Genetics

All individuals should have a three-generation family history obtained to determine if additional family members are at risk of diagnosis. Gene testing is recommended for genetic counseling purposes or when the diagnosis of TSC is suspected or in question but cannot be clinically confirmed (Category 1).

Brain

All individuals suspected of having TSC, regardless of age, should undergo magnetic resonance imaging (MRI) of the brain with and without gadolinium to assess for the presence of cortical/subcortical tubers, subependymal nodules (SEN), other types of neuronal migration defects, and sub-ependymal giant cell astrocytomas (SEGA). If MRI is not available or cannot be performed, computed tomography (CT) or head ultrasound (US) (in neonates or infants when fontanels are open) may be used, although results are considered suboptimal and will not always be able to detect abnormalities revealed by MRI.^18,19 (Category 1)

During infancy, focal seizures and infantile spasms (IS) are likely to be encountered,^20,21 and parents should be educated to recognize these even if none have occurred at time of first diagnosis. All pediatric patients should undergo a baseline electroencephalograph (EEG), even in the absence of recognized or reported clinical seizures. (Category 2A)

If the baseline EEG is abnormal, especially when features of TSC-associated neuropsychiatric disorders (TAND) are also present, this should be followed up with a 24-hour video EEG to assess for electrographic or subtle clinical seizure activity. (Category 3)

TAND is new terminology proposed to describe the interrelated functional and clinical manifestations of brain dysfunction common in TSC, including aggressive behaviors, autism spectrum disorders, intellectual disabilities, psychiatric disorders, and neuropsychological deficits as well school and occupational difficulties.²² All patients should receive a comprehensive assessment at diagnosis to determine a baseline for future evaluations and to identify areas requiring immediate or early intervention. Comprehensive assessment is likely to require multidisciplinary involvement and clinical teams should maintain a low threshold to initiate early interventions and other management strategies. (Category 1)

Parents of school-going age should be considered for an individual education plan (IEP) based on the individual TAND profile. (Category 2A)

Kidney

At the time of diagnosis, abdominal imaging should be obtained regardless of age. As for brain, MRI is the preferred modality for evaluation of angiomyolipomata because many can be fat-poor and hence missed when abdominal CT or US are performed.²³ MRI of the abdomen may be combined in the same session as MRI of the brain, thereby limiting the need for multiple sessions of anesthesia if anesthesia is needed for successful MRI. MRI of the abdomen may also reveal aortic aneurysms or extrarenal hamartomas of the liver, pancreas, and other abdominal organs that also can occur in individuals with TSC. In addition to imaging, accurate blood pressure assessment is important because of increased risk of secondary hypertension. To assess renal function at time of diagnosis, blood tests to determine glomerular filtration rate (GFR) using creatinine equations for adults^24,25 or children.²⁶ Alternatively, measurement of serum cystatin C concentration can be used to evaluate GFR.²⁷ (Category 1)

Lung

To evaluate for LAM, females 18 years or older should have baseline pulmonary function testing, 6-minute walk test, and high-resolution chest computed tomography (HRCT). When possible, low-radiation protocols should be used. A serum vascular endothelial growth factor type D (VEGF-D) level may be helpful to establish a baseline for future LAM development or progression.^28,29 Counseling on smoking risks and estrogen use (such as some oral contraceptive preparations), which can compound the impact of LAM, should also occur in adolescents and adults. (Category 2A)

Skin and teeth

All patients should undergo a detailed clinical dermatologic and dental exam at time of diagnosis to evaluate for facial angiofibromas, fibrous cephalic plaques, hypomelanotic macules or confetti lesions, ungual fibromas, shagreen patch, defects in tooth enamel, and intraoral fibroma. (Category 2A)

Heart

In pediatric patients, especially younger than three years of age, an echocardiogram and electrocardiogram (ECG) should be obtained to evaluate for rhabdomyomas and arrhythmia, respectively. In those individuals with rhabdomyomas identified via prenatal ultrasound, fetal echocardiogram may be useful to detect those individuals with high risk of heart failure after delivery. (Category 1)

In the absence of cardiac symptoms or concerning medical history, echocardiogram is not necessary in adults, but as conduction defects may still be present and may influence medication choice and dosing,³⁰ a baseline ECG is still recommended. (Category 2A)

Eye

A baseline ophthalmologic evaluation, including funduscopic evaluation, is recommended for all individuals diagnosed with TSC to evaluate for hamartomas and hypopigmented lesions of the retina. (Category 1)

Genetics

Genetic testing and counseling should be offered to individuals with TSC when they reach reproductive age, and first-degree relatives of affected individuals should be offered clinical assessment and, where a mutation has been identified in the index case, genetic testing. (Category 1)

Brain

Symptomatic SEGA or SEGA associated with increasing ventricular enlargement, or with unexplained changes in neurological status or TAND symptoms, require intervention or more frequent clinical monitoring and reimaging. For acutely symptomatic individuals, surgical resection is the recommended intervention, and cerebrospinal fluid diversion may also be necessary. For growing but otherwise asymptomatic SEGA, either surgical resection or medical therapy with mTOR inhibitors can be effective.^31,32 Shared decision-making with the patients or their parents in selecting the best treatment option should take the following considerations into account: risk of complications or adverse effects, cost of treatment, expected length of treatment, and potential impact on TSC comorbidities. Patients with unilateral, single, gross total resectable SEGA without individual risk factors or other comorbidities preferentially may benefit from surgery, whereas patients with multisystem disease or multiple or infiltrating SEGA lesions that are not amenable to gross total resection may favor mTOR inhibitor treatment. (Category 1)

Optimal outcome is associated with early detection and treatment,³³ so surveillance by MRI should be performed every 1–3 years in all individuals with TSC until the age of 25 years. The frequency of scans within the recommended range of every 1–3 years should be clinically determined, with scans performed more frequently in those asymptomatic SEGA patients who are younger, whose SEGA are larger or growing, or who are developmentally or cognitively disabled such that they cannot reliably report subtle symptoms. (Category 2A)

Individuals without SEGA by the age of 25 years do not need continued surveillance imaging, but those with asymptomatic SEGA present in childhood should continue to be monitored by MRI for life because of the possibility of growth. There is insufficient evidence to determine the recommended frequency of MRI surveillance in this latter group, but important clinical factors that would favor shorter intervals include SEGA with proximity to foramen of Monro, large size, or recently discovered. However, once stability is clearly established, it may be possible to increase the interval of surveillance monitoring over time. (Category 3)

Strong evidence demonstrates superior efficacy for the treatment of infantile spasms with vigabatrin in patients with TSC^34–37; therefore, vigabatrin should be first-line treatment. However, the prescribing clinician should be aware of possible side effects, particularly possible retinal toxicity, and how to monitor for these. Adrenocorticotropin hormone (ACTH) can be used as second-line therapy if treatment with vigabatrin fails. (Category 1)

Routine EEG is recommended in individuals with known or suspected seizure activity, but frequency should be determined by clinical need rather than a specific defined interval. If changes in sleep, behavior, or cognitive or neurological function are not explained by routine EEG, 24-hour video EEG should be considered to assess for unrecognized or subclinical seizure activity. (Category 2A)

Early epilepsy treatment may be of benefit in infants and children during the first 24 months of life if ictal discharges occur, with or without clinical manifestations.³⁸ Other than for infantile spasms in TSC, there is little evidence to guide specific anticonvulsant treatment. In general, this should follow that of other epilepsies, but it should be noted that the prevalence of medically refractory epilepsy is high in TSC even with adequate trials of currently available anticonvulsant medications.^30,39 Epilepsy surgery and vagus nerve stimulation may be considered for medically refractory TSC patients, but evaluation should take place at epilepsy centers with experience and expertise in TSC, and special consideration should be given to children at younger ages experiencing neurological regression. (Category 2A)

Given that the physical features of TSC such as SEGA, epilepsy, or renal failure may present with TAND-like behaviors, sudden and rapid changes in TAND should prompt an urgent overall physical workup in such individuals. (Category 1)

After detailed initial assessment upon diagnosis, it is imperative to continue to monitor for features of TAND and their impact on daily living through basic questioning and screening procedures at each follow-up clinic visit, with a minimum frequency of once per year. Any areas of concern identified at routine TAND assessment should be followed up with more detailed evaluations by the appropriate developmental, neuropsychological, mental health, behavioral, and educational specialists and coordinated by the TSC expert team. (Category 1)

In addition to screening at each clinical visit, comprehensive, formal evaluations for TAND by an expert team should be performed at key scheduled time points: during the first 3 years of life (0–3 year evaluation), preschool (3–6 year evaluation), before middle school entry (6–9 year evaluation), during adolescence (12–16 year evaluation), and in early adulthood (18–25 year evaluation). In later adulthood, evaluations should be performed as clinical challenges emerge or based on TAND screening. More frequent specialty evaluations or treatment/interventions may be needed if annual screening reveals areas of concern. (Category 2A)

Several studies are under way to investigate the use of mTOR inhibitors as treatment for aspects of TAND. To date there is insufficient evidence to support the use of mTOR inhibitors as treatment for any aspects of TAND. There are no other TSC-specific neuropsychiatric interventions to date. However, there is high level evidence of treatment strategies for individual disorders associated with TAND, such as autism spectrum disorder, attention deficit hyperactivity disorder, and anxiety. Clinical teams should therefore use evidence-based principles to guide therapeutic decisions for best treatment of TAND in individuals with TSC, individualized to each patient. (Category 3)

Kidney

For asymptomatic, growing angiomyolipoma measuring larger than 3 cm in diameter, treatment with an mTOR inhibitor is currently recommended as the most effective first-line therapy in the short term.^8,13,14,40 The demonstrated tolerability so far to date is far preferable to the renal damage caused by angiomyolipoma progression as well as surgical and embolitic/ablative therapies, though studies are still needed to confirm long-term benefits and safety. (Category 1)

Annual clinical assessment of renal function and hypertension is required. Blood pressure control is also critical, so accurate measurement of blood pressure for patients is crucial, using age-specific criteria for children.⁴¹ Patients with hypertension should be treated with an inhibitor of the renin-aldosterone-angiotensin system as first line therapy, but avoiding an angiotensin-converting enzyme inhibitor in those treated with an mTOR inhibitor. (Category 1)

Imaging to diagnose polycystic disease, renal cell carcinoma or other tumors,^42,43 and changes in angiomyolipoma should also be performed. MRI, often obtainable at the same time as brain surveillance imaging, is the preferred imaging modality, but if MRI is not available, CT or US can still provide useful information.⁴⁴ Selective embolization followed by corticosteroids,⁴⁵ kidney-sparing resection, or ablative therapy for exophytic lesions are acceptable second-line therapy for asymptomatic angiomyolipomata. For acute hemorrhage, embolization followed by corticosteroids is more appropriate.⁴⁶ Nephrectomy is to be avoided because of the high incidence of complications and increased risk of future renal insufficiency, end-stage renal failure, and the poor prognosis that results from chronic kidney disease.^12,47 Fat-poor angiomyolipomata are not uncommon in patients with TSC, but if there is doubt and lesions are growing faster than 0.5 cm per year,⁴⁸ a needle biopsy using a sheath technique or an open biopsy may be considered. (Category 2A)

Lung

In individuals at risk for LAM, typically females 18 years of age and older, history at each clinical examination should inquire for symptoms of exertional dyspnea and shortness of breath. In patients with no clinical symptoms and no evidence of lung cysts on their baseline HRCT, repeat HRCT imaging should be performed every 5–10 years, using low-radiation imaging protocols when available. Once cysts are detected, pace of TSC-LAM progression should be determined via HRCT testing every 2–3 years accompanied by annual pulmonary function testing and 6-minute walk test. If many cysts or other evidence of advanced TSC-LAM are present, pulmonary function testing and HRCT may be needed as frequently as every 3–6 months to assist with treatment decision-making. (Category 1)

In select LAM patients with moderate-to-severe lung disease or rapid progression, treatment with an mTOR inhibitor may be used to stabilize or improve pulmonary function, quality of life, and functional performance.^8,13–15 (Category 1)

TSC-LAM patients are candidates for lung transplantation, but it is important to note that antirejection medications may lower seizure threshold and seizure medications may interfere with antirejection medications. TSC comorbidities could also impact transplant suitability. (Category 2A)

Skin and teeth

A skin survey should be performed annually, with focus on rapidly changing or symptomatic (problematic or functionally impacting) lesions and using pathological evaluation when required for diagnosis. Early intervention is indicated for bleeding, symptomatic, or potentially disfiguring TSC skin lesions. There is insufficient evidence to guide choice of treatment—case reports and case series document successful use of surgical excision, lasers, and topical mTOR inhibitors.^49–53 (Category 3)

For TSC-associated dental lesions and oral fibromas, periodic oral evaluation should occur every 3–6 months, consistent with surveillance recommendations for all individuals in the general population. Periodic preventive measures as well as oral hygiene education are important in patient management. Bony jaw lesions (asymmetry, asymptomatic swelling, or abnormal tooth eruption), when present, should be evaluated with a panoramic radiograph and treated with surgical excision or curettage if symptomatic or deforming.⁵⁴ Enamel defects (dental pits) can be treated with restorative treatments if the patient is at high cavity risk, although they rarely cause symptoms or an increased incidence of dental decay.^55,56 Oral fibromas should be excised surgically if symptomatic or if interfering with oral hygiene. Oral fibromas may recur once excised; therefore, periodic oral evaluation is encouraged.⁵⁷ (Category 3)

Heart

Until regression of cardiac rhabdomyomas is documented, follow-up echocardiogram should be performed every 1–3 years in asymptomatic patients. In addition, 12-lead ECG is recommended at minimum every 3–5 years to monitor for conduction defects. In patients with clinical symptoms, additional risk factors, or significant abnormalities on routine echocardiogram or ECG, more frequent interval assessment may be needed and may include ambulatory event monitoring. (Category 1)

Eye

Individuals with no identified ophthalmologic lesions or vision symptoms at baseline, reevaluation is necessary only if new clinical concerns arise. Otherwise, annual evaluation is recommended. For patients on vigabatrin, ophthalmologic evaluation every 3 months is recommended by the United States Food and Drug Administration, although utility of such frequent assessment is questioned, especially in the young and those with developmental disability that limit the extent of ophthalmologic evaluation that can be performed.^30,58 Thus, even in these populations, annual ophthalmologic evaluation is considered more appropriate. (Category 2B)

The 2012 International TSC Clinical Consensus Conference was sponsored and organized by the Tuberous Sclerosis Alliance. The conference was supported by generous sponsors who donated funds to the Tuberous Sclerosis Alliance without playing a role in the planning or having a presence at the conference and the resulting recommendations: the Rothberg Institute for Childhood Diseases, Novartis Pharmaceuticals, Sandra and Brian O’Brien, and Questcor Pharmaceuticals.