Scott Mintzer

Enzyme induction with antiepileptic drugs: Cause for concern?

Several 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, non–enzyme‐inducing AEDs.

Vitamin D Levels and Bone Turnover in Epilepsy Patients Taking Carbamazepine or Oxcarbazepine

Summary:  Purpose: Evidence suggests that enzyme‐inducing 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).

Effects of antiepileptic drugs on lipids, homocysteine, and C-reactive protein†

The widely prescribed anticonvulsants phenytoin and carbamazepine are potent inducers of cytochrome P450 enzymes, which are involved in cholesterol synthesis. We sought to determine whether these drugs have an effect on cholesterol and other serological markers of vascular risk.

Adverse effects of antiepileptic drugs: a brief overview of important issues

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.

Laser interstitial thermal therapy for medically intractable mesial temporal lobe epilepsy

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).

Surgical outcome in PET-positive, MRI-negative patients with temporal lobe epilepsy

Purpose:  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 PET‐positive, MRI‐negative patients and compared them with those of patients with MTS.

Unilateral hippocampal sclerosis with contralateral temporal scalp ictal onset.

Summary:  Purpose: To investigate the clinical characteristics and surgical outcomes in patients with unilateral hippocampal sclerosis whose scalp ictal EEG recordings localize to the opposite temporal lobe.

Metabolic consequences of antiepileptic drugs.

Purpose of reviewChemical properties of the widely used older generation antiepileptic drugs (AEDs) suggest that they might be responsible for a number of medical comorbidities. Recent findingsAEDs which induce the cytochrome P450 system adversely affect bone, lipid, and gonadal steroid metabolism. Specifically, phenytoin causes loss of bone mass in women, and both phenytoin and carbamazepine produce increases in serum lipids and C-reactive protein, as well as decreases in bioactive testosterone in men. Patients treated with inducing AEDs are at increased risk of fracture. Some contradictory data raise the question of whether bone mass is truly related to enzyme induction, and analogously, of whether reductions in testosterone truly account for male sexual dysfunction. Data showing elevations of surrogate cardiovascular and cerebrovascular risk endpoints with epilepsy patients, mostly inducing AED treated, are consistent and concerning, however. Another older AED, valproate, is associated with the occurrence of polycystic ovary syndrome when used in young adulthood or adolescence. SummaryOlder generation AEDs are associated with a panoply of metabolic abnormalities. Although more research is needed to see whether individual drugs are directly tied to specific clinical outcomes (e.g. risk of infarction), extant data are sufficiently concerning to suggest that these drugs may produce significant adverse health consequences. Newer generation AEDs may be preferable.

Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and HLA‐B Genotypes and Phenytoin Dosing

Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index and large interpatient variability, partly due to genetic variations in the gene encoding cytochrome P450 (CYP)2C9 (CYP2C9). Furthermore, the variant allele HLA‐B*15:02, encoding human leukocyte antigen, 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: http://www.pharmgkb.org). The purpose of this guideline is to provide information for the interpretation of HLA‐B and/or CYP2C9 genotype tests so that the results can guide dosing and/or use of phenytoin. Detailed guidelines for the use of phenytoin as well as analyses of cost‐effectiveness are out of scope. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are periodically updated at http://www.pharmgkb.org.

Comorbidity of ictal fear and panic disorder

Purpose. We sought to determine the prevalence of psychiatric conditions, particularly panic disorder, in epilepsy patients with ictal fear.Methods. A consecutive series of 12 patients with ictal fear underwent psychiatric evaluation, via either formal consultation with a psychiatrist or standardized interview using the Mini International Neuropsychiatric Interview; the latter was addended to create an instrument specifically for use in epilepsy patients (MINI-Epi).Results. Four of the twelve patients (33%) with ictal fear had a comorbid diagnosis of panic disorder. One of these developed panic attacks only after epilepsy surgery, and another worsened after surgery, while in the other two panic attacks were not related to any surgical procedure. Two patients had other anxiety disorders. Eight patients (67%) had current or past depression; this did not appear to be related to the presence of panic disorder.Conclusion. A specific comorbidity exists between focal epilepsy with ictal fear and panic disorder. Involvement of the amygdala in both temporal lobe epilepsy and panic disorder may underlie this. The predisposition to panic disorder in these patients may be exacerbated by anterior temporal lobectomy.