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GENERAL INTRODUCTION & OUTLINE OF THE THESIS
and patient compliance.
In summary, current epilepsy management methods are insufficient for about
30% of the patients and there is an urgent need for new therapies. Therefore, research is needed to study the mechanisms of epilepsy and its development (epileptogenesis), and to identify novel targets in order to develop new therapeutic strategies for treating epi- lepsy. In this thesis we will investigate potential targets and novel therapeutic strategies.
Tuberous sclerosis complex
Malformations of cortical development (MCDs) are a common cause of symptomatic intractable epilepsy which often already manifests in young children. Tuberous scle- rosis complex (TSC) is an MCD with an incidence between 1 in 6,000 and 1 in 11,000 births that causes a complex neurologic clinical phenotype including epilepsy, autism and intellectual disability 22-25. Additionally, TSC causes dermatologic manifestations as facial angiofibromas, renal angiomyolipomas and pulmonary lymphangioleiomyomato- sis 26. The neurological abnormalities and cardiac rhabdomyomas, which are the most common pediatric tumors of the heart, can already be diagnosed prenatally (see Fig 1) 27-29. Epilepsy is the most prevalent and severe manifestation of TSC, occurring in 70 to 80% of all patients, often already starting early in life. Any seizure subtype can occur in TSC patients, like focal aware or unaware, or generalized seizures 26. One of the most common and devastating types is infantile spasms, which is often associated with a high degree of mental retardation and poor neurologic prognosis 30. Infantile spams occurs in 20 to 30% of infants with TSC and typically presents in the first year of life, and leaving this condition untreated may lead to cognitive developmental halt or even regression 30.
TSC results from genetic mutations in one of two tumor suppressor genes, TSC1, encoding hamartin, or TSC2, encoding tuberin 31, 32. Approximately two-thirds of TSC cases are caused by de novo (sporadic) germline mutations, the remaining cases are inherited 33-35. TSC2 mutations as a group are usually associated with a worse phe- notype with more severe manifestations, although a clear genotype-phenotype correla- tion is still lacking. TSC1 and TSC2 proteins form a heterodimeric complex, acting as an upstream regulator of the mammalian target of rapamycin (mTOR) signaling pathway (see Fig 2) 36.
Neuropathological examination of TSC brain specimens reveals three major lesions: subependymal nodules, subependymal giant cell tumors, and cortical tubers (see Fig 1 for histological characteristics of TSC and Fig 3 for a schematic overview of the disturbed cortical layers) 37-39. Cortical tubers are believed to represent the neuropatho- logical substrate for epilepsy in TSC patients, and are targeted for surgical resection in TSC patients with drug-resistant epilepsy 40-42. Although epilepsy surgery often results in seizure freedom, increasing evidence supports the importance of the perituberal cortex in TSC 43-48. Focal seizures and interictal epileptiform discharges detected in the center of epileptogenic tubers have been shown to propagate to the tuber rim, perituberal cortex and other epileptogenic tubers 49. The detection of multiple extensive zones with high occurrence rate of interictal high frequency oscillations (HFOs) also supports the presence of a complex and widespread epileptogenic network 50. Accordingly, neuro- pathological examination of post-mortem TSC brain provided evidence of more subtle and dynamic structural abnormalities, present throughout the brain (i.e. “microtubers”,
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