Stanley R. Resor

Comparison and predictors of rash associated with 15 antiepileptic drugs

Objective: To determine predictors and relative incidence of antiepileptic drug (AED)–related rash in patients taking all common AEDs. Methods: We reviewed 1,890 outpatients. Eighty-one variables were tested as potential predictors of rash. We compared the rate of rash attributed to each AED (AED rash) with the average rate of rash attributed to the other AEDs in all adults (aged ≥16 years; n = 1,649) when taking carbamazepine (CBZ), clobazam (CLB), felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), primidone (PRM), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), valproate (VPA), or zonisamide (ZNS). We repeated this analysis for patients with and without the identified nondrug predictors of AED rash. Results: The average rate of AED rash was 2.8%. The only nondrug predictor significant in multivariate analysis was occurrence of another AED rash (odds ratio 3.1, 95% CI 1.8 to 5.1; p < 0.0001); the rate of rash in this subgroup was 8.8%, vs 1.7% in those without another AED rash. Higher AED rash rates were seen with PHT (5.9% overall, p = 0.0008; 25.0% in those with another AED rash, p = 0.001), LTG (4.8%, p = 0.00095; 14.4%, p = 0.025), and CBZ (3.7%, not significant; 16.5%, p = 0.01). Lower rates were seen with LEV (0.6% overall; p = 0.00042), GBP (0.3%, p = 0.00035), and VPA (0.7%, p = 0.01). Rash rates were also low (<1% overall) with FBM, PRM, TPM, and VGB (not significant). These AED differences remained similar in patients with and without other AED rashes. There were four cases of Stevens–Johnson syndrome involving four AEDs. Conclusions: The rate of an antiepileptic drug (AED) rash is approximately five times greater in patients with another AED rash (8.8%) vs those without (1.7%). Rash rates were highest with phenytoin, lamotrigine, and carbamazepine and low (<1%) with several AEDs.

Predictors of Lamotrigine‐associated Rash

Summary:  Purpose: To determine the predictors of lamotrigine‐associated rash (LTG‐rash) and the incidence of serious and benign LTG‐rash to individualize risk assessment in a given patient.

Cross-sensitivity of skin rashes with antiepileptic drug use

Objective: To determine rates of cross-sensitivity of rash among commonly used antiepileptic drugs (AEDs) in patients with epilepsy. Methods: The incidence of AED-related rash was determined in 1875 outpatients (≥12 years), taking carbamazepine (CBZ), clobazam (CLB), felbamate (FBM), gabapentin (GBP), levetiracetam (LEV), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), primidone (PRM), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), valproic acid (VPA), or zonisamide (ZNS). We compared rates of rash for each AED in patients with vs those without a rash to 1) another specific AED; 2) any other AED; 3) any two other AEDs; and 4) any non-epilepsy medication. Results: A total of 14.3% (269/1,875) of patients had a rash attributed to at least one AED; 2.8% had a rash to two or more AEDs. Of patients who had a rash to CBZ and were also prescribed PHT (n = 59), 57.6% had a rash to PHT (abbreviated as CBZ → PHT: 57.6%); of patients who had a rash to PHT and were also prescribed CBZ (n = 81), rate of rash was 42% (i.e., PHT → CBZ: 42%). Other results: CBZ → LTG: 20% (n = 50); LTG → CBZ: 26.3% (n = 38); CBZ → OXC: 33% (n = 15); OXC → CBZ: 71.4% (n = 7); CBZ → PB: 26.7% (n = 30); PB → CBZ: 66.7% (n = 12); LTG → PHT: 38.9% (n = 36); PHT → LTG: 18.9% (n = 74); PB → PHT: 53.3% (n = 15); PHT → PB: 19.5% (n = 41); OXC → LTG: 37.5% (n = 8); LTG → OXC: 20% (n = 15). There was evidence of specific cross-sensitivity between CBZ and PHT, and between CBZ and PB. Conclusion: Cross-sensitivity rates between certain antiepileptic drugs (AEDs) are high, especially when involving carbamazepine and phenytoin. Specific cross-sensitivity rates provided here may be useful for AED selection and counseling in individual patients.

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

OBJECTIVE Psychiatric/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. METHODS We 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. RESULTS Overall, 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. CONCLUSIONS There 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.

Bone mineral density in an outpatient population receiving enzyme-inducing antiepileptic drugs

Antiepileptic drug (AED) use is identified as being associated with increased fracture risk. AEDs commonly associated with osteopathies are inducers of the hepatic cytochrome p450 enzyme system (EIAEDs). We performed a retrospective cross-sectional study assessing bone mineral density (BMD) in an adult outpatient population receiving EIAEDs. Patients were routinely referred for dual-energy X-ray absorptiometry to evaluate BMD. BMD was measured at the femoral neck of hip and lumbar spine. Results were presented as absolute BMD (g/cm(2)), T score, and Z score. T and Z scores were used in this analysis. As a group, those with BMD measurements represent people with intractable epilepsy. There were no statistically significant differences found in the T or Z scores by gender; therefore all analyses combined both men and women. Significant reductions in both T and Z scores were present in men and women <50 and >or=50.

Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy

Idiopathic generalized epilepsy (IGE) is a class of genetically determined, phenotypically related epilepsy syndromes. Linkage analysis identified a chromosome 18 locus predisposing to a number of adolescent-onset IGEs. We report a single-nucleotide polymorphism (SNP) association analysis of the region around the marker locus with the high LOD score. This analysis, which used both case-control and family-based association methods, yielded strong evidence that malic enzyme 2 (ME2) is the gene predisposing to IGE. We also observed association among subgroups of IGE syndromes. An ME2-centered nine-SNP haplotype, when present homozygously, increases the risk for IGE (odds ratio 6.1; 95% confidence interval 2.9-12.7) compared with any other genotype. Both the linkage analysis and the association analysis support recessive inheritance for the locus, which is compatible with the fact that ME2 is an enzyme. ME2 is a genome-coded mitochondrial enzyme that converts malate to pyruvate and is involved in neuronal synthesis of the neurotransmitter gamma-aminobutyric acid (GABA). The results suggest that GABA synthesis disruption predisposes to common IGE and that clinical seizures are triggered when mutations at other genes, or perhaps other insults, are present.

Ect in the Treatment of Status Epilepticus

Introduction Owing to its potent anticonvulsant actions, electroconvulsive therapy (ECT) has been proposed as an intervention for treatment-resistant seizure disorders. Method We review the literature on the use of ECT in treatment-resistant epilepsy and status epilepticus (SE) and present a case of a patient who was in nonconvulsive SE for 26 days and then treated with ECT after all standard pharmacological strategies were exhausted. Because of skull defects, a novel electrode placement was used. Results Owing to massively elevated seizure threshold attributable to concomitant anticonvulsant medications, extraordinarily high electrical dosage was needed for ECT to elicit generalized seizures. Status was terminated after three successful ECT-induced seizures. However, the long-term functional outcome of the patient was poor. Discussion The role of ECT in the treatment algorithm for SE is discussed.

Correlating lamotrigine serum concentrations with tolerability in patients with epilepsy

Objective: To correlate lamotrigine (LTG) serum concentrations (levels) with tolerability in patients with epilepsy. Methods: The charts of 811 outpatients with epilepsy who had received LTG and were seen at the Columbia Comprehensive Epilepsy Center after January 1, 2000, were reviewed. Data gathered included levels, dosage, duration of use, concomitant antiepileptic drugs (AEDs), clinical toxicity, specific side effects, and efficacy. Rates of toxicity, specific side effects, and efficacy were calculated and correlated with serum levels. Results: In total, 3,731 LTG levels were recorded. A regimen was categorized as toxic if the patient experienced side effects that led to a dosage change or discontinuation of LTG. Of 3,919 AED regimens, 9.4% were toxic and 30.7% of patients had at least one toxic regimen. Toxicity increased with increasing LTG levels (p < 0.0001): With levels <5.0 μg/mL, 7% of patients were toxic; with levels of 5 to 10 μg/mL, 14%; with 10 to 15 μg/mL, 24%; with 15 to 20 μg/mL, 34%; and with >20 μg/mL, 59%. The correlation between levels and tolerability was independent of concurrent medication. Increasing efficacy, as measured by seizure freedom for a 6-month period, occurred up to levels of >20 μg/mL. Conclusions: There is a correlation between LTG serum level and tolerability, independent of the use of other AEDs. Adverse effects requiring a dose change are uncommon with the most frequently encountered LTG concentrations (<10 μg/mL) and occur in only 7.4% of patients at levels obtained during the majority of clinical trials (<5 μg/mL). An initial target range of 1.5 to 10 μg/mL is suggested, though higher levels, up to >20 μg/mL, are often tolerated and can lead to additional efficacy in refractory patients.

Effect of age and comedication on levetiracetam pharmacokinetics and tolerability.

Summary:  Purpose: To compare pharmacokinetics and tolerability of levetiracetam (LEV) in older versus younger adults.

Seizure remission and relapse in adults with intractable epilepsy: A cohort study

Purpose: To investigate the cumulative probabilities of ≥12 month seizure remission and seizure relapse following remission, and to test the associations of clinical characteristics with these two study end points in a prevalence cohort of intractable adult epilepsy patients during medical management.