Generic antiepileptic drugs—Safe or harmful in patients with epilepsy?

Generic antiepileptic drugs (AED) are significantly cheaper than brand name drugs, and may reduce overall health care expenditures. Regulatory bodies in Europe and North America require bioequivalence between generic and innovator drugs with regard to area under the plasma concentration–time curve (AUC) and peak plasma concentration (C_max); strict cutoff values have been defined. The main issue is if bioequivalence ensures therapeutic equivalence. Are switches from brand to generic, or between generic AEDs entirely safe or potentially harmful in patients with epilepsy? We summarized and evaluated the available evidence from bioequivalence, health care utilization, and clinical studies on safety of generic AEDs. In most cases, variations in AUC and C_max were negligible when comparing innovator and generic AEDs. Due to interindividual pharmacokinetic and pharmacodynamic variability, measured differences between innovator and generic drugs may be the same as differences between different lots of the same brand. Studies from several countries based on insurance data have reported an increase in health care usage after switch from brand to generic AEDs; switchback rates are significantly higher for AEDs compared to other compounds. Patients may be confused, and nonadherence may increase, when AEDs are switched between manufacturers, perhaps due to changes in medication shape and color. But clinical studies do not report changes in seizure frequency and tolerability attributable to generics. Sufficient evidence indicates that most generics are bioequivalent to innovator AEDs; they do not pose a relevant risk for patients with epilepsy. However, some patients are reluctant towards variations in color and shape of their AEDs which may result in nonadherence. We recommend administering generics when a new AED is initiated. Switches from brand to generic AEDs for cost reduction and between generics, which is rarely required, generally seem to be safe, but should be accompanied by thorough counseling of patients on low risks.     

Prospective audits with newer antiepileptic drugs in focal epilepsy: Insights into population responses?

Despite the availability of a wide range of new antiepileptic drugs (AEDs), there is little evidence that their introduction has substantially altered outcomes. This paper reviews data from 5 consecutive prospective audits with new AEDs using similar methodology. Prospective audits with topiramate (TPM; n = 135), levetiracetam (LEV; n = 136), zonisamide (ZNS; n = 141), pregabalin (PGB; n = 135), and lacosamide (LCM; n = 160) were undertaken in treated patients with uncontrolled partial-onset seizures. Follow-up continued until one of four endpoints was reached: seizure freedom for ≥ 6 months on unchanged dosing; ≥ 50% reduction (responder) in seizure frequency on the highest tolerated dose compared with baseline; < 50% seizure frequency reduction (marginal response) compared with baseline in patients wishing to continue treatment with the new AED; or withdrawal due to lack of efficacy, side effects, or both. A greater proportion of seizure-free patients occurred with LEV (23.5%), LCM (21.9%), and TPM (20.7%) than with ZNS (12.8%) and PGB (10.4%). A higher percentage discontinued treatment with ZNS (41.8%) and PGB (50.4%) than with LEV (32.4%), TPM (31.1%), and LCM (22.5%). Most seizure-free patients responded to the new agent as first or second add-on (TPM 96%; LEV 97%; ZNS 89%; PGB 86%; LCM 97%) often at modest or moderate dosing (TPM 68%, ≤ 200 mg/day; LEV 63%, ≤ 1000 mg/day; ZNS 61%, ≤ 100 mg/day; PGB 86%, ≤ 300 mg/day; LCM 74%, ≤ 200 mg/day). With < 10% of patients discontinuing all AEDs due to lack of efficacy, tolerability was the major factor influencing the number of patients remaining on treatment. Lacosamide was the best (77% patients continued treatment), while PGB was the worst (50% continued treatment) tolerated AED. Overall, seizure freedom was achieved in < 25% of patients in each audit, mainly as a first or second add-on, with best tolerated AEDs producing a higher number of good outcomes. Seizures in very few patients with drug-resistant epilepsy, as defined by the International League Against Epilepsy task force, responded to any of the 5 newer AEDs. These data support the suggestion that the introduction of modern agents has not importantly impacted the outcomes in refractory epilepsy.     

Which seizure-precipitating factors do patients with epilepsy most frequently report?

When treating patients with epilepsy, dealing with seizure-precipitating factors is a partly neglected and underestimated supplement to more traditional therapies. The aim of this study was to investigate the incidence of seizure precipitants in a large epilepsy population and to determine which precipitants patients most often reported. Study participants included twins and their family members ascertained from the Norwegian Twin Panel (NTP), the Danish Twin Registry (DTR), and the Mid-Atlantic Twin Registry (MATR). One thousand six hundred seventy-seven patients with epilepsy were identified and were asked about seizure precipitants using a closed-ended questionnaire. Fifty-three percent reported at least one seizure-precipitating factor, while 30% claimed to have experienced two or more such factors. Emotional stress, sleep deprivation, and tiredness were the three most frequently reported precipitants. Patients with generalized seizures seemed to be more sensitive to sleep deprivation and flickering light than those with partial seizures, while women with partial seizures appeared to be more prone to seizures during menstruation than women with generalized seizures. Knowledge of seizure precipitants has practical implications, not only in patient treatment and counseling, but also for diagnosis, in that it may be helpful in facilitating the appearance of interictal epileptiform discharges in EEG and ictal EEG recordings.     

Dalfampridine in patients with downbeat nystagmus—an observational study

We investigated the effects of dalfampridine, the sustained-release form of 4-aminopyridine, on slow phase velocity (SPV) and visual acuity (VA) in patients with downbeat nystagmus (DBN) and the side effects of the drug. In this proof-of-principle observational study, ten patients received dalfampridine 10 mg bid for 2 weeks. Recordings were conducted at baseline, 180 min after first administration, after 2 weeks of treatment and after 4 weeks of wash-out. Mean SPV decreased from a baseline of 2.12 deg/s ± 1.72 (mean ± SD) to 0.51 deg/s ± 1.00 180 min after first administration of dalfampridine 10 mg and to 0.89 deg/s ± 0.75 after 2 weeks of treatment with dalfampridine (p < 0.05; post hoc both: p < 0.05). After a wash-out period of 1 week, mean SPV increased to 2.30 deg/s ± 1.6 (p < 0.05; post hoc both: p < 0.05). The VA significantly improved during treatment with dalfampridine. Also, 50 % of patients did not report any side effects. The most common reported side effects were abdominal discomfort and dizziness. Dalfampridine is an effective treatment for DBN in terms of SPV. It was well-tolerated in all patients.     

Is antiepileptic drug withdrawal status related to quality of life in seizure-free adult patients with epilepsy?

PurposeThis study aimed to determine factors that influence the quality of life (QOL) of seizure-free adult patients with epilepsy in western China and address whether these determinants vary by antiepileptic drug (AED) withdrawal.MethodsA cross-sectional study was conducted in the epilepsy outpatient clinic of West China Hospital, Sichuan University. Patients with epilepsy who were aged at least 18 years and seizure-free for at least 12 months were interviewed using the Quality of Life in Epilepsy Inventory-31 (QOLIE-31); the National Hospital Seizure Severity Scale (NHS3); the Liverpool Adverse Events Profile (LAEP); the Social Support Rating Scale (SSRS); the Family Adaptation, Partnership, Growth, Affection, and Resolve (APGAR) Questionnaire; and the Scale of Knowledge and Attitudes Toward Epilepsy. Eligible patients were divided into two groups: the nonwithdrawal group and the withdrawal group. The independent-samples t-test was used to compare the QOL between the groups, and linear regression analysis was used to explain the variance of their QOL.ResultsOne hundred and eighty-seven (135 nonwithdrawal and 52 withdrawal) patients were included in the analysis. The QOLIE-31 overall score of the nonwithdrawal group was lower than that of the withdrawal group (p < 0.01). The LAEP score was the strongest predictor of the QOLIE-31 overall score of all subjects, explaining 26.9% of the variance. The second strongest predictor was the SSRS score, explaining 12.9%, and the other predictors were the NHS3 score (5.2%), education level (2.3%), age (1.5%), and marriage (1.0%). Furthermore, the strongest predictors in the nonwithdrawal group were the LAEP and SSRS scores, while in the withdrawal group, the strongest predictors were stigma scores and employment.ConclusionAmong the seizure-free adult patients with epilepsy, those with AED withdrawal experienced better QOL than those continuing AED treatment. Furthermore, the determinants of QOL varied by AED withdrawal. Individual strategies to optimize QOL should be developed based on these differences.     

Is antiepileptic drug use related to depression and suicidal ideation among patients with epilepsy?

Depression and suicide are increased in patients with epilepsy. The U.S. Food and Drug Administration warns that antiepileptic drugs (AEDs) are associated with increased risk of suicidality. This study examines the relationship among depression, suicidal ideation, and AEDs in a prospective cohort of 163 patients with epilepsy from a registry at the University of Florida (January 2006 to August 2008). The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) was used to measure mood and suicidal ideation across two time points (median = 154 days). Groups included: (1) No AED Change, (2) New AED Added, (3) AED Dose Increased, (4) AED Reduced/Stopped, (5) Multiple AED Changes, and (6) Combined Any AED Change (groups 2-5 combined). No group had worsening mood or suicidal ideation. Significant improvements in proportions of depression and suicidal ideation were seen only for the No AED Change group, which differed only with the AED Dose Increased group with respect to suicidal ideation.     

Which electroencephalography (EEG) for epilepsy? The relative usefulness of different EEG protocols in patients with possible epilepsy

Background and aim

Electroencephalography (EEG) is an essential investigative tool for use in young people with epilepsy. This study assesses the effects of different EEG protocols on the yield of EEG abnormalities in young people with possible new epilepsy.

Methods

85 patients presenting to the unit underwent three EEGs with differing protocols: routine EEG (r‐EEG), sleep‐deprived EEG (SD‐EEG), EEG carried out during drug‐induced sleep (DI‐EEG). The yield of EEG abnormalities was compared using each EEG protocol.

Results

98 patients were recruited to the study. Of the 85 patients who completed the study, 33 (39%) showed no discernible abnormality on any of their EEG recordings. 36 patients (43%) showed generalised spike and wave during at least one EEG recording, whereas 15 (18%) had a focal discharge evident at some stage. SD‐EEG had a sensitivity of 92% among these patients, whereas the sensitivity of DI‐EEG and r‐EEG was 58% and 44%, respectively. The difference between the yield from SD‐EEG was significantly higher than that from other protocols (p<0.001). Among the 15 patients showing focal discharges, SD‐EEG provoked abnormalities in 11 (73%). r‐EEG and DI‐EEG each produced abnormalities in 40% and 27%, respectively. 7 patients (47%) had changes seen only after sleep deprivation. In 2 (13%), the only abnormalities were seen on r‐EEG. In only 1 patient with focal discharges (7%) was the focal change noted solely after drug‐induced sleep. These differences did not reach significance.

Conclusion

EEG has an important role in the classification of epilepsies. SD‐EEG is an easy and inexpensive way of increasing the yield of EEG abnormalities. Using this as the preferred protocol may help reduce the numbers of EEGs carried out in young patients presenting with epilepsy.Electroencephalography (EEG) is an essential investigative tool for use in young people with epilepsy.^1,2,3,4,5 The clinical onset of the idiopathic generalised epilepsies (IGEs) is most common in adolescence and early adulthood, and this is when EEG is most valuable.⁵ Differentiation of IGE from partial epilepsy should be done as early as possible, because of the important implications it will have on treatment choice,⁶ planned duration of treatment⁶ and prognosis.⁷ Despite its utility, EEG is not always easily available in many parts of the UK. Clinical targeting is desirable to allow efficient use of this resource.⁸The effect of sleep deprivation on EEG has long been recognised.^2,3,9 For reasons that are unclear, the incidence of epileptiform abnormalities on EEG is increased by sleep deprivation. Some authors feel that this effect leads to an enhanced yield of epileptiform abnormalities even when compared with routine EEG (r‐EEG) that includes a period of sleep,³ although one study did not support the special effect of sleep deprivation.⁴Although the role of the EEG in early epilepsy is widely recognised in this age group, there are few data on the relative sensitivity of EEG protocols in detecting epileptiform changes. One study⁹ looked at the incidence and frequency of epileptiform abnormalities after EEG with drug‐induced sleep (DI‐EEG) and EEG after sleep deprivation (SD‐EEG). This cohort consisted largely of patients already on treatment for localisation‐related epilepsies.Carpay et al¹⁰ repeated SD‐EEG in a cohort of younger people with normal r‐EEG and found that 34% of them showed various epileptiform abnormalities. The age range and selection criteria limit the applicability of these data. An earlier study¹¹ had carried out SD‐EEG in 114 patients who had a previously normal r‐EEG, some of whom were receiving drugs for epilepsy. Despite this, 47 patients exhibited some clearly ictal activity, but this selection precluded direct comparison of elicited epileptiform changes in different protocols.In young adults with newly diagnosed epilepsies, the role of provocative testing (either SD‐EEG or DI‐EEG) remains unclear, as the relative yield of generalised discharges in each protocol has yet to be properly compared. In young adults with newly diagnosed epilepsy, which EEG protocol is best? Should SD‐EEG be the preferred protocol? Is DI‐EEG as sensitive or specific as SD‐EEG in detecting abnormalities?     

Effects of topiramate versus other antiepileptic drugs on the cognitive function of patients With epilepsy

BACKGROUND： Only very large dose of topiramate has neurotoxicity, indicating that topiramate has low neurotoxicity and high safety. The residual rate of topiramate is affected by many cognitive-related adverse effects. Patients who take topiramate often accompany with thought slowness, difficulty in finding words, dyscalculia, blunt reaction, attention decreasing, memory deterioration, etc. OBJECTIVE： To compare the effects of topiramate with traditional anti-epileptic drugs （including carbamazepine and Valproic acid （VPA） on cognitive function of patients with epilepsy. DESIGN： Observational experiment, self-control and intergroup comparison. SETTING： Sichuan Academy of Medical Science. PARTICIPANTS： Eighty-seven inpatients and outpatients with newly diagnosed epilepsy who received preliminary diagnosis and follow-up in the Department of Neurology, Sichuan People＇s Hospital between January 2004 and June 2006 were involved in this survey. They were diagnosed according to disease history and electroencephalogram （EEG）. The onset type was diagnosed following the definition of epilepsy and epileptic syndrome in 1989 International Anti-epileptic League. The involved patients and their relatives were informed of detection and therapeutic regimen. The patients were assigned into two groups according to table of random digit： traditional antiepileptic drugs group （AEDs group, n =44） and topiramate （TPM） group （n =43）. METHODS： （1）Among the patients in AEDs group, carbamazepine was the first choice for 21 patients with partial seizures or partial secondarily generalized seizures, and VPA for 23 patients with generalized seizures. The initial dose of carbamazepine was 300 mg/d, and that of VPA was 500 mg/d. Patients in the TPM group took TPM with the initial dose of 25 mg/d, increased by 25 mg/d each week to target dose 150 mg/d within 8 weeks. （2） Curative effect was graded into 4 degrees： markedly effective, effective, ineffective and aggravated. Total effective rate was calculated. （3） Cognitive function of patients was tested before and 6 months after administration by using Wechsler Adult Intelligence Scale（WAIS） or Wechsler Intelligence Scale for Children （WISC, Chinese edition）, （Higher scores indicated better cognitive function）, Stroop color word interference, test of memory of past numbers, test of telling the names of fruits and vegetables within 1 minute （Shorter time for reading word, telling color and memory of past numbers demonstrated better cognitive function. Less errors in reading words, telling colors and memory of past numbers, numbering and telling the names of fruits and vegetables within 1 minute indicated better cognitive function）, etc. totally 22 items. （4） t test and paired t test were used for measurement data. MAIN OUTCOME MEASURES： Clinical curative effects and adverse reactions as well as neurological tests. RESULTS： Eighty-four pationts praticipated final analysis and 3 dropped out. （1） Inthe AEDS group and TPM group, total effective rate was 86% and 99%, respectively. （2） In the AEDs group, there were no significant changes in the scores of each test of WIS before and after treatment （P 〉 0.05）. In the TPM group, total IQ, word scores, verbal IQ and digit span scores were significantly decreased （ t =2.097 - 4.423, P 〈 0.05 - 0.01 ） .Following treatment, the time for reading word and telling color for patients in the AEDs group was prolonged in Stroop color interference test （ t = - 2.304, - 2.454, P 〈 0.05 ）, and time for reading word and memory of past numbers for patients in the topiramate group was significantly prolonged （ t = - 3.054, 2.272, P 〈 0.01, 0.05 ）. （3）There were no significant differences in scores of WIS before and after treatment in AEDs group and TPM group （P 〉 0.05）. Following treatment, verbal IQ, word scores, total IQ, digit span of patients in the TPM group were significantly lower than those in the AEDs group （t =2.052 - 3.297, P 〈 0.05- 0.01 ） .There were no significant differences in Stroop color word interference, memory of past numbers and telling the names of fruits and vegetables within 1 minute before and after treatment in AEDs group and TPM group （P 〉 0.05）. CONCLUSION： （1） Moderate and small doses of both TPM and AEDs may lead to mild cognitive function impairment of patients, mainly presenting delayed reaction and decreased sensitivity. （2）TPM mainly influences attention, language comprehension ability and fluency, while AEDs cause delayed reaction easily, but influence executive function mainly.     

Which factors determine febrile seizure recurrence? A prospective study

PURPOSE: Many factors have been studied as potential predictors of recurrent febrile seizures (FS), however the available data in literature are inconsistent. The aim of the present paper is to determine which factors are responsible for the first and for multiple recurrences of FS, in a large sample of children with a long-term follow up. METHODS: Two hundred and sixty children were followed after their first FS. The inclusion criteria were: a history of a first febrile seizure; no personal history of afebrile seizures; no previous anticonvulsant medication and age between three months and six years. The median time of follow up was 4.3 years. We had a contact with the families of the children every 4-6 months and also in every recurrence. RESULTS: Very significant prognostic markers for the first FS recurrence were low age at onset, recurrence within the same illness, frequent febrile episodes and maternal preponderance. Powerful prognostic factors that may predispose children who already have one recurrence to a second or more are low age at onset and especially positive family history of FS. Additionally, low temperature prior to the initial seizure is a powerful predictor for three or more recurrences. CONCLUSIONS: Prognostic factors for FS recurrence are a useful tool for the clinician. It is obvious that as many powerful predictors a child has, the greater will be the risk for FS recurrence.     

Enzyme induction with antiepileptic drugs: Cause for concern?

Several commonly prescribed antiepileptic drugs (AEDs)—including phenobarbital, phenytoin, and carbamazepine—stimulate the synthesis of a broad range of monooxygenase and conjugating enzymes. These agents are well known to reduce the duration and action of many lipid‐ and non–lipid‐soluble drugs, including anticoagulants, cytotoxics, analgesics, antiretrovirals, glucocorticoids, statins, antihypertensives, oral contraceptives, psychoactive drugs, immunosuppressants, and of course, other AEDs. This process, therefore, may be associated with a number of clinical problems including higher cancer mortality, progressive AIDS, transplant rejection, and unwanted pregnancy. Withdrawal of enzyme‐inducing AEDs will increase the concentration of induced drugs, bringing with it substantial risk of toxicity if doses are not concomitantly reduced. Yet the potential widespread adverse health consequences of these interactions, both with AED initiation and withdrawal, remain largely underappreciated. Furthermore, induction also affects enzymes involved in endogenous metabolic pathways, and can alter bone biochemistry, gonadal steroids, and lipid markers. Therefore, enzyme‐inducing AEDs may contribute to the development of a number of comorbidities, including osteoporosis, sexual dysfunction, and vascular disease. This process continues as long as the patient takes the inducer. Modern AEDs that do not possess this property have similar efficacy for the common epilepsies. Accordingly, perhaps consideration should be given to starting treatment with, or even switching patients to, non–enzyme‐inducing AEDs.     

Antioxidative–oxidative balance in epilepsy patients on antiepileptic therapy: a prospective case–control study

Oxidative stress has been implicated in various disorders, including epilepsy. The aim of this study was to investigate the oxidant and antioxidant status of patients with epilepsy using antiepileptic drugs regularly and to compare them with healthy subjects. We investigated serum catalase (CAT), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and xanthine oxidase (XO) levels in 58 epilepsy patients and 25 healthy controls. Patients were divided into polytherapy (n = 17) and monotherapy (n = 41) groups, and antioxidant status was compared between the two groups and controls. There was no significant difference between the patient and control groups in terms of age or gender (p > 0.05). The mean duration of illness in the patients was 14.8 years, and the mean duration of treatment was 11.4 years. Comparison of the patient and control groups in terms of oxidative stress and antioxidant defence parameters revealed significantly higher MDA, GSH-Px, XO and lower level of CAT, SOD levels (p < 0.05). There were no differences in CAT, MDA, GSH-Px or SOD levels between the monotherapy and polytherapy groups; but the XO level was higher in the monotherapy group (p < 0.05). Although the XO level was decreased by polytherapy, it was higher than in controls. Our study found significantly low level of antioxidants in patients with epilepsy as compared to control. Thus, antiepileptic treatment did not improve oxidative stress parameters. Furthermore, our results show that polytherapy does not change the situation as compared with monotherapy. Antioxidant replacement therapy may benefit these patients.