Drug-resistant epilepsy in adults: Outcome trajectories after failure of two medications.

OBJECTIVE: To examine the seizure trajectories of adults with epilepsy developing drug-resistant epilepsy (DRE) and to identify the predictors of seizure trajectory outcome. METHODS: Adult patients failing two antiepileptic drugs (AEDs) due to inefficacy and starting their third AED at a tertiary epilepsy center were followed for seizure trajectory outcome during medical management. Seizure trajectories were categorized into one of four patterns: (1) course with constant seizures; (2) fluctuating course; (3) delayed attainment of seizure freedom (seizure freedom delayed for >12 months after start of the study, but patient stayed in seizure freedom); and (4) early attainment of seizure freedom (within 12 months of starting study). Multiple ordinal logistic regression models were used to estimate the association between trajectory categories and clinical factors. RESULTS: Four hundred three adult patients met the eligibility criteria. Of these, 212 (53%) never achieved a seizure-free period of a year or more. The trajectories of 63 patients (16%) had a complex fluctuating trajectory, 62 (15%) had delayed onset of seizure freedom, and 66 (16%) had an early seizure freedom. Independent predictors associated with more favorable outcome trajectories were epilepsy type and length of follow-up. Specifically, compared to patients with focal epilepsy of temporal lobe, patients with focal epilepsy of occipital lobe (OR 3.80, 95% confidence interval [CI] 1.00-14.51, p = 0.04), generalized genetic (OR 3.23, 95% CI 1.88-5.57, p < 0.0001), unclear epilepsy type (OR 3.82, 95% CI 1.53-9.52, p < 0.005), and both focal and generalized epilepsy(OR 11.73, 95% CI 1.69-81.34, p = 0.01) were significantly more likely to experience a better trajectory pattern. SIGNIFICANCE: Examination of patterns of seizure trajectory of patients with incident DRE showed that 31% were in continuous seizure freedom at the end of the observation period.

7T MR spectroscopic imaging in the localization of surgical epilepsy.

PURPOSE: With the success that surgical approaches can provide for localization-related epilepsy, accurate seizure localization remains important. Although magnetic resonance (MR) spectroscopy has had success in earlier studies in medial temporal lobe epilepsy, there have been fewer studies evaluating its use in a broader range of localization-related epilepsy. With improvements in signal-to-noise with ultra-high field MR, we report on the use of high resolution 7T MR spectroscopic imaging (MRSI) in 25 surgically treated patients studied over a 3.5-year period. METHODS: Patients were included in this analysis if the region of MRSI study included the surgical resection region. Concordance between region of MRSI abnormalities and of surgical resection was classified into three groups (complete, partial, or no agreement) and outcome was dichotomized by International League Against Epilepsy (ILAE) I-III and IV-VI groups. MRSI was performed with repetition time/echo time 1.5 s/40 msec in two-dimensional (2D) or three-dimensional (3D) encoding for robust detection of singlets N-acetyl aspartate (NAA), creatine (Cr), and choline with abnormalities in NAA/Cr determined with correction for tissue content of gray matter. KEY FINDINGS: The concordance between MRSI-determined abnormality and surgical resection region was significantly related to outcome: Outcome was better if the resected tissue was metabolically abnormal. All 14 patients with complete resection of the region with the most severe metabolic abnormality had good outcome, including five requiring intracranial electroencephalography (EEG) analysis, whereas only 3/11 without complete resection of the most severe metabolic abnormality had good outcome (p < 0.001). SIGNIFICANCE: This is consistent with the seizure-onset zone being characterized by metabolic dysfunction and suggests that high resolution MRSI can help define these regions for the purposes of outcome prediction.

The effect of age and comedication on lamotrigine clearance, tolerability, and efficacy.

PURPOSE: To compare pharmacokinetics, tolerability, and efficacy of lamotrigine (LTG) in older versus younger adults. METHODS: We studied 686 adult outpatients seen at our center over 5 years. We compared apparent clearance (CL) of LTG in the youngest (16-36 years; n = 247) and oldest (55-92 years; n = 155) tertiles. We analyzed one-year retention for younger and older adults newly started on LTG, frequency of adverse effects causing intolerability, and rates of specific adverse effects. We also investigated 6-month seizure freedom. KEY FINDINGS: Median LTG CL of older adults taking LTG in monotherapy was approximately 22% lower compared to younger adults (28.8 vs. 36.5 ml/h/kg; p < 0.001). LTG CL in older adults was lower compared to younger adults in patients on polytherapy and on polytherapy without enzyme inducers or valproate. One-year retention for LTG was comparable in older (78.1%, 121/155) and younger (72.4%, 179/247) adults. Intolerability to LTG was higher in older (34.8%) versus younger adults (24.2%; p = 0.005). Imbalance, drowsiness, and dizziness were common intolerable side effects in both groups. Older patients had higher rates of intolerability due to imbalance (16% vs. 4%), drowsiness (13% vs. 7%), and tremor (5% vs. 2%) compared with younger patients. Rates of 6-month seizure freedom were comparable, and small numbers of each group benefited from very high levels of LTG (>15 µg/ml). SIGNIFICANCE: LTG CL in monotherapy in older adults is approximately 20% lower than in younger adults. For a given serum LTG level, older adults are twice as likely to have significant adverse effects compared to younger adults. Older patients are more likely to experience imbalance, drowsiness, and tremor than younger patients. Younger adults tolerate LTG better than older adults, but one-year retention is comparable. Some patients may benefit from high serum levels of LTG.

Patient-reported cognitive side effects of antiepileptic drugs: predictors and comparison of all commonly used antiepileptic drugs.

Subjective cognitive side effects (CSEs) are common in patients taking antiepileptic drugs (AEDs). The objective of this study was to predict which patients are at risk for CSEs, and compare the CSE profiles of all commonly used AEDs. In this nonrandomized retrospective study, medical records of 1694 adult outpatients with epilepsy seen at our center over a 5-year period who had taken one or more AEDs were examined. Non-AED predictors of CSEs were investigated, and rates of AED-related CSEs were compared in 1189 patients (546 on monotherapy) newly started on an AED at our center. The average rate of AED-related intolerable CSEs (leading to dosage change or discontinuation) was 12.8%. On multivariate analysis, no significant non-AED predictors of CSEs were found. Significantly more intolerable CSEs were attributed to topiramate (21.5% of 130 patients) than to most other AEDs, including carbamazepine (9.9%), gabapentin (7.3%), levetiracetam (10.4%), lamotrigine (8.9%), oxcarbazepine (11.6%), and valproate (8.3%). CSE rates with zonisamide (14.9%) were significantly higher than those for gabapentin and lamotrigine. After exclusion of CSEs during the first 8 weeks of therapy, rates of CSEs were lower, but relative differences remained unchanged. In monotherapy, significantly more intolerable CSEs occurred with topiramate (11.1% of 18 patients) than with carbamazepine or valproate, and both phenytoin and zonisamide were associated with more CSEs than valproate. From this study, it can be concluded that intolerable patient-reported CSEs are most common with topiramate, followed by zonisamide, phenytoin, and oxcarbazepine. They are least likely to be reported with gabapentin, valproate, lamotrigine, carbamazepine, and levetiracetam.

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

PURPOSE: To investigate the cumulative probabilities of >or=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. METHODS: A retrospective cohort study of intractable epilepsy patients seen in 2001 at a single center was conducted. Kaplan-Meier analysis was used to estimate the cumulative probabilities of seizure remission and subsequent seizure relapse. Cox proportional hazards models were used to estimate the association (1) between clinical factors and >or=12 month seizure remission and (2) between clinical factors and seizure relapse following remission. RESULTS: One hundred eighty-seven subjects met the eligibility criteria for intractable epilepsy. The estimate of probability of remission was about 4% per year. Seizure remission was temporary for some individuals, as 5 out of 20 subjects with remission ultimately relapsed. No clinical factors predicted the likelihood of achieving >or=12 month seizure remission or subsequent seizure relapse. DISCUSSION: Some people with intractable epilepsy achieve >or=12 month seizure remission during medical treatment. Remission, however, is only temporary for some individuals. We were unable to identify clear predictors for remission.

Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy.

BACKGROUND: Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy (IGE) with complex inheritance. Previous studies have suggested maternal inheritance and female excess in IGEs but have not been specific for JME. We investigated evidence for maternal inheritance, female excess and patterns of familial seizure risk in a well-characterized sample of JME families. METHODS: We ascertained 89 families through a JME proband and 50 families through a non-JME IGE proband. JME families were divided into those with and without evidence of linkage to the EJM1 susceptibility locus on chromosome 6. We analyzed transmission in 43 multigenerational families, calculated the adjusted sex ratio for JME, and looked for evidence of seizure specific risk in 806 family members. RESULTS: We found evidence for preferential maternal transmission in both EJM1-linked and unlinked families (2.7:1), evidence even more marked when potential selection factors were excluded. The adjusted female: male risk ratio was very high in JME (RR=12.5; 95% CI: 1.9-83.7). Absence seizures in JME probands increased the overall risk of seizures in first degree relatives (15.8% vs. 7.0%, P=0.011), as well as first-degree relatives' specific risk of absence seizures (6% vs. 1.6%, P=0.01), but not myoclonic seizures. CONCLUSIONS: We have confirmed the finding of maternal inheritance in JME, which is not restricted to JME families linked to the EJM1 locus. The striking female excess in JME may relate to anatomical and/or endocrine sexual dimorphism in the brain. Evidence for independent inheritance of absence and myoclonic seizures in JME families reinforces a model in which combinations of loci confer susceptibility to the component seizure types of IGE.

Effect of antiepileptic drug comedication on lamotrigine clearance.

OBJECTIVE: To investigate the effect of antiepileptic drug (AED) comedication, including all newer AEDs, on lamotrigine clearance (CL). DESIGN: We reviewed 570 medical charts of outpatients 12 years and older seen at the Columbia Comprehensive Epilepsy Center who received lamotrigine as monotherapy or adjunctive therapy. We investigated whether a given comedication contributed to the lamotrigine serum concentration. In addition, we examined whether the mean lamotrigine CL during comedication with each AED differed from the lamotrigine CL during monotherapy. Finally, we examined whether individuals had significantly different lamotrigine CLs when taking or not taking a particular comedication. RESULTS: Comedication with phenytoin, carbamazepine, and valproate sodium were the major AED predictors of lamotrigine serum concentration. Comedication regimens with felbamate, oxcarbazepine, and phenobarbital were small but significant predictors. The mean lamotrigine CL was 43.2 mL/h per kilogram of body weight with lamotrigine monotherapy, significantly higher with comedication with phenytoin (101.3 mL/h per kilogram) and carbamazepine (59.5 mL/h per kilogram) and significantly lower with valproate (16.9 mL/h per kilogram). Patients had significantly higher lamotrigine CL when taking phenytoin, carbamazepine, and phenobarbital than when not taking those comedications and had significantly lower lamotrigine CL when taking valproate. The mean lamotrigine CL was significantly lower than that associated with monotherapy in patients comedicated with valproate plus phenytoin (22.0 mL/h per kilogram) but not in patients comedicated with valproate plus carbamazepine (33.3 mL/h per kilogram). No other AEDs affected lamotrigine CL. CONCLUSION: Phenytoin increases lamotrigine CL by approximately 125%, carbamazepine increases lamotrigine CL by approximately 30% to 50%, and valproate decreases lamotrigine CL by approximately 60%. No newer AED, with the possible exception of oxcarbazepine, has a major impact on lamotrigine CL.

Levetiracetam may be more effective for late-onset partial epilepsy.

BACKGROUND: Many agents are available for treating epilepsy; however, population studies have failed to show overall differences in efficacy for a given seizure type. Clinical experience suggests that certain individuals will respond to a given agent while others with the same seizure type will not. OBJECTIVES: To examine a population of patients who received one of the newer antiepileptic drugs, levetiracetam, and to identify those who had either a dramatic improvement or a significant worsening of seizures. METHODS: Retrospective medical record review of patients with refractory epilepsy. RESULTS: Patients who responded well to levetiracetam therapy were older at the onset of epileptic seizure than those who did not (mean [SD] age, 51 [5] vs 27 [3] years; P<.05). This was also true of the subset of patients who had localization-related epilepsy. Patients with temporal lobe onset were likely to do well whereas patients with frontal lobe onset were not. CONCLUSIONS: These results suggest that certain subpopulations may be particularly likely to respond to levetiracetam therapy. These need to be confirmed in a larger prospective trial; however, looking for specific characteristics of patients who respond to certain drugs may lead to useful guidelines for drug choices in treating epilepsy.

Seizure remission in adults with long-standing intractable epilepsy: an extended follow-up.

Recent studies have provided much needed data on the probability of seizure remission among adults with chronic intractable epilepsy treated medically. Here we provide an extended follow-up to our earlier study in order to provide a more comprehensive picture of long-term prognosis in this patient population during medical treatment. The prevalence cohort was followed for two outcomes-complete seizure remission for ≥ 12 months and subsequent seizure relapse among those attaining a seizure remission. The study outcomes were estimated using Kaplan-Meier analysis. We found that the probability of attaining a ≥ 12 months of complete seizure freedom to be approximately 3-4% per year through 8 years of follow-up. By year 5 since the start of seizure remission, the cumulative probability of seizure relapse was 81%, although only half of the patients with seizure relapse went on to experience their previous seizure frequency.

Comparative effectiveness of 10 antiepileptic drugs in older adults with epilepsy.

OBJECTIVE: To compare the effectiveness of antiepileptic drugs (AEDs) for use in older adults with epilepsy. DESIGN: Retrospective review. SETTING: Columbia Comprehensive Epilepsy Center, New York, New York. PATIENTS: Four hundred seventeen outpatients 55 years and older newly taking any of the 10 most commonly prescribed AEDs between 2000 and 2005. MAIN OUTCOME MEASURE: The percentage of patients who remained taking the AED for 12 or more months (12-month "retention"). We also measured efficacy (12-month seizure freedom) and adverse effects leading to dose change. Retention and seizure-freedom rates were analyzed by pairwise comparisons using chi(2) for the overall group and patients with refractory and nonrefractory disease as well as patients newly taking their first AED. RESULTS: The 10 AEDs newly taken by 10 or more patients were analyzed. There were no significant non-AED predictors of retention. Without controlling for severity, lamotrigine had the highest 12-month retention rate (79%), significantly higher than carbamazepine (48%), gabapentin (59%), oxcarbazepine (24%), phenytoin (59%), and topiramate (56%). The retention rate for levetiracetam (73%) was second highest and significantly higher than carbamazepine and oxcarbazepine. Oxcarbazepine had the lowest retention rate, significantly lower than all other AEDs. Lamotrigine had the highest 12-month seizure-freedom rate (54%), followed by levetiracetam (43%). When stratified into patients with nonrefractory and refractory disease, relative rates of seizure freedom and retention remained comparable with the overall group. Imbalance, drowsiness, and gastrointestinal symptoms were the most common intolerable adverse effects. CONCLUSION: In this study of older adults with epilepsy, lamotrigine was the most effective AED as measured by 12-month retention and seizure freedom, with levetiracetam a close second. Oxcarbazepine was consistently less effective than most other AEDs.

Efficacy of clobazam as add-on therapy for refractory epilepsy: experience at a US epilepsy center.

RATIONALE: Clobazam (CLB) has proven efficacy against multiple seizure types. Although available in many countries, it is not approved by the US Food and Drug Administration. The objective of this study was to evaluate the usage patterns, efficacy, tolerability, and 1-year retention of CLB in patients with refractory epilepsy seen at a tertiary US epilepsy center. METHODS: We retrospectively reviewed the use of CLB, 1 measure of efficacy (6-month seizure freedom), 1-year retention, and tolerability in patients with epilepsy who were prescribed CLB as part of their antiepileptic drug regimen at the Columbia Comprehensive Epilepsy Center over a 5-year period. RESULTS: Two hundred fifty-one patients were prescribed CLB, of which 62 were newly started on CLB at our center during this period (29 male and 33 female subjects; mean age, 43.9 years; range, 8-88 years). Clobazam dose ranged from 5 to 60 mg/d (mean, 23.9 mg/d). The mean number of previous antiepileptic drug trials per patient was 7.7. Of the 62 patients newly started on CLB, 7 patients (11.3%) became seizure-free for at least 6 months after introduction of CLB. Binary logistic regression was unable to identify any significant predictors of seizure freedom or CLB retention. Four patients remained seizure-free on CLB for more than 18 months. The Kaplan-Meier 12-month retention curve (n = 54 eligible patients) showed a 1-year retention rate of 61%. CONCLUSIONS: In this population of patients with highly refractory epilepsy at a US center, 11% of patients became seizure-free for at least 6 months after addition of CLB, and the 1-year retention rate was 61%.

Effect of age and comedication on levetiracetam pharmacokinetics and tolerability.

PURPOSE: To compare pharmacokinetics and tolerability of levetiracetam (LEV) in older versus younger adults. METHODS: As part of the Columbia Antiepileptic Drug Database, we retrospectively studied the pharmacokinetics and tolerability of LEV in patients who had been seen as an outpatient at our center during a 4-year period. We compared apparent clearance (CL) of LEV in the youngest (16-31 years; n=151) and oldest (55-88 years; n=157) quartile of 629 adult outpatients who had taken LEV. We also analyzed the frequency of adverse effects leading to dose change or discontinuation ("intolerability") and specific adverse effects in the younger versus older adults. One-year retention was determined for younger and older adults newly started on LEV at our center. RESULTS: Mean LEV CL differed significantly between older (46.5 ml/h/kg) and younger adults (78.3 ml/h/kg). On average, older patients had a 40% lower LEV CL than younger patients. Comedication with an enzyme-inducing antiepileptic drug (EIAED; mostly carbamazepine) was associated with a 24% higher clearance of LEV compared to those who were not on EIAEDs. This difference was 37% in a subgroup of patients whose LEV CL was compared while they were on and off EIAEDs. Stepwise linear regression identified younger age and comedication with an EIAED as significant predictors of increased LEV CL. A total of 34.3% of the 629 patients (31.7% of younger vs. 40.7% of older patients; p=0.16) reported intolerability to LEV on at least one occasion. This difference in tolerability reached significance in the group of patients newly started on LEV (26.3% vs. 41.0%; p=0.017). Drowsiness and psychiatric/behavioral side effects were the most common adverse effects associated with LEV use in both age groups. One-year retention was 72% in the older group vs. 54% in the younger group (not significant). CONCLUSION: Older adults have lower CL than younger adults and require a mean 40% lower dose of LEV to achieve the same serum level. Comedication with an EIAED increases LEV CL by 24-37%. Younger adults tolerate LEV better than older adults, but 1-year retention was (nonsignificantly) higher in the older group.

Predictors of Lamotrigine-associated rash.

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. METHODS: We reviewed the charts of all 988 outpatients seen at the Columbia Comprehensive Epilepsy Center between January 1, 2000, and December 31, 2003, who received LTG. Charts were reviewed for documentation of rash developing from any medication, including antiepileptic drugs (AEDs) and non-AEDs, and including remote histories of drug-related rashes. Demographics, medical history, and medication variables were tested as potential predictors of LTG-rash. RESULTS: Fifty-six (5.7%) of 988 patients experienced rash attributed to LTG, and 39 (3.9%) discontinued LTG because of rash. No patients experienced toxic epidermal necrolysis or required hospitalization because of LTG-rash. One case of mild probable Stevens-Johnson syndrome occurred. In multivariate analysis, a history of rash after another AED was the strongest predictor of LTG-rash (13.9% vs. 4.6%; OR = 3.62; p < 0.001), with children younger than 13 years also experiencing significantly more LTG-rash (10.7% vs. 4.3%; OR = 2.77; p < 0.001). In children with a rash attributed to another AED, 18.2% experienced LTG-rash, whereas in adults without a rash from another AED, 3% experienced LTG-rash. CONCLUSIONS: Based on this retrospective analysis, a history of another AED-related rash is the greatest risk factor for developing rash to LTG; age younger than 13 years is also a risk factor. Severe rash is rare when using the currently recommended titration rate.

Unusual findings in brain biopsies of two patients with acute magnetic resonance imaging lesions associated with focal seizures.

PURPOSE: Patients with focal seizures often have magnetic resonance imaging (MRI) abnormalities in the brain region of their presumed seizure focus. Neoplasms, ischemic infarctions, inflammatory processes, and other specific pathologic entities have been diagnosed by biopsies of such MRI abnormalities. Two patients with this presentation had brain lesion biopsies with a leading presumptive diagnosis of glial neoplasm but were found to have indistinct histopathology. METHODS: Each patient was initially seen with focal seizures (right parietal region, right hippocampus) corresponding with focally increased T2 signal on MRI. In both patients, the preoperative clinical suspicion was for neoplastic or inflammatory processes. RESULTS: Several weeks after seizure onset, craniotomy in patient 1 and stereotactic needle biopsy in patient 2 revealed mild gliosis with reactive vascular changes and perivascular hemosiderin deposition, not diagnostic of but compatible with venous congestion (or possibly venous thrombosis). Postoperatively, patient 1 had brief sensory seizures that stopped 5 months after surgery, whereas subsequent seizures did not develop in patient 2. Both patients had normalization of their MRI (except for postoperative changes) and have remained seizure free. CONCLUSIONS: We describe two patients who had brain biopsies of striking focal increased T2 signal MRI abnormalities associated with seizures. Pathologic findings contradicted our preoperative suspicions (neoplasm or inflammatory process), compatible with (but not conclusive for) subacute venous congestion/thrombosis. These findings indicate that patients with seizures may have an associated discrete intraaxial MRI lesion that is not neoplastic. To our knowledge, this is the first report of focal seizure-associated MRI lesions with biopsy findings compatible with venous congestion/thrombosis.

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.

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.