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Tuberous sclerosis complex (TSC) is a rare neurocutaneous disorder of mTOR pathway dysregulation resulting from pathogenic variants in the TSC1 or TSC2 genes. Expression of this disorder may involve abnormal tissue growth and dysfunction within the brain, kidneys, heart, lungs, eyes, skin, bones, and teeth. Neurological manifestations can include subependymal giant cell astrocytomas (SEGAs), high rates of infantile spasms, drug-resistant epilepsy, developmental delay, cognitive impairment, autism spectrum disorder, and other neurobehavioral manifestations. Here we review the potential clinical manifestations of TSC by system, recommended diagnostic and surveillance testing, genetic testing, currently available therapeutic options, and considerations for education and social support resources given the unique challenges of this multi-system disorder., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Julich receives salary funding from the Clarke Foundation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) are rare, childhood-onset conditions associated with severe, treatment-resistant epilepsy and developmental issues, including motor and cognitive impairment. Tuberous sclerosis complex (TSC) is a rare genetic disease commonly associated with epilepsy and other neuropsychiatric disorders. This cross-sectional, interview-based study examined the qualitative impact of caring for patients with LGS, DS, and TSC-associated epilepsy on caregivers in Japan, from the perspective of both caregivers and physicians., Methods: The survey included a pre-interview worksheet to describe caregivers' emotional journeys, followed by a ≤ 60-minute one-on-one interview. Eligible participants were Japanese caregivers of patients with LGS, DS, or TSC treated for epilepsy symptoms, and Japan-residing pediatricians or neurologists treating ≥ 3 patients with LGS, DS, and/or TSC. Interview question responses were subjected to content analysis to identify the most common response tendencies and themes., Results: Twenty-six caregivers responded (mean [standard deviation (SD)] age, 45.9 [9.5] years; age range 29-68; 92 % female), caring for patients with LGS (n = 5), DS (n = 10), and TSC (n = 11); patient mean (SD) age, 13.6 (10.0) years; age range 2-44; 27 % adults; 50 % female. Nineteen physicians, treating patients with LGS (n = 9), DS (n = 7), and TSC (n = 10), participated. Caregivers and physicians generally aligned on the factors affecting caregivers' emotional states / quality of life (QoL). The most frequently reported caregiver emotions at the time of diagnosis were shock and discouragement, anxiety for the future, and relief at receiving a diagnosis. Negative emotions throughout disease progression up until the time of survey were mainly caused by worsening of seizures, burden of constant caregiving / lack of free time, and patient's developmental issues. Positive emotions were linked to effective treatment / reduced seizures; more free time owing to the use of facilities, services, or other caregiving support; and developmental progress. Physicians acknowledged that caregivers required consultation services to support their emotional needs. In terms of unmet needs, caregiver and physician responses were aligned on the insufficient availability of services/facilities, the lack of effective treatments, and the uncertainties of adult patient care., Conclusions: Caregivers of patients with LGS, DS, or TSC-associated epilepsy in Japan reported a high degree of emotional burden related to frequent seizures, developmental issues, and constant caregiving. The burden of suboptimal treatment effectiveness, limited access to support services, and uncertainties in long-term care emphasize important unmet treatment needs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [All authors met the International Committee of Medical Journal Editors (ICMJE) authorship criteria and had full access to relevant data. Neither honoraria nor payments were made for authorship. M. LoPresti and Y. Sonohara are employees of INTAGE Healthcare Inc., which received funding from Jazz Pharmaceuticals, Inc. to conduct the fieldwork and data analysis. A. Igarashi has no conflicts of interest. S. Bowditch is an employee of Jazz Pharmaceuticals UK Ltd., and holds stocks/stock options with Jazz Pharmaceuticals UK Ltd.]., (Copyright © 2024 Jazz Pharmaceuticals, Inc. Published by Elsevier Inc. All rights reserved.)

Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the development of hamartomas in the central nervous system, heart, skin, lungs, and kidneys and other manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability. The disease is associated with pathogenic variants in the TSC1 or TSC2 genes, resulting in the hyperactivation of the mTOR pathway, a key regulator of cell growth and metabolism. Consequently, the hyperactivation of the mTOR pathway leads to abnormal tissue proliferation and the development of solid tumors. Kidney involvement in TSC is characterized by the development of cystic lesions, renal cell carcinoma and renal angiomyolipomas, which may progress and cause pain, bleeding, and loss of kidney function. Over the past years, there has been a notable shift in the therapeutic approach to TSC, particularly in addressing renal manifestations. mTOR inhibitors have emerged as the primary therapeutic option, whereas surgical interventions like nephrectomy and embolization being reserved primarily for complications unresponsive to clinical treatment, such as severe renal hemorrhage. This review focuses on the main clinical characteristics of TSC, the mechanisms underlying kidney involvement, the recent advances in therapy for kidney lesions, and the future perspectives.

Cardiac rhabdomyomas are the most common benign pediatric heart tumor in infancy, which are commonly associated with tuberous sclerosis complex (TSC). Most rhabdomyomas are asymptomatic and spontaneously regress over time. However, some cases especially in neonates or small infants can present with hemodynamic instability. Surgical resection of the tumor, which has been the gold standard in alleviating obstruction, is not always possible and may be associated with significant morbidity and mortality. Recently, mammalian target of rapamycin inhibitors (mTORi) have been shown to be safe and effective in the treatment of TSC. We present the outcomes of neonates and an infant who received treatment for symptomatic rhabdomyomas at a tertiary cardiology center. Medical records were reviewed to obtain clinical, demographic, and outcome data. Six patients received interventions for symptomatic rhabdomyomas, median age at presentation was 1 day old (range from 1 to 121 days old), and 67% of the patients had a pathogenic mutation in TSC gene. One patient underwent surgical resection of solitary tumor at right ventricular outflow tract (RVOT) successfully. In the four patients with left ventricular outflow tract (LVOT) obstruction, two patients received combined therapy of surgical debulking of LVOT tumor, Stage I palliation procedure, and mTORi and two patients received mTORi therapy. One patient with RVOT obstruction underwent ductal stenting and received synergistic mTORi. Four of the five patients had good response to mTORi demonstrated by the rapid regression of rhabdomyoma size. 83% of patients are still alive at their latest follow-up, at two to eight years of age. One patient died on day 17 post-LVOT tumor resection and Hybrid stage one due to failure of hemostasis, in the background of familial factor VII deficiency. Treatment of symptomatic rhabdomyoma requires individualized treatment strategy based on the underlying pathophysiology, with involvement of multidisciplinary teams. mTORi is effective and safe in inducing rapid regression of rhabdomyomas. A standardized mTORi prescription and monitoring guide will ensure medication safety in neonates and infants with symptomatic cardiac rhabdomyoma. Although the majority of tumors responded to mTORi, some prove to be resistant. Further studies are warranted, ideally involving multiple international centers with a larger number of patients., (© 2024. The Author(s).)

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the presence of proliferative lesions throughout the body. Management of TSC is challenging because patients have a multifaceted systemic illness with prominent neurological and developmental impact as well as potentially severe kidney, heart and lung phenotypes; however, every organ system can be involved. Adequate care for patients with TSC requires a coordinated effort involving a multidisciplinary team of clinicians and support staff. This clinical practice recommendation was developed by nephrologists, urologists, paediatric radiologists, interventional radiologists, geneticists, pathologists, and patient and family group representatives, with a focus on TSC-associated kidney manifestations. Careful monitoring of kidney function and assessment of kidney structural lesions by imaging enable early interventions that can preserve kidney function through targeted approaches. Here, we summarize the current evidence and present recommendations for the multidisciplinary management of kidney involvement in TSC., (© 2024. Springer Nature Limited.)

Neurocutaneous syndromes comprise a heterogeneous group of congenital or hereditary conditions that are known to be associated with the risk of different disorders and complications. Two of the most common neurocutaneous syndromes are Neurofibromatosis type 1 (NF1) and Tuberous Sclerosis Complex (TSC). Although there appears to be a general consensus on the importance of a multidisciplinary approach in managing these cases, there is still very little emphasis in discussions addressed in the literature on the role of dentistry in accordance with the perspective of comprehensive care. Evidence-based propositions, together with a broad discussion of new insights in this regard, should have the ability to strongly impact related future perspectives, aiming for greater advances and better outcomes for these patients. In this review article, the authors discuss updated general aspects of NF1 and TSC, and the potential additional roles of dentistry, in addition to addressing suggestions for actions in dentistry at related levels of care, as well as priorities for future research., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Although most primary central and peripheral nervous system (NS) tumors occur sporadically, there are a subset that may arise in the context of a cancer predisposition syndrome. These syndromes occur due to a pathogenic mutation in a gene that normally functions as a tumor suppressor. With increased understanding of the molecular pathogenesis of these tumors, more people have been identified with a cancer predisposition syndrome. Identification is crucial, as this informs surveillance, diagnosis, and treatment options. Moreover, relatives can also be identified through genetic testing. Although there are many cancer predisposition syndromes that increase the risk of NS tumors, in this review, we focus on three of the most common cancer predisposition syndromes, neurofibromatosis type 1, neurofibromatosis type 2, and tuberous sclerosis complex type 1 and type 2, emphasizing the clinical manifestations, surveillance guidelines, and treatment options., Competing Interests: None declared., (Thieme. All rights reserved.)

Importance: Tuberous sclerosis is an autosomal dominant genetic disorder that affects multiple organ systems and causes a wide range of physical manifestations. It commonly involves the brain, skin, heart, eyes, kidneys, and lungs. Individuals mostly present with neuropsychiatric symptoms, comprising a noteworthy source of morbidity and mortality., Observation : Ninety percent of individuals with tuberous sclerosis have associated neuropsychiatric manifestations including attention-deficit/hyperactivity disorder, autism spectrum disorder, and intellectual disability, which are typically underidentified and undertreated., Conclusion and Relevance : Lack of specific guidelines for management add to the significant burden of care. An individualized, multifaceted perspective, with particular focus on cognitive and psychosocial comorbidities, is key for managing tuberous sclerosis., Prim Care Companion CNS Disord 2024;26(1):22nr03481 ., Author affiliations are listed at the end of this article., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

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., Competing Interests: Declaration of competing interest We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. N Specchio has served on scientific advisory boards for GW Pharma, BioMarin, Arvelle, Marinus and Takeda; has received speaker honoraria from Eisai, Biomarin, Livanova, Sanofi; has served as an investigator for Zogenix, Marinus, Biomarin, UCB, Roche. R Nabbout has served as principal investigators in clinical trials for Novartis, Nutricia, Eisai, UCB, GW Pharma, Livanova. She received consulting and lecturer honoraria from Biogene, BioMarin, Praxis, GW Pharma, Zogenix, Novartis, Nutricia, Stoke, Ionis, Targeon, Neuraxpharma, Takeda, Nutricia, Biocodex, Advicennes and Eisai. She received unrestricted research grants from Eisai, UCB, Livanova and GW Pharma and academic research grants from EJP-RD (horizons 2020). E Aronica has nothing to disclose. S Auvin is a deputy editor at Epilepsia and has received support from, and/or has served as a paid consultant for Biocodex, Eisai, Encoded, Jazz Pharmaceuticals, GRIN Therapeutics, Neuraxpharm, Nutricia, Orion Pharma, Supernus Pharmaceuticals, Takeda Pharmaceutical Company, UCB Pharma, Vitaflo, Xenon Pharmaceuticals, and Zogenix. M Feucht received speaker and advisory board honoraria as well as scientific grants from Biocodex, Eisai, Gerot, Livanova, Novartis, Nutricia, Shire, UCB and GW Pharma. F Jansen has served as a consultant for Jazz Pharmaceuticals, Nutricia, Novartis and UCB. She was an investigator of the GWEPCARE 1512 trial. L Lagae received grants and is a consultant and/or speaker for Zogenix; LivaNova, UCB, Shire, Eisai, Novartis, Takeda/Ovid, NEL, Epihunter. A Benvenuto, K Kotulska, S Jozwiak, P Curatolo report no conflicts of interest., (© 2023 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

Objective: To evaluate the long-term efficacy of selective arterial embolisation in renal angiomyolipoma (AML), with emphasis on tumour shrinkage, potential regrowth and the necessity of supplementary procedures.  Material and methods: A retrospective review of all 58 consecutive embolisations at two institutions, between 1999 and 2018, was performed. Clinical notes, laboratory data and imaging were reviewed., Results: The overall complication rate was 6.8%, with no Clavien-Dindo grades III-V complications. Kidney function was unaffected by embolisation as measured by creatinine. Median radiological follow-up was 4.8 years (interquartile range [IQR]: 2.8-7.8), and median clinical follow-up was 7.5 years (IQR: 4.7-14.0). Decreasing AML size was observed in 96% of procedures. Maximal shrinkage (30% median diameter decrease; IQR: 15-44) was reached after median 2.2 years (IQR: 0.6-4.8). During follow-up, regrowth occurred in 38% of patients, and four bleeding episodes occurred in three patients with tuberous sclerosis. Growing size and/or rebleeding prompted a redo embolisation in 9% of spontaneous AML and 50% of tuberous sclerosis-associated AML., Conclusions: Being a well-tolerated treatment with few complications, selective arterial embolisation renders a pronounced size-reduction in most patients with AML, and kidney function is preserved. Regrowth is common, and a radiological follow-up is necessary. Tuberous sclerosis is a risk factor for the need of reintervention.

New clinical issues have been raised through an interval of 7 years from the previous version (2016). In this study, we update the "Clinical Practice Guidelines for tuberous sclerosis complex-associated renal angiomyolipoma" as a 2023 version under guidance by the Japanese Urological Association. The present guidelines were cooperatively prepared by the Japanese Urological Association and Japanese Society of Tuberous Sclerosis Complex; committee members belonging to one of the two societies or specializing in the treatment of this disease were selected to prepare the guidelines in accordance with the "Guidance for preparing treatment guidelines" published by Minds (2020 version). The "Introduction" consisted of four sections, "Background Questions (BQ)" consisted of four sections, "Clinical Questions (CQ)" consisted of three sections, and "Future Questions (FQ)" consisted of three sections (total: 14 sections). Concerning CQ, an agreement was confirmed through voting by the committee members based on the direction and strength of recommendation, accuracy of evidence, and recommendation comments. The present guidelines were updated based on the current evidence. We hope that the guidelines will provide guiding principles for the treatment of tuberous sclerosis complex-associated renal angiomyolipoma to many urologists, becoming a foundation for subsequent updating., (© 2023 The Japanese Urological Association.)

Background: Tuberous sclerosis complex (TSC) is associated with a wide range of physical manifestations for which international clinical recommendations for diagnosis and management have been established. TSC is, however, also associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND) that are typically under-identified and under-treated yet associated with a profound burden of disease. The contemporary evidence base for the identification and treatment of TAND is much more limited and, to date, consensus recommendations for the diagnosis and management of TAND have also been limited and non-specific., Methods: The TANDem project was launched with an international, interdisciplinary, and participatory consortium of 24 individuals, including TSC family representatives, from all World Health Organization (WHO) regions but one. One of the aims of the TANDem project was to generate consensus recommendations for the identification and treatment of TAND. At the time of this project, no internationally adopted standard methodology and methodological checklists existed for the generation of clinical practice recommendations. We therefore developed our own systematic procedure for evidence review and consensus-building to generate evidence-informed consensus recommendations of relevance to the global TSC community., Results: At the heart of the consensus recommendations are ten core principles surrounded by cluster-specific recommendations for each of the seven natural TAND clusters identified in the literature (autism-like, dysregulated behavior, eat/sleep, mood/anxiety, neuropsychological, overactive/impulsive, and scholastic) and a set of wraparound psychosocial cluster recommendations. The overarching recommendation is to "screen" for TAND at least annually, to "act" using appropriate next steps for evaluation and treatment, and to "repeat" the process to ensure early identification and early intervention with the most appropriate biological, psychological, and social evidence-informed approaches to support individuals with TSC and their families., Conclusions: The consensus recommendations should provide a systematic framework to approach the identification and treatment of TAND for health, educational, social care teams and families who live with TSC. To ensure global dissemination and implementation of these recommendations, partnerships with the international TSC community will be important. One of these steps will include the generation of a "TAND toolkit" of "what to seek" and "what to do" when difficulties are identified in TAND clusters., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with different initial symptoms and complex clinical manifestations. A 14-year-old female patient presented with persistent fever and severe headache. Medical imaging examinations revealed multiple abnormal intracranial lesions. The patient had previously been misdiagnosed with "encephalitis and acute disseminated encephalomyelitis" after visiting numerous hospitals. Eventually, by combing the characteristics of the case and genetic testing results, the patient was diagnosed with TSC accompanied by Mycoplasma pneumoniae infection. The purpose of this case report and literature review is to improve understanding of the clinical diagnosis and treatment of TSC so as to avoid misdiagnosis, missed diagnosis, and overtreatment., (© 2023. Società Italiana di Pediatria.)

Background and Purpose: Strong emphasis has been placed recently on early (4 postnatal months) detection of tuberous sclerosis complex and the introduction of antiepileptic treatment before seizure onset. This objective can be achieved prenatally: Cardiac rhabdomyomas and the major diagnostic tuberous sclerosis complex sign are detected during fetal ultrasound, and prenatal MR imaging allows detection of cerebral major manifestations: cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas., Materials and Methods: We retrospectively reviewed 50 fetuses with ultrasound-detected cardiac tumors at 19-36 gestational weeks (median, 31 weeks). MR imaging with the use of 1.5T scanners was performed at 24-37 gestational weeks (median, 34 weeks)., Results: In 11 fetuses (22%), cardiac tumors remained the only criterion. In remaining 39 fetuses (78%), MR imaging revealed a prenatal diagnosis of tuberous sclerosis complex, having shown an additional 1-3 major criteria: subependymal nodules in all cases (39/39 = 100.0%), subependymal giant cell astrocytomas in 6 (6/39 = 15.4%), and cortical tubers in 24 (24/39 = 61.5%). Radial migration lines and cerebellar tuber, not published so far, were shown in 1 case each., Conclusions: A schedule of proper care of children with tuberous sclerosis complex can be established during the perinatal period due to education of women to report for mandatory ultrasound examinations during pregnancy, the good quality of ultrasound, and referral to MR imaging if a cardiac tumor is depicted on ultrasound. Gynecologists and pediatric cardiologists performing fetal ultrasound and radiologists performing prenatal MR imaging are a key to early diagnosis of tuberous sclerosis complex in many cases., (© 2023 by American Journal of Neuroradiology.)

Background: To review seizure outcomes in children with tuberous sclerosis complex (TSC) and drug-resistant epilepsy (DRE) treated with the responsive neurostimulation (RNS) System., Methods: We retrospectively reviewed children (<21 years old) with TSC implanted with the RNS System at Texas Children's Hospital between July 2016 and May 2022., Results: Five patients meeting the search criteria were identified (all female). The median age of the RNS implantation was 13 years (range: 5 to 20 years). The median epilepsy duration before the RNS implantation was 13 years (range: 5 to 20 years). Surgeries before RNS implantation included vagus nerve stimulator placement (n = 2), left parietal resection (n = 1), and corpus callosotomy (n = 1). The median number of antiseizure medications tried before RNS was 8 (range: 5 to 12). The rationale for the RNS System implantation included seizure onset in eloquent cortex (n = 3) and multifocal seizures (n = 2). The maximum current density for each patient ranged between 1.8 and 3.5 μC/cm 2 , with an average daily stimulation of 2240 (range: 400 to 4200). There was an 86% median seizure reduction (range 0% to 99%) at a median follow-up duration of 25 months (range: 17 to 25 months). No patient experienced implantation or stimulation-related complications., Conclusions: We observed a favorable improvement in seizure frequency in pediatric patients with DRE secondary to TSC treated with the RNS System. The RNS System may be a safe and effective treatment for DRE in children with TSC., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aim: To investigate the complete clinical spectrum of individuals with paediatric tuberous sclerosis complex in southern Sweden and explore changes over time., Methods: In this retrospective observational study, 52 individuals aged up to 18 years at the study start were followed-up at regional hospitals and centres for habilitation from 2000 to 2020., Results: Cardiac rhabdomyoma was detected prenatally/neonatally in 69.2% of the subjects born during the latest ten years of the study period. Epilepsy was diagnosed in 82.7% of subjects, and 10 (19%) were treated with everolimus, mainly (80%) for a neurological indication. Renal cysts were detected in 53%, angiomyolipomas in 47%, astrocytic hamartomas in 28% of the individuals. There was a paucity of standardized follow-up of cardiac, renal, and ophthalmological manifestations and no structured transition to adult care., Conclusion: Our in-depth analysis shows a clear shift towards an earlier diagnosis of tuberous sclerosis complex in the latter part of the study period, where more than 60% of cases showed evidence of this condition already in utero due to the presence of a cardiac rhabdomyoma. This allows for preventive treatment of epilepsy with vigabatrin and early intervention with everolimus for potential mitigation of other symptoms of tuberous sclerosis complex., (© 2023. The Author(s).)

Background: The present article is an English-language version of the French National Diagnostic and Care Protocol, a pragmatic tool to optimize and harmonize the diagnosis, care pathway, management and follow-up of lymphangioleiomyomatosis in France., Methods: Practical recommendations were developed in accordance with the method for developing a National Diagnosis and Care Protocol for rare diseases of the Haute Autorité de Santé and following international guidelines and literature on lymphangioleiomyomatosis. It was developed by a multidisciplinary group, with the help of patient representatives and of RespiFIL, the rare disease network on respiratory diseases., Results: Lymphangioleiomyomatosis is a rare lung disease characterised by a proliferation of smooth muscle cells that leads to the formation of multiple lung cysts. It occurs sporadically or as part of a genetic disease called tuberous sclerosis complex (TSC). The document addresses multiple aspects of the disease, to guide the clinicians regarding when to suspect a diagnosis of lymphangioleiomyomatosis, what to do in case of recurrent pneumothorax or angiomyolipomas, what investigations are needed to make the diagnosis of lymphangioleiomyomatosis, what the diagnostic criteria are for lymphangioleiomyomatosis, what the principles of management are, and how follow-up can be organised. Recommendations are made regarding the use of pharmaceutical specialties and treatment other than medications., Conclusion: These recommendations are intended to guide the diagnosis and practical management of pulmonary lymphangioleiomyomatosis., Competing Interests: Declaration of Competing Interest Vincent COTTIN has no conflict of interest to disclose in relation with the content of the manuscript. Elodie BLANCHARD has no conflict of interest to disclose in relation with the content of the manuscript. Mallorie KERJOUAN declares research fees paid by Pfizer and Novartis to her institution. Romain LAZOR has no conflict of interest to disclose in relation with the content of the manuscript. Martine REYNAUD-GAUBERT has no conflict of interest to disclose in relation with the content of the manuscript. Romain LAZOR has no conflict of interest to disclose in relation with the content of the manuscript. Camille TAILLE declares consulting fees paid to her by Novartis. Yurdagül UZUNHAN has no conflict of interest to disclose in relation with the content of the manuscript. Lidwine WEMEAU has no conflict of interest to disclose in relation with the content of the manuscript. Claire ANDREJAK has no conflict of interest to disclose in relation with the content of the manuscript. Dany BAUD has no conflict of interest to disclose in relation with the content of the manuscript. Philippe BONNIAUD has no conflict of interest to disclose in relation with the content of the manuscript. Pierre-Yves BRILLET has no conflict of interest to disclose in relation with the content of the manuscript. Alain CALENDER has no conflict of interest to disclose in relation with the content of the manuscript. Lara CHALABREYSSE has no conflict of interest to disclose in relation with the content of the manuscript. Isabelle COURT-FORTUNE has no conflict of interest to disclose in relation with the content of the manuscript. Nicolas DESBAILLETS has no conflict of interest to disclose in relation with the content of the manuscript. Gilbert FERRETTI has no conflict of interest to disclose in relation with the content of the manuscript. Anne GUILLEMOT has no conflict of interest to disclose in relation with the content of the manuscript. Laurane HARDELIN has no conflict of interest to disclose in relation with the content of the manuscript. Marianne KAMBOUCHNER has no conflict of interest to disclose in relation with the content of the manuscript. Violette LECLERC (deceased). Mathieu LEDERLIN has no conflict of interest to disclose in relation with the content of the manuscript. Marie-Claire MALINGE has no conflict of interest to disclose in relation with the content of the manuscript. Alain MANCEL has no conflict of interest to disclose in relation with the content of the manuscript. Sylvain MARCHAND-ADAM declares consulting fees paid by Novartis. Jean-Michel MAURY has no conflict of interest to disclose in relation with the content of the manuscript. Jean-Marc NACCACHE has no conflict of interest to disclose in relation with the content of the manuscript. Mouhamad NASSER has no conflict of interest to disclose in relation with the content of the manuscript. Hilario NUNES has no conflict of interest to disclose in relation with the content of the manuscript. Gaële PAGNOUX has no conflict of interest to disclose in relation with the content of the manuscript. Grégoire PRÉVOT has no conflict of interest to disclose in relation with the content of the manuscript. Christine ROUSSET-JABLONSKI has no conflict of interest to disclose in relation with the content of the manuscript. Olivier ROUVIERE has no conflict of interest to disclose in relation with the content of the manuscript. Salim SI-MOHAMED has no conflict of interest to disclose in relation with the content of the manuscript. Renaud TOURAINE has no conflict of interest to disclose in relation with the content of the manuscript. Julie TRACLET has no conflict of interest to disclose in relation with the content of the manuscript. Ségolène TURQUIER has no conflict of interest to disclose in relation with the content of the manuscript. Stéphane VAGNARELLI has no conflict of interest to disclose in relation with the content of the manuscript. Kaïs AHMAD has no conflict of interest to disclose in relation with the content of the manuscript., (Copyright © 2023 SPLF and Elsevier Masson SAS. All rights reserved.)

Subependymal giant cell astrocytomas (SEGA) are benign cranial tumours typically found in patients with tuberous sclerosis complex (TSC). Surgical resection has been the standard treatment for SEGA, however, medical management through mTOR inhibitors has now predominantly replaced surgery as the primary treatment modality. Additionally, newer treatment modalities have emerged with the hopes of providing safer methods for treating the tumour such as laser interstitial thermal therapy (LITT). However, very few reports have addressed these newer methods and analysed the results.

Tuberous sclerosis is an autosomal dominant disorder almost fully penetrant with highly variable expression. Most cases are de novo and this diagnosis is sometimes considered during prenatal life in case of cardiac tumor, unique or multiple. The couple should be referred to a specialized tertiary prenatal care center for expertise and information. Fetal molecular testing of the two genes TSC1 and TSC2 is often informative. Prognosis determination for Tuberous Sclerosis remains a difficult task. Cardiac tumors can be sometimes worrying but only a minority will have a pejorative issue and most cases are asymptomatic without any therapeutic intervention needed. Only few cases need surgical or medical treatment. Patients with Tuberous Sclerosis can develop skin, eye, kidney or lung lesions later on, but they are either of limited consequence or treatable. The crux of the matter is the neurological involvement with frequent intellectual deficiency and epilepsy that can be drug-resistant. The absence of lesion on fetal brain MRI is not predictive of any prognosis and does not rule out Tuberous Sclerosis. De novo TSC2 mutation is a negative prognosis factor and conversely, an inherited TSC1 mutation is a more favorable one, but with a severe issue still possible. Facing this cautious prognosis, some couple may opt for termination of pregnancy while others decide to pursue it. It is then fundamental to set cardiac and neurological regular follow-up for these newborns. © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved., (Copyright © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Objective: Epilepsy associated with tuberous sclerosis complex (TSC) can be challenging to treat and is associated with significant disease burden. Our objective was to better understand the state of epilepsy care of TSC amongst pediatric neurologists in Canada, identify gaps in care and determine whether access to a dedicated TSC clinic has an impact on epilepsy management., Methods: A survey was developed after a literature review and discussion amongst two pediatric epileptologists and one nurse practitioner with expertise in TSC about the state of epilepsy care of TSC patients in Canada. Canadian pediatric neurologists were asked to participate in sharing their experiences via an anonymous web-based survey through the Canadian League Against Epilepsy (CLAE) and the Canadian Neurological Sciences Federation (CNSF)., Results: Fifty-seven responses were received. Access to a dedicated TSC clinic was reported by 25% (n = 14). Sixty percent (n = 34) reported performing serial EEG monitoring in infants with TSC and 57% (n = 33) started prophylactic antiseizure therapy when EEG abnormalities were detected, regardless of whether there was access to a TSC clinic (P = .06 and P = .29, respectively). While 52% (n = 29) did not feel comfortable prescribing mTORi for epilepsy, 65% (n = 36) indicated they would consider it with additional training. Epilepsy surgery was offered in 93% (n = 13) of centers with a dedicated TSC clinic but only 45% of centers without a TSC clinic (n = 19) (P = .002)., Significance: Our findings demonstrate the variability in neurological care of pediatric patients with TSC as it pertains to epilepsy management. There is a need for the establishment of epilepsy practice guidelines and a national network to support clinical practice, research, and education., (© 2022 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction In the Republic of Ireland, there are no tuberous sclerosis complex (TSC) specialist clinics. Methods A clinical audit was carried out to assess the care received by patients attending two specialist adult epilepsy specialist centres, measuring their care against the UK guidelines. Results Although many baseline investigations are carried out, only one-third of patients had diagnostic genetic testing results available. Neuropsychiatry is largely neglected, and the completion of neuropsychiatric assessments checklists is inadequate. Discussions concerning SUDEP are not happening and access to treatment is limited. Reporting of radiological findings in TSC is inconsistent and the number of adults with TSC accessing specialist epilepsy services appear to be low. Discussion TSC care in the Republic of Ireland is fragmented, difficult to navigate and wasteful of resources due to the complex nature of the disease and no formal clinical setting to manage it. The service gaps echo the demand for an improved care system including consistent radiological reporting of TSC pathology. The absence of a specialist TSC clinic compounds the complexity of navigating care for individuals with TSC, families and healthcare professionals. Extending this audit nationally will give a more complete picture and highlight the resources required to bring care of these patients in line with recommended guidelines., Competing Interests: The authors have no conflicts of interest to declare.

Purpose of Review: Tuberous sclerosis complex (TSC) and neurofibromatosis (NF) are neurocutaneous disorders often encountered by neurologists in clinical practice. This article aims to familiarize adult and pediatric neurologists with common features of these disorders and headache specific evaluation and management., Recent Findings: Non-malignant intracranial tumors in TSC include cortical tubers (glioneuronal hamartomas), subependymal nodules or subependymal giant-cell astrocytomas (SEGA). Headache disorders in TSC are largely secondary and can cause headaches due to increased intracranial pressure, mass effect, obstructive hydrocephalus, or hemorrhage. Neurosurgical intervention is typically required for management of large SEGAs; however, in patients with increased surgical risk, newer treatment modalities may be offered such as neoadjuvant therapy with an mTOR inhibitor (mTORi). Newer studies indicate headache disorders are more prevalent in neurofibromatosis type 1 (NF1). Primary headache disorders can include migraine and tension-type headache, while secondary headache disorders can be due to associated neoplasms such as optic pathway gliomas or brainstem gliomas, or less commonly vasculopathies such as moyamoya syndrome. Selumetinib is an oral, small molecule mitogen-activated protein kinase (MEK) agent with antineoplastic activity which is in ongoing trials for treatment of NF1-associated pediatric low-grade gliomas. NF1 stands out as having a higher association with primary headache disorders such as migraine. This association may be related to effects of mutation of the neurofibromin gene on pathways involved in pain and migraine genesis, however, warrants future study. Care should be taken when formulating a headache treatment plan to address comorbidities and avoid medications that may be contraindicated., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Facial angiofibromas are one of the dermatological hallmarks of tuberous sclerosis complex. Facial angiofibromas often lead to disfigurement and cosmetic concerns, which has a serious negative effect on the quality of life of the patients. There are no guidelines or consensus on the management of facial angiofibromas up to now. We report a patient with extensive facial angiofibromas treated with the combination of photodynamic therapy and ultrapulse carbon dioxide laser, achieving satisfying results. We suggest this might be a promising therapeutic option for facial angiofibromas in tuberous sclerosis complex., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Autism spectrum disorder (ASD) is frequently associated with infants with epileptic encephalopathy, and early interventions targeting social and cognitive deficits can have positive effects on developmental outcome. However, early diagnosis of ASD among infants with epilepsy is complicated by variability in clinical phenotypes. Commonality in both biological and molecular mechanisms have been suggested between ASD and epilepsy, such as occurs with tuberous sclerosis complex. This review summarizes the current understanding of causal mechanisms between epilepsy and ASD, with a particularly genetic focus. Hypothetical explanations to support the conjugation of the two conditions include abnormalities in synaptic growth, imbalance in neuronal excitation/inhibition, and abnormal synaptic plasticity. Investigation of the probable genetic basis has implemented many genes, although the main risk supports existing hypotheses in that these cluster to abnormalities in ion channels, synaptic function and structure, and transcription regulators, with the mammalian target of rapamycin (mTOR) pathway and "mTORpathies" having been a notable research focus. Experimental models not only have a crucial role in determining gene functions but are also useful instruments for tracing disease trajectory. Precision medicine from gene therapy remains a theoretical possibility, but more contemporary developments continue in molecular tests to aid earlier diagnoses and better therapeutic targeting., (© 2021 International League Against Epilepsy.)

Objective: This study investigated the dynamic and long-term efficacy of vagus nerve stimulation (VNS) in patients with drug-resistant epilepsy (DRE) induced by tuberous sclerosis complex (TSC). In addition, the impact of VNS on cognition and emotion after a one-year follow-up was evaluated., Methods: A total of 17 patients diagnosed with DRE induced by TSC were retrospectively recruited between 2008 and 2019. Dynamic changes in seizure frequency were observed in the responders (≥50% reduction of seizure frequency at last follow-up) and non-responders. Clinical characteristics and seizure outcomes were comprehensively analyzed to determine factors associated with seizure outcomes. The Wechsler intelligence scale was applied in a subgroup of six pediatric patients, whereas the Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS) were assessed in a subgroup of nine patients to determine the impact of VNS therapy on cognitive performance and emotional state., Results: The follow-up duration for the 17 patients who underwent VNS treatment ranged from 0.5 to 10 years (mean ± SD: 4.1 ± 3.2 years). Monthly seizures decreased significantly from three months to four years post-treatment (p < 0.05). At the last follow-up, 70.6% of the patients achieved at least a 50% reduction in seizure frequency, and three patients were completely seizure free. Comparatively, non-responder patients experienced deterioration of seizure frequency after the first year. Notably, after one-year follow-up the mean standard score of full-scale intelligence quotient increased from 67.33 to 69.5 (p = 0.078) while the mean, standard score of SDS decreased from 49.22 to 45.67 (p = 0.003) compared to preoperative neuropsychological evaluation results., Conclusion: VNS is a safe and effective treatment for patients with DRE caused by TSC. Although early outcomes were encouraging, a follow-up of at least one-year was required to predict long-term outcomes in patients receiving VNS treatment. Moreover, VNS may improve depressive mood in patients with DRE caused by TSC. Further investigations are needed to validate the present results., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Our study aimed to evaluate the effect of daily oral dose of everolimus in the treatment of patients with tuberous sclerosis complex (TSC) associated with renal angiomyolipoma (RAML), and the feasibility and safety of surgical treatment approach., Methods: We retrospectively investigated a total of 13 patients diagnosed of TSC-associated renal angiomyolipoma (TSC-RAML) who were scheduled for everolimus therapy. At 3-9 months after starting everolimus therapy, 4 of the study patients were symptomatic and underwent partial renal resection surgery. Two of these surgeries were performed open nephron sparing surgery (NSS) after TAE (Trans-arterial embolization), while the remaining 2 underwent robot-assisted partial nephrectomy (RAPN). A multi-slice helical CT scan performed among all the patients every 3 months, which was used to measure the volume and the density of the lesion., Results: Follow-up CT images revealed a significant reduction (P < .05) in the RAML volume, at a rate ranging from 11.6 to 42.5%, in response to everolimus therapy (10 mg/day) in TSC-RAML patients. Further, a significant decrease in the mean tumor density (P < .05), as compared to its baseline value, was also observed. Super-selective renal arterial embolization done prior to NSS was effective in reducing the intraoperative bleeding and stabilizing the patient during the NSS procedure: mean warm ischemia time was 29.5 minutes (range 18-40 minutes) and mean intraoperative bleeding volume was 275 mL (range 200-350 mL). Post-surgical (both NSS and RAPN) follow-up showed a favorable perioperative morbidity profile with good renal functional preservation. At the end of 2 years, all patients were well, with no signs of progression or recurrence of the condition, and demonstrated normal renal function., Conclusions: The results suggested oral everolimus as an effective non-invasive therapy to treat TSC-RAML patients. Post mTOR inhibitor therapy, NSS and RAPN are preferred mode of surgical intervention in symptomatic patients. TAE prior to NSS is beneficial.

Aim: We aimed to describe the experience of a large single-center cohort for the clinical, radiological, and genetic characteristics, as well as to determine the efficacy of different anti-epileptic strategies in children and adults with tuberous sclerosis complex (TSC)., Methods: We carried out a historical cohort study on 91 TSC patients treated in a single center between 2008 and 2018., Results: Our cohort comprised 46 males and 45 females, with a median age of 15.6 years at the last follow-up. Mean follow-up time was 2.5 ± 0.75-5.5 years (range 0-9.5 years). Of those tested, a disease-causing mutation was identified in 90% of patients, 53% in TSC2, and 37% in TSC1. Epilepsy prevalence was similar among TSC1 and TSC2 mutated patients. The most common radiological finding were cortical tubers in 95% of patients, while subependymal giant cell astrocytoma (SEGA) were detected in 36% of patients. Notably, infantile spasms (IS) were diagnosed in 29%, with SEGA representing the only finding significantly different in prevalence between those with and without IS (62% vs. 28%, respectively, p = 0.009). Lastly, we did not find any difference in efficacy between three anti-epileptic treatments: Vagus nerve stimulation (VNS), CBD-based products, and the ketogenic diet, all showing approximately 30%-40% response rates., Significance: Altogether, we provide a comprehensive description of our experience in treating TSC, which could serve to expand current knowledge of the disease and its treatments., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Focal cortical dysplasias (FCDs) represent the most common etiology in pediatric drug-resistant focal epilepsies undergoing surgical treatment. The localization, extent and histopathological features of FCDs are considerably variable. Somatic mosaic mutations of genes that encode proteins in the PI3K-AKTmTOR pathway, which also includes the tuberous sclerosis associated genes TSC1 and TSC2 , have been implicated in FCD type II in a substantial subset of patients. Surgery is the principal therapeutic option for FCD-related epilepsy. Advanced neurophysiological and neuroimaging techniques have improved surgical outcome and reduced the risk of postsurgical deficits. Pharmacological MTOR inhibitors are being tested in clinical trials and might represent an example of personalized treatment of epilepsy based on the known mechanisms of disease, used alone or in combination with surgery., Areas Covered: This review will critically analyze the advances in the diagnosis and treatment of FCDs, with a special focus on the novel therapeutic options prompted by a better understanding of their pathophysiology., Expert Opinion: Focal cortical dysplasia is a main cause of drug-resistant epilepsy, especially in children. Novel, personalized approaches are needed to more effectively treat FCD-related epilepsy and its cognitive consequences.

Purpose: 10-year retrospective study to assess burden of illness in individuals with tuberous sclerosis complex (TSC) identified from German healthcare data., Methods: Patients with TSC were identified by International Classification of Diseases code Q85.1. Patients with epilepsy were identified by epilepsy diagnosis or antiseizure medication (ASM) prescription after TSC diagnosis., Results: Using data from 2016 (final study year), 100 patients with TSC were identified (mean [range] age: 38 [1-86] years; male: 40%); prevalence: 7.9 per 100,000 (TSC), 2.2 per 100,000 (TSC with epilepsy). During the 10-year study period (2007-2016), 256 patients with TSC were identified and followed up for 1,784 patient-years (epilepsy: 36%, 616 patient-years). TSC manifestations/comorbidities (apart from epilepsy) were identified more frequently in patients with epilepsy than without. Mean annual healthcare costs for patients with TSC were €6,139 per patient-year (PPY), mostly attributable to medication (35%) and inpatient care (29%). Patients with epilepsy incurred costs more than double those without. Mean (standard deviation [SD]) annual hospitalisation rate (AHR) and length of stay (LOS) PPY: 0.5 (1.0) and 5.9 (18.6) days for TSC. AHR and LOS were greater in patients with epilepsy than without. Mean (SD) number of ASMs prescribed (TSC with epilepsy): 3.0 (2.3) over the entire observable time per patient. Mortality rates (vs. control): 5.08% (vs. 1.69%, p<0.001) for TSC, 7.53% (vs. 0.98%, p<0.001) for TSC with epilepsy, 3.68% (vs. 2.03%, p = 0.003) for TSC without epilepsy., Conclusion: Healthcare costs, resource utilisation, and mortality were greater in patients with TSC and epilepsy than those without epilepsy., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Tuberous Sclerosis Complex International (TSCi) is a consortium of organizations that supports individuals with tuberous sclerosis complex (TSC) around the world. To improve care for TSC on a global level, TSCi identified the need to expand understanding about existing resources available in other countries, what individuals and caregivers value in TSC care, key gaps between needs and reality in each country, and ways these gaps can be addressed by advocacy organizations around the world., Methods: An iterative, mixed methods approach (the Improving Care project) was adopted to incorporate views from diverse members of TSCi. Through idea generation, a collection of qualitative open-ended responses and concept elicitation, we were able to build consensus where shared experiences and opinions were identified., Results: The research performed as a part of the Improving Care project revealed a significant gap between the guidelines and what is actually available to people with TSC worldwide. Three key priority areas of action to improve this gap were identified: (1) implementation of the guidelines; (2) access to TSC expertise, and (3) coordinated and integrated health care., Conclusions: There are significant opportunities for key stakeholders, including organizations, clinicians, and researchers to improve care for individuals with TSC on both local and global levels. Working across stakeholder groups and utilizing TSC organizations are essential to ensure that the advances in TSC research benefit people living with TSC around the world., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The mammalian target of the rapamycin (mTOR) system plays multiple, important roles in the brain, regulating both morphology, such as cellular size, shape, and position, and function, such as learning, memory, and social interaction. Tuberous sclerosis complex (TSC) is a congenital disorder caused by a defective suppressor of the mTOR system, the TSC1/TSC2 complex. Almost all brain symptoms of TSC are manifestations of an excessive activity of the mTOR system. Many children with TSC are afflicted by intractable epilepsy, intellectual disability, and/or autism. In the brains of infants with TSC, a vicious cycle of epileptic encephalopathy is formed by mTOR hyperactivity, abnormal synaptic structure/function, and excessive epileptic discharges, further worsening epilepsy and intellectual/behavioral disorders. Molecular target therapy with mTOR inhibitors has recently been proved to be efficacious for epilepsy in human TSC patients, and for autism in TSC model mice, indicating the possibility for pharmacological treatment of developmental synaptic disorders.

Objective: Tuberous sclerosis complex (TSC) is a genetic disorder primarily characterized by the development of multisystem benign tumors. Epilepsy is the most common neurologic manifestation, affecting 80%-90% of TSC patients. The diffuse structural brain abnormalities and the multifocal nature of epilepsy in TSC pose diagnostic challenges when evaluating patients for epilepsy surgery., Methods: We retrospectively reviewed the safety experience and efficacy outcomes of five adult TSC patients who were treated with direct brain-responsive neurostimulation (RNS System, NeuroPace, Inc)., Results: The average follow-up duration was 20 months. All five patients were responders (≥50% disabling seizure reduction) at last follow-up. The median reduction in disabling seizures was 58% at 1 year and 88% at last follow-up. Three of the five patients experienced some period of seizure freedom ranging from 3 months to over 1 year., Significance: In this small case series, we report the first safety experience and efficacy outcomes in patients with TSC-associated drug-resistant focal epilepsy treated with direct brain-responsive neurostimulation., (© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Tuberous sclerosis complex (TSC) is a rare, genetic, multisystem disorder characterized by the growth of hamartomas in several organs, including the brain, kidneys, heart, eyes, and lungs. Even though over 90% of patients will have some form of TSC-associated neuropsychiatric disorder (TAND), there is an apparent lack of involvement of mental health professionals (MHPs) in the care of patients with TSC. The aim of this study was to determine the current level of TAND awareness in the TSC community and to identify possible barriers to effective multidisciplinary collaboration between MHPs and other healthcare providers (HCPs) in TAND management., Methods: An electronic survey on current TSC and TAND management was conducted, targeting TSC caregivers/families, psychiatrists, neurologists, TSC specialists, and primary care physicians., Results: The invitation to participate in the survey was emailed to 659 HCPs and was disseminated through social media channels of patient advocacy groups. The survey was open for 4 months, with 359 responses collected. The majority of participants were TSC caregivers/families (73.3% of all responses). Of the 96 HCPs who participated, most were neurologists (61.5%) or TSC specialists (28.1%). Only 6 psychiatrists and 4 primary care physicians participated. Approximately half of patients have never had a neuropsychiatric assessment, and it was their caregivers/families who initiated the discussion of TAND with their providers. Almost 70% of TSC caregivers/families believed that psychiatric treatment could improve their quality of life. However, 54% of patients had difficulty obtaining psychiatric assessment. In turn, only 21% of HCPs believed that psychiatric therapy would help and 74% were concerned that their patients would be stigmatized by psychiatric referral., Conclusions: This study focused on European healthcare systems suggests that current care for mental health issues in patients with TSC is inadequate, despite guideline recommendations for regular neuropsychiatric assessments. This appears to be due to a combination of gaps in diagnosis and surveillance, low frequency of psychiatric referrals, insufficient resources, and stigmatization of mental healthcare. There is a pressing need for further initiatives to study and address the mechanisms underlying the mental health treatment gap. The importance of MHP support must be recognized to optimize TSC management.

Affecting approximately 1 per 6000-10,000 individuals, tuberous sclerosis complex (TSC) is a neurocutaneous disorder that is not only uncommon but at risk to go underrecognized. Similar to other phakomatoses, TSC is a disorder of cellular proliferation and migration producing hamartomas-benign tumors or malignant cancers affecting the skin and brain-and also involving the heart, kidneys, lungs and eyes in ways that can vary across the lifetime. It also occurs and varies across generations. Among medical subspecialists, the pediatric neurologist is often responsible for making the initial diagnosis when the affected individual presents with infantile spasms or another early-onset epilepsy syndrome. In recent decades, the identification of the responsible genes and gene products forming the mechanistic target of rapamycin complex, previously termed the mammalian target of rapamycin, not only has expanded our understanding of tuberous sclerosis pathophysiology, but has also inspired the search for targeted interventions., Competing Interests: Conflicts of Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Abstract: Tuberous sclerosis complex (TSC) is a genetic disorder that affects multiple organ systems but often goes unrecognized, and a delay in diagnosis can lead to multiple complications. Healthcare professionals should be educated on the many signs and symptoms associated with the disorder, know how to treat them symptomatically, and recommend routine screening to assess for complications. Correctly identifying, diagnosing, and treating TSC can give patients a better quality of life and prevent further complications associated with the disorder., (Copyright © 2021 American Academy of Physician Assistants.)

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies., Methods: Members of the European Reference Network for rare and complex epilepsies ( EpiCARE) were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease., Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers., Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers., Competing Interests: Sameer M Zuberi has conducted randomized controlled trials for GW Pharma and Zogenix Ltd in patients with Dravet syndrome. He has participated in advisory boards for Zogenix, GW Pharma, Biocodex, and Encoded Genomics. Katarzyna Kotulska was supported by the 7th Framework Programme of European Commission within the Large‐scale Integrating Project EPISTOP (Proposal No: 602 391‐2; Proposal title: “Long term, prospective study evaluating clinical and molecular biomarkers of epileptogenesis in a genetic model of epilepsy – tuberous sclerosis complex”; www.EPISTOP.eu) and the Polish Ministerial funds for science (years 2014‐2018) for the implementation of international co‐financed project and the grant EPIMARKER of the Polish National Center for Research and Development No STRATEGMED3/306306/4/2016. All other authors have no conflict of interest related to this survey to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (© 2020 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Facial angiofibromas may be present since early childhood in individuals with tuberous sclerosis complex (TSC), causing substantial cosmetic disfigurement. Current therapies are partially effective, but they are uncomfortable, produce scarring, and are especially expensive., Objective: The aim of the present study was to evaluate the efficacy of oral everolimus for TSC-associated angiofibromas., Methods: This retrospective study included TSC patients being treated with oral everolimus for subependymal giant cell astrocytomas (SEGAs) and angiomyolipomas (AMLs). We recorded the changes in facial angiofibromas. Changes in the Angiofibroma Grading Scale (AGS) indicators were recorded according to erythema, average lesion size, lesion density, and percent involvement on the forehead, nose, cheeks, and chin. The scores were recorded before and after the administration of oral everolimus., Results: Twenty-one patients being treated with oral everolimus were enrolled in this study. The mean age was 20.5 years (range 11-44 years, 4 males, and 17 females). The mean dose of oral everolimus was 3.6 mg/day. Clinically meaningful and statistically significant improvement was observed in erythema (p = 0.001), average lesion size (p < 0.001), lesion density (p < 0.001), and percent involvement (p < 0.001). Changes in the AGS findings were statistically significant on the forehead (p = 0.001), nose (p < 0.001) cheeks (p < 0.001), and chin (p = 0.004)., Conclusion: Everolimus shows evident improvement and is approved for TSC-associated SEGAs and AMLs. The current study demonstrated the efficacy of oral everolimus in reducing facial angiofibromas, showing the parallel benefits of the treatment protocol for TSC., (© 2020 S. Karger AG, Basel.)

Background: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder. Due to the various manifestations of TSC and their potential complications, a multidisciplinary care approach is recommended by consensus guidelines., Objectives: Our study aimed to give a complete description of our TSC adult cohort and to evaluate the multidisciplinary and interdisciplinary management model., Methods: Data on each adult patient diagnosed with TSC, including disease manifestations, interventions and outcomes, were collected at baseline and updated annually. A multidisciplinary TSC approach with all the recommended explorations was carried out annually., Results: 90 patients were enrolled in Centre Hospitalier Universitaire de Bordeaux, between January 2000 and September 2018. Median age of patients at inclusion was 37 years (range, 27-47) and 20 years old at diagnosis of TSC. Regarding the occurrence of TSC manifestations, 97% of the patients had cutaneous lesions, 89% had neurological manifestations, 83% had renal manifestations and 100% had dental lesions with pits. More than half the patients had sclerotic bone lesions (68%), TSC-associated neuropsychiatric disorders (64%) and lymphangioleiomyomatosis (59%). A TSC multidisciplinary approach was developed including a global follow-up and an evaluation of TSC targeting organs, according to the recommendations. A satisfaction survey revealed global and entire satisfaction of patients with TSC., Conclusion: We obtained an accurate description of a cohort of adult patients with TSC. Our multidisciplinary approach model allowed us to provide optimal management of patients with TSC with a high level of patient satisfaction., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The management of subependymal giant cells astrocytomas (SEGAs) has been traditionally represented by surgical treatment through an open craniotomic approach. Though open surgery still represents a major option in the management of this kind of tumors, the introduction of mTOR inhibitors in the clinical practice, technological advances in neuroendoscopy and the more recent use of laser interstitial therapy have significantly enlarged the range of available management opportunities., Methods: A thorough review of the literature has been performed. Accordingly, current views in open surgical treatment, medical therapy, endoscopic tumor removal and new trends (such as laser interstitial thermal therapy) are discussed., Results: The risk of significant neurological morbidity (5-50%) complicating open surgery has been for a long time representing a main drawback in the management of SEGAs. More recent series report a significant reduction of morbidity and mortality. The mTOR inhibitors have demonstrated efficacy in both warranting a tumor reduction by up to 60% of the tumor size and helping the control of seizures. However, the reported rate of side effects is as high as 30% and tumor recurrence is a documented occurrence at the time of mTOR inhibitor discontinuation. Endoscopic tumor removal has been more extensively considered an option due to the acquisition of new tools. Limits are still represented by tumor size (< 3 cm) and broad attachment of the tumor to the basal ganglia. Laser interstitial thermal therapy (LITT) is the more recently considered option. Though promising, only short follow-up is available so far, while data on medium- and long-term results of this treatment are completely lacking to date., Conclusions: Surgical treatment remains a mainstay of the management of SEGAs. The indication for an open craniotomic approach should be balanced with an endoscopic tumor removal or LITT according to patient conditions, presence or not of an active hydrocephalus and extension of the attachment of the tumor to the basal ganglia. The mTOR inhibitors do have a definite role both as primary and as adjuvant treatment, but consistent limitations are represented up to now by a not negligible rate of complications and the uncertainties related to the possibility of tumor recurrence once the medical treatment is discontinued.

The most common phacomatoses in children that need surgical attention are neurofibromatosis 1 and 2, tuberous sclerosis complex, Sturge-Weber disease, Von Hippel-Lindau disease, and neurocutaneous melanocytosis. All are rare and, as genetically determined disorders, all complex multisystem diseases with multiple manifestations outside the CNS. Diagnostics, management recommendations, and surgical care are age-specific and require individualization. The lifelong multidimensional disease burden demands a multidisciplinary and well-coordinated management approach. The consequence of these boundary conditions is that management of children with a phacomatosis is everything else but simple, straight forward, and intuitive. This Special Annual Issue is designed to serve as an up-to-date encyclopedic reference for all aspects of management of phacomatoses in the pediatric age group.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder affecting approximately 1 in 6,000 in general population and represents one of the most common genetic causes of epilepsy. Epilepsy affects 90% of the patients and appears in the first 2 years of life in the majority of them. Early onset of epilepsy in the first year of life is associated with high risk of cognitive decline and neuropsychiatric problems including autism. Recently TSC has been recognized as a model of genetic epilepsies. TSC is a genetic condition with known dysregulated mTOR pathway and is increasingly viewed as a model for human epileptogenesis. Moreover, TSC is characterized by a hyperactivation of mTOR (mammalian target of rapamycin) pathway, and mTOR activation was showed to be implicated in epileptogenesis in many animal models and human epilepsies. Recently published studies documented positive effect of preventive or disease modifying treatment of epilepsy in infants with high risk of epilepsy with significantly lower incidence of epilepsy and better cognitive outcome. Further studies on preventive treatment of epilepsy in other genetic epilepsies of early childhood are considered. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

There are more than 150 different rare genetic kidney diseases. They can be classified according to diagnostic findings as (i) disorders of growth and structure, (ii) glomerular diseases, (iii) tubular, and (iv) metabolic diseases. In recent years, there has been a shift of paradigm in this field. Molecular testing has become more accessible, our understanding of the underlying pathophysiologic mechanisms of these diseases has evolved, and new therapeutic strategies have become more available. Therefore, the role of nephrologists has progressively shifted from a mere spectator to an active player, part of a multidisciplinary team in the diagnosis and treatment of these disorders. This article provides an overview of the recent advances in rare hereditary kidney disorders by discussing the genetic aspects, clinical manifestations, diagnostic, and therapeutic approaches of some of these disorders, named familial focal and segmental glomerulosclerosis, tuberous sclerosis complex, Fabry nephropathy, and MYH-9 related disorder.

Introduction: While exercise has been shown to improve respiratory symptoms, exercise tolerance, and bone mineral density in many populations, no supervised exercise training interventions have been undertaken in patients with lymphangioleiomyo-matosis (LAM)., Material and Methods: One patient with TSC-LAM (tuberous sclerosis complex lymphangioleiomyomatosis) participated in two weekly sessions (50-60 min) of supervised aerobic exercise at 80-85% heart rate max for one year. Treadmill ergometry (VO2peak), spirometry (FEV1, FVC, FEV1/FVC, peak flow), and bone mineral density testing were performed prior to every 3 months., Results: After one year of supervised aerobic exercise training we saw dramatic increases in the patient's VO2max (20%), FEV1 (9.5%), FEV1/FVC (9.1%) and peak flow (47%)., Conclusions: The results from this study indicate that supervised exercise training can improve exercise tolerance and pulmonary function in a patient with lymphangioleiomyomatosis. Further research is needed, including longitudinal studies with larger sample sizes, to determine long-term effects and consistency of these findings. Aerobic exercise may offer a viable alternative or com-pliment to pharmacological interventions in the treatment of lymphangioleiomyomatosis. We show that high-intensity exercise training can markedly and safely improve pulmonary function in a patient with TSC-LAM. While we did not record quality of life or mood states, our patient did report improved self-confidence as well as enhanced mood.

Objective: To assess long-term outcome after selective arterial embolization (SAE) as first-line treatment for large or symptomatic AML., Design, Setting, and Participants: Data from a prospectively maintained database on 71 patients who underwent SAE for large or symptomatic AML were reviewed. Patients with sporadic and tuberous-sclerosis-complex (TSC) were included., Outcome Measurements: The main endpoints were re-embolization rates, occurrence of clinical events related to AML, size of AML, and renal function., Results: Thirteen (19.1%) patients reported at least 1 major clinical event. Major complications affected 2 patients (2.9%), both ending in complete loss of renal unit function. Four renal units (5.9%) were eventually treated surgically. The re-embolization rate was 41.1%, with an average time from the initial to a repeat SAE of 2.18 years (range 0.31-10.65 years). The size of the tumor prior to SAE and after 5 and 10 years of follow-up were 8.9 cm (7-12), 6.5 cm (4-7.5), 7 cm (4-7.8), respectively [median (IQR)]. These results are translated to a size reduction of 27% in 10 years follow-up. Patients with TSC had larger tumors on long-term follow-up (77.8 vs 41.3 mm, P = .045). The long-term follow-up estimated average glomerular filtration rate was 81.97 (range 26-196). No patient needed renal replacement therapy, and disease-specific survival was 100%., Conclusions: SAE is a safe treatment option for patients with symptomatic or large AML. It represents a minimally invasive intervention with good long-term outcome. SAE may be offered as first-line treatment in most cases, though, it is associated with high retreatment rates., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Autosomal dominant polycystic kidney disease is defined as an inherited disorder characterized by renal cyst formation due to mutations in the PKD1 or PKD2 gene, whereas tuberous sclerosis complex is an autosomal dominant neurocutaneous syndrome caused by mutation or deletion of the TSC2 gene. A TSC2/PKD1 contiguous gene syndrome, which is caused by a chromosomal mutation that disrupts both the TSC2 and PKD1 genes, has been identified in patients with tuberous sclerosis complex and severe early-onset autosomal dominant polycystic kidney disease. The tumor tissue of patients with breast cancer with contiguous gene syndrome has a high mutation burden and produces several neoantigens. A diffuse positive immunohistochemistry staining for cluster of differentiation 8 + in the T cells of breast cancer tissue is consistent with neoantigen production due to high mutation burden., Case Presentation: A 61-year-old Japanese woman who had been undergoing dialysis for 23 years because of end-stage renal failure secondary to autosomal dominant polycystic kidney disease was diagnosed as having triple-negative breast cancer and underwent mastectomy in 2015. She had a history of epilepsy and skin hamartoma. Her grandmother, mother, two aunts, four cousins, and one brother were also on dialysis for autosomal dominant polycystic kidney disease. Her brother had epilepsy and a brain nodule. Another brother had a syndrome of kidney failure, intellectual disability, and diabetes mellitus, which seemed to be caused by mutation in the CREBBP gene. Immunohistochemistry of our patient's breast tissue showed cluster of differentiation 8 and programmed cell death ligand 1 positivity., Conclusions: Programmed cell death ligand 1 checkpoint therapy may be effective for recurrence of triple-negative breast cancer in a patient with autosomal dominant polycystic kidney disease and tuberous sclerosis complex.