Epileptogenesis in tuberous sclerosis complex-related developmental and epileptic encephalopathy

Abstract

Epileptogenesis in infants with tuberous sclerosis complex (TSC) is a gradual and dynamic process, leading to early onset and difficult-to-treat seizures. Several cellular, molecular and pathophysiologic mechanisms, including mammalian target of rapamycin (mTOR) dysregulation, GABAergic dysfunction and abnormal connectivity, may play a role in this epileptogenic process and may also contribute to the associated developmental encephalopathy. Disease-specific antiseizure medications or drugs targeting the mTOR pathway have proved to be effective in TSC-associated epilepsy. Pre-symptomatic administration of vigabatrin, a GABAergic drug, delays seizure onset and reduces the risk of a subsequent epileptic encephalopathy, such as infantile spasms syndrome or Lennox-Gastaut syndrome. Everolimus, a rapamycin-derived mTOR inhibitor, reduces seizure frequency, especially in younger patients. This evidence suggests that everolimus should be considered early in the course of epilepsy. Future trials are needed to optimize the use of everolimus and determine whether earlier correction of mTOR dysregulation can prevent progression to developmental and epileptic encephalopathies or mitigate their severity in infants with TSC. Clinical trials of several other potential antiseizure drugs (cannabidiol and ganaxolone) that target contributing mechanisms are also underway. This review provides an overview of the different biological mechanisms occurring in parallel and interacting throughout the life course, even beyond the epileptogenic process, in individuals with TSC. These complexities highlight the challenges faced in preventing and treating TSC-related developmental and epileptic encephalopathy.

Keywords: animal model; developmental and epileptic encephalopathy; epileptogenesis; mTOR; tuberous sclerosis complex.

Figure 1

Cellular and molecular mechanisms underlying mTOR-related DEE in TSC. Overview of the complex cellular and molecular mechanisms contributing to the epileptogenic process and developmental disabilities in TSC. mTORC1 signalling plays a central role during brain development, regulating many basic cellular functions, such as energy metabolism and protein synthesis to regulate cell growth, proliferation and migration. mTORC1 is inhibited by the multiprotein complex consisting of TSC1 and TSC2. Loss-of-function mutations in either TSC1 or TSC2 result in prenatal mTOR overactivation; mTOR inhibitors (mTORi; such as everolimus and sirolimus) are powerful inhibitors of mTORC1 activity (for a more detailed illustration of the mTOR pathway, see Curatolo et al.). Knowledge about the complex cellular and molecular consequences of mTORC1 overactivation, affecting different cell types, during brain development is rapidly increasing. Early and sustained oxidative stress and inflammation (with enhanced pro-inflammatory cytokines production and recruitment of the peripheral immune cells), accompanied by blood–brain barrier (BBB) dysfunction/leakage and alterations in the composition of the ECM are observed in TSC brain. Crosstalk among these multiple cellular and molecular can contribute to network dysfunction during brain development. Dysregulation of mTOR signalling itself results in developmental alterations of the balance between excitation and inhibition (i.e. GABAergic system dysfunction). Moreover, mTOR hyperactivity affects the oligodendroglial turnover (with failure to produce proper myelin), further contributing to abnormal cell-signalling and premature activation of mechanisms of neurodegeneration. Glu = glutamate; NFTs = neurofibrillary tangles; ROS = reactive oxygen species.

Figure 2

The early development of a disease network in TSC. (A) Schematic illustration of the levels of complexity from DNA to RNA and proteins, to cells, network and phenotype. The black lines show the relationships between levels from genotype (top) to phenotype (bottom) with emergence of developmental encephalopathy (DE) or DEE. (B) The convergent and divergent relationships between genetic defects (TSC1 and TSC2 mutations) and the abnormal network with hidden levels of complexity at the level of the genetic information (protein-coding or non-coding genes) and structural/cellular and functional abnormalities influencing the phenotype. (C) Hypothetical temporal dynamics of disease progression in TSC (early and late epileptogenesis), highlighting the establishment of an mTOR-related epileptogenesis associated with co-occurring NDDs and accelerated (early) neurodegeneration. ID = intellectual disability.