Fatigue during treatment with antiepileptic drugs: A levetiracetam-specific adverse event?

PurposeTo examine the prevalence and clinical correlates of fatigue as an adverse event (AE) of antiepileptic drug (AED) treatment in patients with epilepsy.MethodsData from 443 adult outpatients with epilepsy assessed with the Adverse Event Profile (AEP) and the Neurological Disorder Depression Inventory for Epilepsy (NDDIE) were analysed.ResultsFatigue is reported by 36.6% of patients as always a problem during AED treatment. Fatigue is more likely to be reported by females (64.8% vs. 35.2%; Chi-Square = 16.762; df = 3; p = 0.001) and during treatment with levetiracetam (42.3% vs. 33.2%; Chi-Square = 11.462; df = 3; p = 0.009). The associations with the female gender and levetiracetam treatment were not mediated by depression, as identified with the NDDIE, and could not be simply explained by the large number of subjects on levetiracetam treatment, as analogous figures resulted from the analysis of a monotherapy subsample (41.7% vs. 30.3%; Chi-Square = 11.547; df = 3; p = 0.009).ConclusionsOne third of patients with epilepsy reports fatigue as a significant problem during AED treatment. Fatigue is more likely to be reported by females and seems to be specifically associated with LEV treatment. However, fatigue is not mediated by a negative effect of LEV on mood.     

Do antiepileptic drugs accelerate forgetting?

The majority of patients with epilepsy become seizure-free with antiepileptic drug therapy. However, seizures in approximately one-third of patients with epilepsy are difficult to treat with antiepileptic drugs and require high doses or polytherapy. High dosages increase the risk of cognitive side effects. We retrospectively investigated 162 patients with refractory temporal lobe epilepsy to determine whether the antiepileptic drugs carbamazepine, phenobarbital, and phenytoin affect the acquisition and retention of verbal and visual information. We found that patients with high serum levels of these antiepileptic drugs were selectively impaired in the retention but not acquisition of new information. Intelligence, age, duration of epilepsy, and seizure frequency were controlled for and were not factors in the observed results. There were no differences in favor of a certain drug with respect to memory functioning. Our results suggest that patients with refractory epilepsy with high serum levels of the antiepileptic drugs studied are at higher risk of accelerated forgetting.     

Tolerability of antiepileptic drugs: can we determine differences?

Patient tolerability of adverse effects is integral to successful treatment. Although standard antiepileptic drugs (AEDs) are well tolerated by many patients, the promise of newer AEDs has been the potential for diminished burden of problems with similar seizure control. This report reviews the prevalence of systemic and neurological adverse effects reported in clinical trials of AED monotherapy. A central finding in this report was the unidirectional higher prevalence of selected adverse effects from standard compared with newer AEDs. A system of questioning every patient at every visit to elicit information may be helpful when balancing benefit-to-risk ratio of individualized therapy during everyday practice.     

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.     

Lacosamide neurotoxicity associated with concomitant use of sodium channel-blocking antiepileptic drugs: A pharmacodynamic interaction?

Lacosamide is a new antiepileptic drug (AED) apparently devoid of major pharmacokinetic interactions. Data from a small postmarketing assessment suggest people who had lacosamide co-prescribed with a voltage-gated sodium channel (VGSC)-blocking AED seemed more likely to discontinue lacosamide because of tolerability problems. Among 39 people with refractory epilepsy who developed neurotoxicity (diplopia, dizziness, drowsiness) on lacosamide treatment given in combination with VGSC-blocking AEDs, we identified 7 (17.9%) without any changes in serum levels of other AEDs in whom the symptoms were ameliorated by dose reduction of the concomitant VGSC-blocking AED. Symptoms in these people seem to have arisen from a pharmacodynamic interaction between lacosamide and other VGSC-blocking AEDs. Slow-inactivated VGSCs targeted by lacosamide might be more sensitive to the effects of conventional VGSC-blocking AEDs. Advising people to reduce concomitantly the conventional VGSC-blocking AEDs during lacosamide uptitration in cases of neurotoxicity might improve the tolerability of combination treatment.     

Chiropractic manipulation: Reasons for concern?

Chiropractic's popularity is rising among the general population. Moreover, few studies have been conducted to properly evaluate its safety. We report three cases of serious neurological adverse events in patients treated with chiropractic manipulation. The first case is a 41 years old woman who developed a vertebro-basilar stroke 48 h after cervical manipulation. The second case represents a 68 years old woman who presented a neuropraxic injury of both radial nerves after three sessions of spinal manipulation. The last case is a 34 years old man who developed a cervical epidural haematoma after a chiropractic treatment for neck pain.

In all three cases there were criteria to consider a causality relation between the neurological adverse events and the chiropractic manipulation. The described serious adverse events promptly recommend the implementation of a risk alert system.     

Do we need any more new antiepileptic drugs?

The last decade has seen the licensing of nine new antiepileptic drugs (AEDs) with more to come. Despite this, only 58 and 63% of patients with localisation-related and newly diagnosed epilepsy, respectively, had been seizure-free for more than a year in separate prospective outcome studies undertaken at the Epilepsy Unit in Glasgow. Data will be presented to support the hypothesis that adolescent and adult epileptic patients comprise two distinct populations. Around 60% will be controlled on monotherapy with the first or second choice AED, while the majority of the remainder is difficult-to-control. It is for this latter group and the many pharmacoresistant paediatric patients with encephalopathic syndromes that we need new AEDs. For a successful clinical outcome, patients must be able to tolerate the treatment. Neurotoxic, sedative, cognitive and psychiatric symptoms, dysmorphic and other long-term side effects, and teratogenesis plague the current crop of AEDs. Pharmacokinetic and pharmacodynamic interactions complicate the situation still further. These problems may, in part, be a consequence of combining drugs with similar mechanisms of action. Unravelling the genetics of the epilepsies will provide a range of tempting targets for pharmacological intervention. We need, also, models of refractory epilepsy to help identify promising therapies. An efficient regulatory trial programme will ensure rapid availability of new AEDs for the many children and adults whose lives continue to be blighted by seizures.     

Acute symptomatic seizures due to single CT lesions: how long to treat with antiepileptic drugs?

The duration of anti epileptic drug therapy for single small enhancing CT lesions (SSECTL) presents a major dilemma. We studied the efficacy of short duration (6 months) antiepileptic drug therapy as compared to long duration (2 years) drug therapy. Seventy three patients presenting with seizures and showing SSECTL on cranial CT scans (plain and contrast) were randomized into group A (6 months therapy) and group B (2 years therapy). There were 47 patients in group A and 26 patients in group B. Patients were followed up for one year after withdrawal of anti epileptic drugs. CT Head (plain and contrast) was repeated after 3 months, or earlier in cases of recurrence to rule out reinfection. 53.2% in group A and 53.8% in group B showed complete resolution and were seizure free on one year follow up. Punctate residual calcification was seen in 46.8% in group A and 46.2% in group B. Eight patients (17%) in group A and three (11.5%) in group B had a recurrence. The difference in recurrence of seizure between the two groups was not statistically significant (p<0.77) in the calcified lesion subset. Since none of the patients in total resolution subset showed recurrence, the difference between calcified and total resolution subset was highly significant. The study shows that a short duration (6 months) AED therapy in patients with total resolution of lesion on follow up scan, may be adequate in comparison to those who have calcific speck as a residue. However, a longer duration of therapy in case of calcific group probably does not alter their chances of recurrence.     

Morningness and eveningness: when do patients take their antiepileptic drugs?

Almost one-third of epilepsy patients continue to have seizures despite adequate drug treatment. Chronotherapy (based on dynamic changes in drug pharmacology and disease-related processes) could be a promising treatment option. We aimed to explore whether different circadian types adjust administration times of anti-epileptic drugs (AEDs) as a step in exploring chronotherapeutic possibilities. We performed a questionnaire-based study to compare behavior of different circadian types in relation to times of taking drugs. Circadian type was determined by the Morningness-Eveningness Questionnaire. Results clearly show that morning types are taking their AEDs significantly earlier than do evening types on free days. Times of taking AEDs in the morning on work days also differ significantly between morning and evening types. Regardless of circadian type, drugs on free days are taken later than on working days. In conclusion, our study shows that patients adapt times of taking medication to their circadian type.     

Which patients become seizure free with antiepileptic drugs? An observational study in 821 patients with epilepsy

Objectives –  Analysis of factors influencing seizure outcome in antiepileptic drug treatment of epilepsy.
Patients and methods –  Retrospective analysis of 500 patients with complete seizure control and 321 patients with refractory epilepsy (mean ages 33.3 and 32.1 years respectively).
Results –  The seizure-free group consisted of 377 patients with symptomatic/cryptogenic epilepsy (SCE; mean seizure control 45 months) and 123 patients with idiopathic generalized epilepsy (IGE; mean seizure control 61 months) ( P  = 0.02). Of the patients with SCE, 35.7% had achieved seizure control with monotherapy (MT), 29.6% with ≥2 AEDs. No single AED was superior in MT. Of the patients with IGE, 35.9% had become seizure free with MT, 15.6% on combination therapy (CT). Valproate MT was more commonly associated with seizure freedom than lamotrigine ( P  < 0.05).
Conclusions –  The results indicate that, in SCE, seizures can be controlled with carefully selected CT more commonly than suggested by previous studies. The seizure prognosis of patients with IGE presenting to a specialist in epilepsy may be worse than previously thought.