Elizabeth Anne Thiele

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.

Summary: Objective: Tuberous sclerosis complex (TSC) is an autosomal‐dominant genetic disorder with highly variable expression. The most common neurologic manifestation of TSC is epilepsy, which affects approximately 85% of patients, 63% of whom develop treatment‐resistant epilepsy. Herein, we evaluate the efficacy, safety, and tolerability of cannabidiol (CBD), a nonpsychoactive compound derived from the marijuana plant, as an adjunct to current antiepileptic drugs in patients with refractory seizures in the setting of TSC.Methods: Eighteen of the 56 patients who have enrolled in our current expanded‐access study of cannabidiol for patients with treatment‐resistant epilepsy carry a diagnosis of TSC. After an initial baseline period of 1 month, patients began treatment with CBD. The initial dose of 5 mg/kg/day was increased by 5 mg/kg/day every week up to a maximum dose of 50 mg/kg/day, if tolerated. Weekly seizure frequencies, percent change in seizure frequencies, and responder rates were calculated during the 2nd, 3rd, 6th, 9th, and 12th month of treatment with CBD.Results: The median weekly seizure frequency during the baseline period was 22.0 (interquartile range [IQR] 14.8–57.4), which decreased to 13.3 (IQR 5.1–22.1) after 3 months of treatment with cannabidiol. The median percent change in total weekly seizure frequency was −48.8% (IQR −69.1% to −11.1%) after 3 months of treatment. The 50% responder rates over the course of the study were 50%, 50%, 38.9%, 50%, and 50% after 2, 3, 6, 9, and 12 months of treatment with CBD, respectively. In patients taking clobazam concurrently with CBD (n = 12), the responder rate after 3 months of treatment was 58.3%, compared to 33.3% in patients not taking clobazam (n = 6). Twelve (66.7%) of 18 patients in this study experienced at least one adverse event thought possibly related to CBD; the most common adverse events were drowsiness (n = 8, 44.4%), ataxia (n = 5, 27.8%), and diarrhea (n = 4, 22.2%).Significance: Although double‐blind, placebo‐controlled trials are still necessary, these findings suggest that cannabidiol may be an effective and well‐tolerated treatment option for patients with refractory seizures in TSC.

Background Sclerotic bone lesions are often seen on chest CT in adults with tuberous sclerosis complex. Objective To characterize bone lesions at abdominal MRI in children with tuberous sclerosis complex. Materials and methods This retrospective review included 70 children with tuberous sclerosis complex who had undergone abdominal MRI for renal imaging. An additional longitudinal study was performed in 50 children who had had two or more MRI scans. Abdominal CT (eight children) and radiographs (three children) were reviewed and compared with MRI. Results A total of 173 sclerotic bone lesions were detected in 51/70 children (73%; 95% confidence interval: 0.61–0.82) chiefly affecting vertebral pedicles. New lesions appeared in 20 children and growth of previous sclerotic bone lesions was documented in 14 children. Sclerotic bone lesions were more frequent in girls and in children with more extensive renal involvement. Conclusion Sclerotic bone lesions are commonly detected by abdominal MRI in children with tuberous sclerosis complex. They usually affect posterior vertebral elements and their number and size increase with age. As current recommendations for tuberous sclerosis complex surveillance include renal MR performed in childhood, recognition of these lesions is useful.

A few cases of thyroid disease have been reported in tuberous sclerosis complex (TSC); however, studies on prevalence and characterization of lesions have not been done. Patients with TSC are routinely screened using chest CT for assessment of lung disease. Incidental thyroid findings on chest CT have been reported in large studies of the general population. The purpose of this study is to evaluate the frequency and type of thyroid anomalies in a cohort of TSC patients. We performed a retrospective review of 93 patients with a definite diagnosis of TSC, who had a chest CT. Images of the thyroid gland and final radiological report were reviewed. Reports of additional thyroid studies performed in some patients were also reviewed. Thyroid abnormalities were present in 19 of 93 (20.4%) patients. They consisted mainly of hypodense lesions categorized as nodules. Multiple nodules were found in 10 patients (52.6%). There was one papillary carcinoma. Thyroid gland lesions may be part of the clinical spectrum of TSC. They are usually asymptomatic. As some cases of thyroid carcinoma have been described in TSC, ultrasound exams are recommended, given that CT is not the gold standard technique for thyroid evaluation.

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.

Children with tuberous sclerosis complex, Sturge-Weber syndrome, and Rasmussen encephalitis all have complex but differing needs in the process of transition/transfer to adult care. All three may be associated with long-term normal intelligence or a varying degree of intellectual disability. In tuberous sclerosis complex, the emphasis of care in adulthood shifts from seizure control and developmental issues to renal and psychiatric disease and other issues. In Sturge-Weber syndrome, the emphasis shifts from seizure control and rehabilitation to management of disability and migraine. In Rasmussen encephalitis, transition may be particularly complex for those with adolescent onset. Those successfully operated on for childhood onset have a static problem and the potential to do well in life.

Aim: Patients with tuberous sclerosis complex (TSC) with brain involvement usually have both tubers and subependymal nodules (SENs) and the occurrence of one lesion without the other seems to be rare. The aim of this study was to assess the specific clinical manifestations and genotype of patients with one type of lesion or the other but not both.Method: The magnetic resonance images of 220 patients with TSC were reviewed, and patients with either tubers or SENs, but not both, were identified.Results: Out of a total of 220 patients (95 males, 125 females; mean age 22y 9mo, range 9mo–81y), six (3%) had tubers without SENs (two males; four females; mean age 34y 10mo, range 11–48y); however, no patients with SENs and without tubers were identified. No mutation was identified (NMI) in any of the six patients who underwent mutational analysis of TSC1 and TSC2. Five of the six patients had three or fewer tubers.Interpretation: We found no patients with SENs but without tubers among our cohort. In all patients with tubers but without SENs, mutational studies of TSC1/TSC2 were negative, and the majority of these had three or fewer tubers. A possible mechanism for patients with NMI and an absence of SENs is a mosaicism with a first postzygotic mutation in the neuroectoderm.

Congenital lymphedema has been described as a possible rare association of tuberous sclerosis complex (TSC), with only six previous cases reported in the literature. TSC is an autosomal dominant, multisystem disorder connected to aberrant regulation of the mammalian target of rapamycin (mTOR) pathway. The aim of this study is to review cases of lymphedema in a large cohort of TSC patients. The medical records of 268 patients seen at The Herscot Center for Children and Adults with Tuberous Sclerosis Complex at the Massachusetts General Hospital from 2002 to 2012 were retrospectively reviewed for reports of lymphedema or edema of unknown etiology. Genotypic and phenotypic data were collected in accordance with institutional review board (IRB) approval. This cohort presents two new cases of congenital lymphedema in TSC patients and acquired lymphedema was found in eight additional cases. Thus, we report 10 new cases of lymphedema in TSC (4%). The two patients with congenital lymphedema were female, as were the previous six reported cases. The frequency of lymphedema reported here (4%) is higher than the estimated prevalence in the general population (0.133–0.144%), suggesting a higher frequency of lymphedema in TSC. This study shows that patients with TSC and lymphedema are more likely to be females with renal AMLs and suggests that congenital lymphedema is a gender‐specific (female) manifestation of TSC. Exploration of the potential role of mTOR antagonists may be important in treatment of lymphedema in TSC patients.