Management of Tuberous Sclerosis Complex
Core Management Principle
All patients with TSC must be referred to an expert center with a multidisciplinary team coordinating care across neurology, nephrology, pulmonology, dermatology, and other specialties, as this approach directly reduces mortality and morbidity from this multi-organ disease 1, 2.
Multidisciplinary Care Structure
- Establish care coordination immediately upon diagnosis with specialists relevant to the patient's specific manifestations, with follow-up at least annually 1, 2.
- Create a formal transition plan from pediatric to adult care that specifies the age of transition, process steps, and identifies adult healthcare professionals, particularly critical for patients with TSC-associated intellectual disability and neuropsychiatric disorders 3, 1.
- Involve nephrology early and maintain annual follow-up, as all patients with TSC-associated kidney lesions technically have CKD stage 1 or higher, and kidney disease is the most common cause of death in adults with TSC 3, 1.
Neurological Management
- Monitor and aggressively treat epilepsy, as it represents a leading cause of mortality in TSC patients 1.
- Perform brain MRI every 1-3 years until age 25 to monitor for subependymal giant cell astrocytomas (SEGAs) 4.
SEGA-Specific Treatment
- For SEGA requiring therapeutic intervention but not curatively resectable, initiate everolimus at 4.5 mg/m² orally once daily 5.
- Monitor everolimus whole blood trough concentrations at 1-2 weeks after initiation, dose modification, or changes in hepatic function, targeting trough levels of 5-15 ng/mL 5.
- Titrate dose using the formula: New dose = current dose × (target concentration ÷ current concentration), with maximum dose increment of 5 mg per titration 5.
Renal Management
Surveillance Protocol
- Begin kidney monitoring from the point of diagnosis, even in young children, as both cysts and angiomyolipomas can develop in the first months of life 1, 2.
- Perform annual assessment of kidney function and proteinuria in all adults and children with kidney involvement on imaging 1.
- Monitor for three major kidney phenotypes: angiomyolipomata (70-80% of patients), cystic disease (~50%), and renal cell carcinoma (3-5%) 4.
Angiomyolipoma Management
- For actively bleeding angiomyolipoma, perform arterial embolization as first-line treatment if available 1, 2.
- Consider preventive arterial embolization for asymptomatic angiomyolipoma >4 cm, especially those with rich angiomatous content 1.
- Reserve partial nephrectomy for cases where embolization fails or is unavailable 1.
- For non-bleeding angiomyolipoma not requiring immediate surgery, initiate everolimus 10 mg orally once daily until disease progression or unacceptable toxicity 5.
Critical pitfall: Ensure effective targeting of angiomatous arteries during embolization to avoid nephron loss from non-target embolization 1.
Renal Cell Carcinoma Management
- Apply nephron-sparing surgical approaches (tumor enucleation preferred over marginal resection when malignancy is not suspected), as TSC-associated RCC has a more indolent course than sporadic RCC with rare mortality 3, 2.
- No specific therapeutic approaches differ from sporadic RCC management in the absence of RCT evidence, though the indolent nature should inform individualized counseling 3.
Hypertension Management
- Measure standardized office blood pressure annually in all children and adults with TSC 3, 1.
- Perform 24-hour ambulatory blood pressure monitoring if office BP ≥120/70 mmHg in adults or ≥95th percentile for age, sex, and height in children 3.
- Initiate ACE inhibitors or ARBs as first-line antihypertensive therapy unless contraindicated 3, 1, 2.
Important consideration: In patients receiving mTOR inhibitors, angiotensin receptor blockers may be preferable to ACE inhibitors due to low but increased risk of angioedema with the combination 3.
- Monitor blood pressure frequently in high-risk patients: those with advanced CKD, high-stage angiomyolipoma, or receiving ACTH/steroids for infantile spasms 3.
- Consider SGLT2 inhibitors for patients with CKD progression, though specific evidence in TSC is limited 1, 2.
mTOR Inhibitor Therapy Monitoring
- Monitor for proteinuria development or worsening during mTOR inhibitor therapy 1, 2.
- For non-infectious pneumonitis Grade 2: Withhold everolimus until improvement to Grade 0-1, then resume at 50% of previous dose 5.
- For non-infectious pneumonitis Grade 3: Withhold until improvement, resume at 50% of previous dose; permanently discontinue if recurs at Grade 3 5.
- For non-infectious pneumonitis Grade 4: Permanently discontinue everolimus 5.
Post-Kidney Transplant Management
- Consider immunosuppressive regimens containing an mTOR inhibitor after kidney transplantation in TSC patients with phenotypes known to respond to mTOR inhibition 1, 2.
- Do not perform routine nephrectomy in TSC patients who have undergone kidney transplant 2.
Family Screening and Genetic Counseling
- Discuss genetic screening with family members who have TSC clinical features, screening for the relevant pathogenic variant if known 3, 1.
- Genetic testing has limited value in family members without clinical features of TSC, though clinical judgment applies for individual families 3.
- Consider pre-implantation genetic diagnosis if a mosaic or heterozygous pathogenic variant has been identified, as prenatal diagnosis and early intervention may improve developmental and cognitive outcomes 3.
Critical Pitfalls to Avoid
- Do not assume TSC is absent based on lack of the classic triad (facial angiofibromata, developmental delay, intractable epilepsy), as <40% of patients have all three features 1, 4.
- Normal kidney imaging and GFR in young children do not exclude future kidney lesions, as median detection ages are 3 years for cysts and 8-13 years for angiomyolipomas 1, 4.
- In patients with low muscle mass from severe neurological complications, use cystatin C-based equations rather than creatinine-based equations, which overestimate eGFR 1.