From Gene to Animal Model to Treatment: Modeling of Specific Epilepsy Subtypes to Develop More Advanced Treatments

S. L. Moshé, MD, of the Albert Einstein College of Medicine and Montefiore Medical Center, discusses the importance of creating disease-specific models of epilepsy in animal models for understanding and treating specific epilepsy subtypes.

S. L. Moshé, MD, of the Albert Einstein College of Medicine and Montefiore Medical Center, discussed the treatment of generalized epilepsies at the 68th annual meeting of the American Epilepsy Society. This session focused on the challenges of epilepsy diagnosis and developing treatments that are specific to each type of generalized epilepsy.

Many forms of seizures exist, including tonic-clonic seizures, absence seizures, and myoclonic seizures. Each of these categories has subtypes, as well. For instance, absence seizures may be typical or atypical, or may have special features, such as myoclonus. Similarly, myoclonic seizures may include atonic and tonic subtypes. Despite the many types of seizures, all are thought to occur as a result of rapid engagement of systems on both sides of the brain.¹

The abnormal activation of the brain that results in epilepsy may be due to brain damage that occurs at any point in life, but in many forms of epilepsy, a genetic predisposition is the major causative factor. These genetic epilepsies include childhood and juvenile absence epilepsy, juvenile myoclonic epilepsy, and familial adult myoclonic epilepsy. Generalized tonic-clonic seizures, in the absence of other epilepsy symptoms, may also be related to genetic factors. Several genetic factors have been identified in association with specific epilepsy subtypes.

It is important to remember that many syndromes may masquerade as generalized epilepsies, which may lead to improper treatment. For instance, glucose transport disorders, West syndrome, Lennox-Gastaut syndrome, and progressive myoclonic epilepsies may mimic generalized epilepsy. However, it is also important to recognize that these syndromes sometimes co-occur with generalized epilepsy.

Because so many types of generalized epilepsies exist, it is important to have adequate animal models for each type, both to better understand the pathophysiology of each condition and to test potential medications for models of specific conditions. Several drugs are available to induce absence seizures, tonic/clonic seizures, and myoclonic seizures in animals. However, more recently, researchers have been using advanced genetic engineering techniques to develop animal models with specific types of epilepsy that more closely approximate human epilepsy conditions.

As animal models develop, the scientific understanding of specific epilepsy syndromes is beginning to improve. Recent developments in the understanding of generalized absence seizures include the discovery that some of the abnormal discharges that initiate absence seizures are typically located in the facial somatosensory cortex of the thalamus.² Other researchers are finding important differences between the pathophysiology of typical and atypical absence seizures.³

Many forms of epilepsy affect males and females unequally, suggesting a role of hormonal modulation in the disease. In a rat study, Moshé examined the role of the GABAA system, and found that an area of the brain often affected in movement disorders, the substantia nigra, is different in male and female rats. In addition, in male rats, the substantia nigra region is responsible for inducing convulsive effects, and is reliant on testosterone for development. Further understanding of the role of sex and hormones may be important to the development of future pharmacotherapies.⁴

As scientists identify more of the genetic factors associated with epilepsy and create animal models of the specific types of epilepsy, the scientific understanding of epilepsy pathophysiology continues to improve. With these improvements in the understanding of epilepsy subtypes, patients and caregivers can be hopeful that more effective treatments will be developed.

References

1. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51(4):676-685.

2. Polack PO, Guillemain I, Hu E, Deransart C, Depaulis A, Charpier S. Deep layer somatosensory cortical neurons initiate spike-and-wave discharges in a genetic model of absence seizures. J Neurosci. 2007;27(24):6590-6599.

3. Onat FY, van Luijtelaar G, Nehlig A, Snead OC rd. The involvement of limbic structures in typical and atypical absence epilepsy. Epilepsy Res. 2013;103(2-3):111-3):111-123.

4. Velísková J, Moshé SL. Sexual dimorphism and developmental regulation of substantia nigra function. Ann Neurol. 2001;50(5):596-601.