Psychosocial outcomes of repeated treatment of seizure clusters with midazolam nasal spray: Results of a phase 3, open-label extension trial.

OBJECTIVE: To evaluate treatment satisfaction, level of anxiety, confidence about traveling with midazolam nasal spray (MDZ-NS), and health-related quality of life in patients with seizure clusters and their caregivers after repeated, intermittent use of MDZ-NS in the outpatient setting. METHODS: We analyzed the psychosocial outcome data from a phase 3, open-label extension trial (ARTEMIS-2; P261-402; NCT01529034) in patients 12 years of age and older with seizure clusters on a stable regimen of antiseizure medications. Caregivers administered MDZ-NS 5 mg when patients experienced a seizure cluster. A second dose could be given if seizures did not terminate within 10 min or recurred from 10 min to 6 h. Treatment Satisfaction Questionnaire for Medication (TSQM), the Intranasal Therapy Impact Questionnaire (ITIQ), and the Short Form-12 Health Survey version 2 (SF-12v2) were self-administered by patients and/or caregivers at prespecified visits. RESULTS: Of the one hundred and seventy-five patients enrolled in ARTEMIS-2, 161 (92.0%) received ≥ 1 dose of MDZ-NS and had a post-treatment seizure-related assessment and were included in the Efficacy Evaluable Set in this analysis, with a total of 1,998 treated seizure clusters over a median duration of 16.8 months. All TSQM scales showed improvement from the baseline of the double-blind ARTEMIS-1 trial (NCT01390220) to the last visit in ARTEMIS-2, indicating greater satisfaction with MDZ-NS across all domains, with a mean change from baseline of 8.8, 6.1, 4.3, and 6.2 for effectiveness (n = 135), side effects (n = 139), convenience (n = 139), and global satisfaction (n = 138), respectively. Change from baseline in TSQM scores generally increased with repeated MDZ-NS use. In both patients and caregivers, anxiety generally lessened with repeated MDZ-NS use, with a mean improvement in ITIQ scores in patients' anxiety since receiving MDZ-NS from 2.5 (n = 138) to 3.5 (n = 145) from visit 1 to the last visit (and from 2.6 [n = 156] to 3.6 [n = 160] for caregivers), respectively. From visit 1 (screening and enrollment in ARTEMIS-2) to visit 10 (after 16 seizure cluster episodes treated with MDZ-NS), the proportions of patients and caregivers who answered "strongly agree" or "agree" for confidence about traveling with an intranasal spray remained ≥ 79% and generally increased over repeated MDZ-NS use. Small positive mean changes in SF-12v2 scores from baseline to the last visit were observed in both patients and caregivers, respectively, for the domains of physical functioning (0.9, 1.1), role-physical (2.4, 0.3), bodily pain (1.7, 0.3), general health (0.6, 1.2), and role-emotional (2.1, 0.3), and in the physical health component (1.6, 1.0). CONCLUSION: Patients and caregivers perceived MDZ-NS favorably, with improvement from baseline on perceived effectiveness, side effects, convenience, and global satisfaction in the TSQM. This is supported by progressively lower anxiety and higher confidence levels about traveling with MDZ-NS over repeated intermittent use in the ITIQ. The positive mean changes observed in SF-12v2 scores from baseline to the last visit were small in magnitude. Limitations of this exploratory analysis include the open-label trial design and that these questionnaires have not been directly validated in epilepsy to identify clinically important changes; however, this does not mean these findings are not clinically meaningful. Overall, MDZ-NS is a socially acceptable drug device for outpatient treatment of seizure clusters that has the potential to improve quality of life and overall independence.

Long-term safety and efficacy of brivaracetam in adults with focal seizures: Results from an open-label, multinational, follow-up trial.

BACKGROUND: This long-term follow-up (LTFU) trial was conducted to evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized doses (maximum of 200 mg/day) in patients with focal seizures. The secondary objective was to evaluate the efficacy of BRV over time. METHODS: Two Phase III, randomized, double-blind, historical-controlled conversion-to-monotherapy trials (N01276: NCT00698581; N01306: NCT00699283) were conducted in patients aged ≥16 years with uncontrolled focal seizures. Patients who completed either of these core trials or who met a protocol-defined exit criterion could enter this LTFU trial (N01315; NCT00761774). Patients entered LTFU at a recommended BRV dose of 100 mg/day, with flexible dosing of 50-200 mg/day, as monotherapy or adjunctive therapy; additional AEDs could be prescribed and adapted in dose if clinically indicated. Safety variables included treatment-emergent adverse events (TEAEs). Efficacy variables included duration of continuous monotherapy, reduction in focal seizure frequency and seizure freedom. Safety and efficacy variables were assessed for all patients in the safety set or efficacy set, respectively, regardless of BRV treatment regimen. In addition, a post hoc subgroup analysis was conducted for patients who completed the BRV monotherapy period in either core trial, and entered the LTFU on BRV monotherapy. For this subgroup, TEAEs were summarized by 3-month time intervals over the first 12 months of LTFU. RESULTS: 108 patients were enrolled in the LTFU trial between November 2008 and February 2010. 79 (73.1 %) patients discontinued the LTFU trial, most commonly due to lack of efficacy [37 (34.3 %)] and adverse events [16 (14.8 %)]. At core trial baseline, patients had a median of 6.3 focal seizures/28 days and 53 (49.1 %) had failed ≥5 previous lifetime AEDs. During LTFU, 70 (64.8 %) patients had ≥12 months and 56 (51.9 %) patients had ≥24 months of BRV treatment. TEAEs were reported by 98 (90.7 %) patients; most commonly (≥15 % of patients) convulsion (17.6 %), nasopharyngitis (17.6 %), depression (16.7 %) and fatigue (15.7 %). Median percent reduction from baseline in focal seizure frequency/28 days was 56.8 %. Among 86 patients who completed at least 6 months of treatment, 29 (33.7 %) patients were seizure-free for ≥6 months and 22 (25.6 %) were seizure-free for ≥12 months. 50/108 patients were included in the BRV monotherapy subgroup; 33/50 (66.0 %) patients reported a TEAE in the core trials, while 26/50 (52.0 %), 15/37 (40.5 %), 14/33 (42.4 %) and 9/27 (33.3 %) patients reported any TEAE during LTFU months 1-3, 4-6, 7-9 and 10-12, respectively. In the BRV monotherapy subgroup, the most common TEAEs (≥5% of patients) during LTFU months 1-3 were fatigue [3/50 (6.0 %)] and dizziness [3/50 (6.0 %)]. INTERPRETATION: Results from the LTFU trial support the long-term safety of BRV at individualized doses of up to 200 mg/day as a well-tolerated, and effective treatment for patients with focal seizures. Efficacy analyses indicate that seizure reductions with brivaracetam were generally maintained over time.

Brivaracetam-induced elevation of carbamazepine epoxide levels: A post-hoc analysis from the clinical development program.

To assess the association, if any, between brivaracetam (BRV)-induced elevated carbamazepine-10,11-epoxide (CBZ-E) and toxicity and efficacy in patients with epilepsy. Data were pooled from three double-blind, placebo-controlled, Phase III studies of adjunctive BRV in adults with uncontrolled focal seizures (N01252/NCT00490035, N01253/NCT00464269, N01358/NCT01261325). Treatment-emergent adverse events (TEAEs) of interest (ataxia, diplopia, dizziness, nystagmus, somnolence, accidental overdose or poisoning, and toxicity), discontinuations due to TEAEs, and serious TEAEs (SAEs) were assessed in subgroups who did/did not receive carbamazepine (CBZ) at study entry (CBZ+ and CBZ-). Logistic regression analysis evaluated CBZ-E/CBZ plasma concentrations and TEAEs. SAEs suggestive of CBZ-E toxicity were summarized from the BRV safety database up to a cut-off of October 1, 2014. Percent reduction in focal seizure frequency over placebo was assessed in subgroups of CBZ-E/CBZ ratios. Data from 1558 patients were included in the pooled safety population. Of these, concomitant CBZ was received by 184/459 (40.1%) placebo-treated and 315/803 (39.2%) BRV-treated patients (≥50 mg/day). In BRV-treated patients, study completion rates were similar in the CBZ+ (92.7%) and CBZ- (88.7%) groups; incidence of TEAEs of interest was similar (CBZ+ 24.4%; CBZ- 24.2%), and did not appear affected by CBZ dosage; SAEs and discontinuations due to TEAEs were CBZ+ 1.6%; CBZ- 3.9% and 2.9%; 9.2%, respectively. Likelihood of TEAEs of interest decreased with increasing CBZ-E/CBZ ratio for BRV-treated patients: odds ratio 0.88 (95% confidence intervals 0.74, 1.03; p = 0.112). In the safety database, five SAEs suggestive of CBZ-E toxicity were identified. Efficacy outcomes did not appear to have a consistent pattern across CBZ-E/CBZ ratio subgroups. This post-hoc analysis does not support an association between CBZ-E levels and TEAEs potentially associated with CBZ-E toxicity, or with increases in efficacy. Overall, current evidence does not suggest that BRV dose adjustment is required with concomitant CBZ.

Conversion to brivaracetam monotherapy for the treatment of patients with focal seizures: Two double-blind, randomized, multicenter, historical control, Phase III studies.

Brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, is a new antiepileptic drug (AED) approved for monotherapy (in the USA) and adjunctive treatment of focal (partial-onset) seizures in adults, at a dose range of 50-200 mg/day taken in two equal doses, with a recommended starting dose of 100 mg/day. Two Phase III, randomized, double-blind, multicenter, historical-controlled, conversion-to-monotherapy studies (N01276, NCT00698581; N01306, NCT00699283) were conducted to evaluate the efficacy, safety, and tolerability of conversion to BRV 50 mg/day monotherapy in adults with uncontrolled focal seizures. Patients aged 16-75 years, with 2-40 focal seizures per 4 weeks during an 8-week baseline, and on stable doses of 1-2 AEDs were enrolled. Patients were randomized to BRV 50 or 100 mg/day (3:1) in two equal doses without titration. The treatment period comprised 1-week BRV add-on, 8-week baseline AED tapering, and 8-week BRV monotherapy periods. Primary efficacy endpoint was Kaplan-Meier estimate of the cumulative exit rate due to pre-defined exit criteria at Day 112 (50 mg/day, efficacy population). The upper 95% confidence interval (CI) was compared with the historical control threshold (0.722). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs; intent-to-treat population). After randomization of 150 patients (N01276: 88; N01306: 62), both studies were terminated due to the confounding effects of a higher-than-expected discontinuation rate. For BRV 50 mg/day, ≥1 exit criterion was met by 26/67 (38.8%) patients (study N01276) and 18/45 (40.0%) patients (study N01306). In both studies, the cumulative exit rate was lower than the historical control threshold (N01276: 0.487, 95% CI 0.347, 0.626; N01306: 0.474, 95% CI 0.310, 0.638). However, with maximum 10% censoring due to early withdrawal (sensitivity analysis), cumulative exit rates were above historical control (N01276: 0.652, 95% CI 0.532, 0.772; N01306: 0.704, 95% CI 0.563, 0.844). Overall incidence of TEAEs was 110/150, 73.3% (treatment period); 78/147, 53.1% (baseline AED tapering period); 41/84, 48.8% (BRV monotherapy period). In conclusion, BRV 50 mg/day monotherapy demonstrated an exit rate lower than historical control. Results should be interpreted with caution as, following termination of both studies, patient numbers were too low to evaluate the efficacy of BRV monotherapy. These are the first published safety and tolerability data for BRV monotherapy. Monotherapy was well tolerated, with a relatively low incidence of TEAEs, though this should be interpreted with the caveat that the majority of common TEAEs were likely to have occurred earlier in the course of treatment with BRV. No new safety concerns were identified, supporting the favorable safety profile of BRV observed in adjunctive studies.

An open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam.

We evaluated nonpsychotic behavioral adverse events (BAEs) in patients receiving levetiracetam (LEV) who switched to brivaracetam (BRV). Patients ≥16 years of age, receiving 2-3 antiepileptic drugs (AEDs), including LEV 1-3g/day, and experiencing BAEs within 16 weeks of LEV treatment initiation, enrolled in an open-label Phase 3b study (NCT01653262) comprising a ≤1-week screening period, an immediate switch from LEV to BRV 200mg/day (without titration), and a 12-week treatment period. The percentages of patients with investigator-assessed clinically meaningful reduction in BAEs, shift in maximum BAE intensity, and change in health-related quality of life (HRQoL) (Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31 [QOLIE-31-P]) were assessed. Of 29 patients enrolled, 26 (89.7%) completed the study. At the end of the treatment period, 27/29 (93.1%) patients switched to BRV had clinically meaningful reductions in BAEs. Physicians reported a reduction in the maximum intensity of primary BAEs in 27/29 (93.1%) patients. Mean change from baseline to Week 12 in QOLIE-31-P total score was 12.1, indicating improved HRQoL. During the treatment period, 23/29 (79.3%) patients reported treatment-emergent adverse events (TEAEs). One patient reported a serious TEAE (suicidal ideation and suicide attempt). Two patients discontinued BRV because of TEAEs. Findings from this small study suggest that patients experiencing BAEs associated with LEV may benefit from switching to BRV.

Efficacy of once-daily extended-release topiramate (USL255): a subgroup analysis based on the level of treatment resistance.

Results from a previously conducted global phase III study (PREVAIL; NCT01142193) demonstrate the safety and efficacy of once-daily USL255, Qudexy™ XR (topiramate) extended-release capsules, as adjunctive treatment of drug-resistant partial-onset seizures (POSs). In this study, we report a post hoc analysis of PREVAIL data according to patient level of treatment resistance (based upon the number of concomitant antiepileptic drugs [AEDs] and lifetime AEDs) at baseline, with patients defined as either having "highly" drug-resistant seizures (≥ 2 concurrent AEDs and ≥ 4 lifetime AEDs) or having "less" drug-resistant seizures (1 concurrent AED or <4 lifetime AEDs) at baseline. For each subgroup, median percent reduction in POS frequency (primary endpoint), responder rate, Clinical Global Impression of Change (CGI-C), and Quality of Life in Epilepsy--Problems (QOLIE-31-P) survey were assessed. Of 249 PREVAIL patients, 115 were classified as having highly drug-resistant seizures (USL255: n = 52, placebo: n = 63), and 134 were classified as having less drug-resistant seizures (USL255: n = 72, placebo: n = 62) at baseline. For the primary endpoint, USL255 resulted in significantly better seizure outcomes compared with placebo regardless of drug-resistant status (P = .004 and P = .040 for "highly" and "less", respectively). Responder rate was also significantly improved in patients with highly drug-resistant group (P = .023). The CGI-C scores indicated significant improvement in both subgroups (P = .003 and P = .013 for "highly" and "less", respectively). On the QOLIE-31-P, a significant improvement on the seizure worry subscale for the group with less drug-resistant seizures was noted in USL255-treated patients compared with placebo-treated patients (P = .003); the overall score and all other subscales were not significantly different for both subgroups. We conclude that USL255 led to significant improvements across multiple outcomes compared with placebo, including in those classified as having highly drug-resistant seizures to prior treatment, making it a valuable treatment option for patients with epilepsy.

Once-daily USL255 as adjunctive treatment of partial-onset seizures: randomized phase III study.

OBJECTIVE: To evaluate the efficacy and safety of USL255, Qudexy(™) XR (topiramate) extended-release capsules, as an adjunctive treatment for refractory partial-onset seizures (POS) in adults taking one to three concomitant antiepileptic drugs. METHODS: In this global phase III study (PREVAIL; NCT01142193), 249 adults with POS were randomized 1:1 to once-daily USL255 (200 mg/day) or placebo. The primary and key secondary efficacy endpoints were median percent reduction in weekly POS frequency and responder rate (proportion of patients with ≥ 50% reduction in seizure frequency). Seizure freedom was also assessed. Safety (adverse events, clinical and laboratory findings), as well as treatment effects on quality of life (QOLIE-31-P) and clinical global impression of change (CGI-C), were evaluated. RESULTS: Across the entire 11-week treatment phase, USL255 significantly reduced the median percent seizure frequency and significantly improved responder rate compared with placebo. Efficacy over placebo was observed early in treatment, in patients with highly refractory POS, and in those with the most debilitating seizure types (i.e., complex partial, partial secondarily generalized). USL255 was safe and generally well tolerated with a low incidence of neurocognitive adverse events. USL255 was associated with significant clinical improvement without adversely affecting quality of life. SIGNIFICANCE: The PREVAIL phase III clinical study demonstrated that once-daily USL255 (200 mg/day) significantly improved seizure control and was safe and generally well tolerated with few neurocognitive side effects.

Pregabalin monotherapy in patients with partial-onset seizures: a historical-controlled trial.

OBJECTIVE: To assess pregabalin monotherapy for partial-onset seizures using a historical-controlled conversion-to-monotherapy design. METHODS: Adults with inadequately controlled partial-onset seizures while receiving 1 or 2 antiepileptic drugs during an 8-week prospective baseline were randomized to double-blind monotherapy with pregabalin 600 or 150 mg/d (4:1) for 20 weeks (8-week conversion and 12-week monotherapy period). The primary endpoint was the seizure-related exit rate for pregabalin 600 mg/d, based on discontinuations due to predefined criteria. Efficacy was declared if the upper limit of the 95% confidence interval for the exit rate was below a historical-control threshold of 74%, with stepwise evaluation using a threshold of 68%. RESULTS: The trial was stopped early for positive efficacy after an interim analysis in 125 patients. The full study population included 161 patients, with 148 evaluable for efficacy. The mean time since epilepsy diagnosis was 14 years. Overall, 54.3% (600 mg/d) and 46.9% (150 mg/d) of patients completed 20 weeks of double-blind treatment. Seizure-related exit rate in the 600 mg/d group (27.5%; 95% confidence interval, 17.8%-37.2%) was significantly below the 74% and 68% thresholds (p < 0.001 for both). Eight patients on 600 mg/d and 2 on 150 mg/d were seizure-free throughout pregabalin monotherapy. Pregabalin's overall safety profile was consistent with prior trials. CONCLUSIONS: Pregabalin monotherapy was safe and efficacious for patients with inadequately controlled partial-onset seizures. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that patients with inadequately controlled partial-onset seizures switched to pregabalin monotherapy have fewer seizure-related exit events compared with historical controls switched to pseudo-placebo monotherapy.

Objective evaluation of personality and psychopathology in temporal lobe versus extratemporal lobe epilepsy.

Previous research has been equivocal on personality trait and psychopathology differences between temporal lobe and other types of epilepsy, as well as between patients with right and left temporal lobe seizure foci. In this study, personality differences between patients with right temporal (n=23), left temporal (n=21), and extratemporal (n=24) epilepsy were investigated using the NEO Personality Inventory-Revised (NEO-PI-R). No statistically significant differences were found on any of the NEO-PI-R domains or facet trait scales. There were also no significant differences between groups on the Minnesota Multiphasic Personality Inventory 2 (MMPI-2), a measure of psychopathology. However, mild elevations were seen in all groups on clinical scales related to physical symptoms, health concern, and depression. These data suggest there are no consistent personality or psychopathology differences, as measured by the NEO-PI-R and the MMPI-2, between patients with left temporal, right temporal, and extratemporal epilepsy whose seizures are localized using video/EEG monitoring.

Effects of lamotrigine compared with levetiracetam on anger, hostility, and total mood in patients with partial epilepsy.

PURPOSE: To assess anger/hostility during treatment with lamotrigine adjunctive therapy versus levetiracetam adjunctive therapy in patients with partial seizures. METHODS: This randomized, double-blind, parallel-group study in adults with partial seizures included an 8-week escalation phase, during which adjunctive lamotrigine (n = 132) or adjunctive levetiracetam (n = 136) was titrated to a target dose, and a 12-week, double-blind maintenance phase, during which dosages of study medication and concomitant antiepileptic drugs were maintained. The primary endpoint was change from baseline to the end of the maintenance phase (week 20) in the Anger-Hostility subscale score of the Profile of Mood States (POMS). RESULTS: Improvement with lamotrigine relative to levetiracetam was observed for mean +/- SD (standard deviation) change from baseline to the end of the maintenance phase (week 20) on the Anger-Hostility subscale (lamotrigine -2.0 +/- 8.2, levetiracetam -0.3 +/- 8.4; p = 0.024) (the primary endpoint); the Anger-Hostility subscale on weeks 5, 6, 7, 8, 9, 11, 12, 14, 16, 18, and 19; and the Total Mood Disturbance score on weeks 6, 7, 8, 9, 11, 12, 17, 19, and 20. Improvement (p < 0.05) with lamotrigine relative to levetiracetam was also observed on the POMS subscales Depression-Dejection, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment. No difference in seizure frequency was observed between groups. The most common adverse events with both medications were headache and dizziness. DISCUSSION: Adjunctive lamotrigine significantly improved Anger-Hostility subscale scores relative to adjunctive levetiracetam in patients with partial seizures at the end of 20 weeks. This difference was consistently observed throughout the treatment period. Similar improvement with lamotrigine versus levetiracetam was observed for other mood symptoms.

Effects of lamotrigine on mood in older adults with epilepsy and co-morbid depressive symptoms: an open-label, multicentre, prospective study.

BACKGROUND: Both epilepsy and depressive symptoms are more prevalent in older individuals than in any other age group. Furthermore, depressive symptoms are among the most common interictal psychiatric co-morbid disorders in people with epilepsy. For these reasons, pharmacological treatment of epilepsy that might also confer antidepressant effects may be particularly beneficial in older patients. In this respect, lamotrigine is of considerable interest amongst antiepileptic drugs (AEDs) because it has proven thymoleptic activity. OBJECTIVE: These analyses, conducted on a data set drawn from a previously reported, open-label, multicentre, prospective study, examined the effect of lamotrigine on mood in adults aged>or=50 years with epilepsy and co-morbid depressive symptoms. All subjects were receiving background AED therapy at baseline. METHODS: Of the 158 subjects enrolled in the initial study, 40 adults (24 women, 16 men) met the age criterion for these analyses. The study consisted of a screening/baseline phase and four treatment phases over 36 weeks: lamotrigine escalation phase (7 weeks); lamotrigine maintenance or adjunctive therapy phase (12 weeks); concomitant AED withdrawal phase (5 weeks); and lamotrigine monotherapy phase (12 weeks). Psychometric evaluation of mood utilized the Beck Depression Inventory (BDI-II), Center for Epidemiological Studies Depression Scale (CES-D), the Neurological Disorders Depression Inventory in Epilepsy (NDDI-E) and the Profile of Mood States (POMS). Scores at the end of the adjunctive and monotherapy phases were compared with baseline scores. Lower scores on these scales indicate less depressive symptomatology. RESULTS: Mean baseline scores for the BDI-II, CES-D, NDDI-E and POMS were 15.8, 24.3, 13.8 and 57.7, respectively. Change scores were statistically significant (p<0.01) compared with baseline at the end of the adjunctive and monotherapy phases for all four psychometric measures of mood, with the exceptions of BDI-II and NDDI-E at the end of the adjunctive phase. CONCLUSIONS: The older adults in these analyses presented with low to moderate levels of depressive symptoms. Addition of lamotrigine to background AED therapy demonstrated antidepressant activity similar to that for the whole sample in the initial study. Given that the onset and prevalence of epilepsy are higher in older adults than in any other age group, pharmacological treatment for epilepsy in older patients that might also confer antidepressant therapy may be particularly beneficial.

Continuous spikes and waves during slow sleep in an adult.

Continuous spikes and waves during slow wave sleep (CSWS) is rare and is considered to be an age-related epileptic syndrome occurring only in children. We report the case of a 21-year-old patient diagnosed with this syndrome. The patient had a history of seizures since the age of 3 and was admitted for continuous video/EEG monitoring to evaluate seizure exacerbation and unprovoked outbursts of anger. During 3 days of monitoring, awake EEG recordings showed focal slow wave activity in the right temporal region. CSWS were observed. After a change in his antiepileptic drug regimen, subsequent EEG recordings showed resolution of CSWS. As shown in our patient, CSWS can be observed in adults. In addition, continuous video/EEG monitoring including sleep is important in the evaluation of patients with sudden deterioration of seizure control accompanied by behavioral changes.

Effectiveness of diazepam rectal gel in adults with acute repetitive seizures and prolonged seizures: a single-center experience.

Many adults with epilepsy have breakthrough seizures despite treatment with antiepileptic drugs (AEDs), requiring them to have a rescue medication as part of a comprehensive treatment plan. We evaluated the effectiveness and tolerability of rectal diazepam in the treatment of breakthrough seizures in adult patients with epilepsy. We identified 50 such patients who had used diazepam rectal gel for clusters of seizures defined as acute repetitive seizures, prolonged seizures, or both, in the previous 18 months. Information on diagnoses, dose, frequency of use, reasons for use, safety, and efficacy was collected. Diazepam rectal gel was effective in stopping seizures in 45 patients (90%). Somnolence was reported in most patients, but no other adverse events were reported. Diazepam rectal gel demonstrates efficacy and tolerability as a seizure rescue medication for adult patients with a variety of seizure types, and may help improve quality of life.

Conversion to lamotrigine monotherapy from valproate monotherapy in older adolescent patients with epilepsy.

BACKGROUND: Pharmacokinetic interactions can make necessary anti-epileptic medication (AED) changes hazardous for children with epilepsy. We report the utility of a dosing algorithm designed to maintain stable trough lamotrigine (LTG) concentrations during conversion from valproate (VPA) to LTG monotherapy in adolescents aged 16-20 years. METHODS: Patients were enrolled into the study if they required a change in their AED regimen due to lack of efficacy or intolerable side effects. Conversion to LTG monotherapy took place in a four part treatment algorithm. Lamotrigine was escalated according to a target dose of 200 mg/day over 8-weeks. Valproate was withdrawn over a period of 2-6 weeks, depending on the initial dose. Lamotrigine dose was further escalated to 500 mg/day and continued for four weeks as mono therapy. Trough serum concentrations of LTG were measured during each phase of the trial. RESULTS: Twelve of 16 patients completed the study. After the LTG escalation to 200 mg/day, mean trough serum concentrations of 8.0 microg/mL did not differ significantly from the 9.5 microg/mL after VPA withdrawal or the 9.2 microg/mL after 4 weeks of monotherapy at 500 mg/day. Adverse events led to premature discontinuation for one subject. Two subjects withdrew due to worsening seizures during LTG monotherapy possibly due to non-compliance. Limitations of the trial include the open label design and small sample size of the sub-analysis. CONCLUSION: In adolescent patients, this algorithm produces stable LTG serum concentrations with favorable tolerability during a transition from VPA to LTG mono therapy.

Lamotrigine in patients with epilepsy and comorbid depressive symptoms.

PURPOSE: This open-label study evaluated the antidepressant qualities of lamotrigine (LTG) in people with epilepsy. METHODS: Eligible patients exhibited low to moderate depressive symptoms and required a change in antiepileptic drug (AED) therapy, but were excluded if they had a major depressive disorder (MDD). Lamotrigine was added onto a stable AED regimen, and self-report instruments were administered to evaluate changes in mood states. Evaluations were conducted at baseline, at the end of 19 weeks of adjunctive treatment, and 36 weeks following conversion to monotherapy. RESULTS: One hundred and fifty-eight patients with epilepsy participated; 96 patients completed adjunctive treatment, and 66 patients completed monotherapy. Intent-to-treat analyses for all instruments showed improvement in depression scores after adjunctive LTG treatment. Improvement was maintained for those converted to monotherapy. CONCLUSIONS: These data suggest that LTG may have antidepressant activity for patients with epilepsy and comorbid low to moderate depressive symptoms, and warrant a randomized controlled trial for validation.

Performance of patients with epilepsy or psychogenic non-epileptic seizures on four measures of effort.

Exaggeration of cognitive symptoms or poor effort on cognitive testing has been addressed primarily in the traumatic brain injury literature. The present investigation aims to extend the evaluation of effort to the epilepsy monitoring setting, where base rates of failure on effort testing remain unknown for patients with intractable epilepsy (ES), psychogenic nonepileptic seizures (PNES), or both conditions (ES+PNES). In addition, this investigation explores how well four measures of effort (DMT, LMT, TOMM, PDRT) distinguish between these diagnostic groups. Results show that 20% of the combined sample failed one or more effort measure. When examining failure rates for each diagnostic group, 22% of epilepsy patients, 24% of PNES patients, and 11% of ES+PNES patients performed suboptimally on one or more measure of effort. The utility of these effort measures to differentiate between these diagnostic groups appears limited. Further research is needed to clarify the base rate of poor effort in the epilepsy monitoring unit setting in general and in these three diagnostic groups specifically.

Relationship of indicators of neuropathology, psychopathology, and effort to neuropsychological results in patients with epilepsy or psychogenic non-epileptic seizures.

Previous research suggests epilepsy and psychogenic non-epileptic seizure (PNES) patients do not show consistent group differences on neuropsychological measures. However, both groups of patients show decreased neuropsychological performance when compared to a normal population (Cragar, Berry, Fakhoury, Cibula, & Schmitt, 2002). Swanson, Springer, Benbadis, and Morris (2000) have suggested epilepsy patients show decreased neurocognitive functioning due to neuropathology whereas PNES patients show decreased neurocognitive functioning due to psychopathology. Effort has also been implicated as an important factor in neuropsychological test results in general (Green, 2003). The purpose of this study was to investigate the relationships of medical history variables (e.g., duration of disorder), neuropathology, psychopathology, and effort to neuropsychological findings in epilepsy and PNES patients. Neuropsychological functioning was divided into six domains: intelligence, memory, language, executive functions, visual-spatial, and motor. Results indicated that medical history variables were related to intellectual, memory, language, and motor functioning. Psychopathology was associated with all cognitive domains except executive functioning. Effort was related to intellectual, memory, language, visual-spatial, and motor functioning. Neuropathology and diagnosis were related only to memory.

Epilepsy and the impact of an epileptology clinic for patients with mental retardation and associated disabilities in an institutional setting.

PURPOSE: Epilepsy is a common problem in institutionalized patients with multiple handicaps. Limited data exist on the characteristics of epilepsy in this patient population and the impact of systematic evaluation by an epilepsy service. METHODS: We evaluated 138 patients with epilepsy, institutionalized at a facility that cares for 324 patients with multiple handicaps. Evaluation included EEG, MRI, and video-EEG monitoring. The medication regimen was changed according to seizure diagnosis and the status of seizure control. Follow-up was available for >or=6 months in 110 patients, 1 year for 89, and 1.5 years for 49 patients. We analyzed the seizure and epilepsy diagnosis in this population, as well as the seizure frequency after evaluation and treatment. RESULTS: The 76 male and 62 female patients' ages ranged from 14 to 73 years. Seventy-three patients had fewer than one seizure per month, whereas 29 patients had at least one seizure per month. Of 131 patients taking antiepileptic drugs (AEDs), 62 were receiving monotherapy, and 69 were receiving two or more AEDs. At the last follow-up, overall 55% of patients had reduced seizure frequency, including 23% who became seizure free. Two of 36 patients had spontaneous seizure recurrence after being seizure free with no AEDs for 4 months in one patient and 3 years for the other. Attempts were made to discontinue phenobarbital, primidone, and clonazepam in 21 patients. However, these were discontinued in only five patients. CONCLUSIONS: Epilepsy is heterogeneous in institutionalized patients with multiple handicaps. It is often responsive to medical therapy. Evaluation and treatment by epilepsy specialists had an overall favorable impact on seizure control.

Stability of salivary concentrations of the newer antiepileptic drugs in the postal system.

Saliva antiepileptic drug (AED) concentrations strongly correlate with serum concentrations. Saliva collection is painless and noninvasive, and untrained personnel can easily be taught the collection process. Remote patients could mail saliva samples to a laboratory for monitoring, and samples could be obtained in the immediate postictal state to provide a "real-time" concentration. The objectives of this study were to assess the stability of saliva lamotrigine (LMT), levetiracetam (LEV), oxcarbazepine (OXC), topiramate (TPM), and zonsiamide (ZNS) concentrations sent through the United States Postal Service (USPS) and to quantify the amount of time needed for patients and the USPS to return samples to clinic. Saliva samples were obtained from patients currently taking 1 of the targeted AEDs. Samples were split into 2 storage vials. One sample was sealed in an addressed envelope, which the patient mailed from home, whereas the other sample was frozen immediately. Postmark date and day returned were collected for mailed samples. Saliva concentrations were determined using HPLC. Wilcoxon rank sum tests were used to compare the immediately-frozen and mailed sample means. Correlations were determined by the Spearman test. Thirty-seven patients were enrolled in the study. The median time between collection and postmark was 1 day (range 0-6 days); and between collection and receipt was 4 days (range 1-160 days). The mean concentrations for mailed and immediately frozen samples were similar for each AED (P > 0.15). Spearman rank order correlations between mailed and immediately frozen aliquots were strong (LMT rs = 1, LEV rs = 1, OXC rs = 0.964, TPM rs = 0.90, and ZNS rs = 1). Saliva samples mailed by patients maintain stability and can be returned in a reasonable length of time. Further studies are needed to assess patient/caretaker capability of obtaining an adequate sample.

Cluster analysis of normal personality traits in patients with psychogenic nonepileptic seizures.

The literature on patients with psychogenic nonepileptic seizures (PNES) suggests that they are a heterogeneous population. This study addresses this heterogeneity by describing subtypes of PNES based on a cluster analysis of normal personality traits in patients with PNES. In addition, the identified PNES subtypes are further described on dimensions of psychopathology as measured by the Minnesota Multiphasic Personality Inventory, Second Edition (MMPI-2), and cognition. Three personality clusters emerged: (1) very high neuroticism, low extraversion, low openness, high agreeableness, low conscientiousness; (2) average on all domains; (3) very high neuroticism, average extraversion, low openness, low agreeableness, average conscientiousness. Patients in clusters 1 and 3 appear to exhibit more severe psychopathology and a broader range of symptoms than those in cluster 2. Based on NEO-PI-R and MMPI-2 findings, tentative descriptions of the clusters are offered. Cluster 1 comprises "depressed neurotics"; cluster 2, "somatic defenders"; and cluster 3, "activated neurotics." Clusters 1 and 3 also differ significantly on neurocognitive testing, with cluster 1 significantly lower than cluster 3 in memory functioning, while cluster 2 individuals show generally average cognition across domains. These results suggest the existence of personality subtypes in patients with PNES that should be considered in the design of interventions for them.