Review articleManagement of epilepsy associated with tuberous sclerosis complex: Updated clinical recommendations
Introduction
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the occurrence of multiple hamartomas in different organs, mainly in the central nervous system. In TSC, mutations of TSC1 or TSC2 cause suppression of mTOR inhibition producing excessive activation of the mTOR signaling pathway and several abnormalities in cell cycle regulation and control.1 Epilepsy is the most prevalent and clinically challenging manifestation of TSC, affecting approximately 85% of patients; infantile spasms are often followed by other seizure types, leading to refractory epilepsy in up to 75% of cases.2 Patients with tuberous sclerosis can present with almost any seizure type including tonic, atonic or tonic-clonic seizures, with about two-thirds having refractory focal-onset epilepsy; focal seizures and epileptic spasms are the most prevalent.3 Seizure onset in the majority of TSC patients occurs before 2 years of age3, 4 and during the first year of life in 62.5–73% of cases.3, 5 Among patients with infantile spasms, 75.4% in one retrospective series developed refractory epilepsy compared with 39.8% without a history of infantile spasms (P < 0.0001).3
Patients with TSC also are at high risk for neurodevelopmental disorders, described as tuberous sclerosis-associated neuropsychiatric disorders (TAND),6 which are strongly related to refractory epilepsy and infantile seizures7, 8, 9 as well as early seizure onset (Fig. 1).10, 11 Specifically, patients TSC and early onset of seizures — especially infantile spasms — experience greater impairment in intellectual development than those without seizures10 and the early appearance of seizures usually results in severe forms of intellectual disability.11
The goal of epilepsy treatment in tuberous sclerosis is to prevent or control seizures as soon as possible after TSC diagnosis, which may improve cognitive neurodevelopment and will enhance quality of life. Cusmai et al. retrospectively evaluated the long-term outcomes of 44 infants with TSC presenting with seizures in the first 12 months who were treated with vigabatrin and were followed for at least 3.5 years.12 At the final evaluation, 55% of patients were still having seizures, 80% had intellectual disability, and 30% had autism. Importantly, early treatment (<1 week) with vigabatrin after seizure onset was accompanied by improved seizure control compared with later treatment (>3 weeks; P < 0.01). Jóźwiak et al. reported two groups of patients with recently diagnosed TSC; one group (n = 31) received standard antiepileptic therapy following the onset of seizures and the other group was treated preventively before seizure onset (n = 14).13 At 24 months of age, intellectual disability was significantly more frequent and severe in the standard treatment group compared with the preventive group (48% vs. 14%, P = 0.031; mean IQ score 68.7 vs. 92.3, P < 0.05).
Clinical recommendations for the management of epilepsy in patients with TSC were published in 2012.14 Since that time, novel studies, reports and expert opinions in preclinical and clinical TSC-related sciences prompted the need for updated recommendations including the potential role of predictive biomarkers, the possible benefits of presymptomatic diagnosis and preventive treatment, and new treatment options including mTOR inhibitors. Accordingly, a consensus meeting was convened in September 2017 to review what had been reported and what had changed in the management of TSC-associated epilepsy since publication of the 2012 clinical recommendations.14 The overall goal of the meeting was to revise and update the clinical recommendations for management of TSC-associated epilepsy. A panel of 15 experts from 11 European countries (Appendix) reviewed the recent literature to answer specific questions, and five experts presented the findings, followed by a general discussion during which all issues were independently reviewed and debated to achieve consensus regarding recommendations. A draft manuscript based on these discussions and recommendations was then circulated several times among the panelists, who added their own comments. All the panelists/authors agreed with the final manuscript, which was then submitted for publication.
The panel addressed epileptogenesis and the need for early diagnosis of TSC-associated seizures, particularly to assess the predictive value of early electroencephalographic (EEG) monitoring for epilepsy in TSC. The panel also considered the potential benefit of vigabatrin in children with subclinical epileptiform EEG discharges as well as other AEDs and the role of adjunctive everolimus for refractory TSC-associated seizures. In addition, the panel discussed epilepsy surgery, the ketogenic diet, and vagus nerve stimulation, particularly in cases of refractory TSC-associated seizures.
This review summarizes the issues discussed at the consensus meeting and provides updated clinical recommendations for currently available therapeutic options for TSC-associated epilepsy.
Section snippets
Epileptogenesis
“Epileptogenesis” originally referred to the time between an initial insult and the appearance of the first unprovoked seizure (also called the seizure-free latent period). However, mounting experimental evidence indicated that the cellular or network processes leading to seizures can progress even after an epilepsy diagnosis and may contribute to the progression of seizures.15, 16, 17, 18 Thus, according to this updated definition, epileptogenesis is a chronic process that can be triggered by
Recommendations, unanswered questions and future research
The need for early diagnosis of TSC-associated seizures is now well established, and early EEG monitoring and the policy of informing and educating parents to recognize seizures as soon as they appear has been adopted in some European countries. However, not all panelists agreed that EEG findings currently represent a biomarker for risk of epilepsy in infants with TSC. According to the experts' opinion, it is still disputable which EEG abnormalities predict the subsequent appearance of epilepsy
Conclusions
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Investing in education and awareness to promote early recognition of infantile spasms and focal seizures in infants should be encouraged, and early diagnosis and treatment will be facilitated by regular EEG monitoring.
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The need for early and close clinical and video EEG monitoring is widely accepted to identify seizure susceptibility and recognize seizures. EEG has a good predictive value for epilepsy in TSC, and early treatment based on EEG monitoring significantly improves the outcomes of
Disclosures
The author(s) have no relevant disclosures related to this manuscript. The meeting was supported by an unrestricted educational grant by Novartis, including honoraria and travel expenses for panelists. The authors did not receive honoraria related to the preparation of this manuscript and were fully responsible for content and editorial decisions. Paolo Curatolo, Rima Nabbout, Lieven Lagae, Eleonora Aronica, Martha Feucht, Christoph Hertzberg, Anna Jansen, Floor Jansen, Katarzyna Kotulska,
Conflicts of interest
The author(s) have no relevant disclosures related to this manuscript.
Paolo Curatolo, Rima Nabbout, Lieven Lagae, Eleonora Aronica, Martha Feucht, Christoph Hertzberg, Anna Jansen, Floor Jansen, Katarzyna Kotulska, Romina Moavero, and Sergiusz Jóźwiak were partly financed by the European Community's Seventh Framework Programme (FP7/2007-2013; EPISTOP, grant agreement No. 602391). Sergiusz Jozwiak was also founded by the Polish Ministerial funds for science (2014-2018) for the implementation of
Acknowledgements
The authors received writing/editorial support in the preparation of this manuscript by Life Science Praxis, funded by Novartis.
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