Psychiatric and cognitive adverse events: A pooled analysis of three phase III trials of adjunctive eslicarbazepine acetate for partial-onset seizures.

OBJECTIVE: To evaluate the nature and incidence of psychiatric and cognitive adverse events (AEs) reported with eslicarbazepine acetate (ESL) used as adjunctive treatment for refractory partial-onset seizures (POS) in adults. METHODS: This was a post-hoc analysis of data pooled from three randomized double-blind, placebo-controlled trials (BIA-2093-301, -302, -304). After an 8-week baseline period, patients received placebo or adjunctive ESL 400mg (studies 301 and 302 only), 800mg, or 1200mg once daily (QD) for 14weeks (2-week titration period, 12-week maintenance period). Psychiatric and cognitive AEs were identified from individual patient data. Suicidality was also evaluated using the Columbia-Classification Algorithm of Suicide Assessment (C-CASA), or the Columbia-Suicide Severity Rating Scale (C-SSRS). P-values were obtained using the chi-square test of independence or Fisher's exact test, without correcting for multiplicity. RESULTS: The analysis population included 1447 patients (ESL, n=1021; placebo, n = 426). Psychiatric treatment-emergent AEs (TEAEs) occurred in 10.8% of patients receiving ESL, and in a comparable proportion (10.3%) of patients receiving placebo (p=0.802). The incidence of depression and suicidality-related TEAEs was higher for ESL (7.4%) vs. placebo (3.8%) (p=0.009). The occurrence of these TEAEs differed between treatment groups (p = 0.010), but there was no notable trend between increasing ESL dose and increasing incidence of depression and suicidality-related TEAEs. Aggression/hostility-related TEAEs occurred in <0.1% of patients taking ESL vs. 0.9% taking placebo. The incidence of cognitive TEAEs was higher for ESL (7.1%) vs. placebo (4.0%) (p=0.023); incidences of memory impairment, attention disturbance, apathy, and aphasia were higher for ESL 1200mg than for other treatment groups. Incidences of psychiatric and cognitive serious AEs (SAEs) were 0.6% and 0.2% with ESL, and 0.5% and 0% with placebo, respectively. Psychiatric and cognitive TEAEs leading to discontinuation occurred in 1.9% and 1.4% of patients taking ESL, and 0.7% and 0.5% taking placebo, respectively. CONCLUSIONS: In phase III clinical trials of adjunctive ESL for treatment-refractory POS, psychiatric and cognitive TEAEs were reported infrequently with ESL and placebo. The incidences of depression and suicidality-related TEAEs and of cognitive TEAEs were higher for patients taking ESL vs. placebo. Incidences of psychiatric and cognitive SAEs, and TEAEs leading to discontinuation, were low with ESL and placebo.

Comparison of visual evoked potential monitoring during spine surgeries under total intravenous anesthesia versus balanced general anesthesia.

OBJECTIVE: To determine the comparison of its clinical utility and safety profile for visual evoked potential (VEP) monitoring during prone spine surgeries under total intravenous anesthesia (TIVA) versus balanced general anesthesia using the SightSaver™ visual stimulator. METHODS: The protocol was designed asa pilot, single center, prospective, randomized, and double-arm study. Subjects were randomized to receive either TIVA or balanced general anesthesia. Following induction and intubation, 8 electrodes were placed subcutaneously to collect VEP recordings. The SightSaver™ visual stimulator was placed on the subject's scalp before prone positioning. VEP waveforms were recorded every 30min and assessed by a neurophysiologist throughout the length of surgery. RESULTS: A total of 19 subjects were evaluated and VEP waveforms were successfully collected. TIVA group showed higher amplitude and lower latency than balanced anesthesia. CONCLUSIONS: Our data suggested that TIVA is associated with higher VEP amplitude and shorter latencies than balanced general anesthesia; therefore, TIVA could be the most efficient anesthesia regimen for VEP monitoring. SIGNIFICANCE: The findings help to better understand the effect of different anesthesia regimens on intra-operative VEP monitoring.

An evaluation of the impact of memory and mood on antiepileptic drug adherence.

RATIONALE: Antiepileptic drugs are the mainstay of treatment for patients with epilepsy. Adherence to the prescribed regimen is a major factor in achieving a reduced seizure burden, which can decrease morbidity and mortality. Patients with epilepsy oftentimes complain about difficulty with memory. Because little is known about the relationship between memory and mood and adherence, the purpose of this project was to determine the impact of the confounding factors of memory and mood on antiepileptic drug adherence in patients with epilepsy. METHODS: One hundred adult patients with epilepsy were recruited from the outpatient neurology clinic for this cross-sectional study. Patients who met the inclusion criteria completed measures of subjective memory (subset of 6 memory questions from the QOLIE-89) and objective memory (Hopkins Verbal Learning Test - Revised), subjective adherence (Morisky scale) and objective adherence (medication possession ratio), and mood (Neurological Disorders Depression Inventory for Epilepsy). Refill records from each patient's community pharmacy were used to objectively assess adherence. Medication possession ratios were calculated based on the antiepileptic drug refill records over the previous 6months. Patients were considered adherent if their MPR was >80%. RESULTS: Women made up the majority of the sample (n=59), and, on average, patients had been living with epilepsy for nearly 20years. Approximately 40% of the sample were on antiepileptic drug monotherapy; most patients (>70%) took their antiepileptic drugs twice daily, and the mean number of total medications was 4.25±2.98. Based on the objective measure of adherence, 35% of the patients were nonadherent. Patients self-reported better adherence than what was objectively measured. Only the retention metric of the objective memory measure differentiated adherent patients from nonadherent patients. Patients in the adherent group had significantly lower depression scores (indicating better mood) compared with those in the nonadherent group (p=0.04). CONCLUSIONS: Objective memory measures were not robustly correlated with adherence. However, we observed that patients with higher depressed mood scores were more likely to be nonadherent. By targeting patients with epilepsy and comorbid depression, practitioners may identify patients at greatest risk of nonadherence and subsequent harm.

Long-term tolerability and safety of lamotrigine extended-release: pooled analysis of three clinical trials.

BACKGROUND: In three randomized double-blind clinical trials, lamotrigine extended-release (lamotrigine XR) was demonstrated to be effective in the adjunctive treatment of intractable partial seizures or primary generalized tonic-clonic seizures and as monotherapy for partial seizures. OBJECTIVE: A pooled analysis of the data from these three clinical trials was performed to determine whether the tolerability and safety profile of lamotrigine XR was similar to lamotrigine immediate-release (lamotrigine IR). METHODS: This report describes results of a pooled analysis of the tolerability and safety data from the double-blind and open-label phases of these three trials. The number of patients in the integrated database exposed to one or more doses of lamotrigine XR was 662. RESULTS: Duration of exposure to lamotrigine XR was ≥26 weeks in 82.5 % of patients and ≥52 weeks in 40.8 % of patients [mean (standard deviation) 39.8 (23.3) weeks]. The number of patients with one or more adverse events during double-blind or open-label treatment was 455 (69 %). The most common treatment-emergent adverse events, regardless of suspected cause, were headache (25 % of patients) and dizziness (16 % of patients). The number of patients with one or more adverse events considered to be reasonably attributed to lamotrigine XR during double-blind or open-label treatment was 202 (31 %). The most common adverse events considered to be reasonably attributed to lamotrigine XR were dizziness (10 % of patients) and headache (6 % of patients). Lamotrigine-attributed rash was reported in 4 % of patients and was the reason for premature withdrawal in 2 %. Adverse events leading to premature withdrawal were reported in 7 % of patients. The incidence of serious lamotrigine-attributed adverse events was 1 %. One case of serious rash was reported. No cases of rash were reported to be Stevens-Johnson syndrome or toxic epidermal necrolysis. Two deaths (acute cardiac failure and acute lamotrigine poisoning) were considered reasonably attributable to lamotrigine XR. No evidence of lamotrigine-attributed changes was observed in clinical laboratory data or vital signs. CONCLUSION: The results show that lamotrigine XR is well tolerated with safety and tolerability profiles similar to those of lamotrigine IR. Given the similar safety, tolerability and efficacy profiles of lamotrigine XR and lamotrigine IR, the extended-release formulation may be preferable for many patients because of its ease of use (with once-daily dosing regardless of concomitant antiepileptic drug), the potential for enhanced compliance with once-daily dosing, and the provision of more stable serum drug concentrations. The benefit of once-daily dosing must be balanced with the potentially greater negative impact of a missed dose.

Antiepileptic drug selection for partial-onset seizures.

OPINION STATEMENT: Effective treatment of seizures resulting from epilepsy relies on several basic principles, regardless of which drug or treatment is selected. Treatment starts with a confident diagnosis that the symptoms are, indeed, seizure. The seizure type should be classified as focal in onset or primary generalized, and there should be a relentless search for the etiology. Many antiepileptic drugs (AEDs) are available to treat partial-onset seizures. Given that the efficacy of AEDs is comparable, selection of the appropriate drug is mostly determined by whether any comorbidities are present, such as migraine, obesity, depression, or chronic pain. In the absence of comorbidities, it depends on the side effect profile, cost, and convenience. Most AEDs, with a few exceptions, must be increased to a maximum tolerated dose before a second drug should be added. Most patients can become seizure free or adequately controlled if continued interventions are considered at each encounter until patients are seizure free.

Oral tocotrienols are transported to human tissues and delay the progression of the model for end-stage liver disease score in patients.

The natural vitamin E family is composed of 8 members equally divided into 2 classes: tocopherols (TCP) and tocotrienols (TE). A growing body of evidence suggests TE possess potent biological activity not shared by TCP. The primary objective of this work was to determine the concentrations of TE (200 mg mixed TE, b.i.d.) and TCP [200 mg α-TCP, b.i.d.)] in vital tissues and organs of adults receiving oral supplementation. Eighty participants were studied. Skin and blood vitamin E concentrations were determined from healthy participants following 12 wk of oral supplementation of TE or TCP. Vital organ vitamin E levels were determined by HPLC in adipose, brain, cardiac muscle, and liver of surgical patients following oral TE or TCP supplementation (mean duration, 20 wk; range, 1-96 wk). Oral supplementation of TE significantly increased the TE tissue concentrations in blood, skin, adipose, brain, cardiac muscle, and liver over time. α-TE was delivered to human brain at a concentration reported to be neuroprotective in experimental models of stroke. In prospective liver transplantation patients, oral TE lowered the model for end-stage liver disease (MELD) score in 50% of patients supplemented, whereas only 20% of TCP-supplemented patients demonstrated a reduction in MELD score. This work provides, to our knowledge, the first evidence demonstrating that orally supplemented TE are transported to vital organs of adult humans. The findings of this study, in the context of the current literature, lay the foundation for Phase II clinical trials testing the efficacy of TE against stroke and end-stage liver disease in humans.

Lamotrigine XR conversion to monotherapy: first study using a historical control group.

The efficacy and safety of lamotrigine extended-release tablets (LTG XR) as monotherapy for partial seizures were evaluated using the conversion-to-monotherapy design, and historical data as the control. This methodology was recently approved by the United States Food and Drug Administration, and this study is the first historical control design in epilepsy to complete enrollment. Patients ≥13 years old with uncontrolled partial epilepsy receiving monotherapy with valproate or a noninducing antiepileptic drug were converted to once-daily LTG XR (250 mg or 300 mg) as monotherapy and were followed up for 12 additional weeks. Efficacy was measured by the proportion of patients meeting predefined escape criteria for seizure worsening compared with aggregated pseudoplacebo control data from 8 previously conducted conversion-to-monotherapy trials. Nonoverlap of the 95% confidence limit for LTG XR and the 95% prediction interval of the historical control denotes efficacy. Of 226 randomized patients, 174 (93 in 300 mg/day group and 81 in 250 mg/day group) started withdrawal of the background AED and were evaluated for escape. In the historical control analysis population, the lower 95% prediction interval of the historical control (65.3%) was not overlapped by the upper 95% confidence limit of either LTG XR (300 mg/day; 37.2%) or LTG XR (250 mg/day; 43.4%). Adverse events were reported in 53% and 61% of patients receiving LTG XR (300 mg/day and 250 mg/day, respectively). LTG XR (250 mg or 300 mg once daily) is effective for conversion-to-monotherapy treatment of partial seizures in patients ≥13 years old.

The impact of marital status on epilepsy-related health concerns.

Social support from marriage has been linked with better health outcomes. Persons with epilepsy (PWE) are significantly less likely to be married than persons without epilepsy. No previous studies have examined the impact of marriage on epilepsy-related health concerns. Outpatient PWE (n=267) were asked to identify their top five concerns on the Epilepsy Foundation Concerns Index. After controlling for clinical factors (seizure frequency, age of epilepsy diagnosis and disability status) PWE who were married were significantly less likely to report "Fear of being injured during a seizure" Odds Ratio (OR) 0.33, "Holding down a job" OR 0.29, "Getting the work or education you want" OR 0.29, "Medical costs of your epilepsy" OR 0.21 and "Lack of people's understanding of epilepsy" OR 0.27. Once we controlled for both clinical factors and demographic factors only one concern "Medical costs of your epilepsy" OR 0.24 remained significant. Our findings support several theories examining the health benefits of marriage related to selection, protection and economic resources. PWE are particularly prone to economic disparities due to lower educational attainment and unemployment. Earlier intervention especially for those with childhood onset epilepsy may help mitigate these disparities and their impact on social relationships and marriage.

Comparing patients' and practitioners' views on epilepsy concerns: a call to address memory concerns.

The objective was to compare practitioners' impressions of patients' concerns with those expressed by the patients themselves. Prior to clinical interaction, adult patients with epilepsy and their established practitioners were asked to choose their top five concerns via a modified version of the Epilepsy Foundation Concerns Index. Patients with epilepsy (n=257) with varying degrees of seizure control from the outpatient clinic practices of five prescribing practitioners completed the modified concerns index. The three most frequent concerns reported by patients were having a seizure unexpectedly, issues related to driving, and memory problems. These were similar to those reported by the practitioners, though memory was much less of a concern expressed by the practitioner. For the paired data, the concern with the largest gap from the patients' perspective was "your memory." Though there was an overlap, patients were concerned more about life issues and practitioners were concerned about clinical issues. This should serve as a major "wakeup call" to address memory problems in patients with epilepsy, regardless of seizure control.

A health literacy assessment of the epilepsy.com website.

Current healthcare guidelines identify low health literacy as a major barrier to optimal health communication. Health literacy is defined as the degree to which individuals can obtain, process and understand basic health information and services needed to make appropriate health decisions. An estimated 90 million people in the U.S. have marginal health literacy. The Institute of Medicine and the U.S. Department of Education recommend that health related information be written at the 6th-8th grade level to address low health literacy. Epidemiological studies demonstrate that persons with epilepsy have significantly lower educational attainment and lower incomes placing them at risk for low health literacy and limited Internet access. While Internet users tend to have higher educational attainment, previous research indicates even good readers prefer simpler rather than more complex medical information. Health educational content that could be printed and given to patients addresses an important need in clinical epilepsy care. Previous reviews of health websites found they exceed recommended readability levels. Two online programs were used to assess the reading level of 1327 web pages on the www.epilepsy.com website using established readability formulas. Based on the Flesch Reading Ease assessment, only 3% of epilepsy.com web pages are written for a 6th grade reading level or below. If 8th grade level or below is used as the standard, only 15% are adequate. Recommendations and examples are provided for improving the readability of epilepsy-specific health education content.

Suicidality, depression screening, and antiepileptic drugs: reaction to the FDA alert.

OBJECTIVE: To determine the reaction of neurology practitioners to the Food and Drug Administration (FDA) alert concerning suicidality (suicidal ideation or behavior) and antiepileptic drugs. METHODS: We designed a 21-question survey asking about the participants' approach to suicidality and depression in patients with epilepsy (PWE), and their reaction to the FDA alert and its impact on their clinical practices. Participants (n = 780) were invited via e-mail to respond to a Zoomerang survey. Two reminders were sent to increase the response. RESULTS: The survey was completed by 175 participants (22%). Most were epilepsy specialists practicing in academic settings. Almost 62% did not use any scale to routinely screen for depression in PWE. For those who used a scale, the Beck Depression Inventory was the most used one. About 42% did not feel comfortable initiating treatment for depression. Although 98% warn about behavioral side effects when starting antiepileptic drugs, only 44% warn specifically about suicidal ideations or behavior. More than half were not aware of patients who attempted to commit suicide or who had committed suicide. The mean scores for the FDA alert clarity, appropriateness, and impact on clinical practice (on a scale from 1 to 10) were low, at 5.3, 4.1, and 3.6. Almost 46% did not feel the alert is going to change their practice. CONCLUSION: The Food and Drug Administration alert did not get a favorable score from the surveyed responders. Participants actively alert patients about behavioral side effects of antiepileptic drugs, but are not specific about suicide.

The impact of 'social determinants of health' on epilepsy prevalence and reported medication use.

There is a limited understanding of the complex relationship between poverty and epilepsy. To address the complex interaction of environmental and psychosocial factors in epilepsy a 'social determinants of health' model is presented where individual factors are influenced through three pathways (social environment, work and material factors). In the 2005 California Health Interview Survey, 246 of 604 (41%) persons with a history of epilepsy were in poverty, defined as <200% Federal Poverty Level (FPL). Multivariable logistic regression analyses revealed persons in poverty are not more likely to report a history of epilepsy compared to those not in poverty. However, persons with a history of epilepsy in poverty were significantly less likely than those not in poverty to report taking medication for epilepsy (OR 0.5) once material factors (annual income and living situation) and healthcare access were controlled for in the final sequential model. Healthcare practitioners must continue to recognize that connection to social services and the cost of medications are significant barriers to optimal care in persons with epilepsy. Improved connection to patient advocacy organizations and medication assistance programs may help close these gaps.

Comorbidity, health screening, and quality of life among persons with a history of epilepsy.

Previous population surveys outside the United States have found an increased prevalence of comorbid conditions in persons with epilepsy. However, the effect of comorbid conditions on health-related quality of life (HRQOL) has not been previously examined in the epilepsy literature from the United States. Results from the California Health Interview Survey (CHIS) indicate an increased prevalence of comorbid conditions in persons with a history of epilepsy compared to those without epilepsy. After controlling for demographics and comorbid conditions, persons with a history of epilepsy were significantly more likely to report poor HRQOL. Although seizure freedom should continue to be a primary clinical goal, optimal care should also include primary and secondary prevention of comorbid conditions, especially cardiovascular and pulmonary diseases. Prevention, early identification, and treatment of comorbid conditions may reduce mortality risk and improve health outcomes in persons with epilepsy.

Patients with epilepsy's perception on community pharmacist's current and potential role in their care.

A cross-sectional study was conducted surveying patients with epilepsy about the current and potential role community pharmacists play/could play in their care. Seventy-five patients (mean age=38.9 years, 66% female) were enrolled, either from the outpatient epilepsy clinic or from the local Epilepsy Foundation database. Patients were asked a series of questions about six aspects of their health care, as well as which of these aspects would be important to discuss with their pharmacist and what type of relationship they currently have/desire with their pharmacist. Results indicated that patients most commonly use their pharmacist for two aspects of their health care: drug interaction information (65%) and adverse effect information (56%). Fewer patients use their pharmacist for the four other aspects of their care: seizure frequency (13%), antiepileptic drug adherence (27%), medication profile (39%), and impact of their disease on their lifestyle (27%). Many patients want their pharmacist to be more involved in their health care, especially regarding drug interactions (76%), discussing adverse effects (74%), and maintaining a complete medication profile (61%). Patients also desired that their pharmacist communicate with their epileptologist about drug interactions (69%) and adverse effects (64%). Although many patients reported having a good relationship with their community pharmacist, a large concern was lack of privacy for holding conversations and lack of desire to pay for such pharmacy services if available. Overall, these results indicate that the majority of patients with epilepsy do not use their pharmacists to their full potential, yet certainly desire to do so, especially regarding drug interactions and adverse effects. Both pharmacists and patients should strive to form better partnerships that would allow them to take advantage of existing opportunities to enhance patient outcomes.

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.

An assessment of patient and pharmacist knowledge of and attitudes toward reporting adverse drug events due to formulation switching in patients with epilepsy.

A survey was developed to gather information from both patients with epilepsy and community pharmacists on the issue of antiepileptic drug (AED) formulation switching, which includes brand to generic, generic to brand, and generic to generic. Data were obtained from 82 patients (or parents of patients) with epilepsy and 112 community pharmacists. More than 92% of patients and 85% of pharmacists agreed that switching between forms of the same AEDs may cause an increase in seizures or adverse effects. More than two-thirds of our patient sample reported having problems with formulation switching; many also reported knowing other patients with problems. Just more than half (51%) of the pharmacists knew of patients who have described problems when they have changed AED formulations. Less than 50% of both populations knew that problems resulting from formulation switching should be reported as adverse drug events to the FDA. Not many pharmacists and far fewer patients use MedWatch to report these problems. We conclude that both patients with epilepsy and pharmacists are underinformed and underinvolved with reporting adverse drug events.

An evaluation of self-management behaviors and medication adherence in patients with epilepsy.

Comprehensive treatment of epilepsy involves many facets including self-management behaviors. The primary purpose of this study was to characterize the self-management behaviors of our patients. Additionally, we wanted to assess if the behaviors differed depending on the level of seizure control. Adult patients with epilepsy were recruited for this cross-sectional study. We used two previously validated scales to assess various self-management behaviors and collected clinical data. Our sample consisted of 50 patients (23 women). The mean overall Epilepsy Self-Management Scale (ESMS) question score was 3.72+/-0.41. The mean question scores on the ESMS subscales Medication Management, Information Management, Safety Management, Seizure Management, and Lifestyle Management were 4.4, 2.7, 3.9, 4.0, and 2.6, respectively. Information Management and Safety Management subscale scores were higher in the patients continuing to have seizures. Based on the Morisky scale, patients fell into either the low (n=2), medium (n=27), or high (n=21) medication-taking behavior category. Self-management skills, beyond medication-taking behaviors, should be emphasized during patient interactions.