Rash from antiepileptic drugs: influence by gender, age, and learning disability

PURPOSE: Cutaneous adverse reactions from antiepileptic drugs (AEDs) are common, but have received little scientific attention from a clinical point of view. We wanted to study the incidence of skin reactions of current AEDs and to explore their relation to clinical parameters such as gender, age, and learning disability. METHODS: Consecutive patients with epilepsy were studied retrospectively. A detailed survey of medical records concerning all treatment with AEDs was performed. RESULTS: A total of 663 patients were included with altogether 2,567 exposures to 15 different AEDs. Skin reactions were found in 14% of the patients and in 5% of the exposures. Ninety-seven percent of the reactions occurred to either carbamazepine (CBZ, 11%), phenytoin (PHT, 8%), lamotrigine (LTG, 8%), oxcarbazepine (8%), or phenobarbital (2%). Skin reactions developed significantly more often in females than in males (19% vs. 8%), and significantly less often in patients with learning disability than in other patients (7% vs. 16%). These differences were significant for CBZ, PHT, and LTG when analyzed separately. Females displayed higher rash frequency during the reproductive years, while men experienced less frequent rash in the same phase of life. CONCLUSIONS: Fertile females have a higher risk for skin reactions compared to males, probably due to hormonal factors. Patients with learning disability appeared to have a lower risk than other patients in this study. Hygiene factors may possibly be underlying.     

Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy

PurposePsychiatric and behavioral side effects (PBSEs) are common, undesirable effects associated with antiepileptic drug (AED) use. The objective of the study was to compare the PBSE profiles of older and newer AEDs in a large specialty practice-based sample of patients diagnosed with epilepsy.MethodsAs part of the Columbia and Yale AED Database Project, we reviewed patient records including demographics, medical history, AED use, and side effects for 4085 adult patients (age: 18 years) newly started on an AED regimen. Psychiatric and behavioral side effects were determined by patient or physician report in the medical record, which included depressive mood, psychosis, anxiety, suicidal thoughts, irritability, aggression, and tantrum. Significant non-AED predictors of PBSE rate were first determined from 83 variables using logistic regression. Predictors were then controlled for in the comparison analysis of the rate of PBSEs and intolerable PBSEs (PBSEs that led to dosage reduction or discontinuation) between 18 AEDs.ResultsPsychiatric and behavioral side effects occurred in 17.2% of patients and led to intolerability in 13.8% of patients. History of psychiatric condition(s), secondary generalized seizures, absence seizures, and intractable epilepsy were associated with increased incidence of PBSE. Levetiracetam (LEV) had the greatest PBSE rate (22.1%). This was statistically significant when compared with the aggregate of the other AEDs (P < 0.001, OR = 6.87). Levetiracetam was also significantly (P < 0.001) associated with higher intolerability rate (17.7%), dose decreased rate (9.4%), and complete cessation rate (8.3%), when compared with the aggregate of the other AEDs. Zonisamide (ZNS) was also significantly associated with a higher rate of PBSE (9.7%) and IPBSE (7.9%, all P < 0.001). On the other hand, carbamazepine (CBZ), clobazam (CLB), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OXC), phenytoin (PHT), and valproate (VPA) were significantly associated with a decreased PBSE rates (P < 0.001). Carbamazepine, GBP, LTG, PHT, and VPA were also associated with lower IPBSE rates when compared individually with the aggregate of other AEDs. All other AEDs were found to have intermediate rates that were not either increased or decreased compared with other AEDs. When each AED was compared to LTG, only CBZ had a significantly lower PBSE rate. The main limitations of this study were that the study design was retrospective and not blinded, and the AEDs were not randomly assigned to patients.ConclusionsPsychiatric and behavioral side effects occur more frequently in patients taking LEV and ZNS than any other AED and led to higher rates of intolerability. Lower PBSE rates were seen in patients taking CBZ, CLB, GBP, LTG, OXC, PHT, and VPA. Our findings may help facilitate the AED selection process.     

Psychiatric and behavioral side effects of the newer antiepileptic drugs in adults with epilepsy

ObjectivePsychiatric/behavioral side effects (PSEs) are common in patients taking antiepileptic drugs (AEDs). The objective of the study described here was to compare the PSE profiles of the newer AEDs.MethodsWe examined the charts of 1394 adult outpatients seen at the Columbia Comprehensive Epilepsy Center who had taken one of the newer AEDs. We compared the rate of AED-related PSEs in patients newly started on the newer AEDs both before and after controlling for non-AED predictors of PSEs.ResultsOverall, 221 of 1394 (16%) patients experienced PSEs. The average rate of AED-related PSEs for a single AED was 8.4%, with 6.1% resulting in dosage change and 4.3% resulting in AED discontinuation. Significantly fewer PSEs were attributed to gabapentin (n = 160, 0.6% incidence, P < 0.001) and lamotrigine (n = 547, 4.8% incidence, P < 0.001), and significantly more PSEs were attributed to levetiracetam (n = 521, 15.7% incidence, P < 0.001; 8.8% discontinued LEV because of PSEs). Vigabatrin, felbamate, and oxcarbazepine were associated with similarly low rates of PSEs in many analyses but with fewer of patients. Tiagabine was associated with high PSE rates (similar to those for levetiracetam), but was used much less commonly at our center. Intermediate rates of PSEs were attributed to topiramate and zonisamide (both nonsignificant). Psychiatric history was the most significant nondrug predictor of AED-related PSEs (PSEs occurred in 23% of patients with a psychiatric history vs 12% of patients without such a history, P < 0.001). The relative rates of AED-related PSEs were similar when controlling for non-AED predictors and when analyzing only patients on monotherapy.ConclusionsThere are significant differences between the newer AEDs in terms of their PSE profiles. Patients taking levetiracetan experience significantly more PSEs than average, and patients taking gabapentin and lamotrigine experience significantly fewer PSEs. Even with the medication with the highest rate of PSEs (levetiracetam), less than 10% of patients discontinued it because of PSEs. A past psychiatric condition is the most significant nondrug predictor of AED-related PSEs.     

Placebo-corrected efficacy of modern antiepileptic drugs for refractory epilepsy: Systematic review and meta-analysis

Although adjunctive treatment with modern antiepileptic drugs (AEDs) is standard care in refractory epilepsy, it is unclear how much of the effect can be attributed directly to the AEDs and how much to the beneficial changes seen with placebo. Therefore, we performed a systematic review and meta-analysis of the evidence to determine the placebo-corrected net efficacy of adjunctive treatment with modern AEDs on the market for refractory epilepsy. Of 317 potentially eligible articles reviewed in full text, 124 (39%) fulfilled eligibility criteria. After excluding 69 publications, 55 publications of 54 studies in 11,106 adults and children with refractory epilepsy form the basis of evidence. The overall weighted pooled-risk difference in favor of AEDs over placebo for seizure-freedom in the total sample of adults and children was 6% [95% confidence interval (CI) 4–8, z = 6.47, p < 0.001] and 21% (95% CI 19–24, z = 17.13, p < 0.001) for 50% seizure reduction. Although the presence of moderate heterogeneity may reduce the validity of the results and limit generalizations from the findings, we conclude that the placebo-corrected efficacy of adjunctive treatment with modern AEDs is disappointingly small and suggest that better strategies of finding drugs are needed for refractory epilepsy, which is a major public health problem.     

Clinical comparability of the new antiepileptic drugs in refractory partial epilepsy: a systematic review and meta-analysis

Purpose: Evaluate the clinical comparability of new antiepileptic drugs (AEDs) in partial refractory epilepsy. Methods: Systematic review of randomized trials (RCTs) comparing a new AED (add‐on treatment) with placebo or another AED. Primary outcomes: responder (≥50% seizure reduction) and withdrawal (tolerability) rates. Pooled estimates of odds ratios (ORs) and number needed treat/harm (NNT/NNH) taking into account baseline risk were derived by random‐effects meta‐analysis. Adjusted frequentist indirect comparisons between AEDs were estimated. Key Findings: Sixty‐two placebo‐controlled (12,902 patients) and eight head‐to‐head RCTs (1,370 patients) were included. Pooled ORs for responder and withdrawal rates (vs. placebo) were 3.00 [95% confidence interval (CI) 2.63–3.41] and 1.48 (1.30–1.68), respectively. Indirect comparisons of responder rate based on relative measurements of treatment effect (ORs) favored topiramate (1.52; 1.06–2.20) in comparison to all other AEDs, whereas gabapentin (0.67; 0.46–0.97) and lacosamide (0.66; 0.48–0.92) were less efficacious, without significant heterogeneity. When analyses were based on absolute estimates (NNTs), topiramate and levetiracetam were more efficacious, whereas gabapentin and tiagabine were less efficacious. Withdrawal rate was higher with oxcarbazepine (OR 1.60; 1.12–2.29) and topiramate (OR 1.68; 1.07–2.63), and lower with gabapentin (OR 0.65; 0.42–1.00) and levetiracetam (OR 0.62; 0.43–0.89). Significance: The differences found are of relatively small magnitude to allow a definitive conclusion about which new AED(s) has superior effectiveness. This uncertainty probably reflects the limitations of conclusions based on indirect evidence. The process of pharmacologic clinical decision making in partial refractory epilepsy probably depends more on other aspects, such as individual patient characteristics and pharmacoeconomics, than on available controlled randomized evidence.     

Long-term retention rates of new antiepileptic drugs in adults with chronic epilepsy and learning disability

We compared the long-term retention rates of several newly licensed antiepileptic drugs (AEDs) in a residential community of adults with chronic epilepsy and learning disability. Data relating to duration of therapy, maximum dose, and tolerability of six new AEDs-gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), tiagabine (TIA), and topiramate (TPM)-were collected. Drug retention at 2 years was 85% (OXC), 57% (LTG), 56% (LEV), 45% (TPM), 24% (TIA) and 15% (GBP). OXC was used mainly as a substitute for carbamazepine. LTG, LEV, and TPM were all associated with retention rates higher than those of GBP or TIA. TPM had the highest rate of adverse event development at the maximum tried dose (60%), whereas LEV had the lowest (16%). Experience from this single epilepsy community study indicated limited impact for GBP or TIA but higher retention of OXC, LEV, LTG, and TPM in patients with chronic epilepsy and learning disability.     

传统抗癫痫药物和妥泰对成年癫痫患者生活质量的影响

目的 评价传统抗癫痫药物和妥泰对成年癫痫患者生活质量的影响。方法 102例临床新确诊的成年癫痫患者被随机分为两组：一组予以传统抗癫痫药物单药系统治疗(AEDs组)，另一组予以妥泰单药治疗(TPM组)。1个月后比较两组的发作频率和不良反应。并用QOLIE-30表对这102例癫痫患者进行生活质量评定。结果 TPM组的发作频率和不良反应均明显低于AEDs组，而生活质量总分明显高于AEDs组，尤其在前五项的评分中更加明显。结论 TPM能提高癫痫患者的生活质量，其改善生活质量的作用主要是通过控制发作和减轻不良反应实现的。     

Monotherapy in epilepsy: role of the newer antiepileptic drugs

BACKGROUND: Monotherapy is the goal for pharmacological treatment of epilepsy. Well-controlled trials have established the efficacy of some of the newer antiepileptic drugs (AEDs) as monotherapy. OBJECTIVE: To review clinical data and expert opinions pertinent to the evaluation of most of the newer AEDs as monotherapy for epilepsy. DATA SOURCES: The MEDLINE database was searched for clinical trials using newer AEDs. Reference sections of review articles were manually searched to identify relevant studies not retrieved in MEDLINE. STUDY SELECTION: The resulting list of references was manually reviewed to identify monotherapy studies. RESULTS: Lamotrigine and oxcarbazepine demonstrated efficacy in randomized active-control trials in patients with newly diagnosed epilepsy and in substitution trials in patients refractory to conventional AEDs. CONCLUSION: Lamotrigine and oxcarbazepine are as effective as conventional AEDs at controlling partial seizures and are better tolerated.     

Plasma free carnitine in epilepsy children, adolescents and young adults treated with old and new antiepileptic drugs with or without ketogenic diet

This study was performed to evaluate carnitine deficiency in a large series of epilepsy children and adolescents treated with old and new antiepileptic drugs with or without ketogenic diet. Plasma free carnitine was determined in 164 epilepsy patients aged between 7 months and 30 years (mean 10.8 years) treated for a mean period of 7.5 years (range 1 month-26 years) with old and new antiepileptic drugs as mono or add-on therapy. In 16 patients on topiramate or lamotrigine and in 11 on ketogenic diet, plasma free carnitine was prospectively evaluated before starting treatment and after 3 and 12 months, respectively. Overall, low plasma levels of free carnitine were found in 41 patients (25%); by single subgroups, 32 out of 84 patients (38%) taking valproic acid and 13 of 54 (24%) on carbamazepine, both as monotherapy or in combination, showed low free carnitine levels. A higher though not statistically significant risk of hypocarnitinemia resulted to be linked to polytherapy (31.5%) versus monotherapy (17.3%) (P=.0573). Female sex, psychomotor or mental retardation and abnormal neurological examination appeared to be significantly related with hypocarnitinemia, as well. As to monotherapy, valproic acid was associated with a higher risk of hypocarnitinemia (27.3%) compared with carbamazepine group (14.3%). Neither one of the patients on topiramate (10), lamotrigine (5) or ketogenic diet (11) developed hypocarnitinemia during the first 12 months of treatment. Carnitine deficiency is not uncommon among epilepsy children and adolescents and is mainly linked to valproate therapy; further studies are needed to better understand the clinical significance of serum carnitine decline.     

Relationship between adverse effects of antiepileptic drugs,number of coprescribed drugs,and drug load in a large cohort of consecutive patients with drug‐refractory epilepsy

Purpose: To evaluate the adverse effects (AEs) of antiepileptic drugs (AEDs) in adults with refractory epilepsy and their relationship with number of coprescribed AEDs and AED load. Methods: Patients with refractory epilepsy were enrolled consecutively at 11 tertiary referral centers. AEs were assessed through unstructured interview and the Adverse Event Profile (AEP) questionnaire. AED loads were calculated as the sum of prescribed daily dose (PDD)/defined daily dose (DDD) ratios for each coprescribed AED. Results: Of 809 patients enrolled, 709 had localization‐related epilepsy and 627 were on polytherapy. AED loads increased with increasing number of AEDs in the treatment regimen, from 1.2 ± 0.5 for patients on monotherapy to 2.5 ± 1, 3.7 ± 1.1, and 4.7 ± 1.1 for those on two, three, and ≥4 AEDs, respectively. The number of spontaneously reported AEs correlated with the number of AEs identified by the AEP (r = 0.27, p < 0.0001). AEP scores did not differ between patients with monotherapy and patients with polytherapy (42.8 ± 11.7 vs. 42.6 ± 11.2), and there was no correlation between AEP scores and AED load (r = ?0.05, p = 0.16). Conclusions: AEs did not differ between monotherapy and polytherapy patients, and did not correlate with AED load, possibly as a result of physicians’ intervention in individualizing treatment regimens. Taking into account the limitations of a cross‐sectional survey, these findings are consistent with the hypothesis that AEs are determined more by individual susceptibility, type of AEDs used, and physicians’ skills, than number of coprescribed AEDs and AED load.