Handbook of Pediatric Electroencephalography by Veena Kander now on ICNApedia VLE

Clinical recommendations on management of epilepsy associated with Tuberous Sclerosis

TuberousSclerosis-RayerA report summarising the current treatment options and directions for future research in the management of epilepsy associated with Tuberous sclerosis complex (TSC) has been published in the European Journal of Paediatric Neurology 2012. The recommendations follow the TSC consensus meeting of European experts for SEGA and Epilepsy management in March 2012, Rome, Italy.


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.

Table 1.Treatment options in the management of epilepsy in patients with TSC.
Treatment Limitations

AED: Vigabatrin

  • First line intervention for TSC associated seizures
  • Response to low-dose therapy initiated early after onset of focal seizures or spasms is rapid and high10,11
  • Possible first line in focal seizures before age 1 although more effective in seizures originating in the parieto-occipital lobes10
  • Ophthalmological toxicity

AED: Combination therapy

  • Second line therapy when AED monotherapy has failed10
  • Combinations addressing multiple seizure mechanisms are most suitable, particularly AEDs that enhance GABAergic inhibition10
  • Careful selection required to achieve maximal synergy with minimal unfavourable interactions and toxicity10


  • Appropriate in TSC-associated epilepsy that is inadequately controlled after trials of 2 AEDs, and for well-defined lesions10,15
  • Data is limited but indicates that 25-90% of patients are seizure-free after surgery10,16
  • Tailored surgical resection of epileptogenic foci stopped seizures in 57% of drug-resistant patients and improved seizure frequency by > 90% in another 18%17
  • Multifocal lesions do not exclude a presurgical assessment when seizures onset is unifocal
  • Success is increased by early intervention and accurate localization of the epileptogenic region 10,16
  • Patients with multiple, and biolateral epileptic foci are not amenable to surgery
  • Seizures recur in one-third of the patients17

Vagus Nerve Stimulation

  • Data is limited but a significant reduction in seizure frequency has been reported18,19
  •  Seizure-free status is very rare

Ketogenic Diet

  • Should be considered in patients in whom AEDs have failed and when surgery is not appropriate20
  • In one small study, 92% of children had a >50% reduction in seizures at 6 months and 67% had a >90% reduction at 5 months20
  •  Growth of SEGA occasionally observed

AED: mTOR inhibitors

  • Data on prevention and treatment of seizures from animal studies are promising3,12,13
  • In a heterozygous animal model of TSC, learning deficits were reduced14
  • Preliminary Phase II data showed that everolimus treatment is able to decrease seizure frequency9
  • Animal studies: possible detrimental effect on brain injury repair
  • Human studies: drug interactions
  • Human studies: long-term safety concerns3

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?


The authors have no relevant disclosures related to this manuscript.


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.


1. Jozwiak J, et al. Possible mechanisms of disease development in tuberous sclerosis. Lancet Oncol 2008;9:73e9.
2. Curatolo P, et al. Tuberous sclerosis. Lancet 2008;372(9639):657e68.
3. Wong M. Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: from tuberous sclerosis to common acquired epilepsies. Epilepsia 2010;51:27e36.
4. Napolioni V, et al. Recent advances in neurobiology of tuberous sclerosis complex. Brain Dev 2009;31:104e13.
5. Chu-Shore CJ, et al. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia 2010;51:1236e41.
6. Cusmai R, et al. Topographic comparative study of magnetic resonance imaging and electroencephalography in 34 children with tuberous sclerosis. Epilepsia 1990;31:747e55.
7. O'Callaghan FJ, et al. The relation of infantile spasms, tubers, and intelligence in tuberous sclerosis complex. Arch Dis Child 2004;89:530e3.
8. Jansen FE, et al. Overlapping neurologic and cognitive phenotypes in patients with TSC1 or TSC2 mutations. Neurology 2008;70:908e15.
9. Krueger DA, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010;363:1801e11.
10. Moavero R, et al. Epilepsy secondary to tuberous sclerosis: lessons learned and current challenges. Childs Nerv Syst 2010;26:1495e504.
11. Hancock E, Osborne JP. Vigabatrin in the treatment of infantile spasms in tuberous sclerosis: literature review. J Child Neurol 1999;14:71e4.
12. Zeng LH, et al. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol 2008;63:444e53.
13. Ljungberg MC, et al. Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of cortical dysplasia. Dis Model Mech 2009;2:389e98.
14. Ehninger D, et al. Reversal of learning deficits in a Tsc2þ/# mouse model of tuberous sclerosis. Nat Med 2008;14:843e8.
15. Guerreiro MM, et al. Surgical treatment of epilepsy in tuberous sclerosis: strategies and results in 18 patients. Neurology 1998;51:1263e9.
16. Wu JY, et al. Noninvasive testing, early surgery, and seizure freedom in tuberous sclerosis complex. Neurology 2010;74:392e8.
17. Jansen FE, et al. Epilepsy surgery in tuberous sclerosis: a systematic review. Epilepsia 2007;48:1477e84.
18. Major P, Thiele EA. Vagus nerve stimulation for intractable epilepsy in tuberous sclerosis complex. Epilepsy Behav 2008;13:357e60.
19. Elliott RE, et al. Refractory epilepsy in tuberous sclerosis: vagus nerve stimulation with or without subsequent resective surgery. Epilepsy Behav 2009;16:454e60.
20. Kossoff EH, et al. Tuberous sclerosis complex and the ketogenic diet. Epilepsia 2005;46:1684e6.
21. Yates JR. Tuberous sclerosis. Eur J Hum Genet 2006;14:1065e73.
22. Jozwiak S, et al. Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex. Eur J Paediatr Neurol 2011;15:424e31.
23. Bombardieri R, et al. Early control of seizures improves longterm outcome in children with tuberous sclerosis complex. Eur J Paediatr Neurol 2010;14:146e9.
24. Bialer M, et al. Progress report on new antiepileptic drugs: a summary of the Seventh Eilat Conference (EILAT VII). Epilepsy Res 2004;61:1e48.
25. Ascaso FJ, et al. Visual field defects in pediatric patients on vigabatrin monotherapy. Doc Ophthalmol 2003;107: 127e30.
26. Talos DM, et al. The interaction between early life epilepsy and autistic-like behavioral consequences: a role for the Mammalian Target of Rapamycin (mTOR) pathway. PLoS One 2012;7. e35885.
27. Muncy J, et al. Rapamycin reduces seizure frequency in tuberous sclerosis complex. J Child Neurol 2009; 24:477.
28. Perek-Polnik M, et al. Effective everolimus treatment of inoperable, life-threatening subependymal giant cell astrocytoma and intractable epilepsy in a patient with tuberous sclerosis complex. Eur J Paediatr Neurol 2012;16: 83e5.


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

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

BTS Guidelines for the Respiratory Management of C...
Inviting proposals for organizing symposia

Related Posts