Review article
Management of epilepsy associated with tuberous sclerosis complex (TSC): Clinical recommendations

https://doi.org/10.1016/j.ejpn.2012.05.004Get rights and content

Abstract

Tuberous sclerosis complex (TSC) is a leading genetic cause of epilepsy. TSC-associated epilepsy generally begins during the first year of life, and is associated with neurodevelopmental and cognitive problems. Management is challenging and seizures tend to persist in a large proportion of patients despite pharmacological and surgical treatment. This report summarizes the clinical recommendations for the management of TSC-associated epilepsy made by a panel of European experts in March 2012. Current treatment options and outstanding questions are outlined.

Introduction

Tuberous sclerosis complex (TSC) is caused by inactivation of the tumour suppressor genes hamartin (TSC1) or tuberin (TSC2),1 and is an autosomal dominant genetic disorder affecting 1 in 6000 to 1 in 14,000 individuals.2 TSC proteins are involved in negative regulation of the mTOR pathway, which is involved in tumour cell proliferation and energy metabolism, cortical development and growth control.3, 4

In addition to causing tumours in the brain, heart, skin, eyes, kidney, lung, and liver, TSC is one of the leading genetic causes of epilepsy, with about 85% of TSC patients presenting with seizures that are often refractory to treatment.2, 5 TSC-associated epilepsy generally begins during the first year of life.5 This type of epilepsy is often focal initially; the seizure semiology and the age at which epileptiform activity manifests depends on the location of the cortical tubers, and may coincide with the functional maturation of the cortex.6 Infantile spasms, the other major type of early seizures in TSC, might precede, coexist or follow focal seizures during the first months.2 Almost all patients with infantile spasms develop another seizure phenotype, and more than half develop multiple seizure types.5 Early seizure onset, mainly infantile spasms, is associated with an increased risk of neurodevelopmental and cognitive problems.5, 7 TSC2 mutation tends to be associated with earlier seizure onset, a lower cognition index, more tubers, and a greater tuber load than TSC1 mutation. Cystic lesions may be more epileptogenic than other types of lesions. Seizures tend to start at an older age in familial TSC than in non-familial cases.8

Several options are available for the management of epilepsy in patients with TSC, including anti-epileptic drugs (AEDs), surgery, and (less commonly) ketogenic diet and vagus nerve stimulation. There is a lack of randomized trials for the management of TSC-associated epilepsy. Despite the current pharmacological and non-pharmacological treatment options, one-third of the patients remain resistant to therapy. Among the new treatment options under investigation, mTOR inhibitors provide a potential therapy based on the pathophysiology of TSC.2, 3 However, limited data is available for epilepsy-related endpoints (e.g. seizure frequency). In a 6-month study that included 28 patients with subependymal giant cell astrocytoma (SEGA), everolimus treatment resulted in clinically meaningful tumour reduction of at least 30% in 75% of the patients, while seizure frequency was reduced in 56% of the 16 patients evaluated with 24-h video EEG between inclusion and 6 months.9 Long-term studies are necessary to investigate seizure control, safety, and neuronal development with this class of agents.3, 9

Thus, the limited understanding of the disease and the potential for expanding treatment options provides an appropriate occasion for a consensus to be taken where clinical recommendations can be communicated. This paper summarizes the clinical recommendations, treatment options, and outstanding questions for the management of epilepsy in patients with TSC, made by a panel of European experts who met in Rome, Italy, in March 2012.

Section snippets

Treatment options

The goal of epilepsy treatment in TSC is to stop seizures as early as possible after diagnosis to optimize cognitive development and improve behaviour as well as the quality of life. Treatment options are outlined in Table 1.3, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20

Infants at risk for TSC-associated epilepsy

  • The diagnosis of TSC is made before seizure onset in a growing number of patients.21 All infants with a pre- or perinatal diagnosis are at a high risk of developing early-onset seizures. Early diagnosis and treatment are aimed to minimize the deleterious impact of early-onset seizures.22, 23

  • Parental education to aid early recognition of subtle focal seizures and infantile spasms may be crucial in reducing the gap between seizure onset and diagnosis. Close EEG monitoring during the first months

Disclosures

The authors have no relevant disclosures related to this manuscript.

Acknowledgments

The meeting was supported by an unrestricted educational grant from Novartis. The authors received writing/editorial support in the preparation of this manuscript provided by Marinella Calle, PhD, of Excerpta Medica, funded by Novartis. The authors did not receive honoraria related to the preparation of this manuscript and were fully responsible for content and editorial decisions for this manuscript.

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    d

    Participants listed in Appendix.

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