Results of Phase 2 Safety and Feasibility Study of Treatment With Levetiracetam for Prevention of Posttraumatic Epilepsy

Klein, Pavel; Herr, Daniel; Pearl, Phillip L.; Natale, JoAnne E.; Levine, Zachary T.; Nogay, Claude; Sandoval, Fabian; Trzcinski, Stacey; Atabaki, Shireen M.; Tsuchida, Tammy N.; Anker, John van den; Soldin, Steven J.; He, Jie; McCarter, Robert

doi:10.1001/archneurol.2012.445

Cited by 85 publications

(56 citation statements)

References 11 publications

(18 reference statements)

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“…In human medicine, the role of prophylactic antiepileptic medication in moderate to severe TBI is still debatable, but there are some recent studies that support their use 38, 39. Randomized controlled double‐blinded trials may be necessary to investigate whether treatment (such as prophylactic antiepileptic medication) of these cases with increased risk of developing PTE can alter outcome.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of Early Magnetic Resonance Imaging in Dogs after Traumatic Brain Injury: 50 Cases

Beltrán

Platt

McConnell

et al. 2014

Veterinary Internal Medicne

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BackgroundThe prognostic value of early magnetic resonance imaging (MRI) in dogs after traumatic brain injury (TBI) remains unclear.ObjectivesDetermine whether MRI findings are associated with prognosis after TBI in dogs.AnimalsFifty client‐owned dogs.MethodsRetrospective study of dogs with TBI that underwent 1.5T MRI within 14 days after head trauma. MRI evaluators were blinded to the clinical presentation, and all images were scored based on an MRI grading system (Grade I [normal brain parenchyma] to Grade VI [bilateral lesions affecting the brainstem with or without any lesions of lesser grade]). Skull fractures, percentage of intraparenchymal lesions, degree of midline shift, and type of brain herniation were evaluated. MGCS was assessed at presentation. The presence of seizures was recorded. Outcome was assessed at 48 h (alive or dead) and at 3, 6, 12, and 24 months after TBI.ResultsSixty‐six percent of the dogs had abnormal MRI findings. MRI grade was negatively correlated (P < .001) with MGCS. A significant negative correlation of MRI grade, degree of midline shift, and percentage of intraparenchymal lesions with follow‐up scores was identified. The MGCS was lower in dogs with brain herniation (P = .0191). Follow‐up scores were significantly lower in dogs that had brain herniation or skull fractures. The possibility of having seizures was associated with higher percentage of intraparenchymal lesions (P = 0.0054) and 10% developed PTE.Conclusions and Clinical ImportanceSignificant associations exist between MRI findings and prognosis in dogs with TBI. MRI can help to predict prognosis in dogs with TBI.

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Section: Discussionmentioning

confidence: 99%

Prognostic Value of Early Magnetic Resonance Imaging in Dogs after Traumatic Brain Injury: 50 Cases

Beltrán

Platt

McConnell

et al. 2014

Veterinary Internal Medicne

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“…However, the most promising drugs, notably levetiraetam and ethosuximide, have not been adequately studied. Whether they can provide clinically useful disease-modifying effects is uncertain, but some attempts are being made to find out [21,64]. Although the emphasis to date in antiepileptogenesis clinical trials has almost exclusively been on antisiezure drugs, it is apparent that an antiepileptogenic agent need not have antiseizure activity, and the evidence from studies of atipamezole and SR141716A indicates that even drugs with proconvulsant activity can have antiepileptogenic properties.…”

Section: Resultsmentioning

confidence: 99%

“…An uncontrolled, retrospective analysis of patients undergoing craniotomy and treated postoperatively with either levetiracetam or phenytoin showed that fewer patients who received levetiracetam (26 %) developed epilepsy after 1 year than those treated with phenytoin (36 %), although the difference did not reach statistical significance [20]. A recent open-label, nonrandomized study in 126 adults and children assessing the safety, tolerability, and pharmacokinetics of levetiracetam treatment in TBI patients for 1 month, initiated within 8 h of the injury, also showed a nonsignificant trend toward fewer patients on levetiracetam treatment (11 %) developing epilepsy after 2 years than those who were untreated (20 %) [21]. An additional pilot study in 40 children aged 6-17 years in which half were treated with levetiracetam within 8 h of injury showed an overall low incidence of posttraumatic epilepsy [64].…”

Section: Levetiracetammentioning

confidence: 96%

“…None was found to have an antiepileptogenic effect. Comparable clinical trials have not been conducted with newer ASDs, although several, including topiramate and levetiracetam, exhibit activity in certain animal antiepileptogenesis models [19], and, to date, human trials with levetiracetam suggest that additional study of this agent is warranted [20,21].…”

Section: Asds With Potential Antiepileptogenic Propertiesmentioning

confidence: 99%

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The Potential of Antiseizure Drugs and Agents that Act on Novel Molecular Targets as Antiepileptogenic Treatments

2014

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A major goal of contemporary epilepsy research is the identification of therapies to prevent the development of recurrent seizures in individuals at risk, including those with brain injuries, infections, or neoplasms; status epilepticus; cortical dysplasias; or genetic epilepsy susceptibility. In this review we consider the evidence largely from preclinical models for the antiepileptogenic activity of a diverse range of potential therapies, including some marketed antiseizure drugs, as well as agents that act by immune and inflammatory mechanisms; reduction of oxidative stress; activation of the mammalian target of rapamycin or peroxisome proliferatoractivated receptors γ pathways; effects on factors related to thrombolysis, hematopoesis, and angiogenesis; inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reducatase; brainderived neurotrophic factor signaling; and blockade of α2 adrenergic and cannabinoid receptors. Antiepileptogenesis refers to a therapy of which the beneficial action is to reduce seizure frequency or severity outlasting the treatment period. To date, clinical trials have failed to demonstrate that antiseizure drugs have such disease-modifying activity. However, studies in animal models with levetiracetam and ethosuximide are encouraging, and clinical trials with these agents are warranted. Other promising strategies are inhibition of interleukin 1β signaling by drugs such as VX-765; modulation of sphingosine 1-phosphate signaling by drugs such as fingolimod; activation of the mammalian target of rapamycin by drugs such as rapamycin; the hormone erythropoietin; and, paradoxically, drugs such as the α2 adrenergic receptor antagonist atipamezole and the CB1 cannabinoid antagonist SR141716A (rimonabant) with proexcitatory activity. These approaches could lead to a new paradigm in epilepsy drug therapy where treatment for a limited period prevents the occurrence of spontaneous seizures, thus avoiding lifelong commitment to symptomatic treatment.

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“…In addition, levetiracetam is one of currently available candidates as the second-line AED for SE (Manno, 2011) and as an anti-epileptogenic drug (Pearl et al, 2013;Klein et al, 2012). Animal studies have shown that levetiracetam possesses anticonvulsant activity and results in neuroprotective effects (Mazarati et al, 2004;Zheng et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Prevention of status epilepticus-induced brain edema and neuronal cell loss by repeated treatment with high-dose levetiracetam

Itoh¹,

Inamine²,

Oshima³

et al. 2015

Brain Research

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Results of Phase 2 Safety and Feasibility Study of Treatment With Levetiracetam for Prevention of Posttraumatic Epilepsy

Cited by 85 publications

References 11 publications

Prognostic Value of Early Magnetic Resonance Imaging in Dogs after Traumatic Brain Injury: 50 Cases

Prognostic Value of Early Magnetic Resonance Imaging in Dogs after Traumatic Brain Injury: 50 Cases

The Potential of Antiseizure Drugs and Agents that Act on Novel Molecular Targets as Antiepileptogenic Treatments

Prevention of status epilepticus-induced brain edema and neuronal cell loss by repeated treatment with high-dose levetiracetam

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