Epilepsy Research Benchmarks Progress Update (2007-2009)

Area I: Prevent epilepsy and its progression.

A. Identify as yet unrecognized causes of epilepsy (e.g., genetic, autoimmune and infectious).

Background: 
Epilepsy has many causes. It may be the result of developmental problems due to genetic mutations that interfere with the normal wiring and activity of the brain. It can also be caused by infection, tumors, stroke, or any kind of injury to the brain. In some cases, there is no obvious cause. Knowing more about how epilepsy develops will increase opportunities for new treatments.

Summary of advances: 
Neurons rely on ion channels in their cell membranes to generate electrical activity and on signaling molecules called neurotransmitters to propagate this activity from one neuron to another.  Mutations affecting ion channels and cell-surface receptors for neurotransmitters disrupt neuronal activity and communication, and many such mutations are known to cause different forms of epilepsy.  However, more recent research points to genetic variations affecting other processes not previously linked directly to epilepsy.  For example:

• Early infantile epileptic encephalopathy with suppression-burst (EIEE), a severe form of early onset epilepsy, has recently been associated with mutations in the gene STXBP1 (or MUNC18-1).  The protein encoded by this gene, synaptic binding protein 1, is involved in the release of neurotransmitter molecules from neurons [1].     
  
  
• A study of epilepsy and mental retardation limited to females (EFMR) led to the identification of mutations in the gene PCDH19, which encodes protocadherin 19, a member of a large group of proteins important in the development of neuronal connectivity in the brain[2].
  
  
• Neurons communicate through both excitatory signaling, which increases a neuron’s activity, and inhibitory signaling, which decreases activity.  Several recent studies have added to a growing recognition of a role for impaired development of inhibitory neuronal connections and signaling in epilepsy [3-9].

Infectious and immune processes are known to contribute to some forms of epilepsy, but a number of recent reports have provided new insights into the mechanisms involved and opportunities for studying the interaction between environmental and genetic risk factors in epilepsy.

• New reports of acute viral infections by the H1N1 flu virus [10] and respiratory syncytial virus (RSV) [11] with acute seizures raise questions about the extent to which these infections will be associated with future epilepsy (or other neurologic disease).  Another study found that maternal genitourinary infection during pregnancy was associated with an increased risk of epilepsy in children[12].
  
  
• Autoimmune-mediated limbic encephalitis can lead to epilepsy.  Prior research has emphasized paraneoplastic causes, in which the body’s immune response to a tumor cross-reacts with proteins normally expressed in the brain, which then become the target of an autoimmune attack.  However, recent case reports are raising awareness of non-paraneoplastic autoimmune-mediated limbic encephalitis and seizures [13].

B. Identify underlying mechanisms of epileptogenesis.

Background: 
Epileptogenesis refers to the process through which brain tissue develops the tendency for spontaneous and chronic seizures. A better understanding of where, how, when, and why epileptogenesis occurs will help researchers answer fundamental questions about how epilepsy develops and persists as a chronic disease and may also point to opportunities to intervene.

Summary of advances:
Recent research has pointed to a number of mechanisms contributing to epileptogenesis, including changes in ion channels and neurotransmitter receptors that mediate neuronal excitability, cell signaling pathways in neurons and other types of brain cells, and immune and inflammatory processes.  (Also see Area ID for examples of research targeting these mechanisms for the development of therapeutic interventions.)  Notable findings include:

• The mammalian target of rapamycin (mTOR) pathway regulates many important physiological processes, such as protein synthesis, metabolism, and the function of synapses – the sites of communication between neurons.  Studies have shown that the mTOR pathway contributes to epileptogenesis in animal models of Tuberous Sclerosis (TSC), status epilepticus, and epilepsy due to traumatic brain injury (post-traumatic epilepsy).  In addition, correlative evidence suggests a role for the mTOR pathway in human epilepsies, including TSC, focal cortical dysplasia, and ganglioglioma.  These findings [14-23] have direct therapeutic applications, as an FDA-approved drug, rapamycin, exists and could be tested in anti-epileptogenic clinical drug trials.
  
  
• The blood-brain barrier (BBB) serves an important function in selectively regulating which substances can access the brain, ideally allowing vital nutrients in while keeping potentially damaging agents out.  However, a breakdown of the BBB can occur under a variety of conditions that lead to inflammation in the brain, such as stroke, central nervous system (CNS) infection, head trauma, and neurodegenerative diseases.  Accumulating evidence indicates a role for BBB breakdown [24-29] and inflammation more generally [30-34] in promoting epileptogenesis, and several recent studies have begun to elucidate the mechanisms involved. 
  
  
• Non-neuronal cell types in the brain called glia, long-viewed as passive support cells, are now acknowledged to have a variety of functions that directly affect brain excitability and signaling.  In addition to playing integral roles in blood-brain barrier maintenance and inflammatory responses mentioned above, glia participate in other mechanisms relevant to epileptogenesis, such as neurogenesis, neuronal migration, synaptic development and plasticity, non-synaptic communication with neurons, regulation of neurotransmitter and ion levels, and direct release of neurotransmitter-like substances.  Therapeutic strategies targeting glia-specific processes could potentially have good efficacy, but fewer side effects, than traditional treatments that primarily target neurons [35, 36].
  
  
• Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian central nervous system.  However, during nervous system development, GABA exposure instead excites certain neurons.  This early GABA-mediated excitation is important for brain development but also contributes to an increased susceptibility to seizure generation in the immature brain.  New research now suggests a role for GABA-mediated excitation in seizures and epilepsy that may not be restricted to early developmental ages.  Studies using surgically removed brain tissue from epilepsy patients show a bias toward GABA-mediated excitation in brain regions involved in temporal lobe epilepsy or intractable focal epilepsies due to cortical malformations [37, 38]. These findings [37-48] point to the potential for therapeutics for epilepsy and epileptogenesis in infancy and beyond that target mechanisms known to mediate the switch from GABA-mediated excitation to inhibition.
  
  
• Other recent research findings have continued to demonstrate the importance of ion channels in epilepsy, and they have also highlighted their roles in novel mechanisms of epileptogenesis [37, 40, 44, 49-56]. For example, one study has shown that a type of calcium ion channel (T-type calcium channels) previously linked to absence epilepsy also mediates epileptogenesis in a model of limbic epilepsy [49].

C. Identify biomarkers for epileptogenesis.

Background:
Biomarkers are biological markers indicating changes in cells, tissues, or organs that are associated with the development or progression of a disease.  Biomarkers for epileptogenesis could be used to identify people who are at higher than average risk of developing epilepsy and could also facilitate research to develop antiepileptogenic therapies by serving as markers of treatment response.

Summary of advances:
With new and improved technologies for imaging the brain and recording brain activity at increasingly fine scales, researchers are identifying structural and functional changes associated with or predictive of seizure generation and epileptogenesis.  Examples of recent advances and ongoing research on potential biomarkers revealed through these new approaches are:

• Studies in both animal models of mesial temporal lobe epilepsy and in patients with focal epilepsies have shown that a type of high frequency oscillation in brain activity called fast ripples can identify epileptogenic areas.  Ongoing studies are investigating the potential for fast ripples to also predict the development of epilepsy as well as the subsequent frequency of seizure generation [57]. 
  
  
• In previous research, magnetic resonance imaging (MRI) following experimentally induced seizures in rats has shown that structural abnormalities in the hippocampus, a brain region involved in temporal lobe epilepsy, predict the subsequent development of spontaneous seizures [58]. Studies are now underway to determine whether similar changes predict the development of epilepsy after prolonged febrile seizures in children[59]. Structural MRI in patients with mesial temporal lobe epilepsy has also identified patterns of hippocampal and neocortical tissue loss that may predict disease progression, resistance to pharmacological treatment, or postoperative outcome [60].

D. Identify approaches to prevent epilepsy or its progression

Background:
Antiepileptic drugs are currently used to control the seizures of people with epilepsy. However, not everyone responds well to the drugs, which can also have troublesome side effects.  A better approach would be to develop treatments that could prevent epilepsy from developing in the first place, or that could stop the disease or its progression once it has begun.

Summary of advances:
Studies in experimental animal models of different forms of acquired epilepsy have identified a number of putative epileptogenic mechanisms occurring during the latent period between an initial insult and the development of spontaneous seizures.  Recent advances suggest these mechanisms may be useful targets for the development of antiepileptogenic interventions.  Additional studies have begun to identify and develop preventive approaches for epilepsies known or presumed to result from genetic mutations or brain malformations.  (Also see additional references [61-64] and Area IB for epileptogenic mechanisms that may be targets for intervention.)

Acquired epilepsies:

• Neurotrophic factors (NTFs) are proteins known to promote the growth and survival of neurons, and they represent an intrinsic repair mechanism in the brain that may be targeted to protect against neuronal damage and loss following an epileptogenic insult.  In a rat model of acquired temporal lobe epilepsy, supplementing fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF) reduced the frequency and severity of spontaneous seizures [65].
  
  
• Building on the hypothesis that BBB breakdown contributes to trauma-induced epilepsy, a recent study in rat brain tissue focused on gene expression and other changes induced by a blood protein called albumin, which can leak into the brain following BBB breakdown [24].  The study showed that blocking a signaling pathway activated by albumin suppressed most albumin-induced changes in gene expression and also prevented the development of epileptiform activity. Additional studies have also shown antiepileptogenic effects by blocking other mechanisms triggered by BBB disruption and inflammation. (See Area IB.)
  
  
• Astrogliosis, or the activation and proliferation of glial cells called astrocytes, has been associated with epilepsy in both animal models and people.  Studies in mice provide evidence that astrocyte-dependent regulation of adenosine, an inhibitory modulator of neuronal activity, links astrogliosis to development of epilepsy and also point to the potential antiepileptogenic benefit of approaches that augment adenosine [66]. 

Dysplastic and genetic epilepsies:

• In a mouse model of TSC, the FDA-approved immunosuppressant drug rapamycin suppressed seizures, reversed structural changes in the hippocampus and cortex, and also improved behavior [19, 67].  Importantly, studies in animal models of acquired temporal lobe epilepsy showed that the epileptogenic potential of rapamycin may extend beyond TSC [14, 22]. (See also Area IB.)
  
• In an animal model of absence epilepsy, treatment with the anticonvulsant drug ethosuximide prevented the development of spontaneous seizures [68].  Interestingly, this model displays features consistent with depression as a comorbiditity, and ethosuximide treatment also prevented development of depression-like symptoms [69]. (See also IIIB.)

E. Develop new animal models to study epileptogenesis

Background:
Animal models for different types of epilepsy can help to answer questions about how epilepsy develops and how repeated seizures affect brain structure and function.  They are also essential tools for the development and preliminary testing of new therapies to prevent epileptogenesis or the progression of epilepsy.

Summary of advances:
Recognizing that the epilepsies represent a heterogeneous class of disorders, researchers are developing a range of animal models that mimic different types of epilepsy in order to better investigate their underlying mechanisms and to test potential interventions to prevent epileptogenesis.  Some examples of recently developed models include:

• Infantile spasms (IS) are one of the most devastating epileptic encephalopathies of infancy, typically evolving to mental retardation and other types of often intractable epilepsies. Classical antiepileptic drugs (AEDs) are not generally sufficient to treat IS, and prolonged treatment with hormones or the drug vigabatrin is not only costly but associated with toxic side effects.  A number of recently reported chronic and acute models of IS may help to better understand this syndrome and identify more effective and safer therapies [7, 9, 70-72].  
  
  
• Infections of the central nervous system increase the risk for development of seizures and epilepsy.  Previous research had shown that infection in mice with Theiler's murine encephalomyelitis virus (TMEV) causes acute seizures.  New findings show that TMEV chronically altered seizure susceptibility in mice, suggesting a new model for studying the development of epilepsy after infection [73].
  
  
• Studies of an animal model of Alzheimer’s disease (AD) (human amyloid precursor protein transgenic mice) have shown that these animals express high levels of amyloid-beta peptides [74] and also exhibit spontaneous nonconvulsive seizure activity in the cortex and hippocampus.  More recent studies speculate that high levels of amyloid beta in the brain cause the recurrent epileptiform activity and cognitive deficits in humans [75]. 

F. Test the efficacy of prevention strategies

Background:
New antiepileptogenic therapies must prove their effectiveness in clinical trials before they can be used in for the prevention of epilepsy in people at risk.

Summary of Advances:
Although a number of studies have begun to test potential antiepileptogenic interventions in animal models (see Area ID), many approaches under development have not yet been tested in people at risk for developing epilepsy.  However, a preliminary clinical report suggested rapamycin might prevent epileptogenesis in people with TSC [76], consistent with its effects in an animal model of the disease.  In addition, clinical trials are ongoing for the prevention of epilepsy following traumatic brain injury, including “Preventing Epilepsy after Traumatic Brain Injury with Topiramate,” (University of Pennsylvania, NCT00598923) and  Federal University of Sao Paulo in Brazil study “Use of Biperiden for the Prevention of Post-traumatic Epilepsy” (Federal University of São Paulo, NCT1048138).