periodic epileptiform discharges superimposed on a relatively flat background. Several factors affect the prognosis of GCSE, including etiology, age, seizure type, gender, and duration. GCSE may lead to systemic complications and neuronal damage and is often fatal if untreated or inadequately treated. Treatment of GCSE should begin with basic life support measures and monitoring. Ideally, pharmacological treatment should be easy to administer and fast acting. Analysis of data on elderly patients with overt GCSE from a Veterans Affairs cooperative study revealed that success rates of first-line treatment were 71.4% for phenobarbital, 63.0% for lorazepam, 53.3% for diazepam followed by phenytoin, and 41.5% for phenytoin alone. In elderly patients with subtle GCSE, success rates for first-line treatment were 30.8% for phenobarbital, 14.3% for lorazepam, 11.8% for phenytoin, and 5.6% for diazepam followed by phenytoin. Because each drug has advantages and disadvantages, the choice of which agent to use as first-line treatment depends on individual patient characteristics.

Levetiracetam: a comprehensive review

Levetiracetam was approved by the US FDA in 1999 after failing the traditional screening tests for antiepileptic drugs. In the 10 years since its introduction, it has become one of the first-line antiepileptic agents and has been evaluated in small uncontrolled studies and case series as an off-label treatment for status epilepticus, for nonepileptic neurological conditions, such as movement disorders, neuropathic pain and headaches, and for some psychiatric conditions. It has not been approved for any indication other than chronic epilepsy. A significant factor in using levetiracetam for seizures and other disorders has been its ease of dosing and tolerability. In this article, we outline how levetiracetam was discovered, the animal and human data showing its antiepileptic activity, its potential use in other neurological conditions and the significant adverse events. We also discuss the direction antiepileptic drug development will take in the future.