What is the management plan for tuberous sclerosis (TSC)?

Management Plan for Tuberous Sclerosis Complex (TSC)

The management of tuberous sclerosis complex requires a coordinated multidisciplinary approach involving specialists from neurology, nephrology, pulmonology, dermatology, and other disciplines to address the multiple organ systems affected by this condition and reduce morbidity and mortality.

Multidisciplinary Care Coordination

• All patients with TSC should be referred to an expert center with a multidisciplinary team to coordinate care across multiple affected organ systems 1
• Regular follow-up should occur at least annually with specialists relevant to the patient's specific manifestations 1
• A transition plan from pediatric to adult care should be established, including specified age of transition, process steps, and identification of adult healthcare professionals 1

Neurological Management

• Monitor for and treat epilepsy, which is a leading cause of mortality in TSC patients 1
• Consider mTOR inhibitors (everolimus) for subependymal giant cell astrocytomas (SEGA) that require intervention but cannot be surgically resected 2, 3
• Initial everolimus dosage for SEGA is 4.5 mg/m² orally once daily, with therapeutic drug monitoring to maintain trough concentrations of 5-15 ng/mL 2
• Evaluate for TSC-associated neuropsychiatric disorders (TAND), which occur in most individuals but are often undertreated 3

Renal Management

• Regular kidney monitoring is essential as kidney disease is the most common cause of death in adults with TSC 1
• Monitor for three major kidney phenotypes: angiomyolipomata (70-80% of patients), cystic disease (50%), and renal cell carcinoma (3-5%) 1
• Begin kidney monitoring from the point of diagnosis, even in young children, as both cysts and angiomyolipomata can develop in the first months of life 1
• For angiomyolipomata:
  • Consider mTOR inhibitors (everolimus 10 mg orally once daily) for treatment 2
  • For actively bleeding angiomyolipoma, arterial embolization is the first-line approach 1
  • Consider preventive arterial embolization for asymptomatic angiomyolipoma >4 cm, especially those with rich angiomatous content 1
  • Partial nephrectomy should be considered when embolization fails or is unavailable 1

Blood Pressure and Kidney Function Monitoring

• Annual standardized office blood pressure measurements for all patients 1
• 24-hour ambulatory blood pressure monitoring if BP ≥120/70 mmHg in adults 1
• Annual assessment of kidney function (eGFR) and proteinuria in adults and children with kidney involvement on imaging 1
• In children without substantial kidney involvement on imaging, blood tests can be less frequent or delayed until adulthood 1
• First-line treatment for hypertension: ACE inhibitors or ARBs 1
• Consider SGLT2 inhibitors for patients with CKD progression, even though specific evidence in TSC population is limited 1

Management After Kidney Transplantation

• Consider immunosuppressive regimens containing an mTOR inhibitor after kidney transplantation in patients with TSC-associated phenotypes known to respond to mTOR inhibition 1

Pulmonary Management

• Monitor for lymphangioleiomyomatosis (LAM), particularly in adult women 4
• Consider mTOR inhibitors for treatment of symptomatic pulmonary LAM 4

Dermatological Management

• Treat facial angiofibromas with topical mTOR inhibitors or laser therapy 4
• mTOR inhibitors may also be effective for other skin manifestations 4

Monitoring and Managing mTOR Inhibitor Therapy

• Monitor everolimus whole blood trough concentrations when initiating therapy, modifying dose, or when there are changes in concomitant medications 2
• Common adverse events requiring management include:
  • Non-infectious pneumonitis: withhold treatment until improvement to Grade 0-1, then resume at 50% of previous dose 2
  • Stomatitis: provide supportive care and dose modifications as needed 2, 4
  • Infections: treat appropriately and consider temporary dose interruption 4
  • Monitor for proteinuria, which may develop or worsen with mTOR inhibitor therapy 1

Family Screening

• Discuss genetic screening with family members 1
• Family members with TSC clinical features should be screened for the relevant pathogenic variant if known 1
• Genetic testing has limited value in family members with no clinical features of TSC 1

Pitfalls and Caveats

• TSC is often not recognized by clinicians without specialist knowledge, as <40% of patients have the classic triad of facial angiofibromata, developmental delay, and intractable epilepsy 1
• Normal kidney imaging and GFR in young children do not preclude future development of kidney lesions 1
• In patients with low muscle mass due to severe neurological complications, standard creatinine-based equations can overestimate eGFR; consider cystatin C-based equations 1
• Avoid nephron loss during interventional procedures by ensuring effective targeting of angiomatous arteries and avoiding non-target embolization 1