Zonisamide discontinuation due to psychiatric and cognitive adverse events: a case-control study.

OBJECTIVES: Zonisamide (ZNS) is an antiepileptic drug (AED) that has been associated with psychiatric adverse events (PAE) and cognitive adverse events (CAE); controlled studies evaluating these adverse events are limited. Our objectives were to 1) determine the incidence of PAE and CAE leading to the discontinuation of ZNS and 2) identify risk factors for PAE and CAE associated with the discontinuation of ZNS. METHODS: All patients exposed to ZNS at MINCEP Epilepsy Care between March 2000 and September 2008 were identified. Reasons for discontinuing ZNS were documented. Separate case-control studies were performed to identify risk factors associated with the discontinuation of ZNS due to PAE or CAE via multivariate binary logistic regression. RESULTS: A total of 544 patients were exposed to ZNS during the study period. PAE and CAE were the most frequently identified reasons for terminating ZNS therapy. The incidence of PAE severe enough to be associated with the discontinuation of ZNS was 6.9%; the incidence of CAE was 5.8%. Factors associated with termination of ZNS therapy due to PAE were past psychiatric history (p = 0.005), symptomatic generalized epilepsy (p = 0.027), and lower maximum ZNS serum concentration (mean = 17.9 mg/L vs 34.7 mg/L, p < 0.001). Independent variables associated with discontinuing ZNS due to CAE were greater number of concomitant AEDs (p = 0.011) and lower maximum ZNS serum concentration (mean = 16.6 mg/L vs 30.6 mg/L, p = 0.002). CONCLUSIONS: We have identified clinically relevant risk factors associated with the discontinuation of ZNS. Our findings support the concept that selected patients are relatively more vulnerable to CNS adverse events when exposed to ZNS.

Discontinuation of levetiracetam because of behavioral side effects: a case-control study.

BACKGROUND: Levetiracetam (LEV) is a recently approved anticonvulsant with proven efficacy and safety in the treatment of partial seizures. LEV may cause behavioral abnormalities that can be severe and require discontinuation of this drug. Risk factors for discontinuing LEV have not been established. OBJECTIVE: To determine incidence of behavioral abnormalities severe enough to require discontinuation of LEV and identify risk factors for such behavioral abnormalities. METHODS: All patients treated with LEV at MINCEP between January 2000 and February 2002 constituted the study population (n = 553). Patients who had discontinued LEV for behavioral reasons were selected as index cases. Case controls were patients starting LEV immediately after the index case. Potential risk factors for LEV discontinuation included age, gender, cognitive function, history of psychiatric diagnosis, epilepsy syndrome, number of antiepileptic drugs, titration rate, maximum dose of LEV, and LEV level at maximum dose. RESULTS: Thirty-eight patients (6.9%) discontinued LEV because of behavioral abnormalities. Variables associated with LEV discontinuation included faster titration rate to maximal dose, history of a psychiatric disorder, and diagnosis of symptomatic generalized epilepsy. Patients who discontinued LEV owing to behavioral reasons had significantly lower maximum LEV doses than controls. CONCLUSIONS: This study identified variables associated with discontinuation of LEV due to behavioral abnormalities. Slower titration of LEV should be considered in those patients at higher risk of discontinuing LEV for behavioral reasons.

A single-blind, crossover comparison of the pharmacokinetics and cognitive effects of a new diazepam rectal gel with intravenous diazepam.

PURPOSE: The objective of this study was to compare the pharmacokinetics and cognitive effects of a new diazepam (DZP) rectal gel (Diastat) with intravenously administered DZP. METHODS: Twenty healthy volunteers were enrolled in a single-blind, randomized, double-dummy, two-period, crossover study. Subjects received either 15 mg of DZP rectal gel or 7.5 mg of DZP by intravenous infusion. Blood samples for DZP and desmethyldiazepam analysis were obtained before the dose and from 3 min to 240 h after the dose. Heart rate and blood pressure were measured over the first 24-h period. Subjects also completed five repetitions of a neuropsychological test battery over the first 8-h period. RESULTS: Diazepam rapidly appeared in plasma after rectal administration, exceeding 200 ng/mL within 15 min and reaching an initial maximum of 373 ng/ml at 45 min and a second maximum of 447 +/- 91.1 ng/ml at approximately 70 min. The absolute bioavailability of DZP rectal gel was 90.4%. Subjects receiving intravenous DZP were less alert and performed less efficiently on the WAIS Digit Symbol test 6 min after the dose. Subjects receiving DZP rectal gel performed less well on the WAIS Digit Span test 1 h after the dose and required more time to complete the Letter Cancellation and Grooved Pegboard tests 1 and 2 h after drug administration. CONCLUSIONS: Diastat displayed rapid, consistent absorption and was well tolerated. Alterations in cognition were mild and dissipated within 4 h of drug administration. This new rectal drug-delivery system offers an easy, safe, and bioavailable method to administer DZP.

Memory performance on the intracarotid amobarbital procedure as a predicator of seizure focus.

The intracarotid amobarbital procedure (IAP) was performed on 56 patients with intractable complex-partial epilepsy who were candidates for temporal lobectomy. Seizure focus was lateralized to one hemisphere, as determined by surface EEG recordings and MRI evidence of temporal lobe disease. IAP memory items were presented following injection of 125 mg of sodium amytal into the internal carotid artery. Verbal, Nonverbal, Design, Pictorial, and Total memory scores were calculated based on recall/recognition of memory stimuli following drug recovery. Poorer memory was observed in the hemisphere ipsilateral to seizure focus on all memory scores. The Total Memory Score was the best memory measure, correctly classifying the largest number of patients. Using optimal cut-off scores on this measure, 75% of the patients with left hemisphere seizure focus and 79% of the patients with right seizure focus were correctly classified. There was a definite tendency for the dominant hemisphere to outperform the non-dominant. This must be taken into account in arriving at optimal cut-off points.

Efficacy of the Continuous Visual Memory Test in lateralizing temporal lobe dysfunction in chronic complex-partial epilepsy.

The Continuous Visual Memory Test (CVMT) was hypothesized to measure nondominant temporal lobe dysfunction in patients with refractory complex-partial epilepsy. Thirty-seven temporal lobectomy candidates, of whom 20 had a right temporal seizure focus (RT) and 17 had a left temporal seizure focus (LT), were selected for study. Contrary to the hypothesis, initial results indicated that the LT group performed below the RT group for both the CVMT Total score and the Delayed Recognition score; however, group differences disappeared after accounting for Full Scale IQ scores. Both CVMT scores correlated positively and significantly with Full Scale IQ, Block Design, and the Meier Visual Discrimination Test, suggesting that overall cognitive functioning and visual-perceptual processing are positively related to CVMT performance. These results are consistent with other recent findings which suggest that extant nonverbal memory tests may be inadequate in lateralizing nondominant hemisphere lesions in complex-partial epilepsy.

Language function after temporal lobectomy without stimulation mapping of cortical function.

We studied 95 patients who underwent standard anterior temporal lobectomy (ATL) without stimulation mapping of language areas, using neuropsychological parameters of language function preoperatively and 1 year postoperatively [Boston Naming Test and Verbal Fluency, and the Information, Comprehension, Arithmetic, Similarities, Digit Span, and Vocabulary subtests of the Wechsler Adult Intelligence Scale (WAIS)]. Verbal IQ (VIQ), Performance IQ (PIQ), Full-Scale IQ (FSIQ), and Verbal Deviation Quotient were also evaluated, as were parameters of memory function. All patients had hemisphere dominance for language assessed by an intracarotid amytal test. Fifty-three patients had a left dominant (LHDL) ATL with a mean extent of lateral resection of 4.8 cm, and 10 had a left ATL with right or mixed hemisphere dominance (RHDL, MDL). Thirty-two patients had a right nondominant ATL. Seizure outcome was 57 and 59% seizure-free for LHDH and right nondominant group, respectively, 1 year after operation. Comparison of preoperative scores showed the LHDL group to have significantly lower scores than the right nondominant group for several parameters of language function and memory. The group undergoing left dominant ATL showed no significant loss of language function postoperatively and actually showed gains in many parameters. Standard ATL without stimulation mapping of language areas and with conservative lateral resection is safe for long-term language function. In addition, evidence shows preexisting language dysfunction in patients undergoing left dominant ATL.

Language function following subdural grid-directed temporal lobectomy.

The purpose of the study was to determine the extent to which a temporal resection may be undertaken without producing risk to temporal language areas. Patients undergoing craniotomy and placement of a subdural electrode array (SEA) for evaluation of intractable epilepsy were studied to determine the variability of distance of temporal language cortex from the temporal pole. Hemisphere dominance was determined by intracarotid sodium amytal injection. Temporal lobe speech arrest (SA) was mapped with a 64 contact point SEA. Thirty-one patients had left dominant hemisphere SEAs. Thirty had SA 5 cm to 9 cm from the temporal pole (median 7 cm). One had SA at 3 cm. Twenty-one patients subsequently had temporal lobectomy (TL). Mean extent of resection was 5.7 cm (range 3 to 9 cm). In 18 TL patients who had neuropsychometric evaluation of language function pre- and post-surgery, there was no significant deterioration. Thirty-nine patients had right non-dominant SEAs placed. Eighteen had TL. Thirteen of these had pre- and post-surgery language evaluation and there was no significant change. Comparison of preoperative scores showed significant superiority of the right non-dominant group over the left dominant group for naming. TL up to 5 cm without stimulation mapping of language areas would be safe in the majority of cases, but one subject (3%) had SA mapped anterior to this and a small number of cases may therefore be at risk to language function following a 5 cm TL. Extensive lateral resections up to 9 cm are possible with preservation of language function with stimulation cortical mapping.

Assessment of recovery from nitrous oxide-oxygen sedation using neuropsychometry.

This study measured changes in adult performance following prolonged exposure (90 minutes) to nitrous oxide at psychosedative levels. Using a repeated-measures randomized blind design, experimenters exposed 12 subjects to four treatment combinations. These included: room air for 90 minutes (baseline); 100% oxygen for 90 minutes; nitrous oxide-oxygen sedation for 90 minutes followed by 100% oxygen for 2 minutes; and 90 minutes of nitrous oxide-oxygen sedation followed by 10 minutes of 100% oxygen. Following each treatment, participants were asked to perform six standard neuropsychological tests together with a rating scale measurement where subjects self-evaluated their respective levels of alertness. The tests were: digit span; digit symbol; paced auditory serial addition; controlled word association; letter cancellation; and grooved pegboard. Two-way analysis of variance revealed significant differences between mean scores for treatments on only two tests, grooved pegboard (P less than 0.05) and controlled word association (P less than 0.05). There was also a significant difference in mean scores obtained for the rating scale (P less than 0.001). These findings indicate that psychomotor performance and verbal fluency were affected by prolonged exposure to nitrous oxide even after recovery periods. No impairment of vigilance, immediate memory, or mental tracking could be detected as measured by the other tests. Subjective reports by the subjects accurately reflected their underlying impaired status.

Adverse behavioral response to clonazepam as a function of Verbal IQ-Performance IQ discrepancy.

Eight of 38 consecutive patients who received clonazepam had significant behavioral side effects. In these 8 patients, the mean absolute IQ discordance between Verbal IQ (VIQ) and Performance IQ (PIQ) was 17.5 points. Thirty of 38 patients had no adverse behavioral side effects while receiving clonazepam. In these 30 patients, the mean absolute VIQ-PIQ discrepancy was 6.5 points. Full neuropsychological testing had been performed on all patients. The only test variable showing a statistically significant difference was the absolute discrepancy between VIQ and PIQ (P less than 0.0001).