Epilepsy Mechanisms in Neurocutaneous Disorders: Tuberous Sclerosis Complex, Neurofibromatosis Type 1, and Sturge–Weber Syndrome

Abstract

Neurocutaneous disorders are multisystem diseases affecting skin, brain, and other organs. Epilepsy is very common in the neurocutaneous disorders, affecting up to 90% of patients with tuberous sclerosis complex (TSC) and Sturge–Weber syndrome (SWS), for example. The mechanisms underlying the increased predisposition to brain hyperexcitability differ between disorders, yet some molecular pathways overlap. For instance, the mechanistic target of rapamycin (mTOR) signaling cascade plays a central role in seizures and epileptogenesis in numerous acquired and genetic disorders, including several neurocutaneous disorders. Potential routes for target-specific treatments are emerging as the genetic and molecular pathways involved in neurocutaneous disorders become increasingly understood. This review explores the clinical features and mechanisms of epilepsy in three common neurocutaneous disorders—TSC, neurofibromatosis type 1, and SWS.

Current concepts on epilepsy management in tuberous sclerosis complex

“…Experimental trails and clinical observations confirmed that inhibition of the mTOR pathway is an attractive therapeutic option, and that it may modify the process of epileptogenesis (Curatolo, 2015;Krueger et al, 2013;Sadowski, Kotulska-Jóźwiak, & Jóźwiak, 2015;Samueli et al, 2016;Stafstrom, Staedtke, & Comi, 2017 (French et al, 2016). The reduction of ≥50% in seizure frequency was significantly higher in patients treated…”

“…Experimental trails and clinical observations confirmed that inhibition of the mTOR pathway is an attractive therapeutic option, and that it may modify the process of epileptogenesis (Curatolo, 2015;Krueger et al, 2013;Sadowski, Kotulska-Jóźwiak, & Jóźwiak, 2015;Samueli et al, 2016;Stafstrom, Staedtke, & Comi, 2017). The largest prospective, randomized, multicenter, placebo-controlled study aiming at assessing the effect of Everolimus on seizure frequency in TSC patients with drug-resistant epilepsy (EXIST-3) documented a positive antiepileptic effect of Everolimus as additional antiepileptic therapy with tolerable safety profile (French et al, 2016).…”

Remodeled cortical inhibition prevents motor seizures in generalized epilepsy

“…We show that the aberrant sprouting of SOM‐INs is dependent on mTORC1 and that blocking mTORC1 signaling with rapamycin prevents this compensatory phenomenon and aggravates the seizure phenotype. Therefore, although mTOR inhibitors have been advocated as potential antiepileptogenic therapies for patients with genetic epilepsies associated with intrinsic hyperactivation of mTOR (such as in tuberous sclerosis), their use in other circumstances might actually prevent beneficial compensatory mechanisms and aggravate seizures.…”

Epilepsy genetics: Current knowledge, applications, and future directions

“…Another vascular disorder commonly associated with focal epilepsy is the recognizable Sturge‐Weber syndrome . The condition is characterized by facial hemangiomas, seizures, and in some, varying degrees of intellectual disability . Recently, somatic mutations in GNAQ were identified as a cause of nearly 80% to 90% of Sturge‐Weber cases .…”

“…98 The condition is characterized by facial hemangiomas, seizures, and in some, varying degrees of intellectual disability. 99 Recently, somatic mutations in GNAQ were identified as a cause of nearly 80% to 90% of Sturge-Weber cases. 100,101 Cerebral cavernous malformations (CCMs) are another vascular anomaly that can predispose to focal epilepsy, strokes, and other neurological deficits.…”