Cognitive Effects of Antiepileptic Drugs

Antiepileptic drugs (AEDs) can adversely affect cognitive function by suppressing neuronal excitability or enhancing inhibitory neurotransmission. The main cognitive effects of AEDs are impaired attention, vigilance, and psychomotor speed, but secondary effects can manifest on other cognitive functions. Although the long-term use of AEDs can obviously elicit cognitive dysfunction in epilepsy patients, their cognitive effects over short periods of up to a year are inconclusive due to methodological problems. In general, the effects on cognition are worse for older AEDs (e.g., phenobarbital) than for placebo, nondrug condition, and newer AEDs. However, topiramate is the newer AED that has the greatest risk cognitive impairment irrespective of the comparator group. Since the cognitive impact of AEDs can be serious, clinicians should be alert to adverse events by evaluating cognitive function using screening tests. Adverse cognitive events of AEDs can be avoided by slow titration to the lowest effective dosage and by avoiding polytherapy.     

Seizures and therapy in adolescents with uncomplicated epilepsy.

PURPOSE: This study aimed to describe seizures and their therapy among Swedish adolescents, aged 13-22, with active but uncomplicated epilepsy. METHOD: The adolescents answered questionnaires (158/193). Data were also obtained from medical records. RESULTS: Epileptic seizure types could be specified in 92.1% of the cases. Predominant types were Primary Generalised Tonic-Clonic Seizures and Partial Complex Seizures with Secondary Generalisation. Clinical diagnoses by physicians were unspecified in 25.8%. Ninety percent were on antiepileptic drugs (AEDs), most commonly valproate and carbamazepine. New AEDs were used in 9.3% of the cases and polytherapy in 13.9%. More than 40% of the respondents had seizures despite AED treatment. Side effects of AEDs were experienced by 61%, most commonly tiredness, concentration difficulties and headache. Patients on polytherapy experienced significantly more side effects. The choice of a new AED over a traditional one was not related to seizure type or seizure control. CONCLUSIONS: Many adolescents had persistent seizures despite treatment at a specialist regional epilepsy centre. This, plus the high reported rate of side effects of AED treatment, suggests that treatment is not optimal for the group studied. As traditional AEDs strongly dominated treatment possibly newly marketed AEDs are underused in this group.     

Long-Term Neuropsychological Consequences of Maternal Epilepsy and Anticonvulsant Treatment During Pregnancy for School-Age Children and Adolescents

PURPOSE: Antiepileptic drugs (AEDs) are potential teratogenic agents. The purpose of this study was to examine the long-term effects of intrauterine AED exposure on neurologic and psychological functioning. METHODS: Of a prospective study, "Epilepsy, pregnancy, and child development," children could be retraced at school age and adolescence. Sixty-seven were born to mothers with epilepsy [no drugs during pregnancy (n = 13), monotherapy (n = 31), polytherapy (n = 23)]; 49 were nonafflicted control children. Assessments included an intelligence test (Wechsler), a neurologic examination (Touwen), and an EEG. Data analyses were performed, controlling for parental social status, type of maternal drug therapy and drug dosage, type of epilepsy, frequency of seizures during pregnancy, the original subgroups, and specific drug effects. RESULTS: Type of maternal epilepsy and type and kind of AED therapy, but not maternal seizures during pregnancy correlated with an increase in abnormal EEG patterns. Minor neurologic dysfunction was diagnosed, with increased frequency from the control to the risk/no drug or monotherapy to the polytherapy group. The compromised intelligence score of the polytherapy group was primarily due to those children who had been exposed to primidone (PRM). Level of IQ was negatively associated with PRM dosage. CONCLUSIONS: Maternal epilepsy and AED therapy during pregnancy appear to have long-term effects on the offspring well into adolescence, as evinced in EEG patterns, minor neurologic dysfunction, and intellectual performance. Severity of effects increased from control group to epilepsy/no-drug group to monotherapy group and was most marked in the polytherapy group. These group differences are assumed to reflect differential neural vulnerability to social and family factors.     

Neurodevelopmental effects of antiepileptic drugs

Although the vast majority of children born to women with epilepsy are normal, these children are at increased risk for both anatomic and cognitive impairments. Current evidence suggests that the defects are the result of in utero antiepileptic drug (AED) exposure combined with a genetic predispositon. However, the exact mechanisms underlying these effects remain to be delineated. AED polytherapy increases the risk, but it remains uncertain if specific AEDs pose an overall greater threat. Most women with epilepsy cannot avoid AEDs during pregnancy because of the greater risks posed by seizures to the mother and fetus. Therefore, current recommendations emphasize definitive diagnosis and the use of AED monotherapy at the lowest effective dose if treatment is indicated. Prenatal folate and multivitamins should also be given routinely to women of childbearing age who require AED therapy.     

Teratogenic Effects of Antiepileptic Drugs: Implications for the Management of Epilepsy in Women of Childbearing Age

Summary: Exposure to antiepileptic drug (AED) treatment in utero occurs in 1 of every 250 newborns. The absolute risk of major malformations in these infants is about 7–10%, ˜3–5% higher than in the general population. Specific risk factors include high maternal daily dosage or serum concentrations of AED, low folate levels, polytherapy, and generalized seizures during pregnancy. Adverse pregnancy outcomes, including congenital heart malformations, facial clefts, spina bifida aperta, hypospadias, growth retardation, and psychomotor and mental retardation, are associated with, although not necessarily caused by, AED exposure. Specific cognitive defects, hypertelorism, and nail hypoplasia can be causally related to specific AED exposures. To prevent teratogenic side effects, the prospective mother should be treated with AEDs only when absolutely necessary. Monotherapy with the AED that is most effective in the lowest possible daily dose (divided into at least two or three administrations) should be prescribed. High-dose folate supplementation (4–5 mg/day) reduces the risk of a neural tube defect in a child whose sibling had such a defect, but its impact on the specific teratogenic risks of AEDs is unknown. A substantial proportion of fetal malformations may be secondarily prevented by prenatal diagnosis, consisting of a fetal structural ultrasound examination at weeks 18 and 20 of gestation and, with VPA or CBZ administration, an α₁-fetoprotein analysis of amniotic fluid at week 16. Determination of a specific defect prevention strategy depends largely on parental attitudes toward prenatal diagnosis and termination of pregnancy, which should be discussed before conception. The availability of many new AEDs, many of which will be used in polytherapy, will make prospective evaluation of large numbers of pregnancy outcome on a population basis even more important in the future.     

Effect of antiepileptic drug polytherapy on urinary pH in children and young adults

Objects  The relationship between antiepileptic drugs (AEDs) polytherapy and urinary pH was studied to demonstrate the effect and difference of AED polytherapy compared to monotherapy. Materials and methods  A total of 271 urine samples from patients receiving AED polytherapy aged from 7 months to 35 years were enrolled. Two AEDs were co-administered to 215 patients, three AEDs to 45 patients, four AEDs to ten patients, and five AEDs to one patient. Results  The distribution of urinary pH shifted to the alkaline range with increasing numbers of co-administered AEDs (p < 0.0001). The distribution of urinary pH shifted to the alkaline side with AED polytherapy that included valproate (p < 0.05) or acetazolamide (p < 0.03). The distribution of urinary pH did not change with or without zonisamide, carbamazepine, phenobarbital, phenytoin, or clonazepam. Conclusions  Urinary pH should be monitored in patients receiving AED polytherapy, particularly those receiving valproate, acetazolamide, or various AEDs in combination.     

The Progression of Epilepsy

Summary:  Prognosis for seizure control and cognitive development varies considerably among syndromes. Several factors may interact to influence outcome of an epilepsy including a causative etiology, ictal and interictal discharges, seizure-related trauma or systemic perturbations, and antiepileptic drug (AED) effects. Clinical evidence convincingly supporting Gowers' hypothesis that seizures beget seizures is lacking. Short-term seizure suppression by early treatment does not appear to influence long-term prognosis.
Malignant epilepsy syndromes usually begin in infancy or childhood, have a high seizure frequency, resist the initial AED, and are often associated with progressive cognitive dysfunction. Prompt management of some severe epilepsy syndromes may lessen cognitive decline. However, aggressive AEDs therapy must be balanced against the potential for cognitive side effects, particularly if multiple AEDs are used.
Several experimental paradigms closely parallel human TLE as both have an initial precipitating injury (IPI), a latent period, then recurrent spontaneous seizures. In humans, an IPI is any medical event with neurological implications. Although transition from a latent period to a seizure disorder certainly constitutes "progression" of the disorder, convincing clinical evidence of subsequent worsening has not emerged. Substantial clinical and experimental evidence indicates some cognitive regression and focal atrophy with time for TLE and other intractable syndromes. However, seizure frequency and severity, established early in the disorder, appear stable in most patients, and even regress in benign syndromes. Factors mitigating or extinguishing epilepsies need to be further sought.     

Cognitive and memory effects of the new antiepileptic drugs

Problems with cognition are common in patients with epilepsy. A series of double-blind, randomized, crossover, healthy volunteer studies have been conducted to avoid a variety of the confounding effects on cognition such as those produced by changes in seizure frequency. All of the older AEDs produced cognitive effects compared to the non-drug conditions. The cognitive effects of several of the new AEDs are described although data are limited. Studies have demonstrated that in utero AED exposure in humans may affect cognitive development. Although the cognitive effects of AEDs are generally modest, these effects can have clinical significance. The available data suggest that some of the new AEDs have fewer effects on cognition and memory than the older AEDs, and these differences can have clinical impact.     

Selection of antiepileptic drug polytherapy based on mechanisms of action: the evidence reviewed

PURPOSE: When monotherapy with antiepileptic drugs (AEDs) fails, combination therapy is tried in an attempt to improve effectiveness by improving efficacy, tolerability, or both. We reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be selected for combination therapy based on their mechanisms of action, and if so, which combinations are associated with increased effectiveness. Because various designs and methods of analysis were used in these studies, it was also necessary to evaluate the appropriateness of these approaches. METHODS: Published papers reporting on AED polytherapy in animals or humans were identified by Medline search and by checking references cited in these papers. RESULTS: Thirty-nine papers were identified reporting on two-drug AED combinations. Several combinations were reported to offer improved effectiveness, but no uniform approach was used in either animal or human studies for the evaluation of pharmacodynamic drug interactions; efficacy was often the only end point. CONCLUSIONS: There is evidence that AED polytherapy based on mechanisms of action may enhance effectiveness. In particular, combining a sodium channel blocker with a drug enhancing GABAergic inhibition appears to be advantageous. Combining two GABA mimetic drugs or combining an AMPA antagonist with an NMDA antagonist may enhance efficacy, but tolerability is sometimes reduced. Combining two sodium channel blockers seems less promising. However, given the incomplete knowledge of the pathophysiology of seizures and indeed of the exact mechanisms of action of AEDs, an empirical but rational approach for evaluating AED combinations is of fundamental importance. This would involve appropriate testing of all possible combinations in animal models and subsequent evaluation of advantageous combinations in clinical trials. Testing procedures in animals should include the isobologram method, and the concept of drug load should be the basis of studies in patients with epilepsy.     

Do antiepileptic drugs or generalized tonic–clonic seizure frequency increase SUDEP risk? A combined analysis

Purpose: In an analysis of four case–control studies of sudden unexpected death in epilepsy (SUDEP), we found that yearly frequency of generalized tonic–clonic seizures (GTCS) and antiepileptic drug (AED) polytherapy were associated with an increased risk for SUDEP. The prior analysis, however, did not evaluate AEDs and GTCS frequency concurrently. Methods: We combined data from the three case–control studies with information on the frequency of GTCS and AED therapy, that is, carbamazepine, phenytoin, valproic acid, and other AED therapy. Number of AEDs was also considered. Lamotrigine and GTCS frequency were considered separately in two of the case–control studies. Logistic regression analysis was used to evaluate GTCS frequency, each of the AEDs, and number of AEDs. Adjusted analysis of the different AEDs accounted for study, age at death, gender, and GTCS frequency. Key Findings: In crude analysis, GTCS frequency, AED polytherapy, and number of AEDs were associated with an increased risk for SUDEP. Analysis of individual AEDs and of number of AEDs, adjusting for GTCS frequency, revealed no increased risk associated with AEDs as monotherapy, polytherapy, or total number. GTCS frequency remained strongly associated with an increased risk for SUDEP. Significance: Our findings—that none of the AEDs considered were associated with increased SUDEP risk as monotherapy or as polytherapy when GTCS frequency was taken into account—provide a consistent message that number of GTCS increases SUDEP risk and not AEDs. These results suggest that prevention of SUDEP must involve increased efforts to decrease GTCS frequency in order to avert the occurrence of this devastating epilepsy outcome.     

Challenging epilepsy with antiepileptic pharmacotherapy in a tertiary teaching hospital in Sri Lanka

The goal of antiepileptic drug (AED) therapy is to achieve a seizure-free state and eliminate the medical and psychosocial risks of recurrent seizures. Burden of epilepsy on the economy of a country may be largely due to the expenditure on AEDs. The adverse effects may influence the compliance to AEDs and effective control of epilepsy. We determined the pattern of AED use, the degree of epileptic control achieved and the adverse effects experienced by the epileptics in a Tertiary Teaching Hospital in Sri Lanka. Carbamazepine was found to be the most frequently used AED. Monotherapy was used on 70.8% of subjects. 86.27% of the study sample had achieved effective control of epilepsy with a 50% or more reduction in seizure frequency. Of them 72.64% were on monotherapy and they were either on carbamazepine, sodium valproate, phenytoin sodium or phenobarbitone. None of the new AEDs were prescribed to these patients. 50.9% on monotherapy and 51.5% on polytherapy reported adverse effects. Somnolence followed by headache was found to be the most frequently reported adverse effects by those on monotherapy and polytherapy both. This study shows that most epileptics can be effectively managed with the conventional AEDs with clinical monitoring.     

The importance of assessing behaviour and cognition in antiepileptic drug trials in children and adolescents

It has long been recognised that uncontrolled childhood epilepsy is detrimental to cognition and behaviour, impacting on a patient’s ability to succeed academically. Patients who experience more frequent and serious seizures are at greater risk for cognitive decline, emphasising the need for more effective epilepsy treatments to bring seizures under control. That said, although more effective antiepileptic drugs (AEDs) have the potential to limit the impact of uncontrolled seizures on cognitive and behavioural function, recently it has been acknowledged that deficits in these functions may be caused by AEDs themselves. The cognitive and behavioural effects of older-generation AEDs have been determined largely from AE reporting rather than from specific assessment. Recently, clinical trials of newer-generation AEDs, such as topiramate, levetiracetam and perampanel, have included standardised neuropsychological tests as outcome measures to assess their impact on cognition and behaviour in children and adolescents. However, to understand how we may limit the cognitive and behavioural side effects of AEDs, it is necessary for us to gain a fuller, more accurate, characterisation of their true impact. Such insight will depend on sophisticated and standardised approaches to the design of AED clinical trials. This review provides a general overview of our current understanding of the impact of both epilepsy and AEDs on cognition and behaviour, before focusing on the AEDs for which more detailed assessment, using standardised cognitive and behavioural measures, has been undertaken. We will then go on to discuss the key elements in the design of future AED clinical trials to address current unmet needs.     

Assessment of CNS effects of antiepileptic drugs by using quantitative EEG measures

PURPOSE: Antiepileptic drugs (AEDs) can be associated with adverse neurologic effects including cognitive dysfunction. Objective methods for recognizing AED effects on the brain could be valuable for long-term management. We compared quantitative EEG measures and cognitive tests in a group of patients beginning or ending AED therapy. METHODS: Subjects included 20 patients beginning AED therapy (AEDon), 12 patients stopping AED therapy (AEDoff), 33 patient controls receiving stable AED therapy (AEDco), and 73 healthy controls (Nco). All subjects underwent structured EEG recording and a cognitive test battery before change in AED dose and again 12-16 weeks later, >or=4 weeks after the last dose change. Four occipital EEG measures (peak frequency, median frequency, relative theta and delta power) were analyzed. Cognitive test changes were scored by using test-retest regression equations based on the Nco subjects. Wilcoxon tests were used for two-group comparisons. RESULTS: AEDons had a significant decrease, and AEDoffs, a significant increase in the peak frequency of the EEG rhythm, as compared with controls. Results for median frequency and theta power were similar. Change in the EEG peak frequency correlated with an aggregate cognitive change measure (r2= 0.71; p < 0.001), individual cognitive measures, and subjective complaints. Of the combined AEDon/AEDoff patients, 58% exceeded the 95% confidence interval for test-retest change in EEG peak frequency. CONCLUSIONS: Quantitative measures derived from the occipital EEG are sensitive to AEDs and correlate with AED-related cognitive effects and subjective complaints. Although this correlation does not indicate a direct relation, quantified EEG may be a practical measure of AED impact on the brain.     

Effects of long-term antiepileptic therapy on the hypothalamic-pituitary axis in man

Effects of long-term antiepileptic therapy on the hypothalamic-pituitary axis were evaluated from the basal and stimulated plasma levels of growth hormone (GH) and prolactin (PRL) and from circadian adrenocorticotropic hormone (ACTH)/cortisol rhythms. Data for patients with well-controlled epilepsy of mild-to-moderate severity were compared with those for normal healthy volunteers. Analysis of the effects of each antiepileptic drug (AED) and of combined AEDs revealed minor abnormalities of stimulated GH secretion in all treated patients. In epileptic men, all individual AEDs (except valproate) and AED polytherapy increased both basal and stimulated plasma levels of PRL. In epileptic women, this effect was more variable and less marked, probably because of early depletion of PRL reserves. Each AED and combined AEDs did not significantly change circadian ACTH/cortisol rhythms in epileptic patients. The effects observed seem not to be related to epilepsy per se. Clinical implications, pathways, and neurotransmitters involved and possible mechanisms of the neuroendocrine effects of long-term AED therapy are discussed.     

A Systematic Review of the Effects of Lamotrigine on Cognitive Function and Quality of Life

Cognitive impairment associated with antiepileptic drug (AED) therapy represents a particular problem, especially in the young and elderly. Lamotrigine (LTG) is a new-generation AED that is effective and well tolerated in both the elderly and children. Existing data suggest that the cognitive deficits commonly associated with AED therapy are not commonly observed in patients receiving LTG as monotherapy, and, when LTG is used as an add-on therapy, any existing cognitive problems are not exacerbated and in some cases are clearly improved. Here we have reviewed previous studies that have examined the impact of LTG therapy on cognitive functioning. We have considered data from monotherapy and add-on clinical studies and also more indirect evidence from volunteer studies and from neurophysiological evaluations in epilepsy patients. These data suggest that the impact of LTG on cognition is at least equivalent to that of existing standard AEDs and, in many cases, the use of LTG is associated with improved cognitive functioning, which is not seen with standard AEDs. We have also considered the wider implications of patient quality of life, accepting that cognitive function may form an integral part of the patient's perceived quality of life.     

Relationship between adverse effects of antiepileptic drugs,number of coprescribed drugs,and drug load in a large cohort of consecutive patients with drug‐refractory epilepsy

Purpose: To evaluate the adverse effects (AEs) of antiepileptic drugs (AEDs) in adults with refractory epilepsy and their relationship with number of coprescribed AEDs and AED load. Methods: Patients with refractory epilepsy were enrolled consecutively at 11 tertiary referral centers. AEs were assessed through unstructured interview and the Adverse Event Profile (AEP) questionnaire. AED loads were calculated as the sum of prescribed daily dose (PDD)/defined daily dose (DDD) ratios for each coprescribed AED. Results: Of 809 patients enrolled, 709 had localization‐related epilepsy and 627 were on polytherapy. AED loads increased with increasing number of AEDs in the treatment regimen, from 1.2 ± 0.5 for patients on monotherapy to 2.5 ± 1, 3.7 ± 1.1, and 4.7 ± 1.1 for those on two, three, and ≥4 AEDs, respectively. The number of spontaneously reported AEs correlated with the number of AEs identified by the AEP (r = 0.27, p < 0.0001). AEP scores did not differ between patients with monotherapy and patients with polytherapy (42.8 ± 11.7 vs. 42.6 ± 11.2), and there was no correlation between AEP scores and AED load (r = ?0.05, p = 0.16). Conclusions: AEs did not differ between monotherapy and polytherapy patients, and did not correlate with AED load, possibly as a result of physicians’ intervention in individualizing treatment regimens. Taking into account the limitations of a cross‐sectional survey, these findings are consistent with the hypothesis that AEs are determined more by individual susceptibility, type of AEDs used, and physicians’ skills, than number of coprescribed AEDs and AED load.     

EpiTrack: tracking cognitive side effects of medication on attention and executive functions in patients with epilepsy

RATIONALE: Achievement of maximum seizure control with preservation or even improvement of patient's cognitive capabilities is the major aim of epilepsy therapy. EpiTrack is a brief screening tool for the tracking of cognitive side effects of antiepileptic drugs. Test selection was based on recent studies on the effects of topiramate on cognition and retrospective inspection of results from patients with antiepileptic drug (AED) side effects. METHODS: The 15-minute screening tool comprises six subtests: the Trail-Making Test (parts A and B), a test of response inhibition, digit span backward, written word fluency, and a maze test. These tests were standardized in 220 healthy subjects, 100 of whom were reevaluated after 5.3 months to obtain information on reliability and practice effects. Criterion validity was determined by correlation to other neuropsychological measures. For a first clinical evaluation, the impact of epilepsy (seizures) and medication on EpiTrack scores was evaluated cross-sectionally in 184 consecutive inpatients with chronic epilepsy. RESULTS: According to the normative data, we developed an easy scoring scheme assigning test scores on a 7-point scale. The EpiTrack is suitable for patients between 18 and 60 years of age. Age corrections were included for patients between 40 and 60 years. EpiTrack scores on subtests for both controls and patients were submitted to principal component analysis. VARIMAX rotation yielded a two-factor solution (verbal/visuo-spatial) that accounted for 63.8% of the total variance in controls. In the patient group, only one factor emerged accounting for 54.7% of variance. EpiTrack correlates with global scores of attention (r=0.85) and language (r=0.67) (P's<0.001). At a cutoff score of 25, only 2.7% of the controls were classified as impaired, while impairment was indicated in 48.4% of the patients. The score is sensitive to monthly frequency of complex partial seizures and to number of AEDs. It shows negative cognitive effects of valproate and topiramate given in mono/polytherapy. CONCLUSION: EpiTrack is a promising 15-minute screening tool for the detection and tracking of cognitive side effects of AEDs and adverse effects of seizures in patients with epilepsy. Future application will show its value in prospective follow-up studies on AED side effects.     

Antiepileptic drug use during pregnancy: Perinatal outcomes

Purpose

This study was undertaken to (1) measure the frequency of AED monotherapy or polytherapy during pregnancy and AED discontinuation prior to pregnancy in a cohort of women with treated epilepsy; and (2) describe the frequency of major congenital malformations according to maternal use of AED during pregnancy.

Methods

A cohort of epileptic pregnant women was identified within the Quebec Pregnancy Registry and was divided into three groups based on maternal AED use during pregnancy: AED monotherapy, AED polytherapy and no AED use.

Results

Of the 349 pregnancies meeting eligibility criteria, 79.6% were exposed to AED monotherapy and 5.8% to polytherapy during pregnancy; 14.6% discontinued AED prior to pregnancy. The most commonly used AEDs were carbamazepine (29.9%) and valproic acid (19.7%); the most common AED polytherapy combination was carbamazepine combined with clobazam (2.5%). Of 111 deliveries in the group of women on monotherapy during pregnancy, 9.9% (n = 11) were born with major congenital malformations; in the group of women treated with polytherapy, 19.0% (n = 8 over 42) of babies had major congenital malformations compared to 20.0% in women who discontinued AEDs prior to pregnancy.

Conclusion

This study demonstrates that the majority of women suffering from epilepsy were treated with monotherapy rather than polytherapy during pregnancy. While most used other agents, an important number of women continued to use valproate in pregnancy despite the long standing evidence of its teratogenicity and increasing evidence of its neuro-toxicity to the fetus.     

Postmarketing experience with topiramate and cognition

Ideal antiepileptic drugs (AEDs) are designed to stop seizures with limited central nervous system (CNS) side effects. However, CNS-related treatment-emergent adverse events (TEAEs) often occur in patients receiving AEDs. Topiramate (TPM) is an AED proven to be safe and effective as adjunctive treatment for epilepsy patients with partial seizures. Double-blind, placebo-controlled, multicenter trials demonstrated potential effects on cognition. The P.A.D.S. (post-marketing antiepileptic drug survey) group, a cooperative group of 14 epilepsy centers that collaborate on obtaining data about new AEDs and devices, prospectively collected standardized data forms before and during treatment with TPM for epilepsy, and analyzed the postmarketing experience of CNS TEAEs with TPM. Our results from 701 treated patients show that cognitive complaints were the most common reason to discontinue TPM. The presence of complaints did have predictive value if the patient would discontinue TPM, although was not specific as to when discontinuation would occur. The spectrum of complaints in our open-label prospective multicenter postmarketing study was similar to those observed in controlled clinical trials. We were unable to demonstrate a specific population, dose titration, or concomitant AED that was at risk to discontinue treatment. We conclude that most patients treated with TPM will continue therapy beyond 6 months. Cognitive complaints and not efficacy reflect the primary reason for discontinuing therapy. Psychomotor slowing was the most common complaint, yet most patients elect to continue treatment, with "better" or "much better" ratings of both seizure and global improvement during treatment.     

Epilepsy Care: Image of the Future

Summary: A number of factors have contributed to improvements in the care of epilepsy during the past decade, including the International League Against Epilepsy classifications, therapeutic antiepileptic drug (AED) monitoring and the concept of monotherapy, new AEDs with novel mechanisms of action, and new insights into etiology that suggest novel therapies. Pharmacologically "clean" AEDs acting on a single known mechanism will be an important element in the future care of patients with epilepsy. Augmentation of GABAergic inhibition is being successfully exploited by AEDs, and there remains much room for further pharmacologic innovation. The potential role of AEDs acting specifically on the GAT-1 or GAT-4 sub-group of γ-aminobutyric acid transporters is a topic of current research. Specifically acting AEDs designed to have a single and known mode of action will permit true monotherapy, one AED with one target as opposed to one AED with several targets, and may open the way to rational polytherapy, i.e., designed use of one AED per mechanism in epilepsies with multifactorial causation. New research demonstrating a possible autoimmune basis for some forms of epilepsy illustrates the potential for novel nonpharmacologic approaches, and the role of prevention must also be emphasized. The image of the future is an optimistic one.