Anticonvulsant

Poststroke Seizures.

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Stroke is the most common cause of seizures in the elderly, and seizures are among the most common neurologic sequelae of stroke. About 10% of all stroke patients experience seizures, from stroke onset until several years later. This review discusses current understanding of the epidemiology, pathogenesis, classification, clinical manifestations, diagnostic studies, differential diagnosis, and management issues of seizures associated with various cerebrovascular lesions, with a focus on anticonvulsant use in the elderly.

Poststroke seizures are a common and treatable phenomenon, whereas the development of epilepsy is relatively rare. Cerebrovascular lesions associated with the development of seizures include the following: intracerebral (parenchymal) and subarachnoid hemorrhage and cerebral venous thrombosis, with or without venous infarction; lesions involving the cerbral cortex; larger neurologic deficits or disability at presentation; and revascularization procedures involving the extracranial internal carotid artery. The treatment of poststroke seizures is no different than the approach to treatment of partial-onset seizures due to other cerebral lesions, and poststroke seizures usually respond well to a single antiepileptic drug. Given their tolerability, the newer generations of anticonvulsant agents hold promise in treating older patients. Given the low incidence of poststroke epilepsy, there is no indication for seizure prophylaxis in patients with acute ischemic stroke who have not had a well-documented first event. The need for chronic anticonvulsant use should be evaluated periodically, perhaps every 6 months. Despite the absence of clinical data documenting effectiveness, most patients presenting with intracerebral or subarachnoid hemorrhage should receive short-term antiepileptic prophylaxis.45– 46

Future areas of research regarding poststroke seizures include assessing their impact on initial lesion size and on delayed patient outcomes, determining the appropriateness of chronic antiepileptic therapy after a single seizure, and establishing risk factors for the reperfusion syndrome. Poststroke epilepsy may also become an important basic model in research that aims to prevent the transformation of injured cerebral tissue into an epileptic focus.

 

Source: JAMA

 

P-glycoprotein expression and function in patients with temporal lobe epilepsy: a case-control study.

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Background

Studies in rodent models of epilepsy suggest that multidrug efflux transporters at the blood—brain barrier, such as P-glycoprotein, might contribute to pharmacoresistance by reducing target-site concentrations of antiepileptic drugs. We assessed P-glycoprotein activity in vivo in patients with temporal lobe epilepsy.

Methods

We selected 16 patients with pharmacoresistant temporal lobe epilepsy who had seizures despite treatment with at least two antiepileptic drugs, eight patients who had been seizure-free on antiepileptic drugs for at least a year after 3 or more years of active temporal lobe epilepsy, and 17 healthy controls. All participants had a baseline PET scan with the P-glycoprotein substrate (R)-[11C]verapamil. Pharmacoresistant patients and healthy controls then received a 30-min infusion of the P-glycoprotein-inhibitor tariquidar followed by another (R)-[11C]verapamil PET scan 60 min later. Seizure-free patients had a second scan on the same day, but without tariquidar infusion. Voxel-by-voxel, we calculated the (R)-[11C]verapamil plasma-to-brain transport rate constant, K1 (mL/min/cm3). Low baseline K1 and attenuated K1 increases after tariquidar correspond to high P-glycoprotein activity.

Findings

Between October, 2008, and November, 2011, we completed (R)-[11C]verapamil PET studies in 14 pharmacoresistant patients, eight seizure-free patients, and 13 healthy controls. Voxel-based analysis revealed that pharmacoresistant patients had lower baseline K1, corresponding to higher baseline P-glycoprotein activity, than seizure-free patients in ipsilateral amygdala (0·031 vs 0·036 mL/min/cm3; p=0·014), bilateral parahippocampus (0·032 vs 0·037; p<0·0001), fusiform gyrus (0·036 vs 0·041; p<0·0001), inferior temporal gyrus (0·035 vs 0·041; p<0·0001), and middle temporal gyrus (0·038 vs0·044; p<0·0001). Higher P-glycoprotein activity was associated with higher seizure frequency in whole-brain grey matter (p=0·016) and the hippocampus (p=0·029). In healthy controls, we noted a 56·8% increase of whole-brain K1 after 2 mg/kg tariquidar, and 57·9% for 3 mg/kg; in patients with pharmacoresistant temporal lobe epilepsy, whole-brain K1 increased by only 21·9% for 2 mg/kg and 42·6% after 3 mg/kg. This difference in tariquidar response was most pronounced in the sclerotic hippocampus (mean 24·5% increase in patients vs mean 65% increase in healthy controls, p<0·0001).

Interpretation

Our results support the hypothesis that there is an association between P-glycoprotein overactivity in some regions of the brain and pharmacoresistance in temporal lobe epilepsy. If this relation is confirmed, and P-glycoprotein can be identified as a contributor to pharmacoresistance, overcoming P-glycoprotein overactivity could be investigated as a potential treatment strategy.

Source: Lancet

Selective Amygdalohippocampectomy vs. Anterior Temporal Lobectomy for Epilepsy

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In a meta-analysis of nonrandomized studies, seizure-free outcome was greater after ATL than after SAH.

 

In the surgical treatment of intractable medial temporal lobe epilepsy (MTLE), an important unanswered question is whether seizure-free outcome is better with standard anterior temporal lobe resection (ATL) or with a more restrictive procedure, selective amygdalohippocampectomy (SAH). In theory, SAH might mitigate some neuropsychological deficits that are associated with ATL. However, seizure freedom also has important psychosocial benefits. To examine this question, researchers conducted an exhaustive systematic review and meta-analysis of published studies on seizure outcomes following either ATL or SAH. They identified 13 studies that compared the two procedures. Nearly all studies were from individual centers, and follow-up was carried out by clinic visits or telephone calls by investigators or unspecified individuals. Duration of outcome measures ranged from 1 year to a median of 10.9 years. Only three studies separated follow-up according to procedure type; in two, follow-up was an average of 14 to 26 months longer for ATL; in the third, follow-up was an average of 2 months longer for SAH. Other differences in study populations were not specified.

From 11 studies that provided dichotomous outcomes (Engel class I vs. Engel class II–IV), 583 participants had SAH and 620 had ATL. Seizure-free outcome was significantly greater with ATL at final follow-up (relative risk, 1.32; risk difference, 8%; number needed to treat, 13). Results were similar with a more conservative random effects model, in the subset of studies with standardized outcome duration, and among patients with only hippocampal sclerosis. Cumulative addition of studies to the meta-analysis demonstrated a stable RR estimate starting before the most recent three studies were added. Five studies providing data on surgical complications in 392 after ATL and 309 after SAH showed no significant difference.

Comment: This thorough meta-analysis exploited a sufficiently large number of cases, roughly balanced between anterior temporal lobe resection and selective amygdalohippocampectomy (SAH), to provide meaningful information regarding the difference in seizure-free outcomes. This study is particularly valuable because a randomized, controlled trial (RCT) — which the authors say is “justified” — is unlikely to be funded. And yet, an RCT is a compelling proposal if only to address the need for balance in each treatment arm of known variables that affect seizure outcome. Further, only an RCT can answer whether the central postulated benefit of SAH — reduced neuropsychological deficits — exists.

 

Source: Journal Watch Neurology

 

 

Zonisamide: A Good Option for Newly Diagnosed Epilepsy?

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A large practical monotherapy trial for the treatment of new-onset epilepsy in adults shows once-daily zonisamide to be generally as effective and safe as controlled-release, twice-daily carbamazepine.

Few new antiepileptic drugs (AEDs) are studied for efficacy as monotherapy, and most such studies involve medically intractable epilepsy. Therefore, despite numerous new-generation AEDs, little guidance is available for choice in newly diagnosed epilepsy patients. Now, researchers have designed a manufacturer-funded, randomized, double-blind, international trial to test the noninferiority of zonisamide (ZNS) to carbamazepine (CBZ) in adults with newly diagnosed epilepsy. The 583 patients enrolled had only generalized tonic–clonic seizures and no evidence of idiopathic generalized epilepsy, new-onset epilepsy (with at least two seizures in the previous year and at least one seizure in the preceding 3 months), and no prior treatment with an AED for >2 weeks. The study was powered such that it met strict noninferiority criteria. The primary endpoint was the proportion of patients achieving 6-month seizure freedom. Secondary endpoints were the proportion achieving 12-month seizure freedom and times to 6- and 12-month seizure freedom. Safety and tolerability were examined by measuring the incidence of treatment-related adverse events, withdrawal, and laboratory abnormalities.

Of the 456 patients who completed the protocol, 79% and 68% taking ZNS achieved 6-month and 12-month seizure freedom, compared with 84% and 75% taking CBZ — fulfilling the strict noninferiority criteria. Intention-to-treat results supported the results of the per-protocol analysis. The times to both 6- and 12-month endpoints were the same in both arms. Few patients in either group withdrew because of treatment-related adverse events — primarily rash, dizziness, fatigue, and memory impairment. Two cases of severe rash occurred in the CBZ arm. One case of mild purpura occurred in the ZNS arm. None of the other eight reported severe adverse events had a clear association with treatment. No clinically significant laboratory abnormalities occurred in either arm.

Comment: This remarkable clinical trial addresses an important clinical question: Whether a newer-generation AED may be used as first-line monotherapy in newly diagnosed epilepsy. Moreover, the trial was designed to reflect typical clinical practice, given the population involved and the use of flexible dosing regimens for a meaningful treatment duration. Both treatment arms were well balanced, including frequency of seizures pretreatment, a strong predictor of prognosis. Because ZNS has few drug interactions and is formulated for once-daily dosing, the finding that ZNS is generally as effective as CBZ may actually change clinical practice.

Source: Journal Watch Neurology