Management of epilepsy associated with tuberous sclerosis complex (TSC)

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 TSCassociated 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 epileptiformactivity manifests depends onthe locationof the cortical tubers, andmay coincide with the functionalmaturation of the cortex.⁶ Infantile spasms, the other major type of early seizures in TSC, might precede, coexist or followfocal seizures during the firstmonths.² Almost all patients with infantile spasms develop another seizure phenotype, andmore than half developmultiple 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 TSC1mutation.

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 themanagement 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-thirdof thepatients remainresistant to therapy.Amongthe 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 patientswith 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. ^2.

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.Clinical recommendations

3.1. 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 earlyonset 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 spasmsmay be crucial in reducing the gap between seizure onset and diagnosis.

Close EEG monitoring during the first months of life allows early detection of electroencephalographic seizures and allows consideration of preventive treatment. Asleep and awake EEG monitoring should be performed every month for the first 6months and then every 6-8 weeks unless there are other abnormalities.

Data available is insufficient to suggest risk factors for progression from focal seizures to infantile spasms; potentially relevant factors include a large number of tubers, cystic-like tubers, and TSC2 mutation.

3.2.Timing of treatment initiation

Existing data is insufficient in supporting preventive treatment without documented seizures. However, treatment should be initiated, in infants and children within 24 months of life if ictal discharges occur, with or without clinical manifestations.

3.3. General treatment recommendations

AED treatment is age related and could differ for infantile spasms and focal seizures. Treatment also depends on the epileptic syndrome and seizure type. AED combinations should be carefully selected to achieve maximal synergy with minimal unfavourable pharmacokinetic interactions and toxicity.

AEDs with multiple mechanisms of action (e.g. topiramate) are preferred because they cover more seizure mechanisms. Complicated AED combinations rarely provide an additional benefit and can be associated with toxicity.^10,24

Treatment for infantile spasms

First line: vigabatrin is the first-line therapy for infantile spasms with TSC. Visual field constriction can develop,²⁵ however, the catastrophic sequelae of infantile spasms and the good response to vigabatrin support this treatment choice. Prescription should be made with the awareness of possible side-effects and how to minimise them (i.e. low doses for brief periods)

Second line: corticosteroids/hormonal therapy if hypsarrythmia is present, topiramate if no hypsarrythmia but focal/multifocal abnormalities are present

Third-line: ketogenic diet, other AEDs e Surgery: should be considered early because a focus or a limited lesion as dysplasia might manifest as infantile spasms

Treatment for focal seizures

First line: vigabatrin for focal seizures before the age of 1 year. OtherAEDsthatenhanceGABAergic inhibition (e.g. topiramate and carbamazepine) after the age of 1 year

Second line: surgery (success depends on accurate localization of the epileptic focus)

Third line: ketogenic diet, vagus nerve stimulation, other AEDs used in focal seizures e Drop attacks and tonic seizures: vagus nerve stimulation, rufinamide e Lennox-Gastaut syndrome: rufinamide

3.4. Surgery

• Surgery should be considered early in patients with drugresistant epilepsy, despite treatment with two AEDs.
• Surgery is usually restricted to those with focal stereotypical seizures and a single EEG focus.
• Even focal lesions can give rise to bilateral seizures and infantile spasms, so surgery should still be considered in these patients.
• Surgery is contraindicated in the case of multiple seizure types, but should be considered if there is a predominant seizure type that alters the quality of life.
• Non-invasive recording might be sufficient when surgery is for a single lesion with clear correlation between EEG, clinical presentation and MRI findings.
• Invasive recording is needed when there is no clear correlation between EEG and MRI findings, and when multiple seizure types are present. Invasive recording is associated with good surgical results, and 76% of the patients remain seizure-free.

3.5. Vagus nerve stimulation

Data is limited but indicate that while many patients respond to this approach, almost none become seizure-free.^18,19 This approach can be combined with a ketogenic diet, particularly in drug-resistant patients who are not amenable to surgery.

3.6. Ketogenic diet

Ketogenic diet can be an effective option, particularly in infancy and early childhood in patients in whom surgery is not appropriate.²⁰

3.7. mTOR inhibitors

In animal models: mTOR inhibitors have shown promise as potential anti-seizure agents, including reducing spasms, and improving learning and autistic behaviour.^12,26 In humans: Data on reduction in seizures from a phase II study (assessing the efficacy on SEGA) and case report are promising. ^9,27,28

A Phase II study assessing the efficacy of everolimus on seizures in patients with TSC is currently ongoing (NCT01070316; www.clinicaltrials.gov).

The available preclinical and clinical data suggest that mTOR inhibitor treatment may need to be continuous and long-term to maintain seizure control.^3,9 Questions about the long-term safety of mTOR inhibitors remain, mainly on a young children group.³ Ongoing Phase II and Phase III studies will highlight the benefit and safety profile of this alternative therapeutic option.

3.8. Outstanding questions and directions for future research

1. A number of questions remain unanswered; these points provide guidance for the future direction of research and multicentre clinical studies:
2. Which tubers are likely to become epileptogenic?
3. What are the risk factors for early seizures, and for infantile spasms?
4. What is the process of evolution from focal seizures to infantile spasms?
5. Should AED therapy be withdrawn in patients who are seizure- or spasm-free?
6. Are there any predictive markers for treatment resistance? " What are the criteria for early surgical treatment?
7. Why is tuber removal sometimes not enough and why is surgery sometimes unsuccessful?
8. What is the role of mTOR inhibition in the therapeutic algorithm of TSC-associated epilepsy?

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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Appendix.

Participants in the TSC Consensus Meeting for SEGA and Epilepsy Management, 12 March 2012, Rome, Italy.

Chairs
Paolo Curatolo,Italy
Sergiusz Jo´ !zwiak,Poland
Rima Nabbout,France

Participants (in alphabetic order)

Miraude Adriaensen,Netherlands
Moncef Berhou, France
Giangennaro Coppola,Italy
Dana Craiu,Romania
Raffaella Cusmai,Italy
Olivier Delalande,France
Anne De Saint Martin,France
Pablo Herna´ iz Driever,Germany
Martine Fohlen,France
Wiesława Grajkowska,Poland
Christoph Hertzberg,Germany
Anna Jansen,Belgium
Floor Jansen,Netherlands
Katarzyna Kotulska,Poland
Marek Mandera,Poland
Romina Moavero,Italy
Finbar O’Callaghan,UK
Emmanuel Raffo,France
Bernard A. Zonnenberg Netherlands

Article published as a Review Article in European Journal of Paediatric Neurology 2012
Citation: Curatolo P, et al., Management of epilepsy associated with tuberous sclerosis complex (TSC): Clinical recommendations, European Journal of Paediatric Neurology (2012), doi:10.1016/j.ejpn.2012.05.004