The European
Commission has
approved
everolimus as
an adjunctive
treatment for
patients with
refractory partial-
onset seizures
associated with
TSC over the age
of two years
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
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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
be considered. There are very limited but promising
data for this non-pharmacological option, which seems
to act with a partial inhibition of mTOR complex. 17
In the few available studies, more than 50% seizure
reduction has been reported in 90% of cases. 18
mTOR inhibition
The identification of a specific molecular pathway
underlying epilepsy in TSC paved the way for
evaluating the efficacy and safety of available mTOR
inhibitors (rapamycin and its analogue everolimus)
in TSC-related epilepsy. Previously available
treatment options for epilepsy in TSC only provided
a symptomatic treatment for seizures, whereas these
drugs act on TSC pathogenesis, even presenting
the potential of representing a disease-modifying
systemic therapy.
A first prospective, multicentre Phase I/II study
enrolled 20 patients, and 72% of the 18 individuals
completing the 48 months observation showed
a ≥50% reduction in seizure frequency. 19,20 In
a German clinical series, 57% of enrolled children
showed 25–100% of seizure frequency reduction
with adjunctive everolimus. 21 In another small
study focusing on children and adolescents, 71%
of subjects treated with 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 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
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
32 | Issue 90 | 2018 | hospitalpharmacyeurope.com
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
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, parallel-
group, 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.
(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 focal-
onset seizures associated with
tuberous sclerosis (EXIST-3):
a phase 3, randomised, double-
blind, 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
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