A Randomized, Double-Blind Study of Phenytoin for the Prevention of Post-Traumatic Seizures

Nr, Temkin; Ss, Dikmen; Aj, Wilensky; Keihm, J.; Chabal, S.; Hr, Winn

doi:10.1056/nejm199008233230801

Cited by 895 publications

(450 citation statements)

References 16 publications

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“…Phenytoin had the most robust effects of the tested anticonvulsants, but resistance eventually developed (Fig. 3C and previous results30), as occurs after human brain injury 55. Thus, many drugs with robust anticonvulsant but not antiepileptogenic effects would be missed in this screen.…”

Section: Discussionmentioning

confidence: 63%

Staged anticonvulsant screening for chronic epilepsy

Berdichevsky

Saponjian

Park

et al. 2016

Ann Clin Transl Neurol

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ObjectiveCurrent anticonvulsant screening programs are based on seizures evoked in normal animals. One‐third of epileptic patients do not respond to the anticonvulsants discovered with these models. We evaluated a tiered program based on chronic epilepsy and spontaneous seizures, with compounds advancing from high‐throughput in vitro models to low‐throughput in vivo models.MethodsEpileptogenesis in organotypic hippocampal slice cultures was quantified by lactate production and lactate dehydrogenase release into culture media as rapid assays for seizure‐like activity and cell death, respectively. Compounds that reduced these biochemical measures were retested with in vitro electrophysiological confirmation (i.e., second stage). The third stage involved crossover testing in the kainate model of chronic epilepsy, with blinded analysis of spontaneous seizures after continuous electrographic recordings.ResultsWe screened 407 compound‐concentration combinations. The cyclooxygenase inhibitor, celecoxib, had no effect on seizures evoked in normal brain tissue but demonstrated robust antiseizure activity in all tested models of chronic epilepsy.InterpretationThe use of organotypic hippocampal cultures, where epileptogenesis occurs on a compressed time scale, and where seizure‐like activity and seizure‐induced cell death can be easily quantified with biomarker assays, allowed us to circumvent the throughput limitations of in vivo chronic epilepsy models. Ability to rapidly screen compounds in a chronic model of epilepsy allowed us to find an anticonvulsant that would be missed by screening in acute models.

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Section: Discussionmentioning

confidence: 63%

Staged anticonvulsant screening for chronic epilepsy

Berdichevsky

Saponjian

Park

et al. 2016

Ann Clin Transl Neurol

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“…The only study that showed a prophylactic effect of PHT in preventing PTE was not blinded [2]. Paradoxically, three studies showed a higher incidence of PTE in patients receiving PHT or PB than in untreated groups [16][17][18].…”

Section: Results Of Randomized Clinical Trials For Prophylaxismentioning

confidence: 99%

“…In addition, several lines of evidence from animal studies suggest that AEDs might interfere with the recovery of brain function after TBI [19]. However, in clinical study, it is difficult to tease out AED cognitive side effects from the direct effects of TBI and from AED inhibition of recovery of brain function after TBI [17].…”

Section: Potential Pitfalls Of Using or Not Using Aed Prophylaxis Aftmentioning

confidence: 99%

Posttraumatic epilepsy and treatment

Chen

Ruff

Eavey

et al. 2009

JRRD

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Abstract-Posttraumatic epilepsy (PTE) is a major long-term complication of traumatic brain injury (TBI). PTE usually develops within 5 years of head injury. The risk for developing PTE varies with TBI type. Both Korean and Vietnam war veterans with penetrating TBI had a 53% risk of developing PTE. The risk of developing PTE is between 10% and 25% in combat-associated closed-head trauma with positive brain imaging and about 5% in moderately severe closed-head injury without imaging finding. We do not know the risk of PTE among Operation Iraqi Freedom/Operation Enduring Freedom veterans with minimal TBI because of blast exposure. Partial seizures may manifest with subtle behavioral alterations that can be mistaken for manifestations of posttraumatic stress disorder and improperly treated. Accidents and medical complications commonly occur during seizures. Sudden unexpected death in epilepsy is most frequent among 20-to 40-year-olds. Seizures increase the likelihood of refractory seizures years after TBI. Seizures are also a social stigma that compromise veterans' reintegration into society. People with uncontrolled epilepsy are not allowed to drive and have difficulty obtaining or maintaining employment. Optimal seizure control is essential to the physical and emotional health of veterans with TBI and to their ability to lead productive lives.

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“…Neither of these trials was able to identify an anti-epileptogenic effect. A number of the early studies purported to show positive effects of phenobarbital and PHT, but more recent randomized controlled trials (RCTs) have demonstrated no useful effects [14] and even suggested that there were additional cognitive side effects associated with these treatments [16]. Similarly, the 1 well-performed RCT with valproic acid also failed to show any beneficial effect [15].…”

Section: Lessons From Epilepsy Prevention Trials Using Asdsmentioning

confidence: 99%

“…Five studies used phenytoin (PHT) alone, 5 used PHT and phenobarbital, and 1 each used phenobarbital, carbamazepine, or valproic acid. Only the 2 performed at the University of Washington (1 PHT [14] and 1 valproic acid [15]) were randomized, double-blind, controlled trials, and these were the 2 trials with the largest number of enrolled participants. Neither of these trials was able to identify an anti-epileptogenic effect.…”

Section: Lessons From Epilepsy Prevention Trials Using Asdsmentioning

confidence: 99%

Anti-epileptogenic Clinical Trial Designs in Epilepsy: Issues and Options

Schmidt¹,

Friedman

Dichter³

2014

Neurotherapeutics

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Although trials with anti-seizure drugs have not shown anti-epileptogenic or disease-modifying activity in humans, new compounds are on the horizon that may require novel trial designs. We briefly discuss the unique challenges and the available options to identify innovative clinical trial designs that differentiate novel anti-epileptogenic and diseasemodifying compounds, preferably early in phase II, from current anti-seizure drugs. The most important challenges of clinical testing of agents for epilepsy prevention include having sufficient preclinical evidence for a suitable agent to proceed with a human trial of an anti-epileptogenic drug, and to demonstrate the feasibility of doing such a trial. Major challenges in trial design to assess agents for disease modification include the choice of suitable study parameters, the identification of a high-risk study population, the type of control, the time and duration of treatment, and a feasible follow-up period.

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A Randomized, Double-Blind Study of Phenytoin for the Prevention of Post-Traumatic Seizures

Abstract: Phenytoin exerts a beneficial effect by reducing seizures only during the first week after severe head injury.

Cited by 895 publications

References 16 publications

Staged anticonvulsant screening for chronic epilepsy

Staged anticonvulsant screening for chronic epilepsy

Posttraumatic epilepsy and treatment

Anti-epileptogenic Clinical Trial Designs in Epilepsy: Issues and Options

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