Rationalized polytherapy for epilepsy

In the past, epilepsy was usually treated with polytherapy, but with little knowledge as to the interactions and side-effects of the combinations of the anti-epileptic drugs used. Adverse events and sparse clinical knowledge led to monotherapy becoming the treatment regime of choice. A new generation of drugs, which are well-tolerated and have few or predictable interactions, have enabled the reassessment of polytherapy for the treatment of epilepsy. Extensive clinical trials of these drugs are allowing the emergence of a new, rationalized approach to polytherapy. In our study, 19 patients with refractory partial epilepsy, and who were 'socially active and integrated into society', received vigabatrin as add-on therapy. Patients were taking a mean of 1.5 drugs, and five patients were taking small doses of drugs which lead to tolerance, such as barbiturates and benzodiazepines. With vigabatrin as add-on therapy, 14 patients (73%) had a greater than 50% reduction in seizure frequency, and 10 (52%) had a greater than 70% reduction in seizure frequency. In one patient, seizure frequency increased, and two patients developed myoclonic jerks. Vigabatrin was not shown to have any harmful effects in extensive laboratory, EEG and cognitive function tests. In fact, a minor improvement occurred in visual memory, which was probably related to the reduction in seizures. Addition of vigabatrin may, therefore, be of benefit to patients with partial epilepsy refractory to monotherapy with standard anti-epilepsy drugs.     

Monotherapy versus polytherapy for epilepsy: a multicenter double-blind randomized study

PURPOSE: Monotherapy has been the gold standard in epilepsy treatment for the last 20 years, partly because of the reputation for increased toxicity of polytherapy. However, monotherapy and polytherapy have not been compared in a double-blind clinical trial. Open trials that compared the two treatments were not optimally designed and compared the two at unequal drug loads (i.e., at nonequivalent dosages). We report on a double-blind clinical trial in which a combination of carbamazepine (CBZ) and valproate (VPA) was compared with CBZ monotherapy. Patients started with equal drug loads, and neurotoxicity was the primary outcome measure. METHODS: The 130 adult patients with untreated generalized tonic-clonic and/or partial seizures were randomized to equal drug loads of either monotherapy (400 mg CBZ per day) or polytherapy (200 mg CBZ plus 300 mg VPA per day). Outcome was measured by seizure counts, clinimetric epilepsy scales, and neuropsychological tests at baseline, at 2 and 12 months, and irregularly between 2 and 12 months. RESULTS: No statistical differences were found between the two treatments in the reduction of seizure frequencies, in overall neurotoxicity, or in overall systemic toxicity. The frequencies and clinimetric scores of certain adverse effects did differ (e.g., more monotherapy patients remained sedated, and more polytherapy patients gained weight). Fewer polytherapy patients withdrew because of adverse effects (14 vs. 22%), although this did not reach statistical significance (p=0.15). Neuropsychological assessment did not show significant differences. CONCLUSIONS: No differences were found in overall neurotoxicity between monotherapy and polytherapy.     

Frequent seizures and polytherapy can impair quality of life in persons with epilepsy

CONTEXT: Careful evaluation of pharmacotherapy, seizure control and quality of life (QOL) are helpful in improving epilepsy care but such data are relatively meager from developing countries. AIMS: To audit pharmacotherapy, seizure control and QOL in persons with epilepsy and to identify factors associated with impaired QOL. SETTINGS AND DESIGN & MATERIALS AND METHODS: The study was carried out using a cross-sectional design in the setting of a tertiary care epilepsy center in India. Persons with epilepsy with > 12 months follow-up at this Center and aged > 16 years were eligible for enrollment. Persons with other disabilities or pregnancy were excluded. Subjects were interviewed with a standard questionnaire and an adapted version of Quality of Life in Epilepsy - 31 (QOLIE-31). Data pertaining to treatment at the time of referral to this center was extracted from medical records. STATISTICAL ANALYSIS USED: Chi-square test, analysis of variance and multiple regression analysis were carried out for statistical significance. RESULTS: One hundred and twelve patients with epilepsy (59 males, mean age 31.2+/-10.7 years) were included. Forty-seven (42%) persons had Generalized Epilepsy (GE) and 65 persons (58%) had Localization-Related Epilepsy (LRE). At entry 24 persons (21.4%) were not on treatment and 59 persons (64.8%) had frequent seizures. At last follow-up 64 persons (57.1%) were seizure-free, 83 persons (74.1%) were on monotherapy and 29 were (25.9%) on polytherapy. Cost of drug at entry was INR 2276 (monotherapy) and INR 3629 (polytherapy) (45 INR = 1 USD). At the time of last follow-up, it was 1898 and 4929 respectively. QOLIE-31 Total Score (TQOL) ranged from 22.6 to 94.4 (mean 68.0 +/- 15.8). Multiple regression analysis showed significant correlation between low TQOL score and polytherapy (P=0.002) and occurrence of one or more seizures per month (P=0.001). CONCLUSIONS: Frequent seizures and polytherapy are associated with lower QOL in persons with epilepsy.     

Monotherapy and polytherapy for intractable epilepsies

A retrospective survey on 66 adults with epilepsy who received multiple drug therapy after the failure of single drugs showed: a reduction of seizure frequency of 75% or more in 16.5%, no change in 67% and an increase in seizure frequency of 100% or more in 16.5%. Multiple drug therapy is of limited value in severe epilepsies.

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Sommario Lo studio comprende una analisi retrospettica su 66 pazienti adulti con epilessia che, dopo non aver ottenuto la scomparsa completa delle crisi con differenti monoterapie, hanno intrapreso un trattamento combinato. Nel 16,5% dei casi si è osservata, con l'introduzione della politerapia, una riduzione delle crisi del 75% ed oltre; nel 67% non si è assistito ad alcuna modificazione della frequenza critica, mentre questa è aumentata del 100% ed oltre in un altro 16,5% dei casi. La politerapia sembra essere di valore limitato nei casi di epilessia farmaco-resistente.

     

Hemispherectomy for intractable epilepsy in adults: the first reported series

Hemispherectomy for intractable unihemispheric epilepsy (IUE) has long been established in pediatric patients. This study reports the first series examining hemispherectomy exclusively in adult patients (>18 years old). Nine adults with IUE underwent hemispherectomy at the University of Minnesota. All patients had unilateral hemiplegia and visual field loss. Seven patients (77.8%) were Engel class I/II at last follow-up. Five (83.3%) of the six patients with >30 years of follow-up were seizure free. No surgery-related mortality, hydrocephalus, or superficial cerebral hemosiderosis occurred. Hemispherectomy is an effective procedure in appropriately selected adult patients, resulting in excellent long-term seizure control and no mortality.     

Evaluating quality of life in epilepsy: The role of screening for adverse drug effects,depression, and anxiety

ObjectiveThe objective of this study was to evaluate the contribution of validated screening tools for antiepileptic drug (AED) adverse effects, depression, and anxiety to measure the quality of life (QoL) in people with epilepsy (PWE).MethodsPatients in a tertiary epilepsy service were screened for quality of life (using QOLIE-31), major depressive disorder (MDD) (NDDI-E), generalized anxiety disorder (GAD) (GAD-7), and AED effects (AEP). Mini International Neuropsychiatric Interview (MINI) generalized anxiety disorder module was also performed. For AEP validation in French, the internal structural validity was analyzed. Dimensional (NDDI-E and GAD-7 scores) and categorical (MDD and GAD) analyses were performed to investigate interactions between QoL and AEP.ResultsA total of 132 (87 females) subjects were included. The French version of the AEP demonstrated satisfactory psychometric properties (Cronbach's α 0.87). Correlations between NDDI-E, GAD-7, AEP, and QOLIE-31 scores were high, and significant for all subscales of QOLIE-31; no effect of seizure-related variables was seen. Some sex differences in QOLIE-31 subscales were found, and mean AEP score was higher in females. Age, sex, NDDI-E, GAD-7, and AEP scores accounted for 61% of variance of QOLIE-31 scores. Differential effects were seen on QOLIE-31 subscales: AEP strongly correlated with all subscales; GAD-7 scores more strongly correlated with “Seizure Worry”; NDDI-E with “Energy-Fatigue”; and both NDDI-E and GAD-7 scores strongly correlated with “Emotional Well-Being”. Categorical analysis of groups with MDD alone, GAD alone, MDD + GAD, and neither MDD nor GAD showed significant differences in AEP and QOLIE-31 scores, with MDD + GAD showing the most AED effects and the poorest QoL.SignificanceThe combination of screening tools for depression (NDDI-E), anxiety (GAD-7), and AED effects (AEP) has a strong power for evaluating QoL in PWE. Coexisting MMD and GAD were associated with the poorest quality of life and the highest AEP scores.     

Relationship between serum mono-hydroxy-carbazepine concentrations and adverse effects in patients with epilepsy on high-dose oxcarbazepine therapy

PURPOSE: To investigate the relationship between the serum concentration of the mono-hydroxy-derivative (MHD) of oxcarbazepine (OXC) and adverse effects (AEs) in epileptic patients on high-dose OXC therapy. PATIENTS AND METHODS: Forty-four consecutive patients, aged 18-65 years, with refractory epilepsy receiving OXC dosages > or = 1500 mg/day (range 1500-3300 mg/day) were assessed at an outpatient clinic. Serum MHD concentrations were determined by a specific HPLC assay in samples collected before the morning dose and 2 h after drug intake. An independent observer assessed AEs at each sampling time. RESULTS: AEs were reported in five patients at the first sampling time, and in 26 patients at the second sampling time. Nystagmus, sedation, blurred vision, and dizziness were the most frequent AEs. MHD concentrations (means +/- S.D.) associated with AEs were 29.6 +/- 5.58 compared with 21.7 +/- 5.0 mg/L when no AEs were detected (p = 0.0001). AEs were minimized in most patients by reducing OXC dose, increasing the number of daily administrations, or both. CONCLUSION: Patients with serum MHD concentrations > or = 30 mg/L are at greater risk of developing AEs. In many patients, AEs occur intermittently in relation to fluctuations in serum MHD. Monitoring MHD concentrations could help in the management of patients on high-dose OXC therapy.     

Topiramate and psychiatric adverse events in patients with epilepsy

PURPOSE: The aim of this study was to determine the prevalence of psychiatric adverse events (PAEs) in patients with epilepsy treated with topiramate (TPM). Classification, relation to TPM dosing, and outcome were evaluated to identify a patient profile at risk of developing PAEs. METHODS: We evaluated the data of the first consecutive and prospectively collected patients in therapy with TPM. RESULTS: Follow-up information was available for 431 patients. PAEs occurred in 103 (23.9%) patients; M/F ratio, 55:48; mean age (+/-SD), 36.5 +/- 11.2. In 46 (10.7%) patients, an affective disorder developed; in 16 (3.7%), a psychotic disorder; in 24 (5.6%), aggressive behavior with or without irritability; in 17 (3.9%), other behavior abnormalities such as agitated behavior, anger/hostility behavior, or anxiety. High starting dose and rapid titration schedule were relevant for the development of PAEs. Family psychiatric history and family history of epilepsy, personal history of febrile convulsions, psychiatric history, and presence of tonic-atonic seizures were found to be significant risk factors. Low seizure frequency before starting TPM and TPM/lamotrigine coadministration had a protective effect for PAEs. CONCLUSIONS: We found that PAEs associated with TPM were related to the titration schedule of the drug and that a unique patient profile is suggested by the clinical history.     

Self and informant report ratings of psychopathology in genetic generalized epilepsy

The psychological sequelae of genetic generalized epilepsies (GGE) is of growing research interest, with up to a third of all adults with GGE experiencing significant psychiatric comorbidity according to a recent systematic review. A number of unexplored questions remain. Firstly, there is insufficient evidence to determine relative prevalence of psychopathology between GGE syndromes. Secondly, the degree to which self-report and informant-report questionnaires accord in adults with epilepsy is unknown. Finally, while epilepsy severity is one likely predictor of worse psychopathology in GGE, evidence regarding other possible contributing factors such as epilepsy duration and antiepileptic drugs (AEDs) has been equivocal. The potential impact of subclinical epileptiform discharges remains unexplored.Self-report psychopathology symptoms across six DSM-Oriented Subscales were prospectively measured in 60 adults with GGE, with informant-report provided for a subset of 47. We assessed the burden of symptoms from both self- and informant-report, and the relationship between clinical epilepsy variables and self-reported symptoms.Results showed elevated symptoms in almost half of the sample overall. Depression and anxiety were the most commonly reported types of symptoms. There was a trend towards greater symptoms endorsement by self-report, and relatively modest interrater agreement. Symptoms of ADHD were significantly positively associated with number of AEDs currently prescribed. Other psychopathology symptoms were not significantly predicted by epilepsy duration, seizure-free duration or total duration of epileptiform discharges over a 24-hour period.The high prevalence of psychological needs suggests that routine screening of psychopathology and provision of psychoeducation may be essential to improving patient care and outcomes. Further investigation is required to better understand predictive and causal factors for psychopathology in GGE.     

More effective assessment of adverse effects and comorbidities in epilepsy: results of a Phase II communication study

Research was conducted to evaluate conversations about epilepsy between community-based neurologists and patients. Adverse effects of antiepileptic drugs and mood/behavioral issues were infrequently discussed, and neurologists and patients disagreed about these issues postvisit. Follow-up research was conducted to assess the impact of a previsit assessment tool on discussions of epilepsy. Twenty neurologists reviewed a tool incorporating questions from validated instruments (Adverse Events Profile [AEP] and Neurological Disorders Depression Inventory for Epilepsy [NDDI-E]). Naturally occurring interactions between neurologists and 60 patients were recorded. Neurologists and patients were interviewed separately. All components were transcribed and analyzed using sociolinguistics. Using the previsit assessment tool increased the number of discussions about adverse effects and mood/behavioral issues and increased neurologist–patient agreement about issues postvisit. Visit length did not increase significantly when the tool was used. Ten months after follow-up research, 50% of neurologists reported continuing to use the tool in everyday practice with patients with epilepsy.     

Risk of adverse events on epilepsy monitoring units: a survey of epilepsy professionals

In 2008 a workgroup of health care professionals from the American Epilepsy Society (AES) was convened to address the lack of consensus regarding patient care in epilepsy monitoring units (EMUs). The group developed a questionnaire designed to identify the extent to which selected adverse events occurred in EMUs, and it was sent via email to all members of the AES. We asked that only one representative from each center report. Seventy responses were received. The number of centers reporting the following adverse events included: falls by 69%, status epilepticus by 63%, and postictal psychosis by 54%. Infrequent events with serious consequences were also reported including pneumonia by 10%, cardiac arrest by 7%, fractures by 6%, and death by 3% (N=2). Of the 58 respondents who reported using intracranial electrodes, 37.9% (N=22) reported that patients pulled out or dislodged electrodes. This study highlights the need for EMUs to identify and address potential safety risks in their environment, patient population, and system of care.     

Simultaneous determination of valproic acid and 2-propyl-4-pentenoic acid for the prediction of clinical adverse effects in Chinese patients with epilepsy

Valproic acid (VPA) is a well-established anticonvulsant drug that has been increasingly used in the treatment of many forms of generalized epilepsy. Although there are many reports of adverse effects of VPA, studies focusing on the concentration-response relationships of VPA and its metabolites in patients with epilepsy are extremely limited. In this study, a rapid and specific high performance liquid chromatography-ultraviolet (HPLC-UV) method to simultaneously detect the concentrations of VPA and its major hepatotoxic metabolite 2-propyl-4-pentenoic acid (4-ene VPA) in human plasma has been established, using 2,4'-dibromoacetophenone and octanoic acid as the derivatization reagent and internal standard, respectively. This method was used to analyze plasma samples (n=64) of Chinese patients with epilepsy. The results revealed that 4-ene VPA concentrations in Chinese patients were much higher than those in patients in other countries such as United States and Iran. Significant correlations between aspartate aminotransferase (AST), alanine aminotransferase (ALT) and 4-ene VPA concentration suggest that the simultaneous determination of VPA and 4-ene VPA is an effective tool for the prediction of clinical hepatotoxicity in epileptic patients. Furthermore, the present study describes a less costly and complex technique for the clinical monitoring of VPA plasma levels and the risk of hepatotoxicity which may be of particular interest in developing countries like China.     

Immunotherapy for Alzheimer disease-the challenge of adverse effects

Amyloid-β (Aβ) plays a crucial part in the pathogenesis of Alzheimer disease (AD), making this peptide an attractive therapeutic target. However, clearance of brain Aβ in clinical trials of Aβ-specific antibodies did not improve cognition in patients with AD, leading to reassessment of the current therapeutic strategies. Moreover, current immunotherapies are associated with autoimmunity-related adverse effects, and mobilization of neurotoxic insoluble Aβ-oligomers. Despite the fact that antibodies to the N-terminal domain of Aβ can promote Aβ production, immunotherapies in ongoing clinical trials predominantly target this peptide region. Here, we address the challenges of adverse effects of immunotherapy for AD. We discuss available evidence regarding the mechanisms of both endogenous and exogenous Aβ-specific antibodies, with a view to developing optimal immunotherapy based on peripheral Aβ clearance, targeting of the toxic domain of Aβ, and improvement of antibody specificity. Such strategies should help to make immunotherapy a safe and efficacious disease-modifying treatment option for AD.     

A preliminary observation of the adverse effects of phenobarbital among patients with convulsive epilepsy in rural West China

BackgroundThis study explored the adverse effect (AE) profile of phenobarbital (PB) among patients with active convulsive epilepsy (ACE) from resource-poor areas.MethodsPatients with ACE were enrolled into an epilepsy management project in rural West China. Information was obtained from monthly follow-up questionnaires. The demographic and clinical features of the patients with AE were firstly described. After that, the occurrence rate was estimated for each subtype of AE at three different severity levels (mild, moderate, and serious). Survival analysis was used to determine the potential risk factors of AEs.ResultsA total of 7231 patients (3780 men) were included in the present cohort. During the follow-up time period (average 33.4 months), the most common AEs were drowsiness (moderate: 4.4%, serious: 0.68%), dizziness (moderate: 3.7%, serious: 0.5%), and headache (moderate: 2.9%, serious: 0.41%). In the confirmed AE groups (moderate and serious severity levels), the symptoms tended to be transient, with durations of less than 3 months. Polytherapy was an independent risk factor for AEs and had an increasing risk when the severity of the AE increased (Hazard Ratio 1.12, 1.55, and 2.52 for mild AE, moderate AE, and serious AE, respectively). Receiving a high dosage of PB (> 180 mg/day) indicated a slightly elevated risk (Hazard Ratio 1.22 and 1.27 for mild AE and moderate AE, respectively).ConclusionPhenobarbital demonstrates overall tolerability, and serious AEs were not common. Patients receiving a high dose of PB or polytherapy are at increased risk of developing AEs.     

Mono- or polytherapy and the severity of epilepsies

1. Out of 295 outpatients who were followed up by our staff for longer than 4 years, a total of 196 patients was subjected to this retrospective study. The inclusion criterion was that they had inevitably been placed on polytherapy of two or more anti-epileptic drugs (AEDs). In other words, they had failed to reach monotherapy for some reasons. 2. One of the determinant factors for the success or failure of monotherapy was the type of epilepsies. Namely, primary generalized epilepsy (PGE) was relatively easy to attain by monotherapy regardless of the seizure type, whereas secondary generalized epilepsy (SGE) with combined seizures and secondary partial epilepsy (SPE) with mixed seizures were not infrequently difficult to be placed on a monotherapy regimen. In the latter case, however, an abrupt withdrawal of AEDs was apt to cause an exacerbation of seizures. 3. There were some patients who could reach a complete freedom from seizures as a result of bi- or polytherapy and became socially adaptable and acceptable. They themselves are, if not all, afraid of a possible relapse of seizures produced by a reduction in the number of AEDs hitherto prescribed. In some cases, a family member may refuse monotherapy, or even physicians are reluctant to switch to monotherapy because the patients have experienced status epilepticus in the past.(ABSTRACT TRUNCATED AT 250 WORDS)     

Non-interventional surveillance study of adverse events in patients with epilepsy

Cruise KE, Bucks RS, Loftus AM, Newton RU, Pegoraro R, Thomas MG. Exercise and Parkinson’s: benefits for cognition and quality of life.
Acta Neurol Scand: 2011: 123: 13–19.
© 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Objectives – The benefits of physical exercise for psychological aspects of quality of life (QoL) are well established in normally ageing adults, yet potential benefits for people with Parkinson’s disease (PD) have received limited attention. This study evaluated the benefits of exercise for cognitive functioning, mood and disease‐specific QoL for people with PD. Methods – Twenty‐eight individuals with PD were allocated to an exercise intervention program (EIP, n = 15) or control group (n = 13). The EIP group undertook a programme of progressive anabolic and aerobic exercise twice weekly for 12 weeks. The control group maintained their usual lifestyle. Results – Exercise was shown to have selective benefits for cognitive functioning by improving frontal lobe based executive function. No significant effects were demonstrated for mood or disease‐specific QoL. Conclusions – These results are consistent with previous research demonstrating selective benefits of exercise for executive function among normal ageing adults and PD.