Review of the treatment options for epilepsy in tuberous sclerosis complex: towards precision medicine

Abstract

Tuberous sclerosis complex (TSC) is a rare genetic disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that antagonise the mammalian isoform of the target of rapamycin complex 1 (mTORC1) – a key mediator of cell growth and metabolism. TSC is characterised by the development of benign tumours in multiple organs, together with neurological manifestations including epilepsy and TSC-associated neuropsychiatric disorders (TAND). Epilepsy occurs frequently and is associated with significant morbidity and mortality; however, the management is challenging due to the intractable nature of the seizures. Preventative epilepsy treatment is a key aim, especially as patients with epilepsy may be at a higher risk of developing severe cognitive and behavioural impairment. Vigabatrin given preventatively reduces the risk and severity of epilepsy although the benefits for TAND are inconclusive. These promising results could pave the way for evaluating other treatments in a preventative capacity, especially those that may address the underlying pathophysiology of TSC, including everolimus, cannabidiol and the ketogenic diet (KD). Everolimus is an mTOR inhibitor approved for the adjunctive treatment of refractory TSC-associated seizures that has demonstrated significant reductions in seizure frequency compared with placebo, improvements that were sustained after 2 years of treatment. Highly purified cannabidiol, recently approved in the US as Epidiolex® for TSC-associated seizures in patients ⩾1 years of age, and the KD, may also participate in the regulation of the mTOR pathway. This review focusses on the pivotal clinical evidence surrounding these potential targeted therapies that may form the foundation of precision medicine for TSC-associated epilepsy, as well as other current treatments including anti-seizure drugs, vagus nerve stimulation and surgery. New future therapies are also discussed, together with the potential for preventative treatment with targeted therapies. Due to advances in understanding the molecular genetics and pathophysiology, TSC represents a prototypic clinical syndrome for studying epileptogenesis and the impact of precision medicine.

Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies

“…hyperactivity and inattention TAND, e.g. range of cognitive, behavioural and psychiatric manifestations including intellectual disability, ASD, ADHD, anxiety, depressed mood, mood swings, obsessions, psychosis and hallucinations a A number of ASMs should be avoided for DS because they may exacerbate seizures, especially in children, sodium channel blockers (carbamazepine, eslicarbazepine acetate, lacosamide, lamotrigine, oxcarbazepine and phenytoin) and ASMs that act on GABA pathways (tiagabine, vigabatrin, gabapentin and pregabalin) b As specified in recent treatment guidance/reviews for DS [ 3 , 5 , 15 – 17 ], LGS [ 18 – 21 ] and TSC [ 2 , 22 – 26 ] c Predominantly in Germany and Japan d Licenced in the USA; undergoing regulatory approval in the European Union e Being evaluated for preventative treatment Bold indicates licenced in the USA and/or European Union…”

“…b As specified in recent treatment guidance/reviews for DS [ 3 , 5 , 15 – 17 ], LGS [ 18 – 21 ] and TSC [ 2 , 22 – 26 ]…”

“…Individuals with DEEs experience frequent severe seizures, often numerous times a day; the seizures can be of many different semiologies and they tend to be refractory to currently available anti-seizure medications (ASMs). Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS) and tuberous sclerosis complex (TSC) are classical examples of DEEs in which advances in the understanding of the underlying aetiology have translated through to the clinic with new drug approvals in recent years (Table 1) [2][3][4][5].…”

“…We have conducted a narrative review of the effects of ASMs on PBAEs, cognition, sedation and sleep, with a focus on ASMs used to treat DEEs/drug-resistant epilepsy (DRE), particularly DS, LGS and TSC, either as approved therapies (bold text in Table 1) or off-label (unbold text in Table 1), as specified in recent treatment guidance/reviews for DS [3,[15][16][17], LGS [18][19][20][21] and TSC [2,[22][23][24][25][26]. Studies of particular interest were those that included patients with DEE/DREs, especially studies whose main objective was to assess these specific outcomes, pooled safety analyses and meta-analyses (as rarer events may only become evident with such analyses), and data from real-world studies (as regulatory clinical trials can often exclude people with suicidal ideation and psychosis) [27,28].…”

“…However, because of differences in study designs and populations, it is not possible to make comparisons between the ASMs. In addition, most ASMs have a precautionary warning for an increased risk of suicidal behaviour and ideation; however, suicidal outcomes are not a specific focus of this As specified in recent treatment guidance/reviews for DS [3,5,[15][16][17], LGS [18][19][20][21] and TSC [2,[22][23][24][25][26] c…”