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 seizures 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 to determine whether earlier correction of the mTOR dysregulation can prevent the 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 facing challenges in the prevention and treatment of TSC-related developmental and epileptic encephalopathy.

Retrospective analysis of presymptomatic treatment in Sturge–Weber syndrome

“…48 Treatment during the presymptomatic phase in tuberous sclerosis complex sets precedence for presymptomatic treatment in other developmental epilepsy disorders, like SWS, where a high percentage of patients will have seizure onset in the first few years of life, and where early age of seizure onset has been repeatedly associated with worse neurological and developmental outcome. [49][50][51] More studies are needed to establish that presymptomatic treatment improves long-term neurological and cognitive outcomes in SWS. In the meantime, however, these results strongly suggest that presymptomatic treatment can significantly delay seizure onset in these infants.…”

“…Presymptomatic treatment in tuberous sclerosis complex has been shown to improve seizure control and reduce the risk of intellectual disability 48 . Treatment during the presymptomatic phase in tuberous sclerosis complex sets precedence for presymptomatic treatment in other developmental epilepsy disorders, like SWS, where a high percentage of patients will have seizure onset in the first few years of life, and where early age of seizure onset has been repeatedly associated with worse neurological and developmental outcome 49–51 . More studies are needed to establish that presymptomatic treatment improves long‐term neurological and cognitive outcomes in SWS.…”

Genetic Advancements in Infantile Epileptic Spasms Syndrome and Opportunities for Precision Medicine

“…The location of tubers is quite heterogeneous, and a recent network analysis study showed that, while no single location was associated with the development of IESS, over 95% of tubers in patients with spasms had functional connectivity with the globi pallidi and cerebellar vermis [ 76 ]. Another mechanism involved in IESS pathophysiology in this patient population is abnormal GABAergic neurotransmission; previous studies have shown dysregulation of interneuron generation as well as a delay in the maturation of GABAergic networks [ 77 ]. Vigabatrin, a GABA–transaminase inhibitor, is known to be particularly efficacious in TSC patients; in addition to elevating brain GABA levels by inhibiting enzymatic degradation of this substrate, it also inhibits mTOR pathway activity specifically [ 77 ].…”

“…Another mechanism involved in IESS pathophysiology in this patient population is abnormal GABAergic neurotransmission; previous studies have shown dysregulation of interneuron generation as well as a delay in the maturation of GABAergic networks [ 77 ]. Vigabatrin, a GABA–transaminase inhibitor, is known to be particularly efficacious in TSC patients; in addition to elevating brain GABA levels by inhibiting enzymatic degradation of this substrate, it also inhibits mTOR pathway activity specifically [ 77 ].…”

“…The first two therapies focus on broadly targeting the immune-mediated pathogenesis of IESS, while vigabatrin targets the GABAergic network involved in the development of spasms. Based on multiple studies, vigabatrin is noted to be particularly efficacious in the TSC patient population and is considered the first choice of treatment in this group [ 77 ]. Importantly, current pharmacologic treatment modalities have a high rate of relapse after initial response; for instance, various studies assessing ACTH treatment found relapse rates ranging from 15 to 34% [ 6 ].…”