Metabolic concerns associated with antiepileptic medications
ABSTRACT Because treatment with antiepileptic drugs (AEDs) is often for years or lifelong, physicians should be aware of the metabolic changes that can be associated with AED use and the potential effects of these changes during long-term therapy. Alterations of bone metabolism leading to decreased bone mineral density, associated particularly but not exclusively with the hepatic enzyme-inducing AEDs, can worsen the risk for fractures, which is already increased in patients with epilepsy by factors such as seizure-related falls and trauma. Some AEDs are associated with weight gain, an effect that is not only distressing to many patients but may be sufficient to increase the risk for cardiovascular disease and other disorders associated with excessive body weight. The carbonic anhydrase-inhibiting properties of some AEDs can lead to metabolic acidosis. The AEDs that inhibit carbonic anhydrase are also associated with an increase in risk for renal stones, as is the ketogenic diet. Awareness of the potential metabolic disturbances associated with AED use is particularly important because many of them are subtle and may take years to become clinically apparent.
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ABSTRACT: Children with refractory epilepsy who are co-treated with the ketogenic diet (KD) and carbonic anhydrase inhibitor (CA-I) anti-epileptic medications including topiramate (TPM) and zonisamide (ZNS) are at risk for urolithiasis. Retrospective chart review of all children treated with ketogenic therapy at our institution was performed in order to estimate the minimal risk of developing signs or symptoms of stone disease. Children (N=93) were classified into groups according to KD+/-CA-I co-therapy. Fourteen patients had occult hematuria or worse, including 6 with radiologically confirmed stones. Three of 6 calculi developed in the KD+ZNS group of 17 patients who were co-treated for a cumulative total of 97 months (3.1 stones per 100 patient months). One confirmed stone was in the KD+TPM group of 22 children who were co-treated for a cumulative total of 263 months (0.4 stones per 100 patient months). All six patients had at least three of five biochemical risk factors including metabolic acidosis, concentrated urine, acid urine, hypercalciuria and hypocitraturia. Standard of care interventions to minimize hypercalciuria, crystalluria and stone formation used routinely by pediatric nephrologists should also be prescribed by neurologists treating patients with combination anti-epileptic therapy. Non-fasting KD initiation, fluid liberalization, potassium citrate prophylaxis as well as regular laboratory surveillance are indicated in this high risk population.Epilepsy research 06/2010; 90(1-2):151-6. DOI:10.1016/j.eplepsyres.2010.04.005 · 2.19 Impact Factor
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ABSTRACT: Bone disease and fractures are common with chronic antiepileptic drug (AED) therapy, but the underlying mechanisms are poorly understood. This study aimed to characterize adverse bone effects of valproate and to identify mouse strains either resistant or sensitive to these effects. Seven mouse strains (n = 40/strain; 10/diet) were screened for the effect of chronic (8 weeks) valproate treatment (0, 2, 4, and 6 g/kg food) on total bone mineral content (BMC, by dual energy x-ray absorptiometry). In a confirmatory study the effect of valproate (0 or 4 g/kg food) over 16 weeks was assessed in five of the mouse strains (n = 60/strain; 30/diet) identified in the screening phase as either sensitive or resistant. Ex vivo volumetric bone measures and structural changes were assessed using peripheral quantitative computed tomography (pQCT) and histomorphometry. Chronic valproate treatment reproducibly affected bone in C3H/HeJ mice, with a 9.1% (p < 0.01) reduction in total BMC and a 10.7% (p < 0.01) reduction in trabecular volumetric density, indicating a sensitive strain to AED-induced bone loss. Histomorphometry was consistent, revealing reductions in trabecular volume (19.6%, p < 0.05) and number (14.3%, p < 0.04), and a 19.9% (p < 0.05) increase in trabecular separation. In contrast the A/J mice were reproducibly resistant to the bone effects. Mouse strains sensitive and resistant to the adverse bone effects of chronic valproate treatment were identified. The strain-specific effects suggest a role of genetic factors in the pathogenesis of AED-induced bone disease. This novel model provides a new, powerful tool to investigate the pathophysiology and therapy of AED-associated bone disease.Epilepsia 02/2010; 51(6):984-93. DOI:10.1111/j.1528-1167.2009.02516.x · 4.58 Impact Factor
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ABSTRACT: The purpose of this review is to examine what is known about cognitive and brain aging in elders with chronic epilepsy. We contend that much remains to be learned about the ultimate course of cognition and brain structure in persons with chronic epilepsy and concern appears warranted. Individuals with chronic epilepsy are exposed to many risk factors demonstrated to be associated with abnormal cognitive and brain aging in the general population, with many of these risk factors present in persons with chronic epilepsy as early as midlife. We suggest that a research agenda be developed to systematically identify and treat known modifiable risk factors in order to protect and promote cognitive and brain health in aging and elder persons with chronic epilepsy.Epilepsia 06/2008; 49(5):731-40. DOI:10.1111/j.1528-1167.2007.01435.x · 4.58 Impact Factor