Overview of the Current Animal Models for Human Seizure and Epileptic Disorders

A diversity of animal models are available for the study of epilepsy and these models have a proven history in advancing our understanding of basic mechanisms underlying epileptogenesis and have been instrumental in the screening of novel antiepileptic drugs. This review addresses the criteria that should be met in a valid animal model and provides an overview of current animal models that are relevant to human conditions. In addition, models not specific for any one human condition but rather exhibiting partial or generalized seizures are discussed. While most human disorders are without any animal model, those models that are clinically relevant have strengths and weaknesses. Finally, although few relevant, well-characterized animal models have been added to the list over recent years, major advancements in molecular genetics are contributing to the discovery of novel pathways involved in epileptogenesis.     

Survey of Seizure Disorders in the French Southwest. I. Incidence of Epileptic Syndromes

An epidemiologic survey began on March 1, 1984, and ended on February 28, 1985. During this period, all neurologists and electroencephalographers of the department of Gironde, an administrative district of the French Southwest (1,128,164 residents in 1982) obtained information by questionnaire from all persons who had experienced an epileptic seizure for the first time in their lives. Recurrent, isolated, and situation-related seizures were included. Febrile convulsions and neonatal seizures were excluded. The global incidence rate of diagnosed epileptic seizures was 71.3/100,000. The incidence rates per year and per 100,000 persons by type of epileptic syndrome were 1.7 for idiopathic and 13.6 for symptomatic localization-related epilepsies, 5.6 for idiopathic and 1.1 for symptomatic generalized epilepsies, 1.9 for undermined epilepsies, 29.0 for situation-related seizures, 18.3 for isolated seizures, and 0.3 for television epilepsies. Other epileptic syndromes were not represented. Using a classification of epileptic syndromes and not of epileptic seizures reduces difficulties in an epidemiologic survey. Diagnosis of an epileptic syndrome is time dependent, however, and at follow-up some patients shift from one group to another.     

Clinically Significant Carbamazepine Drug Interactions: An Overview

Summary: Knowledge of the principles of drug action and distribution contributes to an understanding of the occurrence of drug interactions. The pharmacologic action of most drugs is postulated to occur by the formation of a drug-receptor complex at the site of action that is capable of altering the physiologic response of the target system. The therapeutic response observed depends on the sum of the numerous factors that can affect the disposition pattern of a drug. In an individual, the response to a given drug dose remains relatively constant, but in a large population, a fixed dose can produce a range of plasma concentrations and therefore varied clinical responses. For most drugs, there is a linear relationship between the total dose and the plasma concentration achieved at steady state. Saturation, or zero-order, kinetics accounts for nonlinear increases in drug concentration with dosage increase. Drug-drug interactions with carbamazepine include several types. (1) Autoinduction of carbamazepine metabolism increases the carbamazepine clearance rate, decreases the half-life, and decreases serum concentrations; the clinician must reevaluate a patient's serum levels at 4 to 6 weeks after initiation of therapy. (2) Carbamazepine induces the metabolism of other antiepileptic drugs, enhancing the clearance of phenytoin, primidone, valproic acid, clonazepam, and ethosuximide. (3) Other drugs added to the epileptic patient's drug regimen may induce the metabolism of carbamazepine, causing increased serum concentrations. (4) Inhibition of carbamazepine metabolism by other drugs can also occur; symptoms of drug intoxication rapidly follow. Interactions occur between carbamazepine and macrolide antibiotics, cimetidine, propoxyphene, and isoniazid. Drug-drug interactions are preventable. It is the responsibility of every physician to be alert to the potential for their occurrence whenever a change in the epileptic patient's drug regimen is made.     

Diagnostic Difficulties and Treatment Implications

Summary: Differentiation between types of epileptic seizures has been aided in recent years by the introduction of intensive neurodiagnostic techniques and the development of increasingly detailed classification systems. Paradoxically, these developments have not simplified the task of matching the appropriate antiepileptic drug to a particular seizure type. It is reasonable to assume that anticonvulsant drugs will have different effects on different types of seizures, but faulty, circular reasoning can enter the picture if one also assumes that responses of seizures to different drugs signify different seizure types. There are several examples of differential diagnoses that can fall prey to this problem, including the diagnosis between partial seizures with secondary generalization and generalized tonic-clonic seizures, and the diagnosis between complex partial seizures and absence seizures with automatisms, among others. Considerations of etiology in future classification systems can further complicate the problem: should one then choose an anticonvulsant drug on the basis of individual seizure type or on the basis of the type of epilepsy? Ramifications of this issue extend even to the drug approval process. Official sanction is not given for use of a drug for a seizure type not included in the original efficacy studies, even if later scientific evidence shows that seizure type to be related to a type that is included. New trials must be undertaken. These problems arise from how we choose to classify seizures.     

Valproate Monotherapy in the Management of Generalized and Partial Seizures

Summary: For decades, therapeutic tradition has promoted the concept of polypharmacy in the management of epilepsy. In recent years, however, studies have shown that, for most patients, monotherapy can provide comparable or better seizure control than administration of multiple anticonvulsants, while diminishing the potential for adverse reactions, drug interactions, and poor compliance. Valproate is an important monotherapeutic agent that is highly effective in the control of idiopathic primary and secondarily generalized epilepsies, and partial seizures that do not generalize. Comparative studies have found that valproate is at least as effective as phenytoin and carbamazepine in the treatment of generalized and partial seizures. Given the similar efficacy, other factors such as pharmacokinetics and side effects may therefore determine anticonvulsant selection for monotherapy.     

An Overview of Benzodiazepines in Seizure Management

Summary: Benzodiazepines (BZDs) were first synthesized in 1933 but were not introduced for the treatment of epilepsy until 1965, when Henry Gastaut treated status epilepticus with intravenous diazepam. Since then, BZDs have been widely used in the management of epilepsy in both children and adults. At present, seven different BZDs are used in various countries as antiepileptic drugs. Because of their high lipophilicity, rapid brain penetration, and brain receptor binding, BZDs administered either i.v. or rectally are often first-line agents for acute seizure management. Although they have also been used for epilepsy prophylaxis, chronic treatment with BZDs is sometimes hampered by their propensity to produce sedation and other side effects, including development of tolerance to their anticonvulsant effects. Nevertheless, all patients with a devastating seizure disorder should have the opportunity for prophylaxis with a BZD. Whether or not treatment continues will depend on careful evaluation of the therapeutic response, toxicity, and the development of tolerance.     

The influence of comorbid depression on seizure severity

PURPOSE: To determine the relation between depressive symptoms and seizure severity among people with epilepsy. METHODS: A postal questionnaire was used to survey a nationwide community sample about seizures and depression. The Seizure Severity Questionnaire (SSQ) assessed the severity and bothersomeness of seizure components. The Centers for Epidemiological Studies-Depression scale categorized levels of depression. RESULTS: Respondents categorized as having current severe (SEV, n = 166), mild-moderate (MOD, n = 74), or no depression (NO, n = 443) differed significantly in SSQ scores (all p < 0.0001). People with SEV or MOD reported significantly worse problems than did those with NO depression for overall seizure recovery (mean, 5.3, 4.9, 4.5, respectively); overall severity (5.0, 4.5, 4.2); and overall seizure bother (5.3, 4.8, 4.4) (all p < 0.005). Cognitive, emotional, and physical aspects of seizure recovery also were rated worse among people with SEV than with NO depression (all p < 0.05). Symptoms of depression were significantly correlated with higher levels of all components of generalized tonic-clonic seizure severity (r = 0.33-0.48; all p < 0.0001), and partial seizures (r = 0.31-0.38; all p < 0.01). CONCLUSIONS: Clinically depressed people with epilepsy reported higher levels of perceived severity and bother from seizures, as well as greater problems with overall seizure recovery than did nondepressed people experiencing similar types of seizures. The pervasive influence of depressive symptoms on reports of seizure activity suggests that people with epilepsy should be screened for depression. These data highlight the importance of detecting and treating depression among people with epilepsy.     

Perinatal Factors and Seizure Disorders: An Epidemiologic Review

In this review, we assess the following six aspects of the epidemiological literature addressing the association between perinatal factors and seizure disorders (mainly of the grand mal type): (1) study design; (2) selection of cases; (3) selection of controls; (4) definition and ascertainment method of seizures; (5) definition and ascertainment method of perinatal factors; (6) sample size and power. Needed are studies of perinatal factors in a homogeneous group of seizure patients, such as those with grand mal seizures. Because of the rarity of the seizure disorder, most follow-up studies of this subject suffer from inadequate sample size. Improvements are suggested for case-control studies, which appear, by necessity, to be the more appropriate design.     

An Overview of Pediatric Psychopharmacology

The history and current status of pediatric psychopharmacology and its differences from adult psychopharmacology are reviewed briefly. It is concluded that while psychotropic drugs are as yet of only limited therapeutic value, their potential role in the study of biological factors in childhood psychopathology is substantial. The necessity for child psychiatry to maintain leadership in this area is stressed.     

Classifications of Epileptic Syndromes: Advantages and Limitations for Evaluation of Childhood Epileptic Syndromes in Clinical Practice

The advantages and limitations of the two most recent International League Against Epilepsy classifications of the epilepsies and epileptic syndromes have been assessed after examining the clinical records of 645 consecutive outpatients aged 1 month to 15 years followed at the Children's Epilepsy Center of the University of Milan, Italy, from 1977 through 1985. The percentage of cases that could be classified according to the 1970 and 1985 proposals for classification were 94.1 and 98.1%, respectively. According to the 1985 proposal, partial epilepsies (PE) and generalized epilepsies (GE) were almost equally represented (45.0 vs. 47.2%). Among PE, symptomatic epilepsies were the commonest variety. In the group of GE, idiopathic and/or symptomatic epilepsies were most common. Childhood absence epilepsy was the largest subgroup among idiopathic GE. Newly diagnosed patients, a less biased sample of the epileptic population represented 38.9% of the entire sample, and a proper classification was possible in 96% of cases. Idiopathic epilepsies were about twice as frequent and idiopathic and/or symptomatic GE less frequent in newly diagnosed patients when compared with the remainder. Marked differences in the frequency of the epilepsies were found in comparison with other reports in the literature which used the 1970 classification. This finding probably depends on different diagnostic assessment, selection bias, and different geographic and ethnic components, but it can also reflect the variable interpretation of the clinical and EEG features of a patient with epilepsy in the light of the artifactual categories of the classification.     

Spread of Epileptic Seizure Activity in Humans

A computer-augmented approach to ictal EEG analysis has been developed. A method for determining both the predictability of one signal from another and the time delay between those two signals--the average amount of mutual information (AAMI) method--has been applied to representative seizures of two patients with focal-onset seizures and one patient with generalized seizures. High AAMI values characterized the EEG derived from the sites of the epileptic foci. AAMI values were high in all sampled brain areas in the patient with generalized seizures. Time delays were not consistent in any subject. The results indicate that the AAMI technique can differentiate focal from generalized seizures and identify the site of seizure onset.     

Pediatric Epilepsy Syndromes: An Update and Critical Review

Summary: Epilepsy syndromes occupy an important position in the current nosology of the epilepsies, describing and classifying seizure disorders with shared clinical and EEG features. Increasingly, this schema is being refined as new information becomes available and our understanding of etiology and presentation of each syndrome widens. Advances in neuroimaging and neurogenetics have been particularly important and are likely to fundamentally change our concepts of syndrome classification. At present, the International League Against Epilepsy classification of epilepsy syndromes according to presumed localization (partial, generalized, undetermined) and etiology (idiopathic, cryptogenic, symptomatic). In clinical practice, it is often useful to conceptualize epilepsy syndromes according to their usual age at presentation, which greatly facilitates syndrome identification in new patients and recognizes the age-related expression of many childhood epilepsies. Definitional problems exist for many pediatric epilepsy syndromes, particularly the epileptic encephalopathies of early infancy, the benign epilepsies of infancy and childhood, the myoclonic epilepsies of infancy and early childhood, and the idiopathic generalized epilepsies of childhood and adolescence. It is likely that further input from the fields of molecular genetics and neuroimaging will enable the classification of epilepsies to become more etiologically oriented and disease specific.     

Usefulness of the Newly Proposed International Classification of Epilepsies, Epileptic Syndromes, and Related Seizure Disorders (1989): A Trial on Adult Patients in a Neuropsychiatric Clinic

Abstract: The utility of the "International Classification of Epilepsies, Epileptic Syndromes, and Related Seizure Disorders," proposed by ILAE in 1989, was investigated in a neuropsychiatric clinic with a patient population numbering 300. Two hundred and three patients (67.7%) had localization-related epilepsies (LRE), including one idiopathic case. Sixty-six patients (22%) had generalized epilepsies, 50 idiopathic, 2 Lennox-Gastaut syndrome, and 14 symptomatic. Thirty-one patients (10.3%) with generalized tonic-clonic seizures occurring only during sleep had the epilepsies undetermined whether they are focal or generalized. In the symptomatic LRE cases, 34 cases could not be classified, and 7 of the cases with frontal lobe epilepsies were difficult to subtype. Eleven of the symptomatic LRE cases had some independent seizures, multiple foci in surface EEGs and were intractable. These cases may be defined as "multifocal epilepsies."