Treatment Considerations in Anticonvulsant Monotherapy

Summary: The long-standing practice of polypharmacy in treating epilepsy is giving way to use of monotherapy. Monotherapy can improve seizure control as well as reduce the risk of serious idiosyncratic reactions, dose-related side effects, and complex drug interactions. Monotherapy also offers improved compliance and cost-effectiveness. The basis of monotherapy is accurate diagnosis and assessment of the patient's seizure type(s), followed by selection of a single appropriate anticonvulsant drug. Many patients currently treated with multiple anticonvulsants can be successfully converted to monotherapy with a carefully monitored program in which troublesome and redundant drugs are gradually withdrawn from the therapeutic regimen.     

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.     

Cognitive Dysfunction Associated with Antiepileptic Drug Therapy

Summary: Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.     

Dextromethorphan: Cellular Effects Reducing Neuronal Hyperactivity

Summary: Dextromethorphan is a dextrorotary morphinan without affinity for opioid receptors, commonly used as an antitussive medication. During the past 5 years, interest in the compound and its demethylated derivative, dextrorphan, has been revived because additional neuroprotective and an-tiepileptic properties were found in in vitro studies, animal experiments, and a few clinical cases. Both morphinans are able to inhibit N -methyl-D-aspartate (NMDA) receptor channels and voltage-operated calcium and sodium channels with different potencies. The inhibition of the NMDA receptor is believed to be the predominant mechanism of action responsible for the anticonvulsant and neuroprotective properties of the compounds.     

Carbamazepine Efficacy in Adults With Partial and Generalized Tonic-Clonic Seizures

Summary: Carbamazepine and phenytoin are drugs of choice in initial monotherapy for adult partial and secondarily generalized tonic-clonic seizures. These designations reflect the results of the Veterans Administration Epilepsy Cooperative Study Group of 1985. An earlier comparative study of carbamazepine and phenytoin by Ramsay and associates found both drugs equally effective in controlling new-onset seizures. Among the advantages of carbamazepine is that it causes relatively few cognitive and dysmorphic side effects. Its disadvantages are its unavailability in parenteral formulation and its metabolic autoinduction. The latter must be compensated for by planned dosage increases to maintain therapeutic plasma steady-state levels during the first 2 or 3 months of treatment. Carbamazepine is judged a drug of choice in the treatment of these secondarily generalized tonic-clonic seizures, and the drug of choice in children, adolescents, and women susceptible to the dysmorphic side effects associated with other anticonvulsant agents.     

Etiologic and Preventive Aspects of Epilepsy in the Child–Bridging the Gap Between Laboratory and Clinic

Summary: Four broad categories of basic phenomena are pertinent to developing ways to prevent epilepsy. These include mechanisms of epileptogenesis, ictal initiation and temporary entrainment by the seizure discharge of normally functioning brain, seizure propagation, and control mechanisms that function both to restrain the cascade of epileptic events culminating in a seizure and to arrest the epileptic event and restore the interictal state. In newborns and children, hypoxia-ischemia is a major factor leading to epileptogenesis, and several schemes are proposed to classify, quantify, and prevent hypoxic-ischemic encephalopathy. Control mechanisms must be better understood in order to develop prophylactic recommendations for epilepsy, and an experimental model of "kindling antagonism" may increase our understanding of these. Programs of prevention of seizures in children will evolve only if basic researchers and clinicians work productively together to develop an adequate understanding of factors important in epileptogenesis and antiepileptogenic control mechanisms.     

Pediatric Epilepsy Surgery

Summary: The use of implantable arrays of epidural electrodes has made it possible to carry out extraoperative electrocorticography (ECoG) and functional localization in the awake child. This has permitted cortical excisions that are determined by criteria similar to those obtained during surgical procedures performed under local anesthesia in adults. In addition, the method also permits simultaneous ECoG and video monitoring during the child's symptomatic seizures, providing additional important localizing information that is impractical to obtain in operations under local anesthesia. We report our experience with 75 children, ages 5 months to 15 years, whom we have managed with epidural electrode arrays. The method of extraoperative ECoG is described and illustrative cases are presented to demonstrate its feasibility and utility in children. In addition, we call attention to gliomas as a common cause of chronic focal seizures in children. Of 49 children undergoing resection and followed for from 1 to 14 years (mean of 5.8 years), 32 (65%) are either seizure free or have had a significant reduction in seizure frequency that has unambiguously improved their quality of life. The results are analyzed further by relating the surgical outcome to each of the pathologic entities that caused the seizures. This analysis reveals the variety of neurological conditions that commonly cause intractable focal seizure disorder in children and distinguishes those pathologic entities in which the seizure disorder is apt to respond to surgical intervention from those that will not.     

Predisposing and Causative Factors in Childhood Epilepsy

Summary: We review information from large studies of defined populations, examining the role of known factors and especially of prenatal and perinatal factors in contributing to nonfebrile seizure disorders of early childhood. We depend especially, but not exclusively, on the recently completed analyses from the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, the NCPP. About 4% of children in the NCPP who had at least one non-febrile nonsymptomatic seizure by the age of 7 years had a previous seizure during acute neurologic illness, such as meningitis or during the acute illness after trauma. Many such seizures should potentially be preventable. Of children with seizures, 10% had had a neonatal seizure and 13% had had a febrile seizure. Among the hundreds of prenatal and perinatal factors explored as predictors of childhood seizure disorders, the principal predictors identified were congenital malformations of the fetus, cerebral and noncerebral; family history of certain neurologic disorders; and neonatal seizures. In agreement with the British National Child Development Study, labor and delivery factors in the NCPP appeared to contribute very little to childhood seizure disorders. Maldevelopment, rather than damage at birth to an initially intact nervous system, appeared to be the more common mechanism. Most seizure disorders of early childhood remained unexplained by the large set of prenatal and perinatal characteristics examined.     

Anticonvulsant Drugs and Cognitive Function: A Review of the Literature

Summary: Alterations of cognitive function are separate from disturbances of behavior seen in association with epilepsy. The nature of the cognitive disability may to a certain extent depend on the seizure type. Partial seizures, mainly derived from a temporal lobe focus, impair memory tasks, while generalized seizures seem to have more effect on attentional abilities. A number of studies, reviewed in this paper, suggest that anticonvulsant drugs further impair cognitive function. Maximal impairments are seen in patients receiving polytherapy: rationalization of polytherapy improves cognitive abilities. Studies in children and adults have allowed differentiation of the effects of various commonly used antiepileptic agents. Maximal cognitive deficits are seen with. phenytoin, while phenobarbital and sodium valproate induce moderate disturbances, and carbamazepine seems relatively free from such toxicity. Further research is needed on the interrelationship between types of seizure disorders, types of anticonvulsant medications, and cognitive function.     

Effects of NMD A- and AMPA-Receptor Antagonists on Different Forms of Epileptiform Activity in Rat Temporal Cortex Slices

Summary: Lowering extracellular magnesium induces different patterns of epileptiform activity in rat hippocampus and entorhinal cortex. Short recurrent epileptiform discharges in the hippocampus are stable over time, whereas seizurelike events (SLEs) in the entorhinal cortex, the subiculum, and the neighboring neocortex develop into late recurrent discharges which are not blocked by clinically employed antiepileptic drugs. We tested the sensitivity of the different epileptiform discharge patterns to. /V-methyl-D-aspartate (NMDA)- and non-NMDA-receptor antagonists. As NMDA-receptor antagonist we used dextrorphan, ket-amine, and 2-aminophosphonovalerate (2APV); as α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-receptor antagonist we employed the quinoxaline derivative glutamate 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The findings show that the different patterns of epileptiform activity, including the late recurrent discharges, are sensitive to all NMDA-receptor antagonists. However, when dextrorphan was employed to suppress seizure-like events, later recurrent discharges did not develop during the remaining time course of the experiment. CNQX reversibly suppressed recurrent discharges in the hippocampus and SLEs in the entorhinal cortex. However, late recurrent discharges become insensitive to CNQX, even at a high concentration of 60 μM m. This finding suggests a prominent role for NMDA receptors in the generation of late recurrent discharges.     

Un nouveau cadre conceptuel de travail pour une psychiatrie revisitée ? Introduction à deux articles de E. Kandel

In two articles which appeared in the American Journal of Psychiatry and that were subsequently translated for Évolution Psychiatrique, E. Kandel examines the bases for a reinterpreted psychiatry that is prepared to confront the major challenge of the 3rd millenium: that of insight into the mind and brain. This requires a major reorganization of the discipline, which involves a reinvestment of the scientific approach and a critical  assessment of the data provided by psychoanalytical psychiatry and cognitive neurosciences. Seven concepts have therefore been proposed for interactive re-examination: consciousness, the unconscious, memory, emotion, development, desire, impulse. The dynamic relations existing between genetics and the environment allow one to see how evolutions are possible from actions at different levels, both psychotherapeutic and pharmacological. Imaging and other techniques provide additional objective information to the process of human interaction which remains the basis of psychiatry. A common framework for psychiatry and the neurosciences, a reconsideration and renewal of the psychoanalytical approach are both possible and necessary.     

Opioids and the developing organism: A comprehensive bibliography, 1984–1988

A comprehensive bibliography of the literature concerned with opioids and the developing organism for 1984-1988 is presented. Utilized with companion papers (Neurosci. Biobehav. Rev. 6:439-479; 1982; 8:387-403; 1984), these articles cover the clinical and laboratory references beginning in 1875. For the years 1984, 1985, 1986, 1987, and 1988, a total of 877 citations were recorded. A series of indexes accompanies the citations in order to make the literature more accessible. These indexes are divided into clinical and laboratory topics, and subdivided into such topics as the type of opioid explored and the general area of biological interest (e.g., physiology).     

La biologie et le futur de la psychanalyse : un nouveau cadre conceptuel de travail pour une psychiatrie revisitée

The American Journal of Psychiatry has received a number of letters in response to my earlier “Framework” article (1). Some of these are reprinted elsewhere in this issue, and I have answered them briefly there. However, one issue raised by some letters deserves a more detailed answer, and that relates to whether biology is at all relevant to psychoanalysis. To my mind, this issue is so central to the future of psychoanalysis that it cannot be addressed with a brief comment. I therefore have written this article in an attempt to outline the importance of biology for the future of psychoanalysis.     

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.     

Une phénoménologie de la dépendance à l'alcool. Une expérience primordiale de la « nostrité »

The phenomenological approach to alcoholism interestingly focuses on specific dynamics of interpersonal relationships displaying the founding of the Self from a primary “us” and its original basis in the human feast. Priorities for treatment intervention recommend to involve social setting and relationships of the patients, reaching their active participation to a motivational and long term group treatment, underlying the specific therapeutic effect of world exchanges. Biopsychosocial determination of alcoholism could be primarily based on components of interpersonal relationships. Regarding social background, drinking is one of the most famous supports for the achievement of the feast, a founding marker of present time. Taking an existential point of view, the feast appears as the heart of mankind because it presents a primary “us”, a plural state which indicates the beginning and founding of the Self from the others. During the feast, we regularly have to reach our Self from the “us” while avoiding two main dangers, drunkenness, an increase in the dizziness of upright verticality, and addiction, an opposite vertical surrender to alcohol and falling into in the alcoholic relapse, both situations imply a spatial domination and the disappearance of others. Treatment programs of alcohol addicts need to integrate the necessity of reaching the existential basic trust from the support of a group to the appropriation of the community which can be defined as an original “usness”.     

Facteurs de risque environnementaux à la schizophrénie

Schizophrenia is currently a major concern, its prevalence being estimated at around 1% and its social consequences being severe. The elucidation of the pathophysiology of the disease is difficult due to the great variability of clinical expressions, the instability of the clinical symptoms during the evolution and the absence of reliable biological markers. The existence of a familial aggregation in schizophrenia is well known, the risk of presenting the disease for first-degree relatives of patients being 5 to 10 times higher than the risk observed in the general population. The genetic component was further confirmed by twin and adoption studies. Although the concordance for the disease is higher (40 to 70%) among monozygotic twins as compared with dizygotic twins (15%) it does not reach 100%, which implies that environmental factors modulate the effects of the genotype. However, the role of these factors and especially their interaction with genetic factors remain unclear but the implications of some specific environmental factors are well documented by recent research data. The current literature on sex differences in schizophrenia is consistent. Several studies have suggested that male and female patients may differ in age at the onset and expression of clinical symptoms. Complications during pregnancy or birth-giving may increase the risk of developing schizophrenia later in life. The major complications are oxygen deprivation during pregnancy, bleeding, maternal malnutrition or infection (exposure to influenza, for example). A low birth weight is associated with an increased risk of schizophrenia. Psychoses are more common among people living in an urban environment and among those born during winter months. Schizophrenia is probably more prevalent in people who are living promiscuously, are subject to toxic abuse, poor nutrition and stress but here more precise data are needed. Moreover, immigrants have a higher risk of developing psychotic disorders. In addition, head traumas are associated with an increased risk of schizophrenia. Though they are contentious, some studies suggest that substance abuse (cannabis use in European countries) is related to the development of schizophrenia, especially in people with genetic vulnerability. Moreover, substance misuse may worsen the symptoms. If the environment is sufficiently stressful, people with a high genetic vulnerability will develop some degree of mental illness, including schizophrenia. Conversely, a less stressful or a protective environment may decrease the risk of its onset in persons with a predisposition to schizophrenia.     

Introduction: Goals

Summary: Epilepsy is characterized by recurrent seizures. Many epilepsies with focal seizures as well as convulsive generalized seizures respond satisfactorily to antiepileptic drugs (AEDs) that reduce repetitive firing (e.g., phenytoin, carbamazepine, and valproate) or that augment GABA_A-mediated inhibition (e.g., phenobarbital and benzodiazepines). A number of drugs presently under development, such as NMDA receptor antagonists, loreclezole, losigamone, meth-ysticine, and dextromethorphan, are promising in acute animal models of otherwise drug-resistant convulsant activity. As a result of recent studies in both experimental models and surgically resected human epileptic brain, the prospects for development of AEDs have significantly improved. Several new AEDs recently have reached the commercial market or are in experimental or clinical trials. A comparative presentation of the standing of the new AEDs with respect to their efficacy and side effects is necessary, but still very difficult. Because initial experience with new AEDs is restricted to populations with severe drug-resistant epilepsy, the crucial question whether potential new AEDs can alter prognosis is not yet definitively answered. There is a clear need to compare the effects of standard AEDs and new AEDs in naive patients and over longer follow-up periods. Moreover, because of the strong desire to develop antiepileptic therapy that directly treats the primary etiology of a given epileptic syndrome , or modifies the neurobiological processes that cause recurrent seizures, better experimental epilepsy models for chronic epilepsy and further clinical studies are necessary to increase the knowledge on the pathophysiology of distinct epileptic syndromes. In this respect, studies on the differences between responders and nonresponders to a given AED treatment are extremely valuable.