Epilepsy Research Benchmarks Progress Update (2007-2009)

Area II: Develop new therapeutic strategies and optimize current approaches to cure epilepsy.

A. Identify basic mechanisms of seizure generation (ictogenesis) that will lead to the development of cures.

Background:
Understanding how seizures begin and end in the brain gives researchers opportunities to develop drugs or other treatments that can act before seizures begin, or stop them as soon as they start. 

Summary of advances:
A number of recent investigations into the biological mechanisms that cause seizures have focused on using electrophysiological and computational methods to understand which neurons are involved initiating seizures.  Other studies have centered on the cell-signaling pathways that are involved in propagating and terminating seizures.  A few examples are:

• A number of important computational studies have led to the hypothesis that “hub cells” (cells with a large number of inputs and outputs) may contribute to seizure initiation.  The hypothesis suggests that an increase in connectivity of just a small number of cells in a circuit is sufficient to trigger synchronous activation in the network, contributing to hyperexcitability and an increased probability of seizure activity.  Understanding which cells initiate seizures will help researchers develop therapies that specifically target these cells [79-81].
  
  
• Epileptiform activity requires large amounts of energy in the form of glucose.  Glucose and its metabolites are transported from blood vessels to distant neurons through networks of glial cells coupled to each other by gap junctions, which are protein channels that allow small molecules to pass between cells.  During periods of prolonged activity, there is a neurotransmitter–dependent increase in coupled astrocytes that facilitates delivery of these energetic metabolites to neurons.  Blocking this process can prevent epileptiform activity.  These findings suggest that molecular targets on astrocytes might be an important approach to seizure control [82].
  
  
• Acidosis produced, for example by CO₂ inhalation, is well known to suppress or truncate seizures.  Recent studies have revealed that the Acid Sensing Ion Channel 1a (ASIC1a) likely plays a key role in seizure termination. These findings indicate that ASIC1a is part of a feedback inhibitory system that is activated by seizures and serves to limit seizure severity and duration. This finding is significant because it provides a logical basis for identifying ASIC1a potentiators for treating status epilepticus and perhaps tonic-clonic seizures [83].

B. Develop tools that facilitate the identification and validation of a cure.

Background: 
Research and diagnostic tools such as animal models, biomarkers, and screening techniques facilitate efforts to identify, develop, and test new therapeutic interventions for epilepsy, and they may also inform predictions about which individuals may respond best to which treatments. 

Summary of advances:
The epilepsies are a group of disorders with diverse causes and clinical presentations.  This diversity means that a variety of treatment options need to be available.  Furthermore, variations in the genetic background of individual people with epilepsy may also affect their responses to different treatments.  The examples below highlight advances in identifying new drug targets, understanding and localizing seizure-related brain activity, and screening patients for predictors of treatment response. 

• Neurotoxicity caused by reduced blood flow and oxygen deprivation to the brain, as occurs in stroke or neonatal hypoxia-ischemia, can lead to seizures and the development of chronic epilepsy.  One contributor to increased seizure susceptibility in neonates is a high level at young ages of receptors in neurons for the excitatory neurotransmitter glutamate, which can lead to excessive neuronal activity.  A study in a rat model of neonatal seizures showed that drugs that block a type of glutamate receptors called AMPA receptors reduced H-I seizures and subsequent cognitive deficits [84]. 
  
  
• As epilepsy is a disorder highlighted by synchronous activation of neurons, it comes as no surprise that most therapeutic approaches to date have focused on neuronal activity (e.g., sodium channel blockers, enhanced inhibition through GABA_A receptors, etc.). However, over the past few years, interest in the effects of brain inflammation and immune processes on seizure generation (as well as epileptogenesis, see Area I) has attracted much attention.  For example, based on research in animal models, drugs that target two particular immune signaling molecules, ICE/caspase 1 and IL-1β receptors, show promise as antiepileptics [84-86].
  
  
• Recent innovations in intracranial recording technologies, such as  microarray electrodes for recording high resolution EEG and single neuron activity, have led to the detection of previously uncharacterized electrical events in patients with intractable epilepsy, including microbursts, microseizures, and high frequency oscillations. These patterns of neuronal activity may be valuable biomarkers for localizing epileptogenic networks and understanding seizure generation.  Moreover, they may also inform the development of methods to predict the occurrence of seizures based on brain activity patterns that precede their onset [87-93]. (See also Area IC.)
  
  
• Molecular biomarkers have proven useful for the identification of patients most at risk for adverse drug reactions. A recent study identified a specific gene that makes carbamazepine, a commonly used antiepileptic drug, risky for some populations of patients. The authors report a strong risk for serious and potentially fatal skin reactions to carbamazepine in the subgroup of Asian individuals with the HLA-B*1502 allele [94] .  As a result of this finding, the FDA has recently relabeled carabamazepine with a recommendation to evaluate patients with ancestry across broad areas of Asia, including South Asian Indians, for this genotype and to avoid the use of carbamazepine in those who test positive. 

C.  Optimize existing therapies and develop new therapies and technologies for curing epilepsy.

Background: 
Available antiepileptic medications fail to adequately control seizures in as many as one third of people living with epilepsy, and even when seizures are controlled, long- and short-term side effects of drugs or surgical interventions can further diminish quality of life.

Summary of advances: 
Improvements in current treatments and the development of new therapies focus largely on ways to more specifically target epileptic tissue and cellular pathways.  These include advances in presurgical imaging techniques to more accurately identify epileptic areas of the brain for surgical removal and improvements in drugs and drug delivery methods.  Furthermore, clinical trials to test new antiepileptic drugs and efforts to develop and test non-standard treatment approaches are ongoing. 

• Resective epilepsy surgery remains an established treatment with the potential to permanently arrest seizures in some patients with medically resistant epilepsy. However, this option is limited to people whose seizure focus can be clearly localized and removed without functional loss that outweighs the benefits of reduced seizure frequency. Better ways to localize seizure-generating brain regions could identify more candidates for surgical intervention and improve the success of resective surgery while minimizing cognitive deficits.  Toward this end, the examples below highlight advances in magnetic resonance imaging (MRI), magnetic source imaging (MSI) and magnetoencephalography (MEG) technologies, as well as in the analysis of data from these technologies [95-110]. (Also see Area IIIC for further discussion of mapping functional networks in candidates for epilepsy surgery.)
  
  
• Brain stimulation to prevent or halt seizure activity may provide a viable and effective epilepsy treatment. Efforts are underway to develop and test responsive devices that couple seizure detection and prediction algorithms to electrical stimulation (see Area IIB).   Several ongoing clinical trials that test a variety of surgical and stimulation protocols show a statistically significant reduction in seizure frequency [111]. While these early results are promising, seizure freedom has not been achieved, and further studies will be necessary to refine stimulation parameters [112-116].
  
  
• On the cutting edge of new experimental therapeutic strategies are gene therapies, in which genes are delivered to the affected tissue to replace defective genes or enhance the expression of proteins that reduce excitability.  Neuropeptide systems, such as NPY and galanin, adenosine, and inhibitory neurotransmitter (GABA) signaling pathways are the most popular targets. These strategies have proved effective in animal models, though in general they are not yet ready for clinical application. Current advances in the use of viruses to deliver genes to affected tissues show promise and may move the clinical application of gene therapy forward [117-121].
  
  
• Some antiepileptic compounds cannot be delivered systemically, either because of side effects or because they do not readily cross the blood-brain barrier. Strategies that show promise for improving drug delivery involve the implantation of a catheter to chronically infuse a drug or the implantation of matrices embedded with the drug or with cells engineered to produce large quantities of the compound.  Further studies are necessary to determine whether these strategies will be clinically beneficial [122-124].
  
  
• Significant progress has been made in the clinical testing of new pharmacological treatments.  Phase II/III clinical trials are ongoing or have been completed for several antiepileptic drugs, including retigabine, carisbamate [125], brivaracetam [126, 127], rufinamide [128, 129], lacosamide [130, 131], ganaxolone [132, 133], and eslicarbazepine acetate [134, 135]. A number of other compounds are in earlier stage development, poised to enter either phase II or phase III clinical trials [136, 137]. 
  
  
• In addition to traditional drug trials, randomized, placebo-controlled trials were undertaken for alternative, non-drug therapies. Examples include trials of the ketogenic diet (high-fat, adequate-protein, low-carbohydrate) [138-140], yoga [141], P- glycoprotein blockers [142], and polyunsaturated fatty acids [143]. 
  
  
• Moreover, building on the recognition that patients with drug-resistant epilepsy may achieve seizure control with the ketogenic diet, recent studies have further investigated the potential of pathways involved in energy metabolism as targets for new pharmacological therapies [144-146]. A preliminary clinical trial planned to begin in 2010 will assess the tolerability and efficacy of 2-deoxy-D-glucose (2DG), an analogue of normal sugar that blocks sugar metabolism, for seizure reduction in patients with intractable temporal lobe epilepsy.