Serotonergic therapy in epilepsy.

PURPOSE OF REVIEW: The serotonergic system is implicated in multiple aspects of epilepsy, including seizure susceptibility, sudden unexpected death in epilepsy (SUDEP), and comorbid depression. Despite the complexity of serotonin's effects on various neuronal networks, ongoing research provides considerable insight into the role of serotonin in human epilepsy. This review explores the potential roles of serotonergic therapies to improve clinical outcomes in epilepsy. RECENT FINDINGS: In recent decades, research has markedly increased our knowledge of the diverse effects of serotonin on brain function. Animal models of epilepsy have identified the influence of serotonin on seizure threshold in specific brain regions, serotoninergic augmentation's protective effects on terminal apnea and mortality in SUDEP, and mechanisms underlying behavioral improvement in some models of comorbid depression. Human clinical studies are largely consistent with animal data but the translation into definitive treatment decisions has moved less rapidly. SUMMARY: Evidence for serotonergic therapy is promising for improvement in seizure control and prevention of SUDEP. For some epilepsies, such as Dravet syndrome, basic research on serotonin receptor agonists has translated into a positive clinical trial for fenfluramine. The cumulative results of safety and efficacy studies support the routine use of SSRIs for comorbid depression in epilepsy.

A Trial of Sertraline or Cognitive Behavior Therapy for Depression in Epilepsy.

OBJECTIVE: Limited evidence is available to guide treatment of depression for persons with epilepsy. We evaluated the comparative effectiveness of sertraline and cognitive behavior therapy (CBT) for depression, quality of life, seizures, and adverse treatment effects. METHODS: We randomly assigned 140 adult outpatients with epilepsy and current major depressive disorder to sertraline or weekly CBT for 16 weeks. The primary outcome was remission from depression based on the Mini International Neuropsychiatric Interview (MINI). Secondary outcomes included the Quality of Life in Epilepsy Inventory-89 (QOLIE-89) seizure rates, the Adverse Events Profile (AEP), the Beck Depression Inventory, and MINI Suicide Risk Module. RESULTS: In the intention-to-treat analysis, 38 (52.8%; 95% confidence interval [CI] = ±12) of the 72 subjects assigned to sertraline and 41 (60.3%; 95% CI = ±11.6) of the 68 subjects in the CBT group achieved remission; the lower bound of efficacy for both groups was greater than our historical placebo control group upper bound of 33.7%. Difference in time to remission between groups was 2.8 days (95% CI = ±0.43; p = 0.79). The percent improvement of mean QOLIE-89 scores was significant for both the CBT (25.7%; p < 0.001) and sertraline (28.3%; p < 0.001) groups. The difference in occurrence of generalized tonic-clonic seizures between groups was 0.3% (95% CI = ±8.6; p = 0.95). Suicide risk at final assessment was associated with persistent depression (p < 0.0001) but not seizures or sertraline. INTERPRETATION: Depression remitted in just over one-half of subjects following sertraline or CBT. Despite the complex psychosocial disability associated with epilepsy, improving depression benefits quality of life. Serotonin reuptake inhibition does not appear to increase seizures or suicidality in persons with epilepsy. ANN NEUROL 2019;86:552-560.

Severity and burden of partial-onset seizures in a phase III trial of eslicarbazepine acetate.

OBJECTIVE: The objective of this study was to compare posttreatment seizure severity in a phase III clinical trial of eslicarbazepine acetate (ESL) as adjunctive treatment of refractory partial-onset seizures. METHODS: The Seizure Severity Questionnaire (SSQ) was administered at baseline and posttreatment. The SSQ total score (TS) and component scores (frequency and helpfulness of warning signs before seizures [BS]; severity and bothersomeness of ictal movement and altered consciousness during seizures [DS]; cognitive, emotional, and physical aspects of postictal recovery after seizures [AS]; and overall severity and bothersomeness [SB]) were calculated for the per-protocol population. Analysis of covariance, adjusted for baseline scores, estimated differences in posttreatment least square means between treatment arms. RESULTS: Out of 547 per-protocol patients, 441 had valid SSQ TS both at baseline and posttreatment. Mean posttreatment TS for ESL 1200 mg/day was significantly lower than that for placebo (2.68 vs 3.20, p<0.001), exceeding the minimal clinically important difference (MCID: 0.48). Mean DS, AS, and SB were also significantly lower with ESL 1200 mg/day; differences in AS and SB exceeded the MCIDs. The TS, DS, AS, and SB were lower for ESL 800 mg/day than for placebo; only SB was significant (p=0.013). For both ESL arms combined versus placebo, mean scores differed significantly for TS (p=0.006), DS (p=0.031), and SB (p=0.001). CONCLUSIONS: Therapeutic ESL doses led to clinically meaningful, dose-dependent reductions in seizure severity, as measured by SSQ scores. CLASSIFICATION OF EVIDENCE: This study presents Class I evidence that adjunctive ESL (800 and 1200 mg/day) led to clinically meaningful, dose-dependent seizure severity reductions, measured by the SSQ.

The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: the PuLsE (Open Prospective Randomized Long-term Effectiveness) trial.

OBJECTIVE: To evaluate whether vagus nerve stimulation (VNS) as adjunct to best medical practice (VNS + BMP) is superior to BMP alone in improving long-term health-related quality of life (HRQoL). METHODS: PuLsE (Open Prospective Randomized Long-term Effectiveness) was a prospective, randomized, parallel-group, open-label, and long-term effectiveness study (conducted at 28 sites in Europe and Canada). Adults with pharmacoresistant focal seizures (n = 112) received VNS + BMP or BMP (1:1 ratio). Medications and VNS parameters could be adjusted as clinically indicated for optimal seizure control while minimizing adverse effects. Primary endpoint was mean change from baseline HRQoL (using Quality of Life in Epilepsy Inventory-89 total score; QOLIE-89). Secondary endpoints included changes in seizure frequency, responder rate (≥50% decrease in seizure frequency), Centre for Epidemiologic Studies Depression scale (CES-D), Neurological Disorders Depression Inventory-Epilepsy scale (NDDI-E), Clinical Global Impression-Improvement scale (CGI-I), Adverse Event Profile (AEP), and antiepileptic drug (AED) load. The study was prematurely terminated due to recruitment difficulties prior to completing the planned enrollment of n = 362. Results for n = 96 who had baseline and at least one follow-up QOLIE-89 assessment (from months 3-12) were included in this analysis. Mixed model repeated measures (MMRM) analysis of variance was performed on change from baseline for the primary and secondary endpoints. RESULTS: Significant between-group differences in favor of VNS + BMP were observed regarding improvement in HRQoL, seizure frequency, and CGI-I score (respective p-values < 0.05, 0.03, and 0.01). More patients in the VNS + BMP group (43%) reported adverse events (AEs) versus BMP group (21%) (p = 0.01), a difference reflecting primarily mostly transient AEs related to VNS implantation or stimulation. No significant difference between treatment groups was observed for changes in CES-D, NDDI-E, AEP, and AED load. SIGNIFICANCE: VNS therapy as a treatment adjunct to BMP in patients with pharmacoresistant focal seizures was associated with a significant improvement in HRQoL compared with BMP alone. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Severe hippocampal atrophy is not associated with depression in temporal lobe epilepsy.

Depression in temporal lobe epilepsy (TLE) is common, is a strong predictor of subjective disability, and may have unique pathophysiological characteristics. Previous studies showed that reduced hippocampal volume is associated with significant depressive symptoms in patients with TLE. We utilized regions of interest analysis of high-resolution brain MRI and a reliable and valid measure of depressive symptoms to evaluate 28 consecutive adult subjects with video-EEG-confirmed TLE. Regions of interest were based on prior human and animal studies of mood and behavioral dysfunction. Forty-three percent of the entire group had significant symptoms of depression, defined by a Beck Depression Inventory (BDI) score of greater than 15. Total hippocampal volumes were significantly smaller in the group with BDI<15, (p<0.007). None of the subjects in the quartile with the smallest left hippocampal volume had a BDI score greater than 15 compared with 57% of the subjects in the upper three quartiles (p<0.008). No other limbic brain structures (amygdala, subcallosal gyrus, subgenual gyrus, gyrus rectus), or total cerebral volume were associated with depressive symptoms. Adequate hippocampal integrity may be necessary to maintain depression symptoms in mesial temporal lobe epilepsy. This finding also supports the possibility of a unique mechanism for depression in mesial temporal lobe epilepsy, such as hyperexcitable neuronal influence on the limbic network.

Response to first antiepileptic drug trial predicts health outcome in epilepsy.

PURPOSE: Failure to respond to the initial antiepileptic drug (AED) is a predictor of increased risk of pharmacoresistant epilepsy. Whether response to the first AED also predicts adverse health outcomes is unknown. METHODS: This longitudinal study compared rates of major adverse health outcomes (loss of driving privileges, unemployment, divorce/separation, injury, emergency room admission, hospitalization, and death) in 33 patients who failed the first AED (cases) and 30 patients who became seizure-free with the first AED (controls). Patient data were obtained by chart review and confirmed through a structured interview with each subject at 5-7 years after starting AED treatment. We also assessed between-group differences in quality of life, depression, and adverse AED effects by using standardized instruments completed by each subject at the end of follow-up. KEY FINDINGS: The number of major adverse health outcomes was similarly high during the first year of AED treatment [mean ± standard deviation (SD) 2.64 ± 0.99 for cases and 2.50 ± 1.14 for controls], but thereafter decreased to a greater extent in controls than in cases (p < 0.001). Controls had a higher cumulative probability of experiencing ≥1 year free from major adverse health outcomes compared to cases (p = 0.002). Two cases died during the follow-up, both of sudden unexpected death. Cases had worse quality of life ratings than controls, whereas no significant between-group differences were found for measures of depression and adverse AED effects. In a post hoc analysis limited to cases, patients who became seizure-free with subsequent AED treatments showed for the first 4 years major adverse health outcome rates similar to those recorded in patients with persisting seizures. After 4 years, however, cases who achieved late seizure freedom tended to show a more favorable outcome. SIGNIFICANCE: Patients with epilepsy failing the initial AED trial are at increased risk of experiencing adverse health outcomes, at least for the first 4 years after diagnosis. Incorporating these findings into clinical decision making may aid in reducing delays in surgical referrals for pharmacoresistant epilepsy.

Preference-based quality-of-life measures for neocortical epilepsy surgery.

Critical to decision analysis studies are measures of outcome utilities. In epilepsy surgery the benefit versus risk ratio is of particular interest in neocortical resections. Using the standard gamble, we measured preferences of 30 epilepsy patients for 10 outcome states specific to neocortical epilepsy surgery. Although considered preliminary, the findings suggest that the value of being seizure-free may be greater than that of continued disabling seizures, even if some deficits typical of "eloquent" cortex injury are incurred with surgery. Seizure freedom achieved with polytherapy medical management may be less desirable than that achieved with surgery and monotherapy.

Identifying epilepsy surgery candidates in the outpatient clinic.

Epilepsy is the most prevalent disabling neurological disorder across the life span, and is not controlled by medications in more than one-third of patients. Epilepsy surgery is an accepted treatment, with guidelines supporting utilization in patients with recurrent temporal lobe seizures after two or more trials of antiepileptic medications. Unfortunately, the average delay in presurgical evaluation of appropriate candidates is more than 20 years, and this delay has not improved in recent decades. This offers the international neurological community the opportunity to improve disability, mortality, and quality of life by more effective application of epilepsy surgery and earlier identification of potential candidates. Optimal use of MRI and video/EEG monitoring should allow cost-effective screening of persons with recurrent seizures prior to more detailed presurgical evaluation when indicated.

More effective assessment of adverse effects and comorbidities in epilepsy: results of a Phase II communication study.

Research was conducted to evaluate conversations about epilepsy between community-based neurologists and patients. Adverse effects of antiepileptic drugs and mood/behavioral issues were infrequently discussed, and neurologists and patients disagreed about these issues postvisit. Follow-up research was conducted to assess the impact of a previsit assessment tool on discussions of epilepsy. Twenty neurologists reviewed a tool incorporating questions from validated instruments (Adverse Events Profile [AEP] and Neurological Disorders Depression Inventory for Epilepsy [NDDI-E]). Naturally occurring interactions between neurologists and 60 patients were recorded. Neurologists and patients were interviewed separately. All components were transcribed and analyzed using sociolinguistics. Using the previsit assessment tool increased the number of discussions about adverse effects and mood/behavioral issues and increased neurologist-patient agreement about issues postvisit. Visit length did not increase significantly when the tool was used. Ten months after follow-up research, 50% of neurologists reported continuing to use the tool in everyday practice with patients with epilepsy.

Case Report: PAFAH1B1 Mutation and Posterior Band Heterotopia With Focal Temporal Lobe Epilepsy Treated by Responsive Neurostimulation.

Subcortical band heterotopia (SBH), also known as double cortex syndrome, is a malformation of cortical development caused by inherited or somatic gene variants. We present a case of a young adult with posterior SBH and electroclinical features of focal neocortical temporal lobe epilepsy. Genomic blood analysis identified a pathogenic somatic mosaicism duplication variant of the PAFAH1B1 gene. Despite bilateral cortical MRI abnormalities, the interictal and ictal EEG findings indicated a focal epileptogenic region in the left posterior temporal region. Chronic responsive cortical neurostimulation across two four-contact depth electrodes placed 5 mm on either side of the maximal interictal spiking identified during intraoperative electrocorticography resulted in a consistent 28% reduction in duration of electrographic seizures and as well as constricted propagation. Although electrographic seizures continued, the family reported no clinical seizures and a marked improvement in resistant behaviors. This observation supports that focal neocortical neuromodulation can control clinical seizures of consistently localized origin despite genetic etiology, bilateral structural brain abnormalities, and continuation of non-propagating electrographic seizures. We propose that a secondary somatic mutation may be the cause of the focal neocortical temporal lobe epilepsy.

Seizure-related injuries are underreported in pharmacoresistant localization-related epilepsy.

PURPOSE: To investigate and compare injury rates, associated risk factors, circumstances, and medical record documentation in patients with pharmacoresistant temporal lobe epilepsy (TLE) and extratemporal lobe epilepsy (ETLE). METHODS: The study cohort consisted of fifty-two consecutive adults with treatment-resistant epilepsy and seizure classification confirmed by video-electrocardiography (EEG) (28 with TLE and 24 with ETLE) who consented to participate. All subjects had their seizures classified with prior video-EEG monitoring, were followed in a tertiary-care center in northwest New York City, and received a semistructured phone interview regarding injuries experienced since being diagnosed with epilepsy. RESULTS: Injuries were reported in 16 (57%) of the patients with TLE and 4 (17%) of the patients with ETLE (p = 0.004 after controlling for duration of epilepsy and seizure burden); 83% of all injuries were designated by patients as seizure-related. Most injuries (22 of 41; 54%) were classified as moderate or greater in severity. In addition, one motor vehicle accident (MVA) was reported in the TLE group and one episode of sudden unexpected death (SUDEP) was identified in the ETLE group. More than half (55%) of the injuries were not documented as seizure-related in medical records. CONCLUSION: A substantial number of potentially serious injuries are not documented as seizure related, even in a tertiary-care setting. Patients with pharmacoresistant TLE may be at higher risk for experiencing an injury than patients with pharmacoresistant ETLE.

General surgery among long-term residents with and without active epilepsy at the Kork Epilepsy Centre - a prospective comparative one-year survey.

BACKGROUND/AIMS: We prospectively assessed the frequency, type, severity and cause of treatment among the long-term residents of the Kork Epilepsy Centre in the year 2005. METHODS: All long-term residents were exclusively referred to the general surgeon practicing on the campus. Patients were divided into 2 groups comprising 285 patients with active epilepsy and 53 controls who either never had epileptic seizures or have remained seizure free for at least 4 years. RESULTS: The 1-year incidence of injuries was 54.2% among the active epilepsy group and 36.8% among controls (p = 0.0275). Several admissions due to differing reasons occurred in 16.8% of people with active epilepsy and in 7.5% of the controls (not significant). More than 2 admissions due to various reasons only occurred in patients with active epilepsy (range 3-9). Of all injuries, 41.3% were directly related to seizures. Among patients with active epilepsy, the 3 most frequent injuries were lacerations, bruises and fractures (29.6, 17.0 and 11.7%, respectively). CONCLUSION: According to this prospective study, active epilepsy turned out to be a significant risk factor for injuries under homogenous patient and observer conditions.

Epilepsy treatment as a predeterminant of psychosocial ill health.

Epilepsy is a chronic disorder with complex effects on social, vocational, physical, and psychological well-being. Patient-oriented research has demonstrated that recurrent seizures have a strong adverse effect on health-related quality of life, but also that seizure rate in persons with pharmacoresistant epilepsy has only a modest correlation with quality of life. Although treatment side effects have received limited attention in epilepsy research, available evidence indicates that adverse medication effects may explain more variance in quality of life than any other clinical variable in persons with pharmacoresistant epilepsy. Furthermore, systematic screening for adverse effects has been shown to be associated with significant reduction in subjective toxicity and improvement in quality of life. There has been only limited research on the relative contribution of specific adverse effects to impaired health-related quality of life. The relative importance of reduction of medication burden after resective epilepsy surgery or vagal nerve stimulation has similarly received sparse attention. Existing deficiencies in the available published research present challenges and opportunities to perform further investigations to define and improve best clinical practices in epilepsy care.

Seizure remission and relapse in adults with intractable epilepsy: a cohort study.

PURPOSE: To investigate the cumulative probabilities of >or=12 month seizure remission and seizure relapse following remission, and to test the associations of clinical characteristics with these two study end points in a prevalence cohort of intractable adult epilepsy patients during medical management. METHODS: A retrospective cohort study of intractable epilepsy patients seen in 2001 at a single center was conducted. Kaplan-Meier analysis was used to estimate the cumulative probabilities of seizure remission and subsequent seizure relapse. Cox proportional hazards models were used to estimate the association (1) between clinical factors and >or=12 month seizure remission and (2) between clinical factors and seizure relapse following remission. RESULTS: One hundred eighty-seven subjects met the eligibility criteria for intractable epilepsy. The estimate of probability of remission was about 4% per year. Seizure remission was temporary for some individuals, as 5 out of 20 subjects with remission ultimately relapsed. No clinical factors predicted the likelihood of achieving >or=12 month seizure remission or subsequent seizure relapse. DISCUSSION: Some people with intractable epilepsy achieve >or=12 month seizure remission during medical treatment. Remission, however, is only temporary for some individuals. We were unable to identify clear predictors for remission.

Consensus statement: the evaluation and treatment of people with epilepsy and affective disorders.

Affective disorders in people with epilepsy (PWE) have become increasingly recognized as a primary factor in the morbidity and mortality of epilepsy. To improve the recognition and treatment of affective disorders in PWE, an expert panel comprising members from the Epilepsy Foundation's Mood Disorders Initiative have composed a Consensus Statement. This document focuses on depressive disorders in particular and reviews the appearance and treatment of the disorder in children, adolescents, and adults. Idiosyncratic aspects of the appearance of depression in this population, along with physiological and cognitive issues and barriers to treatment, are reviewed. Finally, a suggested approach to the diagnosis of affective disorders in PWE is presented in detail. This includes the use of psychometric tools for diagnosis and a stepwise algorithmic approach to treatment. Recommendations are based on the general depression literature as well as epilepsy-specific studies. It is hoped that this document will improve the overall detection and subsequent treatment of affective illnesses in PWE.

Epilepsy surgery for pharmacoresistant temporal lobe epilepsy: a decision analysis.

CONTEXT: Patients with pharmacoresistant epilepsy have increased mortality compared with the general population, but patients with pharmacoresistant temporal lobe epilepsy who meet criteria for surgery and who become seizure-free after anterior temporal lobe resection have reduced excess mortality vs those with persistent seizures. OBJECTIVE: To quantify the potential survival benefit of anterior temporal lobe resection for patients with pharmacoresistant temporal lobe epilepsy vs continued medical management. DESIGN: Monte Carlo simulation model that incorporates possible surgical complications and seizure status, with 10,000 runs. The model was populated with health-related quality-of-life data obtained directly from patients and data from the medical literature. Insufficient data were available to assess gamma-knife radiosurgery or vagal nerve stimulation. MAIN OUTCOME MEASURES: Life expectancy and quality-adjusted life expectancy. RESULTS: Compared with medical management, anterior temporal lobe resection for a 35-year-old patient with an epileptogenic zone identified in the anterior temporal lobe would increase survival by 5.0 years (95% CI, 2.1-9.2) with surgery preferred in 100% of the simulations. Anterior temporal lobe resection would increase quality-adjusted life expectancy by 7.5 quality-adjusted life-years (95%, CI, -0.8 to 17.4) with surgery preferred in 96.5% of the simulations, primarily due to increased years spent without disabling seizures, thereby reducing seizure-related excess mortality and improving quality of life. The results were robust to sensitivity analyses. CONCLUSION: The decision analysis model suggests that on average anterior temporal lobe resection should provide substantial gains in life expectancy and quality-adjusted life expectancy for surgically eligible patients with pharmacoresistant temporal lobe epilepsy compared with medical management.

Robotic-Guided Bihippocampal and Biparahippocampal Depth Placement for Responsive Neurostimulation in Bitemporal Lobe Epilepsy.

BACKGROUND: Patients with bitemporal lobe epilepsy are generally not considered for surgical resection. Fortunately, responsive neurostimulation provides another avenue for the management of this challenging disease process. In conjunction with our epileptologist, we consider responsive neurostimulation for patients who have clinical features of temporal lobe epilepsy without clear localization on imaging and stereoelectroencephalography. METHODS: Here we describe our technique for implanting a responsive neurostimulator (NeuroPace, NeuroPace Inc., Mountain View, California) with depth electrodes monitoring the hippocampus and parahippocampus using stereotactic robotic guidance (ROSA, Medtech SA, Montpeillier, France). RESULTS: We have used this technique with 5 patients without morbidity. Four of 5 patients have received clinical benefit (Engel classification I-III). Promisingly, long-term seizure monitoring with use of the NeuroPace system has suggested lateralizing information on 3 of these patients that was not apparent on previous invasive monitoring. CONCLUSIONS: Robotically implanted responsive neurostimulation is a safe and effective treatment for bitemporal epilepsy and can possibly lead to valuable diagnostic information to guide future surgical management in patients who previously were not considered candidates for resective or ablative surgery.

Brain tumors associated with psychogenic non-epileptic seizures: Case series.

OBJECTIVE: The association of psychogenic non-epileptic seizures (PNES) with primary or secondary brain tumors has not been well described in the literature. We aim to discuss their association, and their impact in brain tumor treatment. PATIENTS AND METHODS: We identified four patients retrospectively from our practice. The diagnosis of PNES was based on clinical suspicion and standard EEG, supplemented with video-EEG recording in 2 patients. RESULTS: The initial diagnosis of brain tumor was associated with a new onset seizure prior to diagnosis. The majority of the patients presented with ES followed by recurrent PNES during the course of their disease. Patients were treated with multiple anti-epileptic drugs, requiring frequent schedule adjustments. The preferred tumor treatment modality was chemotherapy, followed by surgical resection. The patients were offered psychological consultation achieving partial control of their events. These patients manifested recurrent disabling clinical events that required multiple medical consultations. None of these patients presented clinical evidence of tumor progression at the time of PNES presentation. CONCLUSION: A high index of suspicion and early psychological consultation referral will likely mitigate the quality of life impact of PNES in these patients.

A Murine Model to Study Epilepsy and SUDEP Induced by Malaria Infection.

One of the largest single sources of epilepsy in the world is produced as a neurological sequela in survivors of cerebral malaria. Nevertheless, the pathophysiological mechanisms of such epileptogenesis remain unknown and no adjunctive therapy during cerebral malaria has been shown to reduce the rate of subsequent epilepsy. There is no existing animal model of postmalarial epilepsy. In this technical report we demonstrate the first such animal models. These models were created from multiple mouse and parasite strain combinations, so that the epilepsy observed retained universality with respect to genetic background. We also discovered spontaneous sudden unexpected death in epilepsy (SUDEP) in two of our strain combinations. These models offer a platform to enable new preclinical research into mechanisms and prevention of epilepsy and SUDEP.

Rapid detection of major depression in epilepsy: a multicentre study.

BACKGROUND: Depression is a common comorbid disorder in epilepsy but is not routinely assessed in neurology clinics. We aimed to create a rapid yet accurate screening instrument for major depression in people with epilepsy. METHODS: We developed a set of 46 items to identify symptoms of depression that do not overlap with common comorbid cognitive deficits or adverse effects of antiepileptic drugs. This preliminary instrument and several reliable and valid instruments for diagnosis of depression on the basis of criteria from the Diagnostic and Statistical Manual IV, depression symptom severity, health status, and toxic effects of medication were applied to 205 adult outpatients with epilepsy. We used discriminant function analysis to identify the most efficient set of items for classification of major depression, which we termed the neurological disorders depression inventory for epilepsy (NDDI-E). Baseline data for 229 demographically similar patients enrolled in two other clinical studies were used for verification of the original observations. FINDINGS: The discriminant function model for the NDDI-E included six items. Internal consistency reliability of the NDDI-E was 0.85 and test-retest reliability was 0.78. An NDDI-E score of more than 15 had a specificity of 90%, sensitivity of 81%, and positive predictive value of 0.62 for a diagnosis of major depression. Logistic regression showed that the model of association of major depression and the NDDI-E was not affected by adverse effects of antiepileptic medication, whereas models for depression and generic screening instruments were. The severity of depression symptoms and toxic effects of drugs independently correlated with subjective health status, explaining 72% of variance. Results from a separate verification sample also showed optimum sensitivity, specificity, and predictive power at a cut score of more than 15. INTERPRETATION: Major depression in people with epilepsy can be identified by a brief set of symptoms that can be differentiated from common adverse effects of antiepileptic drugs. The NDDI-E could enable rapid detection and improve management of depression in epilepsy in accordance with internationally recognised guidelines.