PMID- 30564495
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220330
IS  - 2163-0402 (Print)
IS  - 2163-0933 (Electronic)
IS  - 2163-0402 (Linking)
VI  - 8
IP  - 5
DP  - 2018 Oct
TI  - Everolimus for treatment-refractory seizures in TSC: Extension of a randomized 
      controlled trial.
PG  - 412-420
LID - 10.1212/CPJ.0000000000000514 [doi]
AB  - BACKGROUND: EXamining 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. METHODS: After 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). RESULTS: Of 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). CONCLUSIONS: Sustained 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 
      EVIDENCE: This study provides Class IV evidence that long-term everolimus therapy 
      reduces SF in patients with TSC-associated treatment-refractory seizures.
FAU - Franz, David N
AU  - Franz DN
AD  - Department of Neurology (DNF), Cincinnati Children's Hospital Medical Center, OH; 
      Tuberous Sclerosis Multidisciplinary Management Clinic (JAL), Sydney Children's 
      Hospital, Randwick, New South Wales, Australia; Division of Child Neurology (ZY), 
      Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 
      Turkey; NHO Epilepsy Center (HI), Shizuoka Institute of Epilepsy and Neurological 
      Disorders, Japan; Paediatric Epileptology (TP), Mara Hospital, Bethel Epilepsy 
      Center, Germany; Reference Centre for Rare Epilepsies (RN), Hospital 
      Necker-Enfants Malades, Paris Descartes University, France; Tor Vergata 
      University Hospital (PC), Rome, Italy; Division of Child and Adolescent 
      Psychiatry (PJdV), University of Cape Town, South Africa; Departments of 
      Neurology and Pediatrics (DJD), The Children's Hospital of Philadelphia, Perelman 
      School of Medicine at the University of Pennsylvania; Novartis Pharmaceuticals 
      Corporation (MV, JF, DP), East Hanover, NJ; Novartis Pharmaceuticals SAS (AV), 
      Rueil-Malmaison, France; and NYU Comprehensive Epilepsy Center (JAF), New York.
FAU - Lawson, John A
AU  - Lawson JA
AD  - Department of Neurology (DNF), Cincinnati Children's Hospital Medical Center, OH; 
      Tuberous Sclerosis Multidisciplinary Management Clinic (JAL), Sydney Children's 
      Hospital, Randwick, New South Wales, Australia; Division of Child Neurology (ZY), 
      Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 
      Turkey; NHO Epilepsy Center (HI), Shizuoka Institute of Epilepsy and Neurological 
      Disorders, Japan; Paediatric Epileptology (TP), Mara Hospital, Bethel Epilepsy 
      Center, Germany; Reference Centre for Rare Epilepsies (RN), Hospital 
      Necker-Enfants Malades, Paris Descartes University, France; Tor Vergata 
      University Hospital (PC), Rome, Italy; Division of Child and Adolescent 
      Psychiatry (PJdV), University of Cape Town, South Africa; Departments of 
      Neurology and Pediatrics (DJD), The Children's Hospital of Philadelphia, Perelman 
      School of Medicine at the University of Pennsylvania; Novartis Pharmaceuticals 
      Corporation (MV, JF, DP), East Hanover, NJ; Novartis Pharmaceuticals SAS (AV), 
      Rueil-Malmaison, France; and NYU Comprehensive Epilepsy Center (JAF), New York.
FAU - Yapici, Zuhal
AU  - Yapici Z
AD  - Department of Neurology (DNF), Cincinnati Children's Hospital Medical Center, OH; 
      Tuberous Sclerosis Multidisciplinary Management Clinic (JAL), Sydney Children's 
      Hospital, Randwick, New South Wales, Australia; Division of Child Neurology (ZY), 
      Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 
      Turkey; NHO Epilepsy Center (HI), Shizuoka Institute of Epilepsy and Neurological 
      Disorders, Japan; Paediatric Epileptology (TP), Mara Hospital, Bethel Epilepsy 
      Center, Germany; Reference Centre for Rare Epilepsies (RN), Hospital 
      Necker-Enfants Malades, Paris Descartes University, France; Tor Vergata 
      University Hospital (PC), Rome, Italy; Division of Child and Adolescent 
      Psychiatry (PJdV), University of Cape Town, South Africa; Departments of 
      Neurology and Pediatrics (DJD), The Children's Hospital of Philadelphia, Perelman 
      School of Medicine at the University of Pennsylvania; Novartis Pharmaceuticals 
      Corporation (MV, JF, DP), East Hanover, NJ; Novartis Pharmaceuticals SAS (AV), 
      Rueil-Malmaison, France; and NYU Comprehensive Epilepsy Center (JAF), New York.
FAU - Ikeda, Hiroko
AU  - Ikeda H
AD  - Department of Neurology (DNF), Cincinnati Children's Hospital Medical Center, OH; 
      Tuberous Sclerosis Multidisciplinary Management Clinic (JAL), Sydney Children's 
      Hospital, Randwick, New South Wales, Australia; Division of Child Neurology (ZY), 
      Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 
      Turkey; NHO Epilepsy Center (HI), Shizuoka Institute of Epilepsy and Neurological 
      Disorders, Japan; Paediatric Epileptology (TP), Mara Hospital, Bethel Epilepsy 
      Center, Germany; Reference Centre for Rare Epilepsies (RN), Hospital 
      Necker-Enfants Malades, Paris Descartes University, France; Tor Vergata 
      University Hospital (PC), Rome, Italy; Division of Child and Adolescent 
      Psychiatry (PJdV), University of Cape Town, South Africa; Departments of 
      Neurology and Pediatrics (DJD), The Children's Hospital of Philadelphia, Perelman 
      School of Medicine at the University of Pennsylvania; Novartis Pharmaceuticals 
      Corporation (MV, JF, DP), East Hanover, NJ; Novartis Pharmaceuticals SAS (AV), 
      Rueil-Malmaison, France; and NYU Comprehensive Epilepsy Center (JAF), New York.
FAU - Polster, Tilman
AU  - Polster T
AD  - Department of Neurology (DNF), Cincinnati Children's Hospital Medical Center, OH; 
      Tuberous Sclerosis Multidisciplinary Management Clinic (JAL), Sydney Children's 
      Hospital, Randwick, New South Wales, Australia; Division of Child Neurology (ZY), 
      Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 
      Turkey; NHO Epilepsy Center (HI), Shizuoka Institute of Epilepsy and Neurological 
      Disorders, Japan; Paediatric Epileptology (TP), Mara Hospital, Bethel Epilepsy 
      Center, Germany; Reference Centre for Rare Epilepsies (RN), Hospital 
      Necker-Enfants Malades, Paris Descartes University, France; Tor Vergata 
      University Hospital (PC), Rome, Italy; Division of Child and Adolescent 
      Psychiatry (PJdV), University of Cape Town, South Africa; Departments of 
      Neurology and Pediatrics (DJD), The Children's Hospital of Philadelphia, Perelman 
      School of Medicine at the University of Pennsylvania; Novartis Pharmaceuticals 
      Corporation (MV, JF, DP), East Hanover, NJ; Novartis Pharmaceuticals SAS (AV), 
      Rueil-Malmaison, France; and NYU Comprehensive Epilepsy Center (JAF), New York.
FAU - Nabbout, Rima
AU  - Nabbout R
AD  - Department of Neurology (DNF), Cincinnati Children's Hospital Medical Center, OH; 
      Tuberous Sclerosis Multidisciplinary Management Clinic (JAL), Sydney Children's 
      Hospital, Randwick, New South Wales, Australia; Division of Child Neurology (ZY), 
      Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 
      Turkey; NHO Epilepsy Center (HI), Shizuoka Institute of Epilepsy and Neurological 
      Disorders, Japan; Paediatric Epileptology (TP), Mara Hospital, Bethel Epilepsy 
      Center, Germany; Reference Centre for Rare Epilepsies (RN), Hospital 
      Necker-Enfants Malades, Paris Descartes University, France; Tor Vergata 
      University Hospital (PC), Rome, Italy; Division of Child and Adolescent 
      Psychiatry (PJdV), University of Cape Town, South Africa; Departments of 
      Neurology and Pediatrics (DJD), The Children's Hospital of Philadelphia, Perelman 
      School of Medicine at the University of Pennsylvania; Novartis Pharmaceuticals 
      Corporation (MV, JF, DP), East Hanover, NJ; Novartis Pharmaceuticals SAS (AV), 
      Rueil-Malmaison, France; and NYU Comprehensive Epilepsy Center (JAF), New York.
FAU - Curatolo, Paolo
AU  - Curatolo P
AD  - Department of Neurology (DNF), Cincinnati Children's Hospital Medical Center, OH; 
      Tuberous Sclerosis Multidisciplinary Management Clinic (JAL), Sydney Children's 
      Hospital, Randwick, New South Wales, Australia; Division of Child Neurology (ZY), 
      Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 
      Turkey; NHO Epilepsy Center (HI), Shizuoka Institute of Epilepsy and Neurological 
      Disorders, Japan; Paediatric Epileptology (TP), Mara Hospital, Bethel Epilepsy 
      Center, Germany; Reference Centre for Rare Epilepsies (RN), Hospital 
      Necker-Enfants Malades, Paris Descartes University, France; Tor Vergata 
      University Hospital (PC), Rome, Italy; Division of Child and Adolescent 
      Psychiatry (PJdV), University of Cape Town, South Africa; Departments of 
      Neurology and Pediatrics (DJD), The Children's Hospital of Philadelphia, Perelman 
      School of Medicine at the University of Pennsylvania; Novartis Pharmaceuticals 
      Corporation (MV, JF, DP), East Hanover, NJ; Novartis Pharmaceuticals SAS (AV), 
      Rueil-Malmaison, France; and NYU Comprehensive Epilepsy Center (JAF), New York.
FAU - de Vries, Petrus J
AU  - de Vries PJ
AD  - Department of Neurology (DNF), Cincinnati Children's Hospital Medical Center, OH; 
      Tuberous Sclerosis Multidisciplinary Management Clinic (JAL), Sydney Children's 
      Hospital, Randwick, New South Wales, Australia; Division of Child Neurology (ZY), 
      Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 
      Turkey; NHO Epilepsy Center (HI), Shizuoka Institute of Epilepsy and Neurological 
      Disorders, Japan; Paediatric Epileptology (TP), Mara Hospital, Bethel Epilepsy 
      Center, Germany; Reference Centre for Rare Epilepsies (RN), Hospital 
      Necker-Enfants Malades, Paris Descartes University, France; Tor Vergata 
      University Hospital (PC), Rome, Italy; Division of Child and Adolescent 
      Psychiatry (PJdV), University of Cape Town, South Africa; Departments of 
      Neurology and Pediatrics (DJD), The Children's Hospital of Philadelphia, Perelman 
      School of Medicine at the University of Pennsylvania; Novartis Pharmaceuticals 
      Corporation (MV, JF, DP), East Hanover, NJ; Novartis Pharmaceuticals SAS (AV), 
      Rueil-Malmaison, France; and NYU Comprehensive Epilepsy Center (JAF), New York.
FAU - Dlugos, Dennis J
AU  - Dlugos DJ
AD  - Department of Neurology (DNF), Cincinnati Children's Hospital Medical Center, OH; 
      Tuberous Sclerosis Multidisciplinary Management Clinic (JAL), Sydney Children's 
      Hospital, Randwick, New South Wales, Australia; Division of Child Neurology (ZY), 
      Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 
      Turkey; NHO Epilepsy Center (HI), Shizuoka Institute of Epilepsy and Neurological 
      Disorders, Japan; Paediatric Epileptology (TP), Mara Hospital, Bethel Epilepsy 
      Center, Germany; Reference Centre for Rare Epilepsies (RN), Hospital 
      Necker-Enfants Malades, Paris Descartes University, France; Tor Vergata 
      University Hospital (PC), Rome, Italy; Division of Child and Adolescent 
      Psychiatry (PJdV), University of Cape Town, South Africa; Departments of 
      Neurology and Pediatrics (DJD), The Children's Hospital of Philadelphia, Perelman 
      School of Medicine at the University of Pennsylvania; Novartis Pharmaceuticals 
      Corporation (MV, JF, DP), East Hanover, NJ; Novartis Pharmaceuticals SAS (AV), 
      Rueil-Malmaison, France; and NYU Comprehensive Epilepsy Center (JAF), New York.
FAU - Voi, Maurizio
AU  - Voi M
AD  - Department of Neurology (DNF), Cincinnati Children's Hospital Medical Center, OH; 
      Tuberous Sclerosis Multidisciplinary Management Clinic (JAL), Sydney Children's 
      Hospital, Randwick, New South Wales, Australia; Division of Child Neurology (ZY), 
      Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 
      Turkey; NHO Epilepsy Center (HI), Shizuoka Institute of Epilepsy and Neurological 
      Disorders, Japan; Paediatric Epileptology (TP), Mara Hospital, Bethel Epilepsy 
      Center, Germany; Reference Centre for Rare Epilepsies (RN), Hospital 
      Necker-Enfants Malades, Paris Descartes University, France; Tor Vergata 
      University Hospital (PC), Rome, Italy; Division of Child and Adolescent 
      Psychiatry (PJdV), University of Cape Town, South Africa; Departments of 
      Neurology and Pediatrics (DJD), The Children's Hospital of Philadelphia, Perelman 
      School of Medicine at the University of Pennsylvania; Novartis Pharmaceuticals 
      Corporation (MV, JF, DP), East Hanover, NJ; Novartis Pharmaceuticals SAS (AV), 
      Rueil-Malmaison, France; and NYU Comprehensive Epilepsy Center (JAF), New York.
FAU - Fan, Jenna
AU  - Fan J
AD  - Department of Neurology (DNF), Cincinnati Children's Hospital Medical Center, OH; 
      Tuberous Sclerosis Multidisciplinary Management Clinic (JAL), Sydney Children's 
      Hospital, Randwick, New South Wales, Australia; Division of Child Neurology (ZY), 
      Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 
      Turkey; NHO Epilepsy Center (HI), Shizuoka Institute of Epilepsy and Neurological 
      Disorders, Japan; Paediatric Epileptology (TP), Mara Hospital, Bethel Epilepsy 
      Center, Germany; Reference Centre for Rare Epilepsies (RN), Hospital 
      Necker-Enfants Malades, Paris Descartes University, France; Tor Vergata 
      University Hospital (PC), Rome, Italy; Division of Child and Adolescent 
      Psychiatry (PJdV), University of Cape Town, South Africa; Departments of 
      Neurology and Pediatrics (DJD), The Children's Hospital of Philadelphia, Perelman 
      School of Medicine at the University of Pennsylvania; Novartis Pharmaceuticals 
      Corporation (MV, JF, DP), East Hanover, NJ; Novartis Pharmaceuticals SAS (AV), 
      Rueil-Malmaison, France; and NYU Comprehensive Epilepsy Center (JAF), New York.
FAU - Vaury, Alexandra
AU  - Vaury A
AD  - Department of Neurology (DNF), Cincinnati Children's Hospital Medical Center, OH; 
      Tuberous Sclerosis Multidisciplinary Management Clinic (JAL), Sydney Children's 
      Hospital, Randwick, New South Wales, Australia; Division of Child Neurology (ZY), 
      Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 
      Turkey; NHO Epilepsy Center (HI), Shizuoka Institute of Epilepsy and Neurological 
      Disorders, Japan; Paediatric Epileptology (TP), Mara Hospital, Bethel Epilepsy 
      Center, Germany; Reference Centre for Rare Epilepsies (RN), Hospital 
      Necker-Enfants Malades, Paris Descartes University, France; Tor Vergata 
      University Hospital (PC), Rome, Italy; Division of Child and Adolescent 
      Psychiatry (PJdV), University of Cape Town, South Africa; Departments of 
      Neurology and Pediatrics (DJD), The Children's Hospital of Philadelphia, Perelman 
      School of Medicine at the University of Pennsylvania; Novartis Pharmaceuticals 
      Corporation (MV, JF, DP), East Hanover, NJ; Novartis Pharmaceuticals SAS (AV), 
      Rueil-Malmaison, France; and NYU Comprehensive Epilepsy Center (JAF), New York.
FAU - Pelov, Diana
AU  - Pelov D
AD  - Department of Neurology (DNF), Cincinnati Children's Hospital Medical Center, OH; 
      Tuberous Sclerosis Multidisciplinary Management Clinic (JAL), Sydney Children's 
      Hospital, Randwick, New South Wales, Australia; Division of Child Neurology (ZY), 
      Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 
      Turkey; NHO Epilepsy Center (HI), Shizuoka Institute of Epilepsy and Neurological 
      Disorders, Japan; Paediatric Epileptology (TP), Mara Hospital, Bethel Epilepsy 
      Center, Germany; Reference Centre for Rare Epilepsies (RN), Hospital 
      Necker-Enfants Malades, Paris Descartes University, France; Tor Vergata 
      University Hospital (PC), Rome, Italy; Division of Child and Adolescent 
      Psychiatry (PJdV), University of Cape Town, South Africa; Departments of 
      Neurology and Pediatrics (DJD), The Children's Hospital of Philadelphia, Perelman 
      School of Medicine at the University of Pennsylvania; Novartis Pharmaceuticals 
      Corporation (MV, JF, DP), East Hanover, NJ; Novartis Pharmaceuticals SAS (AV), 
      Rueil-Malmaison, France; and NYU Comprehensive Epilepsy Center (JAF), New York.
FAU - French, Jacqueline A
AU  - French JA
AD  - Department of Neurology (DNF), Cincinnati Children's Hospital Medical Center, OH; 
      Tuberous Sclerosis Multidisciplinary Management Clinic (JAL), Sydney Children's 
      Hospital, Randwick, New South Wales, Australia; Division of Child Neurology (ZY), 
      Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 
      Turkey; NHO Epilepsy Center (HI), Shizuoka Institute of Epilepsy and Neurological 
      Disorders, Japan; Paediatric Epileptology (TP), Mara Hospital, Bethel Epilepsy 
      Center, Germany; Reference Centre for Rare Epilepsies (RN), Hospital 
      Necker-Enfants Malades, Paris Descartes University, France; Tor Vergata 
      University Hospital (PC), Rome, Italy; Division of Child and Adolescent 
      Psychiatry (PJdV), University of Cape Town, South Africa; Departments of 
      Neurology and Pediatrics (DJD), The Children's Hospital of Philadelphia, Perelman 
      School of Medicine at the University of Pennsylvania; Novartis Pharmaceuticals 
      Corporation (MV, JF, DP), East Hanover, NJ; Novartis Pharmaceuticals SAS (AV), 
      Rueil-Malmaison, France; and NYU Comprehensive Epilepsy Center (JAF), New York.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Neurol Clin Pract
JT  - Neurology. Clinical practice
JID - 101577149
PMC - PMC6276348
EDAT- 2018/12/20 06:00
MHDA- 2018/12/20 06:01
PMCR- 2018/10/01
CRDT- 2018/12/20 06:00
PHST- 2018/12/20 06:00 [entrez]
PHST- 2018/12/20 06:00 [pubmed]
PHST- 2018/12/20 06:01 [medline]
PHST- 2018/10/01 00:00 [pmc-release]
AID - NEURCLINPRACT2017025403 [pii]
AID - 10.1212/CPJ.0000000000000514 [doi]
PST - ppublish
SO  - Neurol Clin Pract. 2018 Oct;8(5):412-420. doi: 10.1212/CPJ.0000000000000514.