Nearly a quarter of patients with seizures have drug-resistant epilepsy. This review examines how this diagnosis should be established and how to recognize pseudoresistance. It explains possible mechanisms of drug-resistant epilepsy and presents treatment strategies.

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Drug-Resistant Epilepsy

Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations

Animal models of the epilepsies

Summary: Purpose: Convulsive status epilepticus (CSE) is a major medical and neurological emergency that is associated with significant morbidity and mortality. Despite this high morbidity and mortality, most acute care facilities in the United States cannot evaluate patients with EEG monitoring during or immediately after SE. The present study was initiated to determine whether control of CSE by standard treatment protocols was sufficient to terminate electrographic seizures.



Methods: One hundred sixty-four prospective patients were evaluated at the Medical College of Virginia/VCU Status Epilepticus Program. Continuous EEG monitoring was performed for a minimum of 24 h after clinical control of CSE. SE and seizure types were defined as described previously. A standardized data form entry system was compiled for each patient and used to evaluate the data collected.



Results: After CSE was controlled, continuous EEG monitoring demonstrated that 52% of the patients had no after-SE ictal discharges (ASIDS) and manifested EEG patterns of generalized slowing, attenuation, periodic lateralizing epileptiform discharges (PLEDS), focal slowing, and/or burst suppression. The remaining 48% demonstrated persistent electrographic seizures. More than 14% of the patients manifested nonconvulsive SE (NCSE) predominantly of the complex partial NCSE seizure (CPS) type (2). These patients were comatose and showed no overt clinical signs of convulsive activity. Clinical detection of NCSE in these patients would not have been possible with routine neurological evaluations without use of EEG monitoring. The clinical presentation, mortality, morbidity, and demographic information on this population are reported.



Conclusions: Our results demonstrate that EEG monitoring after treatment of CSE is essential to recognition of persistent electrographic seizures and NCSE unresponsive to routine therapeutic management of CSE. These findings also suggest that EEG monitoring immediately after control of CSE is an important diagnostic test to guide treatment plans and to evaluate prognosis in the management of SE.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1528-1157.1998.tb01177.x

Persistent Nonconvulsive Status Epilepticus After the Control of Convulsive Status Epilepticus

Background Excitotoxic damage due to excess release of neuronal glutamate is hypothesized to play a pivotal role in the pathogenesis of focal cerebral ischemia. Drugs that antagonize excitatory amino acid function are consistently neuroprotective in preclinical models of stroke, and many are now entering clinical trials.

Summary Antagonists of the N -methyl-d-aspartate (NMDA) receptor are furthest advanced in clinical development for stroke. Both noncompetitive (aptiganel hydrochloride, dextrorphan) and competitive (selfotel, d -CPPene) antagonists have undergone tolerability studies in acute stroke and traumatic brain injury. These agents all cause a similar spectrum of neuropsychological symptoms, and several have important cardiovascular effects. Other modulatory sites on the NMDA receptor complex, notably the polyamine and magnesium ion sites, are also the subject of clinical trials. Glycine site antagonists are in early clinical development. Non-NMDA glutamate receptor antagonists remain in preclinical study. Neuroprotection by agents that block glutamate release in vitro may be due to sodium channel blockade in vivo, but some agents (619C89) exhibit neurological effects similar to NMDA antagonists in stroke. The therapeutic index is unknown for different drugs but may be determined by cardiovascular effects, especially hypotension, which may be detrimental after stroke.

Conclusions Excitatory amino acid antagonists are in advanced development in the treatment of stroke and traumatic brain injury. A similar pattern of side effects is apparent with the majority of agents. However, cardiovascular effects may ultimately define therapeutic index for each drug.

Clinical Experience With Excitatory Amino Acid Antagonist Drugs

The modern era of antiepileptic drug therapy began with the use of phenobarbital in 1912. In the years thereafter, many new drugs were introduced, including other barbiturates, hydantoins, succinimides, and oxazolidinediones. Then, for various reasons, the marketing of new antiepileptic drugs was dramatically curtailed. To help reverse this trend, the Epilepsy Branch of the National Institute of Neurological and Communicative Disorders and Stroke sponsored clinical trials of drugs which had already been marketed abroad, resulting in the distribution of clonazepam, carbamazepine, and valproic acid in the U.S. These trials were followed by the establishment of the Antiepileptic Drug Development Program, which encompasses both the preclinical and clinical elements of drug development, including the Anticonvulsant Screening Project, the Toxicology Project, and support for controlled clinical trials.

https://www.ccjm.org/content/ccjom/51/2/293.full.pdf

Antiepileptic Drug Development Program.

The efficacy, bioavailability, and tolerance of carbamazepine in epilepsy were evaluated in a prospective, double-blind study. The study was made in 45 institutionalized patients whose seizures were not controlled completely by combinations of currently available an-tiepileptic drugs in adequate dosages as determined by serum concentrations. In this population, carbamazepine was equal in efficacy to phenobarbital or diphenylhydantoin in controlling seizure frequency, and side effects were minimal. Serum concentrations of carbamazepine were measured up to 13.7 rncg per milliliter, with 70 percent of the values ranging from 5 to 10 mcg per milliliter. Individual episodes of transient leukopenia occurred during the 21-day lest period, but a statistically significant incidence of leukopenia was not observed.

Carbamazepine for epilepsy: A controlled prospective evaluation

Felbamate (2-phenyl-1,3-propanediol dicarbamate) has a favorable preclinical profile in animal models of epilepsy. We present the results of a double-blind, randomized, placebo-controlled clinical trial in patients with partial seizures. Criteria for entry included a requirement for four or more partial seizures per month despite concomitant therapeutic blood levels of phenytoin and carbamazepine. Fifty-six patients (mean age, 31.4 years; 32 men, 24 women) completed the trial. The mean seizure frequencies for the 8-week periods analyzed were felbamate = 34.9, placebo = 40.2. Felbamate was statistically superior to placebo in seizure reduction, percent seizure reduction, and truncated percent seizure reduction. The mean felbamate dosage was 2,300 mg/d. Plasma felbamate concentrations ranged from 18.4 to 51.9 mg/l, mean = 32.5 mg/l. Adverse experiences during felbamate therapy were minor and consisted primarily of nausea and CNS effects. This trial indicates that felbamate is safe and effective in the treatment of comedicated patients with severely refractory epilepsy.

Felbamate for partial seizures: results of a controlled clinical trial.

The efficacy and bioavailability, and tolerance to carbamazepinee when administered with phenobarbital or phenytoin or with both drugs were evaluated in a prospective, double-blind study of patients whose seizures were not completely controlled by currently available antiepileptic drugs in usually therapeutic dosages as determined by serum levels. During each of four 21-day treatment periods, one fourth of the patients received daily doses of: (1) carbamazepine (1,200 mg) and phenytoin (300 mg); (2) carbamazepine (1,200 mg) and phenobarbital (300 mg); (3) phenytoin (300 mg) and phenobarbital (300 mg); or (4) carbamazepine (1,200 mg), with phenytoin (300 mg) and phenobarbital (300 mg). The treatment periods were separated by 2 wk of each patient's usual prestudy medication. Treatment with all three drugs was the most efficacious for seizure control. Serum carbamazepine concentration was significantly decreased when the drug was administered with either phenytoin or phenobarbital or both.

The efficacy of carbamazepine combinations in epilepsy.

Digital and palmar dermatoglyphics were collected from 360 male and 360 female seven year old Caucasians from the greater Boston area. All participants were screened and found to be free of minor anomalies or chronic diseases. All individuals with I.Q. scores below 70 were also excluded. The results were presented in such a way as to give information on bilateral symmetry as well as overall frequencies of the various dermatoglyphic features. The results were compared with those of the corresponding sample of seven year old normal male and female Negrose of the accompanying report.



A review of the distribution of the dermatoglyphic features in different Caucasian populations has also been presented and the overall dermatoglyphics of the Caucasians were discussed in reference to the distribution of the same features in the other major “racial” groups.



The method of collection and selection of the subjects, described in the text, makes this set of data unique and one of the most suitable for use as controls in studying the dermatoglyphics of the individuals with diseases or congenital anomalies.

James J. Cereghino

Papers

Antiepileptic Drug Development Program.

Carbamazepine for epilepsy: A controlled prospective evaluation

Felbamate for partial seizures: results of a controlled clinical trial.

The efficacy of carbamazepine combinations in epilepsy.

The dermatoglyphics of American Caucasians