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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 .
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