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Pediatric Neurology Oct 2021Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric...
BACKGROUND
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations.
METHODS
Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required.
RESULTS
Only two changes were made to clinical diagnostic criteria reported in 2013: "multiple cortical tubers and/or radial migration lines" replaced the more general term "cortical dysplasias," and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals.
CONCLUSIONS
Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families.
Topics: Child; Consensus; Humans; Practice Guidelines as Topic; Tuberous Sclerosis
PubMed: 34399110
DOI: 10.1016/j.pediatrneurol.2021.07.011 -
Anais Brasileiros de Dermatologia Jun 2018Tuberous sclerosis complex is a multisystemic, autosomal dominant genetic disorder with complete penetrance, that can evolve with hamartomas in multiple organs, such as... (Review)
Review
Tuberous sclerosis complex is a multisystemic, autosomal dominant genetic disorder with complete penetrance, that can evolve with hamartomas in multiple organs, such as skin, central nervous system, kidney and lung. Due to the wide phenotypic variability, the disease is often not recognized. Tuberous sclerosis complex affects one in 10,000 newborns and most patients are diagnosed during the first 15 months of life. The diagnostic criteria for tuberous sclerosis were reviewed in 2012, at the second International Tuberous Sclerosis Complex Consensus Conference. The diagnosis is based on genetic criteria, by the identification of inactivating pathogenic mutation of tumor suppressor genes TSC1 and TSC2, and clinical criteria, including cutaneous, renal, pulmonary, cardiac and neurological manifestations. The treatment of tuberous sclerosis complex consists, mainly, in management of the symptoms caused by hamartomas and in prevention of organ failure. Multidisciplinary approach is recommended, in order to obtain better clinical outcomes.
Topics: Hamartoma; Humans; Immunosuppressive Agents; Mutation; Sirolimus; Tuberous Sclerosis
PubMed: 29924239
DOI: 10.1590/abd1806-4841.20186972 -
JAMA Neurology Mar 2021Efficacy of cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Efficacy of cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC).
OBJECTIVE
To evaluate efficacy and safety of 25-mg/kg/day and 50-mg/kg/day cannabidiol dosages vs placebo against seizures associated with TSC.
DESIGN, SETTING, AND PARTICIPANTS
This double-blind, placebo-controlled randomized clinical trial (GWPCARE6) enrolled patients between April 6, 2016, and October 4, 2018; follow-up was completed on February 15, 2019. The trial was conducted at 46 sites in Australia, Poland, Spain, the Netherlands, United Kingdom, and United States. Eligible patients (aged 1-65 years) were those with a clinical diagnosis of TSC and medication-resistant epilepsy who had had at least 8 TSC-associated seizures during the 4-week baseline period, with at least 1 seizure occurring in at least 3 of the 4 weeks, and were currently taking at least 1 antiepileptic medication.
INTERVENTIONS
Patients received oral cannabidiol at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or a matched placebo for 16 weeks.
MAIN OUTCOMES AND MEASURES
The prespecified primary outcome was the change from baseline in number of TSC-associated seizures for cannabidiol vs placebo during the treatment period.
RESULTS
Of 255 patients screened for eligibility, 31 were excluded and 224 were randomized. Of the 224 included patients (median [range] age, 11.4 [1.1-56.8] years; 93 female patients [41.5%]), 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo, with 201 completing treatment. The percentage reduction from baseline in the type of seizures considered the primary end point was 48.6% (95% CI, 40.4%-55.8%) for the CBD25 group, 47.5% (95% CI, 39.0%-54.8%) for the CBD50 group, and 26.5% (95% CI, 14.9%-36.5%) for the placebo group; the percentage reduction from placebo was 30.1% (95% CI, 13.9%-43.3%; P < .001) for the CBD25 group and 28.5% (95% CI, 11.9%-42.0%; nominal P = .002) for the CBD50 group. The most common adverse events were diarrhea (placebo group, 19 [25%]; CBD25 group, 23 [31%]; CBD50 group, 41 [56%]) and somnolence (placebo group, 7 [9%]; CBD25 group, 10 [13%]; CBD50 group, 19 [26%]), which occurred more frequently with cannabidiol than placebo. Eight patients in CBD25 group, 10 in CBD50 group, and 2 in the placebo group discontinued treatment because of adverse events. Twenty-eight patients taking cannabidiol (18.9%) had elevated liver transaminase levels vs none taking placebo.
CONCLUSIONS AND RELEVANCE
Cannabidiol significantly reduced TSC-associated seizures compared with placebo. The 25-mg/kg/day dosage had a better safety profile than the 50-mg/kg/day dosage.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02544763.
Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Diarrhea; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Infant; Internationality; Male; Middle Aged; Seizures; Sleepiness; Treatment Outcome; Tuberous Sclerosis; Young Adult
PubMed: 33346789
DOI: 10.1001/jamaneurol.2020.4607 -
Science Advances Feb 2022Tuberous sclerosis complex subunit 1 () and 2 () are frequently mutated in non-small cell lung cancer (NSCLC), however, their effects on antitumor immunity remained...
Tuberous sclerosis complex subunit 1 () and 2 () are frequently mutated in non-small cell lung cancer (NSCLC), however, their effects on antitumor immunity remained unexplored. A CRISPR screening in murine / (KP) model identified and as potent regulators of programmed cell death ligand 1 (Pd-l1) expression in vitro and sensitivity to anti-programmed cell death receptor 1 (PD-1) treatment in vivo. or knockout (KO) promoted the transcriptional and membrane expression of PD-L1 in cell lines. -deficient tumors manifested an inflamed microenvironment in patient samples and The Cancer Genome Atlas dataset. In syngeneic murine models, KP--KO tumors showed notable response to anti-PD-1 antibody treatment, but -wild-type tumors did not. Patients with /-mutant NSCLC receiving immune checkpoint blockade (ICB) had increased durable clinical benefit and survival. Collectively, / loss defines a distinct subtype of NSCLC characterized as inflamed tumor microenvironment and superior sensitivity to ICB.
Topics: Animals; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Humans; Immune Checkpoint Inhibitors; Lung Neoplasms; Mice; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Microenvironment
PubMed: 35119931
DOI: 10.1126/sciadv.abi9533 -
Science (New York, N.Y.) Jan 2022Evolutionary development of the human brain is characterized by the expansion of various brain regions. Here, we show that developmental processes specific to humans are...
Evolutionary development of the human brain is characterized by the expansion of various brain regions. Here, we show that developmental processes specific to humans are responsible for malformations of cortical development (MCDs), which result in developmental delay and epilepsy in children. We generated a human cerebral organoid model for tuberous sclerosis complex (TSC) and identified a specific neural stem cell type, caudal late interneuron progenitor (CLIP) cells. In TSC, CLIP cells over-proliferate, generating excessive interneurons, brain tumors, and cortical malformations. Epidermal growth factor receptor inhibition reduces tumor burden, identifying potential treatment options for TSC and related disorders. The identification of CLIP cells reveals the extended interneuron generation in the human brain as a vulnerability for disease. In addition, this work demonstrates that analyzing MCDs can reveal fundamental insights into human-specific aspects of brain development.
Topics: Brain; Brain Neoplasms; Carcinogenesis; Cell Lineage; Cell Proliferation; Disease Progression; ErbB Receptors; Gene Expression Profiling; Humans; Induced Pluripotent Stem Cells; Interneurons; Loss of Heterozygosity; Neural Stem Cells; Organoids; RNA-Seq; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein
PubMed: 35084981
DOI: 10.1126/science.abf5546 -
European Journal of Paediatric... Nov 2023Children with tuberous sclerosis complex (TSC), may experience a variety of seizure types in the first year of life, most often focal seizure sand epileptic spasms. Drug... (Review)
Review
Children with tuberous sclerosis complex (TSC), may experience a variety of seizure types in the first year of life, most often focal seizure sand epileptic spasms. Drug resistance is seen early in many patients, and the management of TSC associated epilepsy remain a major challenge for clinicians. In 2018 clinical recommendations for the management of TSC associated epilepsy were published by a panel of European experts. In the last five years considerable progress has been made in understanding the neurobiology of epileptogenesis and three interventional randomized controlled trials have changed the therapeutic approach for the management of TSC associated epilepsy. Pre-symptomatic treatment with vigabatrin may delay seizure onset, may reduce seizure severity and reduce the risk of epileptic encephalopathy. The efficacy of mTOR inhibition with adjunctive everolimus was documented in patients with TSC associated refractory seizures and cannabidiol could be another therapeutic option. Epilepsy surgery has significantly improved seizure outcome in selected patients and should be considered early in all patients with drug resistant epilepsy. There is a need to identify patients who may have a higher risk of developing epilepsy and autism spectrum disorder (ASD). In the recent years significant progress has been made owing to the early identification of risk factors for the development of drug-resistant epilepsy. Better understanding of the mechanism underlying epileptogenesis may improve the management for TSC-related epilepsy. Developmental neurobiology and neuropathology give opportunities for the implementation of concepts related to clinical findings, and an early genetic diagnosis and use of EEG and MRI biomarkers may improve the development of pre-symptomatic and disease-modifying strategies.
Topics: Child; Humans; Tuberous Sclerosis; Autism Spectrum Disorder; Epilepsy; Seizures; Drug Resistant Epilepsy
PubMed: 37669572
DOI: 10.1016/j.ejpn.2023.08.005 -
Neurosciences (Riyadh, Saudi Arabia) Oct 2019
Topics: Child; Humans; Magnetic Resonance Imaging; Male; Neurology; Tuberous Sclerosis
PubMed: 31872817
DOI: 10.17712/nsj.2019.4.20190107 -
Cleveland Clinic Journal of Medicine Jul 2021
Topics: Humans; Tuberous Sclerosis
PubMed: 34210708
DOI: 10.3949/ccjm.88a.20075 -
The Cochrane Database of Systematic... Jul 2016Previous studies have shown potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex. Although everolimus (a rapalog) is currently... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Previous studies have shown potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex. Although everolimus (a rapalog) is currently approved by the FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency) for tuberous sclerosis complex-associated renal angiomyolipoma and subependymal giant cell astrocytoma, applications for other manifestations of tuberous sclerosis complex have not yet been established. A systematic review is necessary to establish the clinical value of rapamycin or rapalogs for various manifestations in tuberous sclerosis complex.
OBJECTIVES
To determine the effectiveness of rapamycin or rapalogs in people with tuberous sclerosis complex for decreasing tumour size and other manifestations and to assess the safety of rapamycin or rapalogs in relation to their adverse effects.
SEARCH METHODS
Relevant studies were identified by authors from the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, and clinicaltrials.gov. Relevant resources were also searched by the authors, such as conference proceedings and abstract books of conferences, from e.g. the Tuberous Sclerosis Complex International Research Conferences, other tuberous sclerosis complex-related conferences and the Human Genome Meeting. We did not restrict the searches by language as long as English translations were available for non-English reports.Date of the last searches: 14 March 2016.
SELECTION CRITERIA
Randomized or quasi-randomized studies of rapamycin or rapalogs in people with tuberous sclerosis complex.
DATA COLLECTION AND ANALYSIS
Data were independently extracted by two authors using standard acquisition forms. The data collection was verified by one author. The risk of bias of each study was independently assessed by two authors and verified by one author.
MAIN RESULTS
Three placebo-controlled studies with a total of 263 participants (age range 0.8 to 61 years old, 122 males and 141 females, with variable lengths of study duration) were included in the review. We found high-quality evidence except for response to skin lesions which was judged to be low quality due to the risk of attrition bias. Overall, there are 175 participants in the treatment arm (rapamycin or everolimus) and 88 in the placebo arm. Participants all had tuberous sclerosis complex as proven by consensus diagnostic criteria as a minimum. The quality in the description of the study methods was mixed, although we assessed most domains as having a low risk of bias. Blinding of treatment arms was successfully carried out in all of the studies. However, two studies did not report allocation concealment. Two of the included studies were funded by Novartis Pharmaceuticals.Two studies (235 participants) used oral (systemic) administration of everolimus (rapalog). These studies reported response to tumour size in terms of the number of individuals with a reduction in the total volume of tumours to 50% or more relative to baseline. Significantly more participants in the treatment arm (two studies, 162 participants, high quality evidence) achieved a 50% reduction in renal angiomyolipoma size, risk ratio 24.69 (95% confidence interval 3.51 to 173.41) (P = 0.001). For the sub-ependymal giant cell astrocytoma, our analysis of one study (117 participants, high quality evidence) showed significantly more participants in the treatment arm achieved a 50% reduction in tumour size, risk ratio 27.85 (95% confidence interval 1.74 to 444.82) (P = 0.02). The proportion of participants who showed a skin response from the two included studies analysed was significantly increased in the treatment arms, risk ratio 5.78 (95% confidence interval 2.30 to 14.52) (P = 0.0002) (two studies, 224 participants, high quality evidence). In one study (117 participants), the median change of seizure frequency was -2.9 in 24 hours (95% confidence interval -4.0 to -1.0) in the treatment group versus -4.1 in 24 hour (95% confidence interval -10.9 to 5.8) in the placebo group. In one study, one out of 79 participants in the treatment group versus three of 39 in placebo group had increased blood creatinine levels, while the median percentage change of forced expiratory volume at one second in the treatment arm was -1% compared to -4% in the placebo arm. In one study (117 participants, high quality evidence), we found that those participants who received treatment had a similar risk of experiencing adverse events compared to those who did not, risk ratio 1.07 (95% confidence interval 0.96 - 1.20) (P = 0.24). However, as seen from two studies (235 participants, high quality evidence), the treatment itself led to significantly more adverse events resulting in withdrawal, interruption of treatment, or reduction in dose level, risk ratio 3.14 (95% confidence interval 1.82 to 5.42) (P < 0.0001).One study (28 participants) used topical (skin) administration of rapamycin. This study reported response to skin lesions in terms of participants' perception towards their skin appearance following the treatment. There was a tendency of an improvement in the participants' perception of their skin appearance, although not significant, risk ratio 1.81 (95% confidence interval 0.80 to 4.06, low quality evidence) (P = 0.15). This study reported that there were no serious adverse events related to the study product and there was no detectable systemic absorption of the rapamycin during the study period.
AUTHORS' CONCLUSIONS
We found evidence that oral everolimus significantly increased the proportion of people who achieved a 50% reduction in the size of sub-ependymal giant cell astrocytoma and renal angiomyolipoma. Although we were unable to ascertain the relationship between the reported adverse events and the treatment, participants who received treatment had a similar risk of experiencing adverse events as compared to those who did not receive treatment. Nevertheless, the treatment itself significantly increased the risk of having dose reduction, interruption or withdrawal. This supports ongoing clinical applications of oral everolimus for renal angiomyolipoma and subependymal giant cell astrocytoma. Although oral everolimus showed beneficial effect on skin lesions, topical rapamycin only showed a non-significant tendency of improvement. Efficacy on skin lesions should be further established in future research. The beneficial effects of rapamycin or rapalogs on tuberous sclerosis complex should be further studied on other manifestations of the condition.
Topics: Administration, Oral; Administration, Topical; Angiolipoma; Astrocytoma; Brain Neoplasms; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Randomized Controlled Trials as Topic; Seizures; Sirolimus; Skin Diseases; Tuberous Sclerosis; Tumor Burden
PubMed: 27409709
DOI: 10.1002/14651858.CD011272.pub2 -
Ideggyogyaszati Szemle Mar 2017Tuberous sclerosis complex (TSC) is an autosomal dominant disease due to the uncontrolled differentiation, proliferation, and migration of cells in several organs.... (Review)
Review
Tuberous sclerosis complex (TSC) is an autosomal dominant disease due to the uncontrolled differentiation, proliferation, and migration of cells in several organs. Clinical expression is highly variable, from mild skin findings and asymptomatic brain lesions to seizures, mental retardation, autism, and potentially fatal kidney, cardiac, or pulmonary disease. Aim of this paper is to summarize the diagnostic criteria, surveillance and therapeutic issues of this multisystemic disorder emphasizing the most important neurological consequences. Presenting the state-of-the-art management recommendations and comparing them with the local protocols, we hope that our review might help in the proper assessment of one of the most important single gene disorder.
Topics: Female; Humans; Male; Tuberous Sclerosis
PubMed: 29870614
DOI: 10.18071/isz.70.0097