ArticleNeurology. Clinical practice2018
Everolimus for treatment-refractory seizures in TSC: Extension of a randomized controlled trial.
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Article in Neurology. Clinical practice, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers, 1 of them a synthesis that pooled it.
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53citing papers in PubMed, 1 pooled it
8.5field-weighted citation impact, top 2% of its field
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Who cites it
53 citing papers in PubMed, 1 synthesis or guideline pooled it, 106 citations in OpenAlex.
- Rapamycin and rapalogs for tuberous sclerosis complex.The Cochrane database of systematic reviews · 2023Pooled it
- Efficacy and safety of everolimus for patients with focal cortical dysplasia type 2.Epilepsia open · 2025Trial
- Bridging the Gap: Harnessing Phytochemical-Loaded Nanocarriers for Enhanced Epilepsy Treatment.Molecular neurobiology · 2026Review
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- Cell-Intrinsic Regulation of Epilepsy-Associated Pathology by mTORC1 and mTORC2.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Cannabidiol in Developmental Epilepsy: Organoid-Guided Precision Medicine Across Critical Neurodevelopmental Windows.International journal of molecular sciences · 2026Review
- Infantile Spasms (West Syndrome): Integrating Genetic, Neurotrophic, and Hormonal Mechanisms Toward Precision Therapy.Medicina (Kaunas, Lithuania) · 2025Review
- Epilepsy and autophagy modulators: a therapeutic split.Autophagy · 2025Review
- Application of population pharmacokinetic modeling of SVG-101 to evaluate proper dose selection.Translational and clinical pharmacology · 2025Article
- Brain Tumor Related Epilepsy: Pathophysiology and Multimodal Approach to Management.Current oncology reports · 2025Review
- Insights into Tuberous Sclerosis Complex : From Genes to Clinics.Journal of Korean Neurosurgical Society · 2025Article
- Seizures in brain tumors: pathogenesis, risk factors and management (Review).International journal of molecular medicine · 2025Review
- NS-Pten knockout mice exhibit sex and hippocampal subregion-specific increases in microglia/macrophage density.Epilepsy research · 2024Article
- Developmental and epileptic encephalopathies.Nature reviews. Disease primers · 2024Review
- Preventative treatment of tuberous sclerosis complex with sirolimus: Phase I safety and efficacy results.Annals of the Child Neurology Society · 2024Article
- mTOR and neuroinflammation in epilepsy: implications for disease progression and treatment.Nature reviews. Neuroscience · 2024Review
- PI3K-AKT/mTOR Signaling in Psychiatric Disorders: A Valuable Target to Stimulate or Suppress?The international journal of neuropsychopharmacology · 2024Review
- A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes.American journal of human genetics · 2024Article
- Further advances in epilepsy.Journal of neurology · 2023Review
- Revisiting the concept of drug-resistant epilepsy: A TASK1 report of the ILAE/AES Joint Translational Task Force.Epilepsia · 2023Article
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Authors and funding
14 authors at 8 institutions in 6 countries.
David N FranzDepartment 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.
John A LawsonDepartment 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.
Zuhal YapiciDepartment 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.
Hiroko IkedaDepartment 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.
Tilman PolsterDepartment 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.
Rima NabboutDepartment 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.
Paolo CuratoloDepartment 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.
Petrus J de VriesDepartment 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.
Dennis J DlugosDepartment 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.
Maurizio VoiDepartment 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.
Jenna FanDepartment 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.
Alexandra VauryDepartment 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.
Diana PelovDepartment 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.
Jacqueline A FrenchDepartment 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.
National Epilepsy Center · JPNovartis (France) · FRUniversité Paris Cité · FRIstanbul University · TRChildren's Hospital of Philadelphia · USCincinnati Children's Hospital Medical Center · USSydney Children's Hospital · AUUniversity of Cape Town · ZA
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 EVIDENCE: This study provides Class IV evidence that long-term everolimus therapy reduces SF in patients with TSC-associated treatment-refractory seizures.
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