Adverse antiepileptic drug effects in new-onset seizures: a case-control study.

OBJECTIVE: Adverse effects (AEs) are a major concern when starting antiepileptic drug (AED) treatment. This study quantified the extent to which AE reporting in people with new-onset seizures started on AEDs is attributable to the medication per se, and investigated variables contributing to AE reporting. METHODS: We pooled data from 2 large prospective studies, the Multicenter Study of Early Epilepsy and Single Seizures and the Northern Manhattan Study of incident unprovoked seizures, and compared adverse event profile (AEP) total and factor scores between adult cases prescribed AEDs for new-onset seizures and untreated controls, adjusting for several demographic and clinical variables. Differences in AEP scores were also tested across different AED monotherapies and controls, and between cases and controls grouped by number of seizures. RESULTS: A total of 212 cases and 206 controls were identified. Most cases (94.2%) were taking low AED doses. AEP scores did not differ significantly between the 2 groups. Depression, female gender, symptomatic etiology, younger seizure onset age, ≥2 seizures, and history of febrile seizures were associated with higher AEP scores. There were no significant differences in AEP scores across different monotherapies and controls. AEP scores increased in both cases and controls with increasing number of seizures, the increment being more pronounced in cases. CONCLUSIONS: When AED treatment is started at low doses following new-onset seizures, AE reporting does not differ from untreated individuals. Targeting specific factors affecting AE reporting could lead to improved tolerability of epilepsy treatment.

Hippocampal 1H-MRSI correlates with severity of depression symptoms in temporal lobe epilepsy.

OBJECTIVE: To investigate the association of an indicator of hippocampal function with severity of depression symptoms in temporal lobe epilepsy. METHODS: We evaluated 31 patients with video/EEG-confirmed temporal lobe epilepsy using creatine/N-acetylaspartate ratio maps derived from a previously validated (1)H magnetic resonance spectroscopic imaging ((1)H-MRSI) technique at 4.1 T. We also assessed depression symptoms, epilepsy-related factors, and self-perceived social and vocational disability. We used conservative nonparametric bivariate procedures to determine the correlation of severity of depression symptoms with imaging and clinical variables. RESULTS: The extent of hippocampal (1)H-MRSI abnormalities correlated with severity of depression (Spearman rho = 0.65, p value < 0.001), but other clinical factors did not. CONCLUSION: The extent of hippocampal dysfunction is associated with depression symptoms in temporal lobe epilepsy and may be a more important factor than seizure frequency or degree of disability.

Evaluating functional MRI procedures for assessing hemispheric language dominance in neurosurgical patients.

Two methods of quantifying hemispheric language dominance (HLD) in neurosurgical patients are compared: (1) an average magnitudes (AM) method, which is a calculation of the average signal intensity variation in regions of interest for each patient that were predefined in a group analysis for each task, and (2) a lateralization indices (LI) method, which is based on the number of activated pixels in regions of interest predefined in each individual patient. Four language tasks [a living/nonliving (LNL) judgment, word stem completion (WSC), semantic associate (SA) and a phonological associate (PA) task] were compared with "gold standard" measures such as the Wada test or electrocortical stimulation. Results showed that the LI method was more accurate (73% agreement with gold standard methods) than the AM method (only 40% agreement) across tasks and subjects. Furthermore, by varying the threshold used for determining laterality, the ability of functional magnetic resonance imaging (fMRI) to predict HLD was influenced for the AM method, whereas the LI method was relatively unaffected by changing the threshold. Using the LI method, the SA task was the most accurate for quantifying HLD (100% agreement with gold standard methods) with respect to the other three language tasks (80% accuracy for WSC, 65% for the LNL and 63% for phonological task). Depending on the method and the task, fMRI may be a promising tool for assessing HLD in neurosurgical patients.

Epilepsy--success in clinical practice: translating trials to practice.

Success in clinical practice results from the combination of a clinician's experience, an understanding of patient preferences and factors that influence patient perceptions, and careful interpretation of data from clinical trials. However, successful clinical trials fulfil rigid methodological requirements in order to provide a basis from which to evaluate the place of a drug within a therapeutic strategy. Their translation into practice is therefore complicated by an intrinsic tension between the requirements for scientific methods that minimize error, and the need for clinically relevant data. In practice, the clinician has the flexibility to individualize epilepsy management to maximize benefits and minimize adverse effects of antiepileptic drug (AED) therapy. AED adverse effects and psychiatric comorbidity, in particular depression, have a profound impact on subjective health status; systematic screening for these confounding variables can guide clinical management and optimize quality of life. In addition, patient preferences can be acknowledged in any management plan. To achieve success in clinical practice, we need to remember that the information gleaned from clinical trials provides only part of the picture and needs to be augmented by our clinical experience, patient assessment (including routine screening for adverse effects and depression) and patient preference.

Systematic screening allows reduction of adverse antiepileptic drug effects: a randomized trial.

OBJECTIVE: To determine the effectiveness of systematic screening with a brief 19-item self-report instrument, the Adverse Events Profile (AEP), to reduce adverse effects of antiepileptic drugs (AEDs) and improve subjective health status. METHODS: The authors performed a prospective randomized trial comparing the use of the AEP with usual care without the AEP. Sixty-two patients with an AEP score of >or=45 were enrolled from a consecutive group of 200 consenting adults with epilepsy. RESULTS: The mean percent improvement in AEP scores was greater in the patient group for which clinicians received the AEP compared with the usual care group (25% vs 5%; p < 0.01). Mean change in Quality of Life in Epilepsy Inventory (QOLIE)-89 total scores was not different between groups, but for the entire sample QOLIE-89 change was greater for patients having a 15-point improvement in AEP scores than for those with a 0- to 15-point improvement or a worsened score (24 vs 12 vs 3; analysis of variance, p < 0.008). More patients in the AEP group had a >15-point improvement in QOLIE-89 score (p < 0.03). Use of the AEP was associated with a 2.8-fold increase (95% CI, 1.7 to 4.8) in AED modifications. No difference in seizure rates was observed. CONCLUSIONS: Systematic screening for antiepileptic drug side effects may increase identification of toxicity and guide medication changes to reduce adverse effects and possibly improve subjective health status.

Occurrence of seizure clusters and status epilepticus during inpatient video-EEG monitoring.

OBJECTIVE: To investigate the occurrence of status epilepticus and seizure clusters, and the duration until first seizure at epilepsy monitoring units in the United States. METHODS: The authors examined the inpatient video-EEG monitoring reports of 514 consecutive patients admitted to five comprehensive epilepsy centers during the year 2000. Time to first seizure, seizure clustering, and seizure duration were ascertained from reports and entered into a database. RESULTS: In 169 admissions with complex partial seizures (CPSs) or secondarily generalized tonic-clonic (2GTC) seizures, there were 5 (3.0%) patients with status epilepticus, 30 (17.8%) with 4-hour seizure clusters, and 82 (48.5%) with 24-hour seizure clusters. There were no statistically significant differences between centers, except that seizure clusters were observed to be less common at the one center with a formal drug withdrawal protocol. The average time to CPS or 2GTC seizure was 2.1 days; the average number of days to nonepileptic event was 1.2 days (p = 0.001). CONCLUSIONS: Although status epilepticus is uncommon at epilepsy monitoring units, clusters of seizures are common. Intensive monitoring with drug withdrawal must be performed in a highly supervised, hospitalized setting. Inpatient video-EEG monitoring is efficient, with recording of the first epileptic or nonepileptic events in 2 days or less.

A dose-comparison trial of topiramate as monotherapy in recently diagnosed partial epilepsy.

OBJECTIVE: To evaluate topiramate as monotherapy in adults and children with recently diagnosed, localization-related epilepsy, comparing two dosages of topiramate in a multicenter, randomized, double-blind study. METHODS: Adults and children (>/=3 years of age) were eligible if the maximum interval since epilepsy diagnosis was 3 years and patients had one to six partial-onset seizures during a 3-month retrospective baseline. At study entry, patients (N = 252) were untreated or receiving one antiepileptic drug for less than 1 month. After randomization to 50 or 500 mg/d topiramate (25 or 200 mg/d if weight

Bilateral hippocampal atrophy: consequences to verbal memory following temporal lobectomy.

BACKGROUND: Bilateral hippocampal damage is a risk factor for memory decline after anterior temporal lobectomy (ATL). OBJECTIVE: To investigate verbal memory outcome in patients with temporal lobe epilepsy (TLE) with either unilateral or bilateral hippocampal atrophy as measured by MRI. METHODS: The authors selected 60 patients with TLE who had undergone ATL (left = 31, right = 29). They determined normalized MRI hippocampal volumes by cursor tracing 1.5-mm slices from three-dimensional MRI acquisition. Hippocampal volumes were defined as atrophic if the volumes were below 2 SD for control subjects. Bilateral hippocampal atrophy was present in 10 patients with left TLE and 11 patients with right TLE. The authors assessed acquisition, retrieval, and recognition components of verbal memory both before and after ATL. RESULTS: Groups did not differ across age, education, intelligence, age at seizure onset, or seizure duration. Seizure-free rates after ATL were 70% or higher for all groups. Before surgery, patients with left TLE displayed worse verbal acquisition performance compared with patients with right TLE. Patients with left TLE with bilateral hippocampal volume loss displayed the lowest performance across all three memory components. After surgery, both groups of patients with left TLE exhibited worse verbal memory outcome compared with patients with right TLE. Bilateral hippocampal atrophy did not worsen outcome in the patients with right TLE. A higher proportion of patients with left TLE with bilateral hippocampal atrophy experienced memory decline compared with the other TLE groups. CONCLUSION: Bilateral hippocampal atrophy in the presence of left TLE is associated with worse verbal memory before and after ATL compared with patients with unilateral hippocampal volume loss or right TLE with bilateral hippocampal volume loss.

Wisconsin Card Sorting performance in patients with temporal lobe epilepsy: clinical and neuroanatomical correlates.

PURPOSE: A sizable proportion of patients with temporal lobe epilepsy (TLE) display impairments on tests of executive function. Previous studies have suggested several factors that may explain such performance, including the presence of hippocampal sclerosis, electrophysiological disruption to extratemporal regions, and early age of seizure onset. However, no clear determinants have been found that consistently explain such executive dysfunction. The present study investigated the contribution of several clinical variables and temporal lobe neuroanatomic features to performance on the Wisconsin Card Sorting Test (WCST) in a series of patients with TLE. METHODS: Eighty-nine patients with lateralized TLE (47 left, 42 right) were examined. Seventy-two patients from this series underwent anterior temporal lobectomy (ATL). Regression analysis was used to examine the effects of age, education, age at seizure onset, seizure duration, seizure laterality, history of secondary generalized seizures, and MRI-based volumes of the right and left hippocampi on preoperative WCST performance (number of categories completed, perseverative errors). Further univariate analyses examined whether the presence of bilateral hippocampal sclerosis, mesial temporal lobe abnormalities beyond the hippocampus, or temporal neocortical abnormalities affected preoperative WCST performance. In addition, we examined whether becoming seizure free after ATL affected change in WCST performance. RESULTS: Overall regression analysis was not significant. However, an examination of individual partial correlations revealed that patients with a history of secondary generalized seizures performed more poorly on the preoperative WCST than did patients without such history. In addition, patients who were seizure free after ATL did not exhibit better WCST outcome than patients who did not become seizure free. The presence of bilateral hippocampal sclerosis, extrahippocampal mesial temporal atrophy, or temporal neocortical lesions did not affect WCST performance. CONCLUSIONS: These results indicate that the presence of temporal lobe structural abnormalities do not significantly affect executive function as measured by the WCST. The present study does suggests that the critical determinants of WCST performance in patients with TLE lie outside the temporal lobe and likely relate to metabolic disruption to frontostriatal neural network systems.

Investigation of executive function change following anterior temporal lobectomy: selective normalization of verbal fluency.

The nociferous cortex hypothesis predicts that electrophysiological normalization to distal extratemporal brain regions following anterior temporal lobectomy (ATL) will result in improvements in executive functioning. The present study examined the effects of seizure laterality and seizure control on executive function change. The authors administered the Wisconsin Card Sorting Test (WCST), Trails B, and the Controlled Oral Word Association Test to 174 temporal lobe epilepsy patients who underwent ATL. No significant changes were found on the WCST or Trails B tests, regardless of surgery side or seizure-free status. However, verbal fluency significantly improved in seizure-free patients. Findings were consistent with the nociferous cortex hypothesis suggesting selective executive function improvement following ATL. These findings are discussed in terms of recent research demonstrating extrahippocampal metabolic normalization following surgery.

Visual confrontation naming and hippocampal function: A neural network study using quantitative (1)H magnetic resonance spectroscopy.

Prior research on the relationship between visual confrontation naming and hippocampal function has been inconclusive. The present study examined this relationship using quantitative (1)H magnetic resonance spectroscopy ((1)H-MRS) to operationalize the function of the left and right hippocampi. The 60-item Boston Naming Test (BNT) was used to measure naming. Our sample included 46 patients with medically intractable, focal mesial temporal lobe epilepsy who had been screened for all pathology other than mesial temporal sclerosis. Statistics included Pearson correlations and neural network analysis (multilayer perceptron and radial basis function). Baseline BNT performance correlated significantly with left (1)H-MRS hippocampal ratios. Thirty-six per cent of the variance in baseline BNT performance was explained by a neural network model using left and right (1)H-MRS ratios(creatine/N-acetylaspartate) as input. This was elevated to 49% when input from the right hippocampus was lesioned mathematically. In a second model, left (1)H-MRS hippocampal ratios were modelled using measures of semantic and episodic memory as input (including the BNT). Explained variance in left (1)H-MRS hippocampal ratios fell from 60.8 to 3.6% when input from BNT and another semantic memory measure was degraded mathematically. These results provide evidence that the speech-dominant hippocampus is a significant component of the overall neuroanatomical network of visual confrontation naming. Clinical and theoretical implications are explored.

MRI extrahippocampal volumes and visual memory: correlations independent of MRI hippocampal volumes in temporal lobe epilepsy patients.

Limbic system atrophy and memory dysfunction are common in patients with temporal lobe epilepsy (TLE). However, the relationship between extrahippocampal limbic structures and memory functioning within TLE has received little attention. The present study examined associations of MRI volumetric measurements of the mammillary body, fornix, amygdala, and hippocampus to measures of episodic verbal and visual memory. The Logical Memory and Visual Reproduction subtests from the Wechsler Memory Scale were administered to 47 unilateral TLE patients (25 right, 22 left). Normalized right and left MRI volumes were determined for each patient by cursor tracing 1.5 mm slices from 3D-MRI. Significant associations were found between left hippocampal volume and the immediate, delayed, and percent retention scores of the Logical Memory Test; between the left mammillary body volume and the Logical Memory Test delayed and percent retention scores; immediate Visual Reproduction performance was significantly related to the right and left amygdala volumes, and right mammillary body volume; only the right amygdala and right mammillary body volume were associated with the delayed Visual Reproduction trial. However, neither right nor left hippocampal volumes were related to visual memory performance. Multiple limbic system structural volumes were independently associated with verbal and nonverbal memory performance. Results suggest that visual memory, as measured by the Visual Reproduction Test, may be uniquely associated with extrahippocampal volumes in patients with TLE.

Improved health care resource utilization following video-EEG-confirmed diagnosis of nonepileptic psychogenic seizures.

The economic burden of epilepsy is well recognized. However, empirical investigation establishing costs associated with the diagnosis and treatment of non-epileptic psychogenic seizures (NEPS) is lacking. We studied 20 patients with video/EEG monitoring-confirmed NEPS to determine the effect of definitive diagnosis and treatment on medical costs and utilization. A medical resource utilization questionnaire and inpatient medical chart review were employed to calculate utilization information. Medication usage, outpatient visits, emergency room admissions, and diagnostic testing over a 6-month pre-diagnosis and a 6-month post-diagnosis period were compared. There was an 84% average reduction in total seizure-related medical charges in the 6 months following NEPS diagnosis. Average diagnostic testing charges declined 76%, average medication charges decreased 69%, outpatient clinic visits declined 80%, and emergency room visits reduced by 97%. A majority of patients obtaining a definitive inpatient video/EEG-seizure-monitoring-confirmed NEPS diagnosis experience substantial reductions in health care utilization and dollar costs.

Individual memory change after anterior temporal lobectomy: a base rate analysis using regression-based outcome methodology.

PURPOSE: To characterize patterns of base rate change on measures of verbal and visual memory after anterior temporal lobectomy (ATL) using a newly developed regression-based outcome methodology that accounts for effects of practice and regression towards the mean, and to comment on the predictive utility of baseline memory measures on postoperative memory outcome. METHODS: Memory change was operationalized using regression-based change norms in a group of left (n = 53) and right (n = 48) ATL patients. All patients were administered tests of episodic verbal (prose recall, list learning) and visual (figure reproduction) memory, and semantic memory before and after ATL. RESULTS: ATL patients displayed a wide range of memory outcome across verbal and visual memory domains. Significant performance declines were noted for 25-50% of left ATL patients on verbal semantic and episodic memory tasks, while one-third of right ATL patients displayed significant declines in immediate and delayed episodic prose recall. Significant performance improvement was noted in an additional one-third of right ATL patients on delayed prose recall. Base rate change was similar between the two ATL groups across immediate and delayed visual memory. Approximately one-fourth of all patients displayed clinically meaningful losses on the visual memory task following surgery. Robust relationships between preoperative memory measures and nonstandardized change scores were attenuated or reversed using standardized memory outcome techniques. CONCLUSIONS: Our results demonstrated substantial group variability in memory outcome for ATL patients. These results extend previous research by incorporating known effects of practice and regression to the mean when addressing meaningful neuropsychological change following epilepsy surgery. Our findings also suggest that future neuropsychological outcome studies should take steps towards controlling for regression-to-the-mean before drawing predictive conclusions.

Contribution of neuropsychological data to the prediction of temporal lobe epilepsy surgery outcome.

PURPOSE: We empirically examined the contribution of neuropsychological data to the prediction of postoperative seizure control relative to base rate information in an existing series of patients undergoing anterior temporal lobectomy (ATL). METHODS: A discriminant function predicting surgery outcome (seizure-free vs. non-seizure-free) was computed separately for samples of patients with left (n = 79) and right (n = 62) temporal lobectomy (LATL, RATL). Predictor variables included 14 measures tapping five neurocognitive domains. The predicted base rates were compared with the actual base rates in the two samples. Finally, overall predictive accuracy was examined in optimal versus suboptimal ATL patients. RESULTS: The base rate of seizure freedom in the LATL group was 74.70%; that in the RATL group was 66.10%. The predictive function for the LATL group achieved a hit rate of 80.00% and a positive predictive power of 92.11%. The function for the RATL group achieved a hit rate of 83.33% and a positive predictive power (PPP) of 89.66%. The overall predictive accuracy for the optimal group was only 55%, but that in the suboptimal group was 72%. CONCLUSIONS: Neuropsychological data used in a multivariate statistical fashion may be able to offer an incremental increase in the prediction of postoperative seizure freedom relative to existing base rates of surgery success in patients with ATL epilepsy. The use of neuropsychological data may be of greatest predictive value in a population of ATL candidates with suboptimal findings with a lower base rate of postoperative seizure freedom, but may actually reduce predictive accuracy in a group of ATL candidates from an optimal population with an already high base rate of surgical success.

Is the intracellular pH different from normal in the epileptic focus of patients with temporal lobe epilepsy? A 31P NMR study.

We performed in vivo 31P NMR spectroscopic studies of human brain on a 4.1 T whole-body NMR system. Based on a control group of 20 healthy volunteers, the normal pHi was 7.05 (SD, 0.06; SEM, 0.01) in the left temporal lobe and 7.04 (SD, 0.04; SEM, 0.01) in the right temporal lobe. We also studied a patient group consisting of 13 individuals with unilateral temporal lobe epilepsy. The mean pHi was 7.02 (SD, 0.04; SEM, 0.01) in the ipsilateral lobe and 7.02 (SD, 0.05; SEM, 0.01) in the contralateral lobe. These results clearly show that no statistically significant difference in pHi is observed between the two lobes, either in normal controls or in patients. Also, no significant pHi difference exists between the control group and the patient group. Lateralization in each of the 13 patients with unilateral epilepsy, based on their individual pHi difference between the ipsilateral lobe and contralateral lobe (delta pHi), showed that three patients were nondiagnostic cases because their delta pHis were not significantly different from zero (< or = 0.02), five patients showed small delta pHis consistent with their clinical lateralization, whereas the remaining five patients showed delta pHi-based lateralization opposite to the clinical findings. These results seem to indicate an essentially random distribution around delta pHi = 0 within a very small experimental error of +/-0.02 pH units. pHi obtained from eight different areas in each of the 13 unilateral patients also did not show any significantly nonzero delta pHi values. These results led to the conclusion that even at the excellent spectral resolution and reproducibility of the 4.1 T machine (typical SD of 0.05 pH units), no significant pHi effect, induced by temporal lobe epilepsy, could be detected. Therefore, in this study, delta pHi does not appear to be a clinically useful tool for the lateralization of epileptic foci in patients with temporal lobe epilepsy.

Normalization of contralateral metabolic function following temporal lobectomy demonstrated by 1H magnetic resonance spectroscopic imaging.

We studied 10 medically intractable temporal lobe epilepsy (TLE) patients prior to surgery using proton magnetic resonance spectroscopic imaging (MRSI) to localize seizure foci. We found significantly elevated creatine/N-acetylaspartate (Cr/NAA) unilaterally in 8 and bilaterally in 2 patients. Five patients have been studied again 1 year after surgery. In the 2 patients with bilateral temporal seizure onsets, MRSI showed normalization of Cr/NAA in the unoperated contralateral tissue following surgical elimination of seizures. This study suggests that metabolic recovery can occur in contralateral temporal areas following surgical treatment of partial epilepsy.

Significance of spontaneous epileptiform abnormalities associated with a photoparoxysmal response.

Spontaneous epileptiform abnormalities (SEAs) are reported to occur in up to 65% of patients with a photoparoxysmal response (PPR). Although the PPR is usually assumed to indicate primary generalized epilepsy, the clinical significance of associated SEAs is not known. We conducted the first study designed to correlate seizure classification with type of SEA in photosensitive patients. We examined seizure classifications and SEAs in 115 consecutive patients who had a PPR. A PPR was the only epileptiform abnormality in 47 patients (41%). Twenty-seven patients (24%) had focal SEAs and 41 (36%) had only generalized SEAs. Seventeen patients (15%) had partial seizures and 40 (35%) had only generalized seizures. Seizure classification was strongly associated with type of SEA (p < 0.0001). Patients with focal SEAs tended to have partial seizures, while patients with generalized SEAs tended to have only generalized tonic-clonic or absence seizures. Also, the presence of SEAs was significantly associated with a history of seizures (p < 0.0001), compared with patients who had a PPR but no SEAs. Although the PPR is often presumed to signify primary generalized epilepsy, most patients with a PPR and focal SEAs have partial seizures.