Long-term treatment of epilepsy with everolimus in tuberous sclerosis.
OBJECTIVE
To evaluate the long-term benefit and safety of everolimus for the treatment of medically refractory epilepsy in patients with tuberous sclerosis complex (TSC).


METHODS
Everolimus was titrated over 4 weeks and continued an additional 8 weeks in a prospective, open-label, phase I/II clinical trial design. Participants demonstrating initial benefit continued treatment until study completion (48 months). The primary endpoint was percentage of patients with a ≥50% reduction in seizure frequency compared to baseline. Secondary endpoints assessed absolute seizure frequency, adverse events (AEs), behavior, and quality of life.


RESULTS
Of the 20 participants who completed the initial study phase, 18 continued extended treatment. Fourteen of 18 (78%) participants completed the study, all but 1 of whom reported ≥50% reduction in seizure frequency at 48 months. All participants reported at least 1 AE, the vast majority (94%) of which were graded mild or moderate severity. Improvements in behavior and quality of life were also observed, but failed to achieve statistical significance at 48 months.


CONCLUSIONS
Improved seizure control was maintained for 4 years in the majority of patients with TSC with medically refractory epilepsy treated with everolimus. Long-term treatment with everolimus is safe and well-tolerated in this population. Everolimus may be a therapeutic option for refractory epilepsy in TSC.


METHODS
This study provides Class IV evidence that for patients with TSC with medically refractory epilepsy everolimus improves seizure control.
From the Departments of Pediatrics and Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.), University of Cincinnati College of Medicine; Division of Child Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.) and Pediatric Neurology (A.A.W., C.M.T.), Texas Children's Hospital, Baylor College of Medicine, Houston. krueger_darcy@cchmc.org.
Darcy A
DA
Krueger
From the Departments of Pediatrics and Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.), University of Cincinnati College of Medicine; Division of Child Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.) and Pediatric Neurology (A.A.W., C.M.T.), Texas Children's Hospital, Baylor College of Medicine, Houston.
Angus A
AA
Wilfong
From the Departments of Pediatrics and Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.), University of Cincinnati College of Medicine; Division of Child Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.) and Pediatric Neurology (A.A.W., C.M.T.), Texas Children's Hospital, Baylor College of Medicine, Houston.
Maxwell
M
Mays
From the Departments of Pediatrics and Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.), University of Cincinnati College of Medicine; Division of Child Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.) and Pediatric Neurology (A.A.W., C.M.T.), Texas Children's Hospital, Baylor College of Medicine, Houston.
Christina M
CM
Talley
From the Departments of Pediatrics and Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.), University of Cincinnati College of Medicine; Division of Child Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.) and Pediatric Neurology (A.A.W., C.M.T.), Texas Children's Hospital, Baylor College of Medicine, Houston.
Karen
K
Agricola
From the Departments of Pediatrics and Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.), University of Cincinnati College of Medicine; Division of Child Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.) and Pediatric Neurology (A.A.W., C.M.T.), Texas Children's Hospital, Baylor College of Medicine, Houston.
Cindy
C
Tudor
From the Departments of Pediatrics and Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.), University of Cincinnati College of Medicine; Division of Child Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.) and Pediatric Neurology (A.A.W., C.M.T.), Texas Children's Hospital, Baylor College of Medicine, Houston.
Jamie
J
Capal
From the Departments of Pediatrics and Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.), University of Cincinnati College of Medicine; Division of Child Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.) and Pediatric Neurology (A.A.W., C.M.T.), Texas Children's Hospital, Baylor College of Medicine, Houston.
Katherine
K
Holland-Bouley
From the Departments of Pediatrics and Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.), University of Cincinnati College of Medicine; Division of Child Neurology (D.A.K., M.M., K.A., C.T., J.C., K.H.-B., D.N.F.) and Pediatric Neurology (A.A.W., C.M.T.), Texas Children's Hospital, Baylor College of Medicine, Houston.
David Neal
DN
Franz
D000293:Adolescent; D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D000069279:Drug Resistant Epilepsy / Q000150:complications* / Q000188:drug therapy*; D000068338:Everolimus / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D012640:Seizures / Q000150:complications / Q000188:drug therapy; D013997:Time Factors; D016896:Treatment Outcome; D014402:Tuberous Sclerosis / Q000150:complications* / Q000188:drug therapy*; D055815:Young Adult
D000927:Anticonvulsants; D000068338:Everolimus