Sustained reduction in seizure frequency with adjunctive everolimus for treatment-refractory seizures associated with tuberous sclerosis complex (TSC) in children under 6 years of age: Results from the phase 3 EXIST-3 extension phase

2017 ◽  
Vol 21 ◽  
pp. e33
Author(s):  
P. Curatolo ◽  
D.N. Franz ◽  
J.A. Lawson ◽  
Z. Yapici ◽  
H. Ikeda ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Seizure Frequency ◽  
Tuberous Sclerosis Complex ◽  
Extension Phase ◽  
Phase 3 ◽  
Sustained Reduction ◽  
Refractory Seizures ◽  
Treatment Refractory

Everolimus Reduces Seizure Frequency in Tuberous Sclerosis Complex

2017 ◽  
Vol 48 (S 01) ◽  
pp. S1-S45
Author(s):  
T. Stapper ◽  
D. Valcheva ◽  
T. Höll ◽  
T. Rosenbaum
Keyword(s):  
Tuberous Sclerosis ◽  
Seizure Frequency ◽  
Tuberous Sclerosis Complex

Treatment of medically refractory seizures with responsive neurostimulation: 2 pediatric cases

2018 ◽  
Vol 21 (4) ◽  
pp. 421-427 ◽  
Author(s):  
Malgosia A. Kokoszka ◽  
Fedor Panov ◽  
Maite La Vega-Talbott ◽  
Patricia E. McGoldrick ◽  
Steven M. Wolf ◽  
...  
Keyword(s):  
Seizure Frequency ◽  
Therapeutic Benefit ◽  
Adjunctive Treatment ◽  
Type I ◽  
Seizure Focus ◽  
Off Label ◽  
Parietal Lobes ◽  
Intractable Seizures ◽  
Sustained Reduction ◽  
Refractory Seizures

The responsive neurostimulation (RNS) system, an adjunctive treatment for pharmacoresistant partial-onset seizures with 1 or 2 foci, has been available to patients aged 18 years or older since the device’s FDA approval in 2013. Herein, the authors describe their off-label application of this technology in 2 pediatric patients and the consequent therapeutic benefit without surgical complications or treatment side effects. A 14-year-old nonambulatory, nonverbal male with severe developmental delay was considered for RNS therapy for medically and surgically refractory epilepsy with bilateral seizure onsets in the setting of a normal radiological examination and a known neuropathological diagnosis of type I cortical dysplasia. The RNS system was implanted with strip electrodes placed on the left lateral frontal and right lateral temporal neocortex. At 19 months’ follow-up, cortical stimulation resulted in sustained reduction in both seizure frequency—3 seizures per day down from 15 to 30 per day—and seizure severity. The patient subsequently underwent a trial of corticothalamic stimulation with a right temporal cortical strip and a left thalamic depth electrode, which resulted in a further 50% reduction in seizure frequency. In a second case, a 9-year-old right-handed female with radiological evidence of a small watershed infarct on the left and medically refractory seizures was referred for presurgical evaluation. Invasive monitoring revealed an unresectable seizure focus in the eloquent cortex of the left posterior frontal and parietal lobes. The RNS device was implanted with cortical leads placed at the putative seizure focus. At 21 months after surgery, the patient had been seizure free for 4 months, following a 17-month period in which the seizure frequency had decreased from 12 per month to 2 per month, with associated functional and behavioral improvement. The authors’ results suggest that RNS may be a palliative option for children with intractable seizures whose condition warrants off-label use of the surgical device. The improved therapeutic effect noted with time and sustained RNS treatment points to a possible neuromodulatory effect.

scholarly journals Everolimus for treatment-refractory seizures in TSC

2018 ◽  
Vol 8 (5) ◽  
pp. 412-420 ◽  
Author(s):  
David N. Franz ◽  
John A. Lawson ◽  
Zuhal Yapici ◽  
Hiroko Ikeda ◽  
Tilman Polster ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Open Label ◽  
Median Percentage ◽  
The Core ◽  
Open Label Extension ◽  
Core Phase ◽  
Refractory Seizures ◽  
Treatment Refractory ◽  
Over Time

BackgroundEXamining everolimus In a Study of Tuberous sclerosis 3 (EXIST-3) demonstrated significantly reduced seizure frequency (SF) with everolimus vs placebo. In this study, we evaluate the long-term efficacy and safety of everolimus for tuberous sclerosis complex (TSC)-associated treatment-refractory seizures.MethodsAfter completion of the core phase, patients could enter an open-label extension phase and receive everolimus (target exposure, 3–15 ng/mL) for ≥48 weeks. Efficacy end points included change from baseline in average weekly SF expressed as response rate (RR, ≥50% reduction) and median percentage reduction (PR).ResultsOf 366 patients, 361 received everolimus in core/extension phases. The RR was 31% (95% CI, 26.2–36.1; N = 352) at week 18, 46.6% (95% CI, 40.9–52.5; N = 298) at 1 year, and 57.7% (95% CI, 49.7–65.4; N = 163) at 2 years. Median PR in SF was 31.7% (95% CI, 28.5–36.1) at week 18, 46.7% (95% CI, 40.2–54) at 1 year, and 56.9% (95% CI, 50–68.4) at 2 years. Ninety-five patients (26.3%) discontinued everolimus before 2 years; 103 (28.5%) had <2 years of follow-up at study cutoff, and 40% were exposed to everolimus for ≥2 years. An analysis classifying discontinued patients as nonresponders showed an RR of 30.2% (95% CI, 25.5–35.2; N = 361) at week 18, 38.8% (95% CI, 33.7–44.1; N = 358) at 1 year, and 41% (95% CI, 34.6–47.7; N = 229) at 2 years, suggesting sustained benefit over time. The incidence of grade 3/4 adverse events (AEs) (any cause) was 40.2%, and 13% discontinued because of AEs (pneumonia [1.7%] and stomatitis [1.4%]). Two deaths were suspected to be treatment-related (pneumonia and septic shock).ConclusionsSustained reductions in TSC-associated treatment-refractory seizures over time were achieved with adjunctive everolimus. The safety profile was consistent with the core phase with no new safety concerns.Classification of evidenceThis study provides Class IV evidence that long-term everolimus therapy reduces SF in patients with TSC-associated treatment-refractory seizures.

scholarly journals Everolimus dosing recommendations for tuberous sclerosis complex-associated refractory seizures

Epilepsia ◽  
2018 ◽  
Vol 59 (6) ◽  
pp. 1188-1197 ◽  
Author(s):  
David N. Franz ◽  
John A. Lawson ◽  
Zuhal Yapici ◽  
Christian Brandt ◽  
Michael H. Kohrman ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Refractory Seizures

scholarly journals The Putative Role of mTOR Inhibitors in Non-tuberous Sclerosis Complex-Related Epilepsy

2021 ◽  
Vol 12 ◽  
Author(s):  
Hannah E. Goldstein ◽  
Jason S. Hauptman
Keyword(s):  
Tuberous Sclerosis ◽  
Seizure Frequency ◽  
Tuberous Sclerosis Complex ◽  
Refractory Epilepsy ◽  
Mtor Inhibitors ◽  
Serine Threonine Kinase ◽  
Cortical Dysplasias ◽  
Highly Correlated ◽  
Medically Refractory Epilepsy

Epilepsy affects ~5 out of every 10,000 children per year. Up to one-third of these children have medically refractory epilepsy, with limited to no options for improved seizure control. mTOR, a ubiquitous 289 kDa serine/threonine kinase in the phosphatidylinositol 3-kinase (PI3K)-related kinases (PIKK) family, is dysregulated in a number of human diseases, including tuberous sclerosis complex (TSC) and epilepsy. In cell models of epilepsy and TSC, rapamycin, an mTOR inhibitor, has been shown to decrease seizure frequency and duration, and positively affect cell growth and morphology. Rapamycin has also been shown to prevent or improve epilepsy and prolong survival in animal models of TSC. To date, clinical studies looking at the effects of mTOR inhibitors on the reduction of seizures have mainly focused on patients with TSC. Everolimus (Novartis Pharmaceuticals), a chemically modified rapamycin derivative, has been shown to reduce seizure frequency with reasonable safety and tolerability. Mutations in mTOR or the mTOR pathway have been found in hemimegalencephaly (HME) and focal cortical dysplasias (FCDs), both of which are highly correlated with medically refractory epilepsy. Given the evidence to date, a logical next step is to investigate the role of mTOR inhibitors in the treatment of children with medically refractory non-TSC epilepsy, particularly those children who have also failed resective surgery.

scholarly journals Rapamycin Reduces Seizure Frequency in Tuberous Sclerosis Complex

2009 ◽  
Vol 24 (4) ◽  
pp. 477-477 ◽  
Author(s):  
Jennifer Muncy ◽  
Ian J. Butler ◽  
Mary Kay Koenig
Keyword(s):  
Tuberous Sclerosis ◽  
Seizure Frequency ◽  
Tuberous Sclerosis Complex
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