What is the approach to treating tuberous sclerosis?

Treatment of Tuberous Sclerosis Complex

Core Treatment Principle

All patients with tuberous sclerosis complex (TSC) must receive coordinated multidisciplinary care from a specialized center involving neurology, nephrology, pulmonology, dermatology, and other relevant specialists to reduce mortality and morbidity. 1, 2, 3

Initial Management Framework

Baseline Assessment at Diagnosis

Upon TSC diagnosis, perform the following immediately: 1, 3

• Complete clinical history focusing on seizures, developmental delays, and organ-specific symptoms 1
• Kidney/abdominal imaging (MRI preferred to avoid radiation) 1
• Assessment of kidney function, proteinuria, and blood pressure 1, 3
• Neurological evaluation for epilepsy and cognitive function 4
• Cardiac imaging in pediatric patients 5

Surveillance Schedule

• Annual follow-up with all relevant specialists, ideally coordinated on the same day 1, 2, 3
• Annual kidney monitoring including imaging, kidney function tests, proteinuria assessment, and blood pressure measurement 2, 3
• Annual blood pressure monitoring with 24-hour ambulatory monitoring if BP ≥120/70 mmHg in adults 3

Pharmacological Treatment: mTOR Inhibitors

Indications for Everolimus

Everolimus is the first-line treatment for: 6, 7

• Renal angiomyolipoma requiring treatment (not requiring immediate surgery) 6
• Subependymal giant cell astrocytoma (SEGA) requiring intervention but not curatively resectable 6
• Fat-poor renal lesions requiring non-urgent treatment 1

Dosing Regimens

For TSC-associated renal angiomyolipoma: 6

• 10 mg orally once daily until disease progression or unacceptable toxicity

For TSC-associated SEGA: 6

• Starting dose: 4.5 mg/m² orally once daily
• Target whole blood trough concentration: 5-15 ng/mL
• Monitor trough levels at 1-2 weeks after initiation or dose changes 6

Duration of mTOR Inhibitor Therapy

Continue mTOR inhibition indefinitely if the patient responds and tolerates treatment. 1

• Minimum 12-month trial before assessing response for angiomyolipoma 1
• If no response by 12 months, reassess adherence, dosage, confirm diagnosis, and consider alternative treatments 1
• Stop or pause only for active severe infection or grade ≥3 adverse effects 1

Monitoring During mTOR Inhibitor Therapy

Monitor for the following adverse effects: 1, 2

• Aphthous stomatitis (most common) 1
• Irregular menstruation 1
• Hypercholesterolemia/hypertriglyceridemia 1
• Proteinuria (may develop or worsen) 1, 2
• Interstitial lung disease 1
• Electrolyte abnormalities, glucose, and liver function 1

Management of Renal Angiomyolipoma

Risk Stratification for Bleeding

Substantial bleeding risk exists with: 1

• Angiomyolipoma diameter >4 cm, especially with rich angiomatous content and distinct arterial supply 1
• Multiple risk factors present on assessment 1

Treatment Algorithm for Angiomyolipoma

For acute hemorrhage with hemodynamic compromise: 1

• Radiological intervention (arterial embolization) is mandatory as first-line treatment if available on-site 1, 2
• If embolization unavailable, proceed immediately to surgery with nephron-sparing approach 1
• Use steroid prophylaxis to prevent post-embolization syndrome 1

For angiomyolipoma at substantial bleeding risk (asymptomatic): 1

• Start mTOR inhibition as first-line therapy 1
• If no response or contraindication to mTOR inhibitors, consider radiological intervention or surgery 1

For angiomyolipoma not responding to mTOR inhibitors: 1

• Offer radiological interventions as next step 1
• Tailor intervention type based on patient and tumor features (blood supply selectivity, RENAL score, comorbidities, number/position of lesions) 1

Management of Renal Cell Carcinoma

For histology-proven RCC in TSC patients: 1

• Surgical intervention is mandatory 1
• Nephron-sparing approach is strongly recommended due to multiplicity and recurrent nature of kidney tumors in TSC 1, 2
• Tumor enucleation is preferred over resection with margin in cases without suspected malignancy 1
• Treatment strategies generally follow those for sporadic RCC, but with heightened emphasis on preserving kidney function 1, 2

Hypertension Management

First-line antihypertensive agents: 2, 3

• ACE inhibitors or ARBs are recommended as first-line treatment 2, 3
• Consider SGLT2 inhibitors for patients with CKD progression, though TSC-specific evidence is limited 2, 3

Post-Kidney Transplant Management

Nephrectomy is NOT typically performed in TSC patients undergoing kidney transplantation. 1

Consider pre-transplant nephrectomy only if: 1

• Large ipsilateral kidney preventing heterotopic transplantation 1
• Suspicion of concomitant malignancy 1
• High risk of angiomyolipoma bleeding with multiple risk factors 1
• Symptomatic angiomyolipoma unresponsive to mTOR inhibition 1

Post-transplant immunosuppression: 1, 2

• Consider mTOR inhibitor-based regimens for patients with TSC-associated phenotypes known to respond to mTOR inhibition (angiomyolipoma, SEGA, epilepsy, skin manifestations, LAM) 1, 2

Neurological Management

Epilepsy treatment: 4, 8, 9

• Epilepsy occurs in 96% of TSC patients and is often severe and intractable 8
• Use standard antiepileptic drugs, with newer agents showing benefit 8, 9
• Consider cannabidiol as treatment option 9
• Consider ketogenic diet 9
• Epilepsy surgery (tuberectomy) should be considered for drug-resistant patients with well-defined seizure origin, even with multiple cerebral lesions 8, 9

Family Screening and Genetic Counseling

Discuss genetic screening with all family members. 3

• Screen family members with TSC clinical features for the relevant pathogenic variant if known 3
• Genetic testing has limited value in family members without clinical features 3

Critical Pitfalls to Avoid

Avoid unnecessary nephrectomies: 10

• TSC patients are at high risk for advanced CKD; preserve nephrons whenever possible 10
• Nephron-sparing strategies are essential given the multiplicity and recurrent nature of kidney tumors 1, 10

Do not delay kidney surveillance in young children: 2, 3

• Both cysts and angiomyolipomas can develop in the first months of life 2, 3
• Normal kidney imaging in young children does not preclude future lesion development 3

Monitor for overestimation of kidney function: 3

• In patients with low muscle mass due to severe neurological complications, creatinine-based eGFR equations overestimate function 3
• Consider cystatin C-based equations in these patients 3

Ensure effective arterial embolization technique: 3

• Target angiomatous arteries specifically and avoid non-target embolization to prevent nephron loss 3

Recognize all TSC patients with kidney lesions have at least CKD stage 1: 3, 10

• Annual nephrology follow-up is mandatory 3, 10