The long term retention of levetiracetam in a large cohort of patients with epilepsy

Levetiracetam (Lev) is a new antiepileptic drug with a distinct mechanism of action, shown in regulatory trials to be effective. These controlled trials do not always predict how useful a drug will be in day to day clinical practice. Retention rates can provide a better indication of efficacy and tolerability in everyday use. Patients attending a tertiary referral centre for epilepsy and who received Lev in the first 2 years of its marketing were assessed (n = 811) to determine continuation rates of treatment with this drug. At the last follow up, 65% of patients were still taking Lev, and the estimated 3 year retention rate was 58%. In total, 11% attained seizure freedom of at least 6 months. Patients taking greater numbers of concurrent antiepileptic drugs (AEDs) were more likely to discontinue Lev, and those reaching higher maximum daily dosages were less likely to discontinue Lev. The retention rate for Lev compares favourably with that of other new AEDs.     

Long‐term course of oxaliplatin‐induced polyneuropathy: a prospective 2‐year follow‐up study

This prospective study sought to identify the potential reversibility of oxaliplatin‐induced peripheral neuropathy (OXAIPN) by following‐up its long‐term course 2 years after discontinuation of oxaliplatin (OXA)‐based chemotherapy. Participants were 91 colorectal cancer patients treated with OXA‐based chemotherapy. Neurological assessment, clinical Total Neuropathy Score© (TNSc©) and nerve conduction studies were performed at baseline (T0), the end of chemotherapy (T1) and 2 years (T2) after discontinuation of chemotherapy. A total of 73 of 91 (80%) patients experienced OXAIPN at T1. At a median follow‐up of 25 months, persistence of chronic OXAIPN was present in 61 of 73 patients (84%) and complete resolution was present in 12 patients (17%). Longitudinal comparison of TNSc© values between T1 and T2 revealed that the overall severity of OXAIPN in those 61 patients significantly decreased over time. Median TNSc© values were nine (range: 2–15) at T1 vs. four (range: 2–12) at T2 (P < 0.001). Likewise, sensory nerve conduction measures at T2 significantly improved in all sensory nerves tested, compared with T1. Severity of OXAIPN at T2 was significantly associated (P < 0.001) with high severity of OXAIPN at T1. In conclusion, persistence of OXAIPN beyond 2 years after finishing chemotherapy is common. Clinical and neurophysiological improvement is observed, although recovery is often incomplete.     

Long‐term safety and effectiveness of brexpiprazole in Japanese patients with schizophrenia: A 52‐week,open‐label study

Aim

This study assessed the long‐term safety, tolerability, and maintenance of the therapeutic effect of brexpiprazole in Japanese patients with schizophrenia.

Methods

This 52‐week, open‐label, flexible‐dose (1–4 mg/day) study included patients with schizophrenia who continued treatment from a short‐term randomized placebo‐controlled fixed‐dose (1, 2, or 4 mg/day) trial and de novo patients who switched from other antipsychotics.

Results

A total of 282 patients (184 de novo and 98 rolled over from short‐term trial) entered the 52‐week treatment with brexpiprazole, and 150 (53.2%) patients completed the week‐52 assessment. Treatment‐emergent adverse events (TEAE) were experienced by 235/281 patients (83.6%), and TEAE reported by ≥10% of all patients were nasopharyngitis (23.1%) and worsening of schizophrenia (22.4%). During the study, most of the TEAE were mild or moderate in severity, and there were no deaths, and no clinically meaningful mean changes in laboratory values, vital signs, or electrocardiogram parameters. Mean scores for the Positive and Negative Syndrome Scale total and Clinical Global Impression–Severity remained stable until week 52.

Conclusion

Brexpiprazole was generally safe and well tolerated and maintained therapeutic effects in the long‐term treatment of Japanese patients with schizophrenia.     

Exploring efficacy and tolerability outcomes in patients with difficult‐to‐treat epilepsy receiving adjunctive topiramate at different titration rates – an exploratory study

Objective – To compare rapid vs regular titration of topiramate concerning efficacy and safety. Materials and methods – Open‐label, prospective, single‐center study exploring efficacy and tolerability of two adjunctive dosing regimens of topiramate (TPM) in adult patients with difficult‐to‐treat epilepsy. Based on investigator judgment, 21 of 50 consecutive patients received a rapid titration (starting dose 50 mg/day, stepwise increase with 50 mg/day after 3 days each until reaching the target dose), while the other 29 patients received titration according to the German prescribing information (starting dose 25 mg/day, stepwise increase with 25–50 mg/day every 7 days). Patients were observed until the target dose was reached and 3 months thereafter. Results – Mean final dosages were 136 mg/day (regular titration) and 213 mg/day (rapid titration). Efficacy and tolerability measures did not differ significantly. Forty‐six percent of all patients experienced a seizure reduction of ≥50%; 14% became seizure free. No serious adverse events occurred. The most common adverse effects were tiredness (20%), memory and language difficulties (18% each), slowness in thinking and speech (10%), psychomotor disturbance (8%) and paresthesia (8%). Conclusions – This study suggests that rapid and conventional titration generate similar tolerability, safety and effectiveness in selected patients.     

A post hoc analysis of the long‐term safety and efficacy of perampanel in Asian patients with epilepsy

This post hoc analysis assessed the long‐term safety, tolerability, and efficacy of perampanel in Asian patients with refractory focal seizures; an additional analysis assessed the effect of perampanel on focal impaired awareness seizures (FIAS) with focal to bilateral tonic‐clonic (FBTC) seizures. In this subanalysis, data from Asian patients ≥12 years of age who had focal seizures with FBTC seizures despite taking one to 3 concomitant antiepileptic drugs at baseline, and who had entered either the long‐term extension phase of 3 phase‐3 perampanel trials (study 307) or the 10‐week extension phase of study 335, were analyzed for the effect of perampanel on duration of exposure, safety, and seizure outcomes. Of 874 Asian patients included in the analysis, 205 had previously received placebo during the double‐blind phase‐3 trials and 669 had previously received perampanel 2‐12 mg/day; 313 had FIAS with FBTC seizures at core study baseline. The median duration of exposure to perampanel was 385.0 days, and the retention rate at one year was 62.6%. Overall, during the first 52 weeks of perampanel treatment, 777 patients (88.9%) had treatment‐emergent adverse events (TEAEs), most of which were mild to moderate in severity. The most frequent TEAEs were dizziness (47.1%), somnolence (22.3%), and nasopharyngitis (17.4%). During the first 52 weeks of perampanel treatment, median percent change in seizure frequency per 28 days from pre‐perampanel baseline for all focal seizures was ?28.1%, and ?51.7% for FIAS with FBTC seizures. The 50% responder rate relative to pre‐perampanel baseline for all focal seizures was 33.8%, and 51.1% for FIAS with FBTC seizures. Long‐term treatment with perampanel in Asian patients had safety, tolerability, and efficacy similar to that of the global population in the phase‐3 trials and extension study 307. The safety profile and response rate suggest benefit for an Asian population of patients with refractory epilepsy.     

Use of levetiracetam in treating epilepsy associated with other medical conditions

OBJECTIVE: This prospective, open-label study was conducted to evaluate the effectiveness, tolerability, and safety of levetiracetam in patients with epilepsy in whom unfavorable metabolism, complex drug interactions, or direct toxic effects of antiepileptic drugs (AEDs) had caused a worsening of comorbid conditions. METHODS: Study design included the introduction of levetiracetam, discontinuation of other AEDs, and a serial assessment comprising electroencephalograms and blood tests at baseline and 2, 6, and 12 months. Of 21 patients, 16 had partial and five generalized epilepsy. Concomitant pathologies were gastroenterological (six), vascular (four), endocrinological (four), or complex conditions including hematological (four) or dermatological (three) disease. A change of regimen was necessitated by drug-drug interactions in four patients, direct real or potential toxic effects of previous AEDs in 13, and a combination of interactions/toxic effects in four. RESULTS: After 12 months, 12 patients were seizure-free, nine had reductions in seizure frequency of 50-75%, and improvement in concomitant medical conditions was observed. No side effects were reported. CONCLUSION: Levetiracetam appears to be effective, well tolerated, and safe in patients with epilepsy and other medical conditions that are difficult to manage because of drug interactions or AED-related side effects.     

Long‐term outcome in posterior cerebral artery stroke

Introduction: Previous studies on posterior cerebral artery (PCA) strokes focused mainly on topography and underlying pathophysiology. However, there are no data on long‐term prognosis and its association with the localization of the infarct. Methods: All consecutive PCA strokes registered in the Athens Stroke Outcome Project between 01/1998 and 12/2009 were included in the analysis. The New England Posterior Circulation Registry criteria were applied to classify them in relation to topography: (i) pure PCA infarcts, including pure cortical‐only and combined cortical/deep PCA infarcts (groups A and B respectively), and (ii) PCA‐plus strokes, including cortical‐only and combined cortical/deep PCA strokes with ≥1 concomitant infarcts outside PCA territory (groups C and D respectively). Patients were prospectively followed up to 10 years after stroke. Results: Amongst 185 (8.1%) PCA patients that were followed up for 49.6 ± 26.7 months, 98 (53%), 24 (13%), 36 (19.5%), and 27 (14.6%) were classified in group A, B, C, and D, respectively. Infections and brain edema with mass effect were more frequently encountered in PCA‐plus strokes compared to pure PCA (P < 0.05 and <0.01 respectively). At 6 months, 56% of cortical‐only PCA patients had no or minor disability, compared to 37%, 36%, and 26% in the other groups (P = 0.015). The 10‐year probability of death was 55.1% (95%CI: 42.2–68.0) for pure PCA compared to 72.5% (95%CI: 58.8–86.2) for PCA‐plus (log‐rank 14.2, P = 0.001). Long‐term mortality was associated with initial neurologic severity and underlying stroke mechanism. Conclusions: Patients with pure PCA stroke have significantly lower risk of disability and long‐term mortality compared to PCA strokes with coincident infarction outside the PCA territory.     

The effects of intra‐hippocampal L‐thyroxine infusion on long‐term potentiation and long‐term depression: A possible role for the αvβ3 integrin receptor

Although the effects of long‐term experimental dysthyroidism on long‐term potentiation (LTP) and long‐term depression (LTD) have been documented, the relationship between LTP/LTD and acute administration of L‐thyroxine (T4) has not been described. Here, we investigated the effects of intra‐hippocampal administration of T4 on synaptic plasticity in the dentate gyrus of the hippocampal formation. After a 15‐minute baseline recording, LTP and LTD were induced by application of high‐ and low‐frequency stimulation protocols, respectively. Infusions of saline or T4 and tetraiodothyroacetic acid (tetrac), a T4 analog that inhibits binding of iodothyronines to the integrin αvβ3 receptor, either alone or together, were made during the stimulation protocols. The averages of the excitatory postsynaptic potential (EPSP) slopes and population spike (PS) amplitudes, between 55 to 60 minutes, were used as a measure of the LTP/LTD magnitude and were analyzed by two‐way univariate ANOVA with T4 and tetrac as between‐subjects factors. The input–output curves of the infusion groups were comparable to each other, as shown by the non significant interaction observed between stimulus intensity and infused drug. The magnitude of the LTP in T4‐infused rats was significantly lower as compared to saline‐infused rats. Both the PS amplitude and the EPSP slope were depressed more markedly with T4 infusion than with saline, tetrac, and T4 + tetrac infusion. Data of this study provide in vivo evidence that T4 can promote LTD over LTP via the integrin αvβ3 receptor, and that the effect of endogenous T4 on this receptor can be suppressed by tetrac in the hippocampus. © 2016 Wiley Periodicals, Inc.     

Review: Molecular characteristics of long‐term epilepsy‐associated tumours (LEATs) and mechanisms for tumour‐related epilepsy (TRE)

Brain tumours are the second most common cause of seizures identified in epilepsy surgical series. While any tumour involving the brain has the potential to cause seizures, specific subtypes are more frequently associated with epilepsy. Tumour‐related epilepsy (TRE) has a profound impact on patients with brain tumours and these seizures are often refractory to anti‐epileptic treatments, resulting in long‐term disability and patient morbidity. Despite the drastic impact of epilepsy‐associated tumours on patients, they have not traditionally enjoyed as much attention as more malignant neoplasms. However, recently a number of developments have been achieved towards further understanding of the molecular and developmental backgrounds of specific epilepsy‐associated tumours. In addition, the past decade has seen an expansion in the literature on the pathophysiology of TRE. In this review, we aim to summarize the mechanisms by which tumours may cause seizures and detail recent data regarding the pathogenesis of specific developmental epilepsy‐associated tumours.