Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use.

OBJECTIVE: To determine whether 1) combined oral contraceptive (COC) use affects serum levels of valproate (VPA) as well as lamotrigine (LTG) and 2) the naturally occurring high (mid-luteal) and low (early-mid follicular) reproductive steroid level phases of the menstrual cycle might affect antiepileptic drug levels as well. METHODS: This investigation compared serum antiepileptic drug levels at two timepoints during a single menstrual cycle in four groups of women with epilepsy: 12 on VPA, 12 on VPA plus COC (VPA-COC), 12 on LTG, and 12 on LTG plus COC (LTG-COC). RESULTS: Both VPA and LTG levels were lower (p < 0.01) on active COC than on inactive pill with median declines of 23.4% for the VPA-COC group and 32.6% for the LTG-COC group. Serum LTG levels showed a notable but not significant 31.3% median decline during the mid-luteal phase compared to the early-mid follicular phase in the non-COC group. The non-COC valproate group showed the least change of any group between the two measured timepoints with a decline of 8.3% (p = NS). CONCLUSIONS: The findings suggest that valproate (VPA), like lamotrigine (LTG), has substantially and significantly lower serum levels while women take active combined oral contraceptives as compared to inactive pills. Larger sample sizes will be required to determine whether LTG levels may drop significantly also during the luteal (high steroid) phase of natural menstrual cycles and whether VPA levels may show greater stability in levels across the phases of the menstrual cycle.

Post-transplant acute limbic encephalitis: clinical features and relationship to HHV6.

BACKGROUND: Acute limbic encephalitis has been reported in the setting of treatment-related immunosuppression and attributed to human herpesvirus-6 (HHV6) infection. Clinical and laboratory features of the syndrome, however, have not been well characterized. METHODS: We describe the clinical, EEG, MRI, and laboratory features of nine patients with acute limbic encephalitis after allogeneic hematopoietic stem cell transplantation (HSCT). To explore the relationship between HHV6 and this syndrome, we reviewed available CSF HHV6 PCR results from all HSCT patients seen at our center from March 17, 2003, through March 31, 2005. RESULTS: Patients displayed a consistent and distinctive clinical syndrome featuring anterograde amnesia, the syndrome of inappropriate antidiuretic hormone secretion, mild CSF pleocytosis, and temporal EEG abnormalities, often reflecting clinical or subclinical seizures. MRI showed hyperintensities within the uncus, amygdala, entorhinal area, and hippocampus on T2, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI) sequences. CSF PCR assays for HHV6 were positive in six of nine patients on initial lumbar puncture. All patients were treated with foscarnet or ganciclovir. Cognitive recovery varied among long-term survivors. The one brain autopsy showed limbic gliosis and profound neuronal loss in amygdala and hippocampus. Among 27 HSCT patients with CSF tested for HHV6 over a 2-year period, positive results occurred only in patients with clinical limbic encephalitis. CONCLUSIONS: Patients undergoing allogeneic hematopoietic stem cell transplantation are at risk for post-transplant acute limbic encephalitis (PALE), a distinct neurologic syndrome. Treatment considerations should include aggressive seizure control and, possibly, antiviral therapy. PALE can be associated with the CSF presence of human herpesvirus-6, but the pathogenic role of the virus requires further exploration.

Prognosis of status epilepticus: role of aetiology, age, and consciousness impairment at presentation.

BACKGROUND: Identification of outcome-predictive factors could lower risk of under- or over-treatment in status epilepticus (SE). Older age and acute symptomatic aetiology have been shown to predict mortality, but other variables are controversial and level of consciousness has received relatively little attention. The objective of this study was to assess variables predictive of mortality, particularly those available at presentation. METHODS: The discharge database (1997-2004) of two university hospitals was screened for adult patients with EEG confirmed SE, excluding cerebral anoxia. Outcome at discharge (mortality, return to baseline clinical conditions) was analysed in relation to demographics, clinical features, and aetiology. Aetiologies were also classified based on whether or not they were potentially fatal independently of SE. RESULTS: Mortality was 15.6% among 96 patients with a first SE episode, 10 of whom also experienced recurrent SE during the study period. Eleven other patients had only recurrent SE. Mortality was 4.8% among these 21 patients with recurrent SE. Return to baseline condition was more frequent after recurrent than incident SE (p=0.02). For the first SE episode, death was associated with potentially fatal aetiology (p=0.01), age>or=65 (p=0.02), and stupor or coma at presentation (p=0.04), but not with gender, history of epilepsy, SE type, or time to treatment>or=1 h. CONCLUSIONS: At initial evaluation, older age and marked impairment of consciousness are predictive of death. Surviving a first SE episode could lower the mortality and morbidity of subsequent episodes, suggesting that underlying aetiology, rather than SE per se, is the major determinant of outcome.

The value of multichannel MEG and EEG in the presurgical evaluation of 70 epilepsy patients.

OBJECTIVE: To evaluate the sensitivity of a simultaneous whole-head 306-channel magnetoencephalography (MEG)/70-electrode EEG recording to detect interictal epileptiform activity (IED) in a prospective, consecutive cohort of patients with medically refractory epilepsy that were considered candidates for epilepsy surgery. METHODS: Seventy patients were prospectively evaluated by simultaneously recorded MEG/EEG. All patients were surgical candidates or were considered for invasive EEG monitoring and had undergone an extensive presurgical evaluation at a tertiary epilepsy center. MEG and EEG raw traces were analysed individually by two independent reviewers. RESULTS: MEG data could not be evaluated due to excessive magnetic artefacts in three patients (4%). In the remaining 67 patients, the overall sensitivity to detect IED was 72% (48/67 patients) for MEG and 61% for EEG (41/67 patients) analysing the raw data. In 13% (9/67 patients), MEG-only IED were recorded, whereas in 3% (2/67 patients) EEG-only IED were recorded. The combined sensitivity was 75% (50/67 patients). CONCLUSION: Three hundred and six-channel MEG has a similarly high sensitivity to record IED as EEG and appears to be complementary. In one-third of the EEG-negative patients, MEG can be expected to record IED, especially in the case of lateral neocortical epilepsy and/or cortical dysplasia.

Theta oscillations in human cortex during a working-memory task: evidence for local generators.

Cortical theta appears important in sensory processing and memory. Intracanial electrode recordings provide a high spatial resolution method for studying such oscillations during cognitive tasks. Recent work revealed sites at which oscillations in the theta range (4-12 Hz) could be gated by a working-memory task: theta power was increased at task onset and continued until task offset. Using a large data set that has now been collected (10 participants/619 recording sites), we have sufficient sampling to determine how these gated sites are distributed in the cortex and how they are synchronized. A substantial fraction of sites in occipital/parietal (45/157) and temporal (23/280) cortices were gated by the task. Surprisingly, this aspect of working-memory function was virtually absent in frontal cortex (2/182). Coherence measures were used to analyze the synchronization of oscillations. We suspected that because of their coordinate regulation by the working-memory task, gated sites would have synchronized theta oscillations. We found that, whereas nearby gated sites (<20 mm) were often but not always coherent, distant gated sites were almost never coherent. Our results imply that there are local mechanisms for the generation of cortical theta.

Differential effects of antiepileptic drugs on sexual function and hormones in men with epilepsy.

OBJECTIVE: To compare sexual function and reproductive hormone levels among men with epilepsy who took various antiepileptic drugs (AEDs), untreated men with epilepsy, and normal controls. METHODS: Subjects were 85 men with localization-related epilepsy (25 on carbamazepine [CBZ], 25 on phenytoin [PHT], 25 on lamotrigine [LTG], and 10 untreated for at least 6 months [no AED]) and 25 controls. Sexual function scores (S-scores), hormone levels (bioactive testosterone, estradiol), hormone ratios (bioactive testosterone/bioactive estradiol), and gonadal efficiency (bioactive testosterone/luteinizing hormone) were compared among the five groups. RESULTS: S-scores, bioactive testosterone levels, bioactive testosterone/bioactive estradiol, and bioactive testosterone/luteinizing hormone were significantly greater in the control and LTG groups than in the CBZ and PHT groups. Sex hormone binding globulin was significantly higher in the CBZ and PHT groups than in all other groups. S-scores were below the control range in 20% of the men with epilepsy, including 32.0% on CBZ, 24% on PHT, 20% on no AEDs, and 4% on LTG (chi2: p = 0.08 for all four groups; chi2: p = 0.02 for the three AED groups). Bioactive testosterone was below the control range in 28.2%, including 48% on CBZ, 28% on PHT, 20% on no AEDs, and 12% on LTG (chi2: p = 0.02). Among men with epilepsy who had low S-scores, 70.6% had bioactive testosterone levels below the control range as compared to 17.6% among men with normal S-scores (chi2: p < 0.0001). Among men with epilepsy who had abnormally low bioactive testosterone, 50.0% had low S-scores; among men with normal bioactive testosterone, 8.2% had low S-scores (chi2: p < 0.0001). Bioactive testosterone decline with age was significantly greater among men with epilepsy than among controls and notably greater in the CBZ and PHT groups than in the LTG and untreated groups. CONCLUSIONS: Sexual function, bioavailable testosterone levels, and gonadal efficiency in men with epilepsy who took lamotrigine were comparable to control and untreated values and significantly greater than with carbamazepine or phenytoin treatment.

Ictal asystole with convulsive syncope mimicking secondary generalisation: a depth electrode study.

Ictal bradycardia is rare and its localising value is debated. Bradyarrhythmias are, however, important because of their potential connection to sudden death and ability to affect clinical seizure manifestations. Cerebral hypoperfusion induces loss of consciousness, at times with myoclonic jerks, whose clinical differentiation from a generalised convulsive seizure may prove difficult. Two invasive and five surface monitored seizures recorded over two years in a 51 year old woman with post-traumatic epilepsy characterised by seizure-triggered asystole were analysed. All seven seizures showed left temporal onset. Both intracranially recorded events started in the left anterior hippocampus/amygdala, spreading to the contralateral hippocampus in 35 and 25 seconds. Within 10 seconds an electrocardiogram showed asystole lasting 21 and 28 seconds, associated with suppression of recorded cerebral electrical activity, except a polyspike suppression pattern remaining in the hippocampi. Clinically, the patient, concomitantly with the cerebral suppression, developed myoclonic twitches of the limbs. A dual chamber cardiac pacemaker was implanted; at 11 months follow up, the patient has experienced only infrequent partial seizures, with none involving falls or shaking. Left temporal lobe seizures produced convulsive syncope initiated by ictal asystole. These observations suggest that intertemporal spread is necessary, though not sufficient, to produce bradycardia and asystole. Furthermore, pacemakers may decrease seizure severity, as well as potentially protect against malignant bradyarrhythmias.

Reset of human neocortical oscillations during a working memory task.

Both amplitude and phase of rhythmic slow-wave electroencephalographic activity are physiological correlates of learning and memory in rodents. In humans, oscillatory amplitude has been shown to correlate with memory; however, the role of oscillatory phase in human memory is unknown. We recorded intracranial electroencephalogram from human cortical and hippocampal areas while subjects performed a short-term recognition memory task. On each trial, a series of four list items was presented followed by a memory probe. We found agreement across trials of the phase of oscillations in the 7- to 16-Hz range after randomly timed stimulus events, evidence that these events either caused a phase shift in the underlying oscillation or initiated a new oscillation. Phase locking in this frequency range was not generally associated with increased poststimulus power, suggesting that stimulus events reset the phase of ongoing oscillations. Different stimulus classes selectively modulated this phase reset effect, with topographically distinct sets of recording sites exhibiting preferential reset to either probe items or to list items. These findings implicate the reset of brain oscillations in human working memory.

Comparison between the QOLIE-31 and derived QOLIE-10 in a clinical trial of levetiracetam.

PURPOSE: to determine whether the QOLIE-10, an abbreviated quality of life questionnaire, provides results similar to the more detailed QOLIE-31 instrument when the ten items are derived from the QOLIE-31. METHODS: the QOLIE-31 was completed by 246 patients participating in UCB protocol N132 at baseline and after 18 weeks of treatment with levetiracetam (LEV 1000 or 3000 mg) or placebo added to standard therapy. QOLIE-10 components and total scores were calculated from the QOLIE-31 data. RESULTS: baseline QOLIE-10 components and total score correlated highly with corresponding QOLIE-31 scores, both at baseline and follow-up (range 0.70-0.95). Changes from baseline to follow-up were significantly different (ANCOVA) among treatment groups for both the QOLIE-10 and QOLIE-31 for the total score (P = 0.02, P = 0.009, respectively), seizure worry (P = 0.005, P = 0.0003) and cognitive functioning (P = 0.01, P = 0.01). One subscale (overall QOL) showed significant change with the QOLIE-31 (P = 0.04), but not with the QOLIE-10 (P = 0.07). Differences in QOLIE-10 scores were found between responders (> or = 50% partial onset seizure reduction) and non-responders for the total score (P = 0.0001) and two components (overall QOL P = 0.002, social function P = 0.0003). In the QOLIE-31, the total score and six subscale scores (all except medication effects) were significantly different. Both instruments were able to detect change over time. Responsiveness assessed by effect sizes (- 0.1 for non-responders, 0.4 for responders, 0.8 for seizure-free patients) and the Guyatt statistic (0.1, 0.6 and 1.0, respectively) was similar for both instruments. CONCLUSIONS: although the QOLIE-10 was designed as a screening tool, it can be scored and used in research. The total score did discern differences among treatments in a clinical trial. Nonetheless, questionnaires with multiple, multi-item subscales provide more detailed information than abbreviated forms. The QOLIE-31 is preferred where time and resources are available.

The impact of a single seizure on health status and health care utilization.

PURPOSE: To assess the health status of patients after a single seizure. METHODS: We compared single-seizure patients (SS) with patients who had well-controlled epilepsy (WC), and uncomplicated hypertension (HT). Patients were adults screened from emergency and outpatient units of two urban teaching hospitals using predefined criteria. The 83 patients (SS, 30; WC, 29; HT, 24) were interviewed by phone about functional status (SF-36), comorbid illness, cause of illness, number of visits to health providers, and drug side effects. RESULTS: No significant differences were found among groups for health status, SF-36 domain, or occurrence of drug side effects. SS patients had significantly lower scores on vitality (p < 0.03) and a trend toward lower role physical function (p < 0.07) compared with age-adjusted population norms. SS reported more visits to health providers than WC or HT, and the number of visits remained high at interview 1 year later. Patient knowledge of the "reason" for the seizure was not associated with health status or number of visits. CONCLUSIONS: Health status of patients within 1 year of a single seizure is similar to that of patients with well-controlled epilepsy or hypertension, but SS patients have greater health care utilization.

Clozapine-induced seizures and EEG abnormalities in ambulatory psychiatric patients.

OBJECTIVE: To examine the seizure characteristics and electroencephalogram (EEG) abnormalities in psychiatric patients taking clozapine, given the estimate of a 10% cumulative risk of generalized seizures in this population. DESIGN: We reviewed all consecutive EEGs of ambulatory psychiatric patients taking clozapine performed at our laboratory during 1996 and 1997. SETTING: A university-affiliated urban teaching hospital. SUBJECTS: Twelve patients (4 F/8 M; mean age 40.1 y, range 20-63) had either presented with de novo ictal events within the first month of clozapine therapy (n = 8) or had EEGs recorded to assess seizure risk (n = 4). RESULTS: According to clinical history and interictal EEG findings, the patients were subdivided as follows: three patients with generalized tonic-clonic seizures, two with generalized myoclonic jerks (1 associated with simple partial seizures), two with complex partial seizures, and one with simple partial seizures. The EEGs revealed interictal epileptiform abnormalities (IEDs) in eight patients, two of whom had not had seizures. IEDs were focal or multifocal, with a predominance of left temporal foci. One patient showed a paroxysmal response to photic stimulation. CONCLUSIONS: Patients taking clozapine may be prone to partial seizures and focal EEG abnormalities as well as to generalized seizures and EEG abnormalities, as previously reported.

The health status of adults with epilepsy compared with that of people without chronic conditions.

STUDY OBJECTIVES: To examine the feasibility of administering and the psychometric properties of a general health status questionnaire in adults with epilepsy, and to assess the health status of these patients. DESIGN: Prospective, cross-sectional, observational study. SETTING: Neurology clinic of a tertiary care medical center. PATIENTS: One hundred forty-eight ambulatory adults with epilepsy. INTERVENTIONS: Patients completed the SF-36, a general health status questionnaire. Respondent burden and data quality as well as psychometric characteristics were evaluated. Patients' SF-36 scale scores, adjusted for comorbidities, were compared with those of 641 people without chronic conditions with the same sociodemographic characteristics. MEASUREMENTS AND MAIN RESULTS: Administering the SF-36 to adult outpatients with epilepsy is feasible and results are psychometrically sound. Compared with those who were not ill, patients had significantly (p < 0.001) lower (0 = worst, 100 = best) scores in six of the eight SF-36 domains: general health perceptions (57.7 vs 82.1), mental health (61.3 vs 79.6), vitality (53.5 vs 67.8), role limitations owing to physical (69.6 vs 95.0) and emotional problems (67.2 vs 88.4), and social functioning (75.2 vs 89.9). CONCLUSIONS: Lower SF-36 scores may reflect patients' assessments of the balance among epilepsy, seizures, and antiepileptic drug therapy-related effects. Incorporating health status information into therapeutic decision making may help to attain the ultimate goal of improving patients' health.

Carbamazepine and phenytoin: combination versus single drug therapy.

The records of 18 patients with intractable partial seizures who were observed on an in-patient epilepsy unit during single drug treatment with carbamezepine (CBZ) or phenytoin (PHT) and during combination therapy with both drugs were evaluated retrospectively. Seizure frequency was significantly lower during combination therapy (p < 0.01) and toxicity, as measured by an eight point objective scale, did not increase significantly (p > 0.10). In addition subjective signs of clinical toiicity (e.g. nausea, ataxia, etc.) increased only slightly during combination versus monotherapy. These findings were consistently seen whether the data were evaluated in total (i.e. treatment periods at least 7 weeks) or evaluated by using standardized 35 day treatment periods. In the absence of a blinded clinical trial evaluating PHT/CBZ combination, these findings support consideration of this combination in Intractable patients who have failed rigorously administered mono-therapy trials, recognizing however that only a small percentage of patients will improve on combination therapy.

Lateralization of memory for the visual attributes of objects: evidence from the posterior cerebral artery amobarbital test.

We used the posterior cerebral artery amobarbital test to examine how each temporal lobe mediates memory for objects. Temporal lobectomy candidates were presented with four objects while one hemisphere was anesthetized. We assessed recall and recognition following recovery from the drug. Verbal recall was significantly better following object presentation to the left hemisphere when the left hemisphere was not the seizure focus. Recognition memory, tested with two identical objects, two objects that shared the same name but had different physical characteristics, and two foils, was superior following object presentation to the right hemisphere. Only the right hemisphere could discriminate identical objects from same-name foils. These data confirm that the left temporal lobe has an advantage in encoding the verbal representation of an object and suggest that the right temporal lobe is critical for memory of specific visual attributes of objects.

Temporal lobectomy for uncontrolled seizures: the role of positron emission tomography.

We evaluated the role of positron emission tomography (PET) with [18F]deoxyglucose (FDG) (FDG-PET) for planning surgery in 53 patients who had temporal lobectomy for uncontrolled seizures at National Institutes of Health from 1981 to 1990. Investigators blinded to PET data used results of telemetered video-electroencephalographic ictal monitoring and other standard criteria to decide whether subdural electrodes (22 patients, i.e., the "invasive" group) should be implanted or surgery performed. PET scans were analyzed using a standard regional template. Mean lateral but not mesial temporal asymmetry was significantly higher in patients who became seizure free (p < 0.03). Patients with > or = 15% hypometabolism were significantly more likely to be seizure free in the entire study population and the invasive subgroup. Visual identification of hypometabolism was less accurate. When a clear temporal ictal surface electroencephalographic focus was present, FDG-PET provided less additional information. FDG-PET may be particularly valuable if the surface electroencephalographic scan is nonlocalizing. In addition to helping to identify the seizure focus, it may allow limitation of invasive electrode placement to those necessary for functional mapping. When PET is used to identify epileptic foci, quantitative measurements of asymmetry should be made.