Cancer Predisposition Syndromes in Neuro-oncology.

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.

The emotional burden of caring for patients with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex-associated epilepsy: A qualitative study in Japan.

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.

Cardiac Rhabdomyomas Presenting with Critical Cardiac Obstruction in Neonates and Infants: Treatment Strategies and Outcome, A Single-Center Experience.

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.

Childhood tuberous sclerosis complex in southern Sweden: a paradigm shift in diagnosis and treatment.

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.

Clinical Practice Guidelines for tuberous sclerosis complex-associated renal angiomyolipoma by the Japanese Urological Association: Summary of the update.

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.

Recent management trends of subependymal giant cell astrocytoma associated with tuberous sclerosis complex.

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.

The epilepsy-autism spectrum disorder phenotype in the era of molecular genetics and precision therapy.

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.

Safety and Effectiveness of Medical Therapy and Surgical Intervention for Renal Angiomyolipoma Associated With Tuberous Sclerosis Complex.

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.

Vagus nerve stimulation for drug-resistant epilepsy induced by tuberous sclerosis complex.

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 ±â€¯SD: 4.1 ±â€¯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.

Description of a multidisciplinary model of care in a French cohort of adult patients with tuberous sclerosis complex.

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.

Managing Headache Disorders Associated with Tuberous Sclerosis and Neurofibromatosis.

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.

Tuberous Sclerosis: A Rare Disease with an Orphan Complex.

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.

The Efficacy of Everolimus for Facial Angiofibromas in Tuberous Sclerosis Complex Patients Treated for Renal Angiomyolipoma/Subependymal Giant Cell Astrocytoma.

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.

An Israeli tuberous sclerosis cohort: the efficacy of different anti-epileptic strategies.

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.

Brain Symptoms of Tuberous Sclerosis Complex: Pathogenesis and Treatment.

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.

Tuberous sclerosis complex: A multisystem disorder.

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.

Current trends in the management of subependymal giant cell astrocytomas in tuberous sclerosis.

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.

Phacomatoses in the pediatric age group.

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.

Pathophysiology and management of glaucoma associated with phakomatoses.

The phakomatoses, encephalotrigeminal angiomatosis (ETA; Sturge-Weber Syndrome), neurofibromatosis type 1 (NF1 or von Recklinghausen disease), Von Hippel-Lindau (VHL) disease, tuberous sclerosis (TSC), oculodermal melanocytosis (ODM), and phakomatosis pigmentovascularis are a group of neurocutaneous disorders that have characteristic systemic and ocular manifestations. Through many different mechanisms, they may cause glaucomatous damage of the optic nerve and subsequent vision loss varying from mild to severe. Glaucoma commonly affects patients with ETA (43-72%), orbito-facial NF1 (23-50%), and ODM (10%). Rarely, it may present as neovascular glaucoma in VHL and TSC. In ETA, glaucoma typically occurs ipsilateral to the port-wine stain, which is caused by a mutation in the GNAQ gene. Specifically, mechanical malformation of the anterior chamber angle and elevated episcleral venous pressure has been implicated as causes of glaucoma in ETA. In NF1, which is caused by a mutation in the NF1 tumor suppressor gene, glaucoma commonly occurs ipsilateral to lid plexiform neurofibromas. Histological studies of eyes with NF1 have revealed direct anterior chamber infiltration by neurofibromas, secondary angle closure, fibrovascularization, and developmental angle abnormalities as mechanisms of glaucoma. Lastly, phakomatosis pigmentovascularis is a rare combination of ODM and port-wine stain. Affected patients are at very high risk of developing glaucoma. Despite the many different mechanisms of glaucomatous damage, management follows similar principles as that for congenital glaucoma and primary open angle glaucoma. First-line therapy is topical intraocular pressure-lowering eye drops. Surgical management, including goniotomy, trabeculotomy, trabeculectomy, and tube shunt placement may be required for more severe cases.

Experience of follow-up, quality of life, and transition from pediatric to adult healthcare of patients with tuberous sclerosis complex.

INTRODUCTION: Tuberous sclerosis complex (TSC) is a multisystemic genetic disease with high clinical variability and age-related manifestations. These characteristics add to the complexity of transition to adulthood. This study aimed to explore the perception of medical follow-up and transition experience in a large group of patients with TSC who presented epilepsy in childhood. METHOD: This multicenter French study included patients with TSC aged 18 years or older who developed epilepsy before the age of 16 years. A questionnaire specifically designed for the study explored patients' opinion through 270 questions covering different aspects of their social, familial, professional, and medical courses. RESULTS: The questionnaire was sent to 72 patients, and 60 patients were included in the study (83% response rate) with a mean age of 32 years (18-55 years). Cognitive impairment was present in 80% of patients, and half of questionnaires were completed by the family. Pediatric care was coordinated by the child neurologist and was more regular and multidisciplinary than adult care. Epilepsy had the best follow-up followed by renal issues. Unmet needs were identified for psychiatric and behavioral disorders, both in children and adults. Respondents considered the help in achieving autonomy better in adult care. Only 50% of patients with a normal intellectual development had clear knowledge about their disease and the need for a regular monitoring. Two-thirds of respondents estimated that they had a transition experience between 16.5 and 21-year-old, considered as good in 60% of them. Seventy percent felt continuity between pediatric and adult care, and only 3% of respondents felt that their care would have been better if they were still followed in pediatric healthcare system. The change of care structure and/or caregivers was the most stressful factor during transition and transfer. CONCLUSION: This study highlights persistent issues in the regularity and coordination of the follow-up of patients with TSC despite established international guidelines. Although most patients had a positive transition experience, there is still an urgent need to optimize transition programs. This would be essential to maintain care continuity between pediatric and adult health systems, especially for patients with TSC with epilepsy and high rate of cognitive and psychiatric impairments.