HHE 2018 | Page 120

everolimus showed a reduction in seizure frequency ≥50 %. 22
Furthermore, a recent open-label, single centre study enrolled 15 patients under the age of 18 years and found a responder rate of 80 %( 12 / 15), with 58 % of patients( 7 / 12) seizure-free. 23 Positive results have also been obtained in a randomised controlled trial evaluating efficacy of everolimus in 23 children, with 75 % of them showing a ≥50 % reduction in seizure frequency. 24
A Phase III, double-blind, placebo-controlled study( Examining Everolimus in a Study of Tuberous Sclerosis Complex; EXIST-3), compared the efficacy and safety of two dosing regimens of add-on everolimus versus placebo in patients with TSC and refractory focal epilepsy. 25 This study included an initial 8-week baseline
Based on the positive results of this trial, the European Commission approved everolimus as an adjunctive treatment for patients with refractory partial-onset seizures associated with TSC over the age of two years
phase, followed by an 18-week core phase and a 48-week extension phase. During the core phase with 366 patients enrolled, a greater reduction in seizure frequency was obtained with the two targeted exposure ranges of everolimus( 3 – 7ng / ml and 9 – 15ng / ml) in comparison with placebo. The response rate, defined as a seizure frequency reduction ≥50 %, was 15.1 % in the placebo group, 28.2 % in the low-exposure everolimus group, and 40.0 % in the high-exposure everolimus group. Everolimus-related adverse events were quite common but based on the positive results of this trial, the European Commission approved everolimus as an adjunctive treatment for patients with refractory partial-onset seizures associated with TSC over the age of two years.
Future perspectives Despite all the recent progress and the introduction of new anti-epileptic drugs, the management of TSC-related epilepsy still represents a real challenge for clinicians, with about two-thirds of patients presenting refractory seizures. 3
Neuropsychiatric comorbidity also represents a significant burden; therefore timing of treatment is crucial. Also considering that TSC can be increasingly diagnosed before or soon after birth, before any neurological symptoms appear, a preventive anti-epileptic treatment before the onset of seizures has been proposed. This was aimed to try to minimise the impact of early onset seizures; 26 however, actual evidence is still insufficient to recommend this treatment approach. Two trials are undergoing to try to solve this issue: EPISTOP( Long-term, prospective study evaluating clinical and molecular biomarkers of EPIleptogenesiS in a genetic model of epilepsy – Tuberous sclerOsis complex); and PREVeNT( Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex). The EPISTOP trial – a long-term, prospective, randomised, parallelgroup, triple-masked( participant, care provider, and investigator) multicentre European study tracking epileptogenesis, epilepsy and neurodevelopment in infants with TSC – has as a primary objective the identification of the clinical and molecular biomarkers of epileptogenesis in patients with TSC. The secondary objective is to compare the effects of administration of standard antiepileptic treatment after presentation with clinical seizures versus preventive treatment after recorded epileptiform EEG discharges without seizures. The PREVeNT trial is a randomised, triple-blind( participant, care provider, and investigator), placebo-controlled study of infants with TSC having the developmental impact of early versus delayed treatment with vigabatrin as primary outcome.
Hopefully the results of these studies will provide some practical tips to suggest the best time to initiate treatment to guarantee an optimal treatment approach for all infants with a pre-symptomatic diagnosis of TSC.
References 1 Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008; 372( 9639): 657 – 68. 2 Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol 2015; 14( 7): 733 – 45. 3 Chu-Shore CJ et al. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia 2010; 51( 7): 1236 – 41. 4 Prabowo AS et al. Fetal brain lesions in tuberous sclerosis complex: TORC1 activation and inflammation. Brain Pathol 2013; 23( 1): 45 – 59. 5 Crino PB. Molecular pathogenesis of tuber formation in tuberous sclerosis complex. J Child Neurol 2004; 19( 9): 716 – 25. 6 Curatolo P. Mechanistic target of rapamycin( mTOR) in tuberous sclerosis complex-associated epilepsy. Pediatr Neurol 2015; 52( 3): 281 – 9. 7 Curatolo P et al. mTOR
dysregulation and tuberous sclerosis-related epilepsy. Expert Rev Neurother 2018; 18( 3): 185 – 201. 8 Widjaja E et al. Diffusion tensor imaging identifies changes in normal-appearing white matter within the epileptogenic zone in tuberous sclerosis complex. Epilepsy Res 2010; 89( 2-3): 246 – 53. 9 Moavero R et al. White matter disruption is associated with persistent seizures in tuberous sclerosis complex. Epilepsy Behav 2016; 60:63 – 7. 10 Chiron C et al. Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Res 1997; 26( 2): 389 – 95. 11 Bombardieri R et al. Early control of seizures improves long-term outcome in children with tuberous sclerosis complex. Eur J Paediatr Neurol 2010; 14:146 – 9. 12 Cusmai R et al. Long-term
neurological outcome in children with early-onset epilepsy associated with tuberous sclerosis. Epilepsy Behav 2011; 22( 4): 735 – 9. 13 Zhang B et al. Vigabatrin inhibits seizures and mTOR pathway activation in a mouse model of tuberous sclerosis complex. PLoS One 2013; 8( 2): e57445. 14 Curatolo P et al. Management of epilepsy associated with tuberous sclerosis complex( TSC): clinical recommendations. Eur J Paediatr Neurol 2012; 16( 6): 582 – 6. 15 Wu JY et al. Noninvasive testing, early surgery, and seizure freedom in tuberous sclerosis complex. Neurology 74( 5): 392 – 8. 16 Zamponi N et al. Vagus nerve stimulation for refractory epilepsy in tuberous sclerosis. Pediatr Neurol 2010; 43( 1): 29 – 34. 17 McDaniel SS et al. The ketogenic diet inhibits the mammalian target of rapamycin( mTOR) pathway. Epilepsia
2011; 52( 3): e7 – 11. 18 Kossoff EH et al. Tuberous sclerosis complex and the ketogenic diet. Epilepsia 2005; 46( 10): 1684 – 6. 19 Krueger DA et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol 2013; 74( 5): 679 – 87. 20 Krueger DA et al., Long-term treatment of epilepsy with everolimus in tuberous sclerosis. Neurology 2016; 87( 23): 2408 – 15. 21 Wiegand G et al. Everolimus in tuberous sclerosis patients with intractable epilepsy: a treatment option? Eur J Paediatr Neurol 2013; 17( 6): 631 – 8. 22 Cardamone M et al. Mammalian target of rapamycin inhibitors for intractable epilepsy and subependymal giant cell astrocytomas in tuberous sclerosis complex. J Pediatr 2014; 164( 5): 1195 – 200. 23 Samueli S et al. Efficacy and safety of everolimus in children with TSC-associated
epilepsy – Pilot data from an open single-center prospective study. Orphanet J Rare Dis 2016; 11( 1): 145. 24 Overwater IE et al. Sirolimus for epilepsy in children with tuberous sclerosis complex: A randomized controlled trial. Neurology 2016; 87( 10): 1011 – 18. 25 French JA et al. Adjunctive everolimus therapy for treatment-resistant focalonset seizures associated with tuberous sclerosis( EXIST-3): a phase 3, randomised, doubleblind, placebo-controlled study. Lancet 2016; 388( 10056): 2153 – 63. 26 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( 5): 424 – 31.
120
HHE 2018 | hospitalhealthcare. com