Epilepsy Biomarkers

Engel, Jerome; Surges, Rainer

doi:10.1002/9781118936979.ch8

Cited by 52 publications

(88 citation statements)

References 40 publications

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“…EEG = electroencephalography onset and progression of epilepsy in a susceptible patient would be enormously valuable for evaluating the therapeutic response to a potential antiepileptogenic or disease-modifying therapy. Validated biomarkers of epileptogenesis and ictogenesis, as suggested by Engel et al [22], could be used to "(a) predict the development of an epilepsy condition, (b) identify the presence and severity of tissue capable of generating spontaneous seizures, (c) measure progression after the condition is established, (d) create animal models for more cost-effective screening of potential antiepileptogenic and anti-seizure drugs and devices, and (e) reduce the cost of clinical trials of potential antiepileptogenic interventions by enriching the trial population with patients at high risk for developing epilepsy". In this regard, the wide range of etiologically relevant animal epilepsy models could play an important role in the identification and validation of biomarkers.…”

Section: Biomarkers For Epileptogenesis and Antiepileptogenesismentioning

confidence: 99%

“…As discussed by other authors in this issue, a number of biomarkers have emerged that may provide predictive insight into the process of epileptogenesis. These include alterations in hippocampal magnetic resonance images, as suggested by the FEBSTAT study, presence of interictal spikes and highfrequency oscillations in the EEG, altered seizure threshold, and the presence of blood markers suggestive of brain inflammation or neurodegeneration [3,22]. In addition, genetic biomarkers have the potential to predict outcome and inform treatment for the selected patient population.…”

Section: Biomarkers For Epileptogenesis and Antiepileptogenesismentioning

confidence: 99%

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Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

White

Löscher²

2014

Neurotherapeutics

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A major unmet medical need is the lack of treatments to prevent (or modify) epilepsy in patients at risk, for example, after epileptogenic brain insults such as traumatic brain injury, stroke, or prolonged acute symptomatic seizures like complex febrile seizures or status epilepticus. Typically, following such brain insults there is a seizure-free interval ("latent period"), lasting months to years before the onset of spontaneous recurrent epileptic seizures. The latent period after a brain insult offers a window of opportunity in which an appropriate treatment may prevent or modify the epileptogenic process induced by a brain insult. A similar latent period occurs in patients with epileptogenic gene mutations. Studies using animal models of epilepsy have led to a greater understanding of the factors underlying epileptogenesis and have provided significant insight into potential targets by which the development of epilepsy may be prevented or modified. This review focuses largely on some of the most common animal models of epileptogenesis and their potential utility for evaluating proposed antiepileptogenic therapies and identifying useful biomarkers. The authors also describe some of the limitations of using animal models in the search for therapies that move beyond the symptomatic treatment of epilepsy. Promising results of previous studies designed to evaluate antiepileptogenesis and the role of monotherapy versus polytherapy approaches are also discussed. Recent data from both models of genetic and acquired epilepsies strongly indicate that it is possible to prevent or modify epileptogenesis, and, hopefully, such promising results can ultimately be translated into the clinic.

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Section: Biomarkers For Epileptogenesis and Antiepileptogenesismentioning

confidence: 99%

Section: Biomarkers For Epileptogenesis and Antiepileptogenesismentioning

confidence: 99%

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

White

Löscher²

2014

Neurotherapeutics

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“…Early treatment before epilepsy is established is most likely to be successful. For many epilepsy types, this will require predictive biomarkers, which are not available at present [178]. Also, new clinical trial designs are urgently required [5].…”

Section: Resultsmentioning

confidence: 99%

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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“…A biomarker for epileptogenesis is an objectively measurable characteristic of a biological process that reliably identifies the development, presence, severity, progression, or localization of an epileptogenic abnormality [36][37][38]. An epileptogenic abnormality refers to the pathophysiological substrate(s) responsible for the initiation and/or maintenance of epilepsy.…”

Section: Biomarker For Epileptogenesismentioning

confidence: 99%

Past and Present Definitions of Epileptogenesis and Its Biomarkers

2014

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Descriptions of epileptic seizures and epilepsy date back to antiquity, and research into fundamental mechanisms of epilepsy in animal models, as well as patients, has been carried out for over a century. Studies of epileptogenesis, however, as distinct from ictogenesis, have been pursued for only a few decades, and antiepileptogenesis, the prevention of epilepsy or its progression, and the reversal of the epileptogenic process or cure, are relatively recent interests of the basic research community. The goal to develop antiepileptogenic interventions would be greatly facilitated by the identification of reliable biomarkers of epileptogenesis that could be used to create cost-effective, high-throughput screening models for potential antiepileptogenic compounds, as well as enrich patient populations and serve as surrogate endpoints for clinical trials. Without such biomarkers, the cost for clinical validation of antiepileptogenic interventions would be prohibitive. Epileptogenic mechanisms, antiepileptogenic interventions, and biomarkers are likely to be specific for the many different causes of epilepsy, which include genetic influences, cell loss and synaptic plasticity, malformations of cortical development, and autoimmune disorders, to name but a few. A high priority is currently being placed on investigations to elucidate fundamental mechanisms of epileptogenesis and identify biomarkers for specific models of human epilepsy, such as mesial temporal lobe epilepsy with hippocampal sclerosis, traumatic brain injury, and a variety of pediatric diseases, including tuberous sclerosis and West syndrome.

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Epilepsy Biomarkers

Cited by 52 publications

References 40 publications

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

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

Past and Present Definitions of Epileptogenesis and Its Biomarkers

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