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.
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 .
- 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
B. Develop tools that facilitate the identification and validation of a cure.
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 .
- 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 GABAA 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  . 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.
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
- 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 . 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
- 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 , 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,
- 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 , P- glycoprotein
blockers , and polyunsaturated fatty acids .
- 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.