SUMMARYObjective: To describe mesial temporal lobe ablated volumes, verbal memory, and surgical outcomes in patients with medically intractable mesial temporal lobe epilepsy (mTLE) treated with magnetic resonance imaging (MRI)-guided stereotactic laser interstitial thermal therapy (LiTT). Methods: We prospectively tracked seizure outcome in 20 patients at Thomas Jefferson University Hospital with drug-resistant mTLE who underwent MRI-guided LiTT from December 2011 to December 2014. Surgical outcome was assessed at 6 months, 1 year, 2 years, and at the most recent visit. Volume-based analysis of ablated mesial temporal structures was conducted in 17 patients with mesial temporal sclerosis (MTS) and results were compared between the seizure-free and not seizure-free groups. Results: Following LiTT, proportions of patients who were free of seizures impairing consciousness (including those with auras only) are as follows: 8 of 15 patients (53%, 95% confidence interval [CI] 30.1-75.2%) after 6 months, 4 of 11 patients (36.4%, 95% CI 14.9-64.8%) after 1 year, 3 of 5 patients (60%, 95% CI 22.9-88.4%) at 2-year followup. Median follow-up was 13.4 months after LiTT (range 1.3 months to 3.2 years). Seizure outcome after LiTT suggests an all or none response. Four patients had anterior temporal lobectomy (ATL) after LiTT; three are seizure-free. There were no differences in total ablated volume of the amygdalohippocampus complex or individual volumes of hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus between seizure-free and non-seizure-free patients. Contextual verbal memory performance was preserved after LiTT, although decline in noncontextual memory task scores were noted. Significance: We conclude that MRI-guided stereotactic LiTT is a safe alternative to ATL in patients with medically intractable mTLE. Individualized assessment is warranted to determine whether the reduced odds of seizure freedom are worth the reduction in risk, discomfort, and recovery time. Larger prospective studies are needed to confirm our preliminary findings, and to define optimal ablation volume and ideal structures for ablation.

SUMMARYSeveral commonly prescribed antiepileptic drugs (AEDs)-including phenobarbital, phenytoin, and carbamazepine-stimulate the synthesis of a broad range of monooxygenase and conjugating enzymes. These agents are well known to reduce the duration and action of many lipid-and non-lipid-soluble drugs, including anticoagulants, cytotoxics, analgesics, antiretrovirals, glucocorticoids, statins, antihypertensives, oral contraceptives, psychoactive drugs, immunosuppressants, and of course, other AEDs. This process, therefore, may be associated with a number of clinical problems including higher cancer mortality, progressive AIDS, transplant rejection, and unwanted pregnancy. Withdrawal of enzyme-inducing AEDs will increase the concentration of induced drugs, bringing with it substantial risk of toxicity if doses are not concomitantly reduced. Yet the potential widespread adverse health consequences of these interactions, both with AED initiation and withdrawal, remain largely underappreciated. Furthermore, induction also affects enzymes involved in endogenous metabolic pathways, and can alter bone biochemistry, gonadal steroids, and lipid markers. Therefore, enzyme-inducing AEDs may contribute to the development of a number of comorbidities, including osteoporosis, sexual dysfunction, and vascular disease. This process continues as long as the patient takes the inducer. Modern AEDs that do not possess this property have similar efficacy for the common epilepsies. Accordingly, perhaps consideration should be given to starting treatment with, or even switching patients to, nonenzyme-inducing AEDs.

Switching epilepsy patients from the enzyme-inducers carbamazepine or phenytoin to the noninducing drugs levetiracetam or lamotrigine produces rapid and clinically significant amelioration in several serological markers of vascular risk. These findings suggest that phenytoin and carbamazepine may substantially increase the risk for cardiovascular and cerebrovascular disease.

Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index and large inter-patient variability partly due to genetic variations in CYP2C9. Furthermore, the variant allele HLA-B*15:02 is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotype (also available on PharmGKB: www.pharmgkb.org).

Summary:Purpose: Evidence suggests that enzymeinducing antiepileptic drugs (AEDs) may decrease serum 25-hydroxyvitamin D (25-OHD) levels and increase bone turnover. We sought to determine whether these are affected by treatment with carbamazepine (CBZ) or oxcarbazepine (OXC).Methods: We measured serum levels of 25-OHD, parathyroid hormone (PTH), osteocalcin (OCLN), bone alkaline phosphatase (BAP), and urinary N-telopeptides of type I collagen cross-links (NTX) in normal controls (n = 24) and in epilepsy patients taking CBZ (n = 21) or OXC (n = 24) in monotherapy. CBZ patients were subsequently switched overnight to OXC monotherapy, and after 6 weeks, the tests were repeated.Results: 25-OHD levels were lower in each drug-treated group (OXC, 19.4 ± 2.3 pg/ml; CBZ, 20.4 ± 2.4) than in the controls (27.5 ± 2.8) (ANOVA, p = 0.052). This difference was significant for the OXC group (p < 0.05). PTH, BAP, and NTX did not differ significantly among groups. OCLN levels were somewhat elevated in the OXC group (2.79 ± 0.47 ng/ml) and more clearly and significantly elevated in the CBZ group (3.63 ± 0.36) compared with controls (2.38 ± 0.41) (p = 0.053). Because the data were very similar between OXC and CBZ groups, they were combined to increase statistical power. The combined drug-treatment group had significantly higher BAP (p = 0.02) and lower 25-OHD (p = 0.015) than did controls. The latter remained significant even after accounting for the confounding effects of age on 25-OHD levels (p < 0.05). No significant differences were found after CBZ patients were switched to OXC.Conclusions: Epilepsy patients taking OXC or CBZ have significantly lower 25-OHD than do normal controls, with a pattern of changes in other bone biomarkers suggestive of secondary hyperparathyroidism. It may be prudent for patients taking CBZ or OXC to be prescribed 25-OHD replacement. Key Words: Carbamazepine-Oxcarbazepine-25-OHD.Patients with epilepsy often express concerns about the potential for chronic side effects with the use of antiepileptic drugs (AEDs). One area of considerable interest is that of the effects of AEDs on bone density. Questions about possible bone loss and increased fracture risk have been present for more than three decades (1). The prevailing notion has been that those drugs that are inducers of the hepatic cytochrome P 450 system (CYP450) promote the metabolism of 25-hydroxyvitamin D (25-OHD) to less biologically active analogues, resulting in decreased bone mineralization, decreased intestinal calcium absorption, increased calcium mobilization from the skeleton to maintain eucalcemia, and decreased bone density (2). Evidence to support this mechanistic hypothesis is mixed, however. The inducing AED phenytoin (PHT) has been shown rather convincingly to be associated with decreased bone density (3).

All medications have some adverse effects, ranging from mild to acute and serious or chronic. Antiepileptic drugs (AEDs) differ in the type and severity of adverse effects, mostly during initiation and early treatment. Some concerns are related to pharmacodynamic tolerance often affected by the dose and rate of initiation, while other concerns are idiosyncratic responses to the drug (rare and not predictable). Thus, lack of tolerability is a common reason for changing medication, quantified in studies as treatment retention. Although adverse effects can occur with all AEDs, and CNS effects are most prevalent, selected effects are hallmarks of specific drugs. The failure of an AED regimen may be the result of unacceptable adverse effects (intolerance), inadequate seizure control (inefficacy) or a combination of both. Although some diminution in adverse effects is typical when a drug is used in monotherapy, the potential for most issues remains if they are dose-related or idiosyncratic. This article describes three categories of prevalent adverse effects (CNS, behavioral and general medical issues) comparing profiles of second- and third-generation AEDs.

SUMMARYPurpose: Fluorodeoxyglucose positron emission computed tomography (FDG-PET) hypometabolism is important for surgical planning in patients with temporal lobe epilepsy (TLE), but its significance remains unclear in patients who do not have evidence of mesial temporal sclerosis (MTS) on magnetic resonance imaging (MRI). We examined surgical outcomes in a group of PETpositive, MRI-negative patients and compared them with those of patients with MTS. Methods: We queried the Thomas Jefferson University Surgical Epilepsy Database for patients who underwent anterior temporal lobectomy (ATL) from 1991 to 2009 and who had unilateral temporal PET hypometabolism without an epileptogenic lesion on MRI (PET+/MRI)). We compared this group to the group of patients who underwent ATL and who had MTS on MRI. Patients with discordant ictal electroencephalography (EEG) were excluded. Surgical outcomes were compared using percentages of Engel class I outcomes at 2 and 5 years as well as KaplanMeier survival statistic, with time to seizure recurrence as survival time. A subgroup of PET+/MRI) patients who underwent surgical implantation prior to resection was compared to PET+/MRI) patients who went directly to resection without implantation. Key Findings: There were 46 PET+/MRI) patients (of whom 36 had 2-year surgical outcome available) and 147 MTS patients. There was no difference between the two groups with regard to history of febrile convulsions, generalized tonic-clonic seizures, interictal spikes, depression, or family history. Mean age at first seizure was higher in PET+/MRI) patients (19 ± 13 vs.14 ± 13 years, Mann-Whitney test, p = 0.008) and disease duration was shorter (14 ± 10 vs. 22 ± 13 years, student's t-test, p = 0.0006). Class I surgical outcomes did not differ significantly between the PET+/MRI) patients and the MTS group (2 and 5 year outcomes were 76% and 75% for the PET+/MRI) group, and 71% and 78% for the MTS group); neither did outcomes of the PET+/MRI) patients who were implanted prior to resection versus those who went directly to surgery (implanted patients had 71% and 67% class I outcomes at 2 and 5 years, whereas. nonimplanted patients had 77% and 78% class I outcomes, p = 0.66 and 0.28). Kaplan-Meier survival statistics for both comparisons were nonsignificant at 5 years. Dentate gyrus and hilar cell counts obtained from pathology for a sample of patients also did not differ between groups. Significance: PET-positive, MRI-negative TLE patients in our study had excellent surgical outcomes after ATL, very similar to those in patients with MTS, regardless of whether or not they undergo intracranial monitoring. These patients should be considered prime candidates for ATL, and intracranial monitoring is probably unnecessary in the absence of discordant data.

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