Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations.

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.

Cerebellar lesions are associated with TSC2 mutations in tuberous sclerosis complex: a retrospective record review study.

AIM: Cerebellar lesions are present in approximately 30% of patients with tuberous sclerosis complex. Although several prior studies have characterized these lesions, our study provides the first description of the specific distribution of these lesions within the cerebellum and the first genotype-phenotype correlation yet to be published. METHOD: We retrospectively reviewed magnetic resonance images from 220 paediatric and adult patients with tuberous sclerosis complex (95 males, 125 females; mean age 22.7y, range 9mo-81y). Sex, age, and genotype of patients with cerebellar lesions were recorded and specific characteristics, including signal intensity, number, shape, presence of enhancement, calcification or haemorrhage, and location within the cerebellar lobules were noted. RESULTS: Fifty-eight patients (26.4%) had 106 cerebellar lesions (62 right, 44 left). The mean number of cerebellar lesions per patient was 1.8 (range 1-6). Enhancement was present in 42.4% of lesions and folial retraction in 84%. Calcification was detected in 86.8% of lesions. Patients with calcified lesions were older (mean age 21.6y) than patients without calcification (11.5y). TSC2 mutations were detected in 41/42 (97.6%) of patients with cerebellar tubers who had genetic testing and one patient had no mutation identified. None of the patients had TSC1 mutation. INTERPRETATION: We provide new information regarding cerebellar lesions in tuberous sclerosis complex: cerebellar lesions are significantly much more frequent in patients with TSC2 mutations than TSC1 mutations or patients with no mutation identified, and Crus II is the most frequent location of cerebellar lesions. New studies are needed to assess the clinical significance of these lesions.

Sclerotic bone lesions in tuberous sclerosis complex: A genotype-phenotype study.

Tuberous sclerosis complex (TSC) is due to pathogenic variants in TSC1 or TSC2 genes resulting in hyperactivation of the mTOR pathway. Many organ systems can be affected, such as brain, skin, eye, heart, bone, kidney, or lung. Sclerotic bone lesions have been reported as frequent findings in TSC although they are not considered diagnostic criteria. The objective of this study is to characterize sclerotic bone lesions detected by chest CT in a large cohort of adult TSC patients and to correlate with genotype. Chest CT scans of 92 adult patients with a definite clinical diagnosis of TSC were reviewed. Sclerotic bone lesions were found in 82 cases (89%) and affected mainly the posterior vertebral elements. Patients without bone lesions had negative mutational studies of TSC1/TSC2 in 86%. Awareness of these lesions in TSC is important to avoid misdiagnosis with osteoblastic metastases.

Rib and vertebral bone fibrous dysplasia in a child with tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by benign hamartomas in multiple organ systems, primarily the skin, brain, heart, kidneys, lungs, and eyes. The skeletal system is commonly affected in patients with TSC, but these bone lesions are generally asymptomatic and have not been well characterized. We present clinically significant bone growth in two ribs and vertebrae in an 8-year-old male patient with TSC and discuss the effects of mammalian target of rapamycin (mTOR) inhibitors as a possible treatment for these osseous abnormalities. This report suggests that skeletal lesions may hold more clinical significance than previously assumed and that further research should be directed toward understanding bone involvement in TSC.

Arachnoid cysts in tuberous sclerosis complex.

OBJECTIVE: Some clinical findings in tuberous sclerosis complex (TSC), such as hypomelanotic macules or angiofibromas are related to problems in development of the neural crest, which is also the origin of cranial leptomeninges. Arachnoid cysts have been reported in two TSC patients to date. The purpose of this study was to assess the prevalence and characteristics of arachnoid cysts in a large cohort of TSC. MATERIALS AND METHOD: We performed a review of brain MRIs of 220 TSC patients searching for arachnoid cysts. RESULTS: Arachnoid cysts were found in 12 (5.5%) (general population: 0.5%), including ten males (83.3%). Four patients (33.3%) had also autosomal dominant polycystic kidney disease (ADPKD) due to a contiguous deletion of the TSC2-PKD1 genes. Three patients (25%) had two or more arachnoid cysts, of whom two also had ADPKD. One patient with an arachnoid cyst did not have tubers, subependymal nodules or white matter migration lines. CONCLUSION: Our study suggests that arachnoid cysts are part of the clinical spectrum of TSC and may be also present in TSC patients without other typical TSC brain lesions.

Klüver-Bucy syndrome after unilateral frontotemporal resection in a child with tuberous sclerosis.

Klüver-Bucy syndrome (KBS) is a behavioral phenotype that appears most often after bilateral temporal damage. The main features of KBS are compulsion to examine objects orally, increased sexual activity, placidity, hypermetamorphosis (irresistible impulse to notice and react to everything within sight), visual agnosia, and problems with memory. It is more rarely reported in children than in adults. We present a case of KBS in a 2-year-old boy with tuberous sclerosis complex (TSC) after left frontotemporal resection for refractory epilepsy. This is the first KBS after unilateral temporal resection in a child, although it has already been reported in two adult cases. It also is the first case reported in a TSC patient.

Managing epilepsy in tuberous sclerosis complex.

Epilepsy is very common in tuberous sclerosis complex and occurs in 80 to 90% of affected individuals during their lifetime. Onset usually occurs during childhood, and up to one third of children with tuberous sclerosis complex will develop infantile spasms. Although not completely understood, the incidence of epilepsy is thought to relate to the neuropathologic features of the disorder, including cortical tubers and other dysgenetic features. Individuals with tuberous sclerosis complex frequently have epileptiform features to their electroencephalograms. Treatment of epilepsy in tuberous sclerosis complex is similar to epilepsy resulting from other causes and includes anticonvulsant medications, the vagus nerve stimulator, and the ketogenic diet. Vigabatrin has been shown to be particularly effective in treating infantile spasms in the setting of tuberous sclerosis complex. Epilepsy surgery has a very important role in the management of children and adults with pharmacoresistant epilepsy in tuberous sclerosis complex.