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Tuberous sclerosis complex: Management and prognosis

Tuberous sclerosis complex: Management and prognosis
Literature review current through: Jan 2024.
This topic last updated: Jan 19, 2024.

INTRODUCTION — Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder that is characterized by pleomorphic features involving many organ systems, including developmental delay and multiple benign hamartomas of the brain, eyes, heart, lung, liver, kidney, and skin. The expression of the disease varies substantially among individuals and within families. Some individuals with TSC may demonstrate only dermatologic features of the disease, while others may develop more serious neurologic or systemic manifestations.

The management and prognosis of TSC will be reviewed here. Other aspects of TSC are discussed elsewhere:

(See "Tuberous sclerosis complex: Genetics and pathogenesis".)

(See "Tuberous sclerosis complex: Clinical features".)

(See "Tuberous sclerosis complex: Evaluation and diagnosis".)

(See "Renal manifestations of tuberous sclerosis complex".)

(See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults".)

MULTIDISCIPLINARY CARE AND MONITORING — The management of TSC is directed at its neurologic and systemic manifestations, which include epilepsy, brain tumors, TSC-associated neuropsychiatric disorders (TAND), skin lesions, renal disease, pulmonary disease, cardiac involvement, and an increased risk of malignant tumors. Information regarding baseline evaluations, ongoing surveillance (table 1), and therapeutic interventions for these problems is provided in the sections that follow.

Specialized clinics — Ideally, children with TSC should be cared for by specialized TSC clinics that have been established in many countries to address the medical needs and psychosocial challenges of affected patients and their families and caregivers [1,2]. The TSC Alliance provides on online list of TSC Clinics.

Skin lesions — Nearly all patients with TSC have one or more of the skin lesions characteristic of the disorder. The most common skin lesions in TSC are hypopigmented macules (picture 1), angiofibromas (picture 2), shagreen patches (picture 3), fibrous plaques (picture 4), ungual fibromas (picture 5), confetti lesions, and intraoral fibromas. (See "Tuberous sclerosis complex: Clinical features", section on 'Dermatologic manifestations'.)

Monitoring – International guidelines for TSC recommend performing a detailed skin examination at the time of diagnosis and annually thereafter for children with TSC (table 1) [1].

Management – Good sun protection is recommended for individuals with TSC, since hypopigmented macules are susceptible to sunburn and ultraviolet-induced deoxyribonucleic acid (DNA) damage may play a role in the development of facial angiofibromas [3,4]. There is no significant risk of malignant transformation of skin lesions associated with TSC, which tend to be stable after puberty.

When not prominent, the skin lesions do not require treatment. However, closer surveillance and intervention is recommended for skin lesions that rapidly change in size or number and for those that cause pain, bleeding, functional impairment, or social problems [3].

Many patients complain about the cosmetic impact of the facial angiofibromas. Disfiguring lesions (particularly the forehead plaque) may improve with laser therapy and dermabrasion [5-7]. Sirolimus topical gel received US Food and Drug Administration (FDA) approval in 2022 for the treatment of facial angiofibroma associated with TSC in patients age ≥6 years [8]. We offer this to patients with TSC and facial angiofibromas. Limited data suggest that topical mechanistic target of rapamycin (mTOR) inhibitors such as sirolimus (rapamycin) are effective for the treatment of facial angiofibromas [9-12], ungual fibromas [13], and hypomelanotic macules [14].

Patients, particularly teens, should be counseled that ointments marketed for acne are not effective; their use should be discouraged.

Ophthalmic involvement — Ophthalmic findings in TSC include both retinal and nonretinal abnormalities. (See "Tuberous sclerosis complex: Clinical features", section on 'Ophthalmic manifestations'.)

Monitoring – International TSC guidelines recommend a complete eye examination (table 1), including dilated funduscopy, at the time of diagnosis and annually thereafter to look for retinal abnormalities and visual field defects [1].

Vigabatrin-associated vision loss – Of special concern, children treated with vigabatrin (eg, for infantile spasms in TSC) can develop irreversible retinal dysfunction and visual field constriction. Therefore, the FDA recommends that patients on vigabatrin should have a baseline ophthalmologic evaluation at initiation of therapy and every three months until three to six months after treatment has been discontinued. However, monitoring for vigabatrin-associated vision loss is challenging as visual fields are difficult to assess in infants and in those with developmental disability. Thus, the international TSC guidelines consider annual ophthalmologic evaluation to be more appropriate even for children receiving vigabatrin [1].

Dental and oral lesions — Patients with TSC may develop intraoral fibromas, gingival hyperplasia, dental enamel pits, and deforming jawbone cysts. (See "Tuberous sclerosis complex: Clinical features", section on 'Oral and dental manifestations'.)

Monitoring – International guidelines for TSC recommend performing a detailed dental and oral inspection or examination at the time of diagnosis (table 1) to assess for dental enamel defects (pits) and intraoral fibromas [1]. Thereafter, the guidelines recommend a dental and oral evaluation every six months, as well as periodic preventive measures including oral hygiene. Due to the risk of jaw bone cyst formation, panoramic radiographic evaluation is recommended by age six or seven years, or earlier if there is asymmetry, asymptomatic swelling, or delayed or abnormal tooth eruption [3].

Management – Dental pits are rarely symptomatic but can be treated with sealants if the patient is at increased risk of developing dental caries [1]. Oral fibromas that are symptomatic or interfering with oral hygiene can be surgically removed but may recur. Symptomatic or deforming jawbone lesions should be treated with surgical excision or curettage.

Cardiac involvement — The characteristic cardiac feature of TSC is a rhabdomyoma, a benign tumor that often presents as multiple lesions in neonates with TSC. Most regress spontaneously during infancy, and resection is not required unless the child is symptomatic. (See "Cardiac tumors", section on 'Rhabdomyomas'.)

Fetal rhabdomyoma – Cardiac rhabdomyomas may be visualized antenatally by fetal ultrasound scan. For individuals with rhabdomyoma identified via prenatal ultrasound, fetal echocardiography may be useful to detect those with a high risk of heart failure after delivery [1]. Although most cardiac rhabdomyomas regress spontaneously, some can cause significant hemodynamic compromise or arrhythmias. In a report of three fetuses with cardiac rhabdomyomas, prenatal treatment with maternal sirolimus at doses ranging from 1 to 6 mg/day was associated with a gradual decrease in the size of the rhabdomyomas in all three patients without significant adverse effects [15]. Other small studies have also reported that maternal treatment with mTOR inhibitors (sirolimus or everolimus) is associated with regression of fetal TSC-related rhabdomyoma [16-19].

Monitoring in childhood – Children with TSC, particularly those younger than three years of age, should have baseline echocardiography and electrocardiography (ECG) to evaluate for rhabdomyoma and arrhythmia, respectively (table 1). Adults with TSC and no cardiac history or symptoms do not require echocardiography. However, baseline ECG is recommended to assess for cardiac conduction defects.

For follow-up, the guidelines recommend that asymptomatic children with TSC and rhabdomyoma have echocardiography every one to three years until regression of cardiac rhabdomyoma is documented [1]. Asymptomatic patients of all ages should have an ECG every three to five years to monitor for conduction defects. Patients with symptoms or additional risk factors may need more frequent or advanced assessments, such as ambulatory event monitoring.

Renal disease — TSC is frequently associated with renal lesions. The most common are angiomyolipomas, while renal cystic disease is the second most common. Other renal manifestations include renal cell carcinoma, oncocytoma, interstitial disease, focal segmental glomerulosclerosis, and other lesions.

Monitoring – For all patients with TSC, renal surveillance with magnetic resonance imaging (MRI) is recommended at the time of diagnosis (table 1), with repeat testing every one to three years because of the potential for renal lesion development and growth [1]. Other guideline recommendations include at least annual assessment of blood pressure, proteinuria, and estimation of glomerular filtration rate [1].

The surveillance, diagnosis, and treatment of TSC-associated renal disease is discussed in detail separately. (See "Renal manifestations of tuberous sclerosis complex".)

Pulmonary disease — Some adults with TSC develop pulmonary disease that is indistinguishable from the diffuse interstitial fibrosis known as lymphangioleiomyomatosis. This condition can result in significant limitation in pulmonary function. The most common presenting features are dyspnea and pneumothorax. (See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults", section on 'Clinical manifestations'.)

The evaluation, diagnosis, and management of TSC-related pulmonary involvement are discussed in detail elsewhere. (See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults".)

Risk of invasive malignancy — TSC is associated with a variety of benign hamartomatous tumors such as angiofibromas, rhabdomyomas, and angiomyolipomas. However, both children and adults with TSC are at risk for malignant tumors, primarily in the kidneys, brain, and soft tissues. In a report that analyzed 16,564 cases of childhood cancer, 509 cases were diagnosed in patients with genetic diseases, and of those, children with TSC accounted for 20 cases (4 percent) [20]. Based upon an estimated prevalence of TSC of 1 in 15,000 children in the United Kingdom, the relative risk of malignancy in children with TSC was 18-fold higher than for those without TSC. This was almost entirely due to the increased incidence of brain tumors and rhabdomyosarcoma. It has been suggested that the risk of invasive cancer is higher in patients with pathogenic variants involving TSC2 compared with those in TSC1 [21].

Specific observations regarding malignancy are as follows:

Spontaneous malignant transformation of subependymal giant cell astrocytomas (SEGAs) has been rarely described [21].

Adults with TSC are at increased risk for the development of renal cell carcinoma. (See "Renal manifestations of tuberous sclerosis complex", section on 'Renal cell carcinoma' and "Renal manifestations of tuberous sclerosis complex".)

Some angiomyolipomas can become malignant, and these are usually of the epithelioid type.

Although rare, there is an increased risk for rhabdomyosarcoma in both children and adults with TSC [20,22]. Since they are not localized to one organ system, there is no specific surveillance for these tumors.

The periodic surveillance that is recommended for all patients with TSC is predominantly focused on monitoring the development of benign and malignant tumors.

Role of mTOR inhibitor therapy — Everolimus is a macrolide immunosuppressant and a mechanistic (mammalian) mTOR inhibitor, which has antiproliferative and antiangiogenic properties. The role of the hamartin-tuberin complex in cellular signaling mediated by the mTOR signaling pathway led to the evaluation of targeted inhibitors of this pathway as a treatment for patients with TSC [23-27]. (See "Tuberous sclerosis complex: Genetics and pathogenesis", section on 'Mechanism of tumor formation'.)

Use in patients with TSC

Everolimus for refractory epilepsyEverolimus is approved for the adjunctive treatment of patients ≥2 years of age with TSC-associated partial-onset seizures [28]. The role of everolimus in the treatment of TSC-associated epilepsy is reviewed below. (See 'Refractory epilepsy' below.)

Everolimus for SEGAsEverolimus is approved for patients ≥1 year of age with TSC for the treatment of symptomatic SEGAs that cannot be cured by surgery [28]. The role of everolimus in the treatment of SEGAs is reviewed below. (See 'Brain tumor treatment' below.)

mTOR inhibitors for systemic involvement – mTOR inhibitors (sirolimus or everolimus) may be useful for the treatment of facial angiofibromas, renal angiomyolipomas, and pulmonary lymphangioleiomyomatosis associated with TSC [9,29,30]. (See 'Skin lesions' above and "Renal angiomyolipomas (AMLs): Management" and "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults", section on 'mTOR inhibitors'.)

Everolimus dose and administration — The recommended initial dose of everolimus to treat TSC-associated partial-onset seizures is 5 mg/m2 orally once daily [28]. The recommended initial dose of everolimus for patients with SEGA is 4.5 mg/m2 [28]. For both indications, the dose should be adjusted in increments not exceeding 5 mg to attain trough concentrations of 5 to 15 ng/mL [31].

Everolimus is metabolized in the liver primarily by cytochrome P450 3A4 (CYP3A4) and is a substrate of the P-glycoprotein (PgP) transporter. Several antiseizure medications typically used for patients with TSC are either inducers or substrates of these enzymes. Therefore, the dose of everolimus should be reduced for patients with severe hepatic impairment and for patients taking concomitant PgP or CYP3A4 inhibitors, whereas the dose should be increased for patients taking concomitant PgP or CYP3A4 inducers.

Adverse effects of everolimus — The most frequent adverse reactions to everolimus are stomatitis, diarrhea, pyrexia, and respiratory tract infections. Uncommon but potentially serious adverse effects include hypersensitivity reactions, infection, renal failure, angioedema, myelosuppression, hyperlipidemia, hyperglycemia, and fetal toxicity [32]. Long-term use of everolimus may be associated with an increased risk of diabetes [33].

EPILEPSY — The most common and difficult aspect of management in TSC is the detection and treatment of seizures. Many children with TSC develop focal seizures and infantile spasms during infancy. Therefore, international TSC guidelines recommend that parents and caregivers should be educated to recognize these types of seizures even if none have occurred at the time of initial diagnosis [1]. (See "Tuberous sclerosis complex: Clinical features", section on 'Seizures and epilepsy'.)

EEG monitoring — Newly diagnosed infants with TSC should have baseline electroencephalography (EEG) even if seizures are not evident. However, routine EEG is not needed for children two years of age and older if there are no clinical events suspicious for seizures.

TSC guidelines from an international consensus panel recommend routine EEG monitoring (table 1) for individuals with TSC who have known or suspected seizure activity. The frequency of such monitoring should be determined by clinical need rather than a defined time interval [1].

For infants without seizures, a discussion should be had about the frequency of EEG surveillance. TSC guidelines recommend that EEG monitoring for asymptomatic infants with TSC should be done every six weeks up to age 12 months and every three months up to age 24 months [1]. Prolonged video EEG (≥24 hours) is appropriate when seizure occurrence is unclear or when there are unexplained changes in sleep, behavior, or cognitive or neurologic function.

Preemptive therapy in infants — An unproven approach involves frequent video EEG monitoring for all infants with no seizures beginning at the time of TSC diagnosis along with preemptive (preventive) antiseizure medication (ASM) treatment with vigabatrin started when epileptiform activity is first detected on EEG before seizure onset [32,34-36]. The evidence for this approach is inconsistent. Compared with starting vigabatrin at seizure onset, the preemptive strategy failed to delay onset or lower the incidence of focal seizures or refractory epilepsy in a randomized controlled trial (PREVeNT) of 56 infants with TSC [37]. By contrast, pooled data from randomized and nonrandomized infants with TSC and no seizures enrolled in the EPISTOP study found that preventive treatment was associated with a reduced risk of clinical seizures, infantile spasms, and drug-resistant epilepsy [38]. Limitations to these studies include small patient numbers and nonrandomized treatment assignment for half of the patients in the EPISTOP study.

Initial ASM therapy — Appropriate choice of an ASM depends upon the type of seizure. ASM treatment should be directed by an epileptologist or neurologist with experience in managing TSC.

Infantile spasms – Many children with TSC have infantile spasms, which can be hard to control. For the treatment of infantile spasms and TSC, vigabatrin is first-line, as it is considered the most effective treatment in this population [1,2,35,39]. Corticotropin (adrenocorticotropic hormone [ACTH], corticotropin injection gel) or prednisolone are adjunctive or alternative ASMs. Dosing recommendations are listed in the table (table 2).

Comparative data are sparse. In the only trial, 22 patients with infantile spasms due to TSC were randomly assigned to treatment with vigabatrin or hydrocortisone [39]. The number of patients achieving spasm-free status was 11 (100 percent) with vigabatrin and 5 (45 percent) with hydrocortisone (Peto odds ratio [OR] 13.8; 95% CI 2.2-86.4) [40]. (See "Infantile epileptic spasms syndrome: Management and prognosis", section on 'Vigabatrin for patients with tuberous sclerosis' and "Infantile epileptic spasms syndrome: Management and prognosis", section on 'Corticotropin (ACTH)'.)

Focal seizures – We treat focal seizures with an appropriate ASM following the principles used to select seizure treatment in the general population [1,2]. Options include (but are not limited to) oxcarbazepine, levetiracetam, and zonisamide. Vigabatrin is often used as a first-line ASM for treating focal seizures in children less than one year of age [35].

The management of focal epilepsy is discussed in detail separately. (See "Seizures and epilepsy in children: Initial treatment and monitoring" and "Initial treatment of epilepsy in adults".)

Other seizure types – Other seizure types can occur with TSC and may require different ASMs. The ASM chosen for initial therapy should be one that is effective for a particular seizure type or syndrome; other considerations include ASM dose formulation, dose frequency, the relative risk of certain adverse effects, the potential for drug-drug interactions, and individual patient characteristics and comorbid conditions. A broad-spectrum ASM can be used if there is ambiguity about whether the seizures are focal or generalized, while a narrow-spectrum ASM can be used for focal-onset seizures.

Failure of initial ASM therapy

Failure of initial ASM monotherapy for infantile spasms – For patients with infantile spasms that do not abate within two weeks of vigabatrin treatment (along with resolution of the hypsarhythmia pattern if present on EEG), ACTH, synthetic ACTH, or prednisolone can be added (table 2) [1].

Everolimus – Adjunctive treatment with everolimus is an option for patients with epilepsy associated with TSC. Everolimus significantly reduced seizures in patients with TSC and treatment-resistant epilepsy, as shown in the randomized, double-blind EXIST-3 trial [41]. The dose, administration, and adverse effects are discussed above. (See 'Everolimus dose and administration' above and 'Adverse effects of everolimus' above.)

EXIST-3 enrolled 366 subjects (ages 2 to 56 years; median age 10 years) with TSC and treatment-resistant seizures [41]. Subjects were maintained on their pre-study ASMs and were randomly assigned in a 1:1:1 ratio to placebo, low-exposure everolimus, or high-exposure everolimus. The dose of everolimus was adjusted during an initial six-week titration phase to attain trough everolimus concentration levels of 3 to 7 ng/mL for the low-exposure group and 9 to 15 ng/mL for the high-exposure group.

At 18 weeks, the proportion of subjects in EXIST-3 achieving a ≥50 percent reduction in seizure frequency was significantly greater for the low- and high-exposure everolimus groups (28 and 40 percent respectively, versus 15 percent for the placebo group) [41]. The median reduction in seizure frequency was also significantly greater for the low- and high-exposure everolimus groups (29 and 40 percent, compared with 15 percent for placebo). Seizure reduction with everolimus was noted among multiple seizure types. Few patients became seizure-free; for the low- and high-exposure everolimus groups, seizure-free rates were approximately 5 and 4 percent, compared with <1 percent for the placebo group.

Serious adverse events were more frequent in the low- and high-exposure everolimus groups compared with placebo (14, 14, and 3 percent, respectively), but treatment discontinuation rates were low in all groups (5, 3, and 2 percent, respectively) [41]. Similar to other studies, the most common adverse events associated with everolimus were stomatitis, diarrhea, and pyrexia.

Longer-term data from the open-label extension and post-extension phases of the EXIST-3 trial reported sustained reductions in TSC-associated seizures [42,43].

These results suggest that everolimus is an effective and safe adjunctive treatment option for patients with TSC and treatment-resistant epilepsy. Everolimus is also used for the treatment of subependymal giant cell astrocytomas associated with TSC for patients who are not candidates for surgical resection. (See 'Brain tumor treatment' below.)

Cannabidiol – A placebo-controlled trial evaluated cannabidiol (pharmaceutical) versus placebo in patients (n = 224) with TSC and inadequately controlled seizures despite a least one ASM, with or without vagus nerve stimulation or ketogenic diet [44]. Over the 16-week treatment, the median frequency of TSC-associated seizures for patients assigned to cannabidiol 25 mg/kg per day was reduced by 49 percent, versus 27 percent with placebo. Based upon this trial and other clinical data, the US Food and Drug Administration (FDA) in August 2020 approved cannabidiol (pharmaceutical) for the treatment of seizures associated with TSC in patients one year of age and older [45,46]. In a subsequent open-label extension trial of 129 patients, the median reduction of TSC seizures at 48 weeks of cannabidiol treatment (mean modal dose 27 mg/kg per day) was 54 percent [47]. The most common adverse events were diarrhea, seizure, and decreased appetite.

The dose, administration, and adverse effects of cannabidiol (pharmaceutical) are reviewed separately. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Cannabidiol'.)

Note that co-administration of cannabidiol and sirolimus (used to treat TSC-associated lymphangioleiomyomatosis) can increase sirolimus blood levels and the risk of sirolimus toxicity. (See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults", section on 'mTOR inhibitors'.)

Refractory epilepsy — Approximately 40 to 60 percent of patients with TSC and epilepsy develop medically refractory epilepsy, defined by the failure of two ASMs [48-50]. For such patients, treatment options include epilepsy surgery, a ketogenic diet, and neurostimulation (eg, vagus nerve stimulation). For patients with TSC and refractory epilepsy, referral to a comprehensive epilepsy center is appropriate to determine eligibility for epilepsy surgery and other treatment modalities [51].

Epilepsy surgery – Surgery is a first-line treatment option for patients with TSC and drug-resistant epilepsy, especially when a glioneuronal hamartoma or tuber is identified as the primary epileptogenic focus [1,35,52]. Eligibility for epilepsy surgery is determined by a comprehensive evaluation that includes efforts to identify the epileptogenic zone and a determination of the extent to which it can be resected safely. (See "Seizures and epilepsy in children: Refractory seizures", section on 'Surgical evaluation' and "Surgical treatment of epilepsy in adults", section on 'Surgical evaluation'.)

A 2022 systemic review identified 40 studies that reported seizure outcomes for over 1100 patients with TSC after surgical interventions including any combination of resection, disconnection, and ablation [52]. An "excellent” outcome (indicating seizure freedom or only nondisabling focal seizures or auras since surgery) was reported for 59 percent. A 2021 systematic review with data from 34 studies and 1026 patients with TSC-associated medically refractory epilepsy reported that postsurgical freedom rates ranged from 65 to 75 percent but declined to 48 to 57 percent with longer follow-up [51].

Concordance between the predominant interictal focus and the site of ictal electrographic onset may predict a better surgical outcome. Increased use of sophisticated neuroimaging techniques may improve the efficacy of surgical treatment [53]. (See "Neuroimaging in the evaluation of seizures and epilepsy" and "Seizures and epilepsy in children: Refractory seizures", section on 'Epilepsy surgery'.)

A retrospective review of 70 patients with TSC who had surgery for relief of epilepsy associated poorer surgical outcomes with younger age at seizure onset, infantile spasms, and bilateral interictal EEG discharges [54]. Other EEG findings that may predict refractory epilepsy include higher hypsarhythmia severity scores, background disorganization, and absent normal sleep patterns [55].

Ketogenic dietary therapies – A version of the ketogenic diet may help control seizures and should be considered along with other nonpharmacologic interventions for patients with TSC who have drug-resistant epilepsy, particularly those who are not surgical candidates or who have refractory seizures after epilepsy surgery [56-59]. In addition to the classic ketogenic diet, ketogenic dietary therapies include the modified Atkins diet, the medium-chain triglyceride diet, the low glycemic index treatment, and modified ketogenic diet. (See "Ketogenic dietary therapies for the treatment of epilepsy".)

Neurostimulation Vagus nerve stimulation is the best studied neurostimulation treatment option for patients with TSC who are not deemed surgical candidates or who have refractory seizures after epilepsy surgery [60-64]. The efficacy of vagus nerve stimulation for patients with TSC and epilepsy appears to be in the same range as that seen for patients with other causes of medically refractory epilepsy that is not surgically amenable.

In the United States, vagus nerve stimulation is approved as adjunctive treatment for patients ≥4 years of age with focal seizures that are refractory to ASMs. In Europe, vagus nerve stimulation is approved, unrestricted by age, as adjunctive therapy for patients whose epileptic disorder is dominated by focal seizures (with or without secondary generalization) or generalized seizures that are refractory to ASMs. (See "Vagus nerve stimulation therapy for the treatment of epilepsy".)

Responsive neurostimulation is another option for patients with TSC and drug-resistant epilepsy, but it has been studied in only small numbers of patients with TSC [65]. (See "Evaluation and management of drug-resistant epilepsy", section on 'Responsive cortical stimulation' and "Seizures and epilepsy in children: Refractory seizures", section on 'Responsive neurostimulation'.)

Epilepsy remission — Although epilepsy can be difficult to manage in TSC, approximately one-third of patients achieve epilepsy remission. In a report of 291 patients with TSC-related epilepsy, refractory epilepsy developed in 62.5 percent, while epilepsy remission was achieved by 33.5 percent, including nearly 20 percent of patients with a history of refractory epilepsy [48].

For patients who become seizure-free for at least two years with ASM treatment, tapering off medication is a reasonable consideration, with 30 of 33 such patients remaining seizure-free in one study [48].

BRAIN LESIONS — Central nervous system abnormalities characteristic of TSC include cortical glioneuronal hamartomas (also known as cortical tubers) (image 1), subependymal nodules (image 2), subependymal giant cell astrocytomas (SEGAs) (also known as subependymal giant cell tumors [SGCTs]) (image 3), and white matter heterotopia. (See "Tuberous sclerosis complex: Clinical features", section on 'Brain lesions'.)

Surveillance for and treatment of these lesions is discussed in the sections that follow.

Brain imaging — Brain imaging should be obtained every one to three years for patients with TSC until age 25 years (table 1) to monitor for the development of SEGAs [1]. The international TSC guidelines recommend more frequent MRI brain scans for patients with asymptomatic SEGAs that are large, growing, or causing ventricular enlargement, and for patients with developmental or cognitive disabilities who are unable to reliably report subtle symptoms [1]. The patients and their families and caregivers should be informed about the potential of new symptoms.

MRI versus CT – MRI is the test of choice for screening patients with TSC [66]. Head computed tomography (CT; or head ultrasound in neonates or infants when fontanels are open) may be used if MRI is not available or cannot be performed, but the overall sensitivity of CT and ultrasound is suboptimal compared with MRI. Head CT is more sensitive than MRI for detecting calcified subependymal nodules, but this advantage has no clinical utility. Furthermore, MRI is preferred over CT to minimize radiation exposure in syndromes such as TSC that predispose to cancer and require multiple imaging studies. (See "Radiation-related risks of imaging".)

Role of contrast – In agreement with TSC guidelines, we avoid contrast agents for brain imaging unless there is an enlarging lesion or clinical suspicion for SEGA [1]. Contrast enhancement on MRI or CT is seen with a majority of subependymal nodules and SEGAs but does not appear to provide any significant prognostic information.

Duration of monitoring – International TSC guidelines recommend that individuals without SEGAs by the age of 25 years do not need continued surveillance imaging, whereas those with asymptomatic SEGAs in childhood should continue to be monitored with MRI for life because of the possibility of growth [1]. In a series of 134 patients seen at a single center, no patient over the age of 20 required surgical resection of a SEGA [66]. It is atypical for a patient who has been screened every one to three years to present with a new SEGA after the age of 21. By comparison, a SEGA diagnosed at a younger age may not become symptomatic until many years later and would require routine monitoring throughout life.

Brain tumor treatment — The main treatment options for brain tumors associated with TSC are laser ablation, open surgical resection, and medical therapy with everolimus [67-69]. The choice among these options will depend upon individual circumstances, and shared decision-making is advised [1]. In most cases, we offer a trial of everolimus prior to laser treatment or open surgery. Some patients with acutely symptomatic SEGAs will require surgical resection. Other small, stable lesions may be followed expectantly with serial imaging (table 1), as described (see 'Brain imaging' above). For patients with multiple and/or enlarging lesions, the choice between laser treatment, open surgical resection, and everolimus is individualized.

The dose, administration, and adverse effects are discussed above. (See 'Everolimus dose and administration' above and 'Adverse effects of everolimus' above.)

Growing but asymptomatic SEGA – Laser interstitial thermal therapy (LITT), open surgical resection, or medical therapy with a mechanistic target of rapamycin (mTOR) inhibitor (everolimus) can be effective for growing but otherwise asymptomatic SEGAs [1]. Neoadjuvant treatment with everolimus may be useful to manage large tumors and facilitate surgery.

Laser interstitial thermal therapy (LITT) – Tumor shrinkage or ablation with MRI-guided LITT is our preferred treatment option for most growing SEGAs since it is less invasive than surgical resection [70]; exceptions include very large SEGAs (eg, ≥2 cm), active hydrocephalus or risk of acute hydrocephalus, and/or broad attachment of the tumor to the basal ganglia [71,72]; in these situations, open surgical resection is generally preferred. However, long-term outcome data are lacking for LITT in the management of TSC-related brain tumors [1,73].

Open surgical resection – Limited retrospective evidence and clinical experience suggest that early surgery (eg, for a small but growing asymptomatic SEGA) may be of greater benefit than later surgery (eg, for a larger SEGA that has progressed to cause symptoms or hydrocephalus) [74,75]. In a retrospective series evaluating surgical resection of 64 SEGAs in 57 subjects with TSC (mean age 9.7 years), there were no surgical complications among 13 patients with SEGAs <2 cm size, whereas surgical complication rates were high among patients with SEGAs ≥2 cm, bilateral SEGAs, and children younger than three years of age [76]. The mortality rate following surgery was 6 percent. The most common surgical complications persisting beyond 12 months were hemiparesis and cognitive decline (13 and 5 percent, respectively). A poor surgical outcome was reported in another institutional series for children age 11 years and older at the time of resection [66].

Everolimus – The multicenter EXIST-1 trial randomly assigned children and adults (median age 9.5 years, range 0.8 to 26.6) with TSC and growing SEGAs to treatment with everolimus (n = 78) or placebo (n = 39) [25]. At a median follow-up of approximately 10 months, the proportion of patients experiencing a ≥50 percent reduction in volume of SEGAs was significantly greater for the everolimus group compared with placebo (35 versus 0 percent). In addition, the proportion of subjects with SEGA progression (defined as increase in SEGA volume, worsening of nontarget SEGAs, appearance of new lesions, or new hydrocephalus) was significantly lower for the everolimus group (0 versus 15 percent). In the open-label extension phase of EXIST-1, everolimus treatment was associated with a sustained reduction in tumor volume [77].

In an earlier open-label study of 28 patients with TSC and SEGAs who were treated with oral everolimus, the median patient age was 11 years (range 3 to 34 years) and the median treatment duration was 22 months (range 4 to 34 months) [26]. Some tumor volume decrease was seen in all evaluable patients at 6 and 12 months, and a decrease in tumor volume of ≥30 percent at one year was observed in 21 patients (75 percent), a result that was clinically meaningful and statistically significant. In addition, there was a statistically significant reduction in seizure frequency.

Symptomatic SEGA – Surgical resection for acutely symptomatic SEGAs may be required for some patients [1]. In certain cases, a cerebrospinal fluid shunt may also be necessary. The indications for surgery vary, but they include the presence of hydrocephalus, increased intracranial pressure, new focal neurologic deficits, behavioral change, and/or increased seizure frequency attributable to the tumor [1,66,78,79].

For patients with TSC and symptomatic SEGAs who are not good candidates for surgical resection, such as those with multiple or infiltrating SEGAs and those with multisystem disease and/or comorbidities that may increase the risk of surgery, treatment with everolimus may be preferred.

Recurrent SEGAs – Despite their benign nature, some SEGAs show massive hemorrhage, rapid growth, and local recurrence following resection [80]. Treatment with everolimus may be preferred for SEGAs that recur after surgery and are symptomatic or growing.

Avoidance of radiation therapy – The risk of malignant transformation is increased in patients with underlying tumor susceptibility syndromes such as the neurofibromatoses and TSC [81-83]. This realization has resulted in recommendations to avoid radiation therapy whenever possible in this group of disorders.

NEUROPSYCHIATRIC DISORDERS — Although patients with TSC may have normal intelligence, most patients have one or more of the conditions that comprise TSC-associated neuropsychiatric disorders (TAND). These include intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, behavioral problems, psychiatric disorders, neuropsychologic deficits, school problems, and occupational difficulties. TAND can be a significant source of stress for patients, parents, and caregivers. (See "Tuberous sclerosis complex: Clinical features", section on 'TSC-associated neuropsychiatric disorders (TAND)'.)

Evaluation – All patients with newly diagnosed or suspected TSC should be evaluated for TAND using a validated screening instrument such as the TAND checklist [1]. Thereafter, patients with TSC should be screened for TAND at least once a year (table 1). In addition, the guidelines recommend a comprehensive formal evaluation for TAND at key developmental time points including infancy (0 to 3 years of age), preschool (3 to 6 years), pre-middle school (6 to 9 years), adolescence (12 to 16 years), early adulthood (18 to 25 years), and as needed thereafter. Any sudden neurobehavioral change should also prompt an evaluation to identify and treat possible medical causes such as subependymal giant cell astrocytomas, seizures, or renal disease.

Depending on patient age, the following assessments and interventions are recommended [84,85]:

Gross and fine motor skills

Social-communication skills

Global cognitive ability

Receptive and expressive language

Attentional-executive skills

Visuospatial skills

Memory

Vocational assessment with knowledge of cognitive strengths and weaknesses

Adaptive behavior and daily living skills

Social care needs

Management – Management should be directed by the TAND profile of each patient and optimal treatment of individual disorders (eg, autism spectrum disorder, attention deficit hyperactivity disorder, anxiety disorder); additional measures may include early intervention and individual education programs; special education services; other scholastic, social, and vocational support; and psychiatric evaluation and treatment [1,84].

(See "Autism spectrum disorder in children and adolescents: Overview of management".)

(See "Attention deficit hyperactivity disorder in children and adolescents: Overview of treatment and prognosis".)

(See "Attention deficit hyperactivity disorder in adults: Treatment overview".)

(See "Pharmacotherapy for anxiety disorders in children and adolescents".)

(See "Generalized anxiety disorder in adults: Management".)

PROGNOSIS — TSC is a progressive disorder, and the individual features tend to emerge at different times.

Variable severity — The severity of disease can vary substantially among affected individuals; some may demonstrate only dermatologic features of the disease, while others may develop more serious neurologic or systemic manifestations. The natural history of TSC is described in greater detail separately. (See "Tuberous sclerosis complex: Clinical features", section on 'Variable phenotype' and "Tuberous sclerosis complex: Clinical features", section on 'Presentation'.)

Mortality — Complications in major organ systems are the predominant source of morbidity in adolescents and young adults with TSC, and they contribute to an increased mortality [86]. In one report of 355 patients from the Mayo Clinic, there were 40 deaths that were attributable to TSC, which was more than expected in the general population [87]. The most common causes of mortality were neurologic disease (including 10 patients who died as a result of subependymal giant cell astrocytomas [SEGAs] and 13 patients who died as a consequence of severe mental handicaps leading to status epilepticus or pneumonia) and renal disease (including 11 patients who died because of renal carcinoma, hemorrhage into angiomyolipoma, or renal failure). Other causes of mortality included pulmonary disease in four patients, all of whom died at age 40 or older from lymphangioleiomyomatosis, and bronchopneumonia [87]. Several children with severe developmental delay and refractory seizures died from pneumonia, and cardiac rhabdomyoma resulted in the death of one infant.

In a report of 284 patients with TSC from the United Kingdom, there were 16 deaths (at a median age of 33 years) attributed to complications of TSC [88]. Of these, eight were caused by renal disease and four by sudden unexpected death in epilepsy (SUDEP). Of the remainder, two deaths were secondary to complications of lymphangioleiomyomatosis, one was from a SEGA, and one was due to pancreatic cancer.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Tuberous sclerosis" and "Society guideline links: Lymphangioleiomyomatosis".)

SUMMARY AND RECOMMENDATIONS

Multidisciplinary care and monitoring

Specialized clinics – Children with tuberous sclerosis complex (TSC) should be cared for by specialized TSC clinics, where available. The management of TSC is directed at its neurologic and systemic manifestations. (See 'Multidisciplinary care and monitoring' above and 'Specialized clinics' above.)

Skin – Children with TSC should have a detailed skin examination at the time of diagnosis and annually thereafter (table 1). Disfiguring skin lesions in TSC may improve with laser therapy, dermabrasion, and possibly with topical mechanistic target of rapamycin (mTOR) inhibitors. (See 'Skin lesions' above.)

Eye – Monitoring involves a complete ophthalmologic examination at the time of diagnosis and annually thereafter to look for retinal abnormalities and visual field defects (table 1). Patients on vigabatrin should have an ophthalmologic evaluation at the start of therapy and every three months until three to six months after treatment has been discontinued.

Dental and oral – Patients with TSC should have periodic dental and oral examinations to assess for dental enamel defects (pits) and intraoral fibromas (table 1). Due to the risk of jawbone cyst formation, panoramic radiographic evaluation is recommended by age seven years. (See 'Dental and oral lesions' above.)

Cardiac – Children with TSC, particularly those younger than three years of age, should have baseline echocardiography and ECG to evaluate for rhabdomyoma and arrhythmia, respectively (table 1). Asymptomatic children with TSC and a rhabdomyoma should have echocardiography every one to three years until regression of the rhabdomyoma is documented. Asymptomatic patients of all ages should have an ECG every three to five years to monitor for conduction defects. (See 'Cardiac involvement' above.)

Renal – TSC is frequently associated with renal lesions including angiomyolipomas and renal cystic disease. The surveillance, diagnosis, and treatment of TSC-associated renal disease are discussed in detail separately. (See "Renal manifestations of tuberous sclerosis complex".)

Pulmonary – Some individuals with TSC, most often women 18 years of age or older, develop pulmonary lymphangioleiomyomatosis. The evaluation, diagnosis, and management of TSC-related pulmonary involvement is discussed in detail elsewhere. (See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults".)

Neurologic monitoring and management

Epilepsy management – The most common and difficult aspect of treating TSC is the control of seizures. (See 'Epilepsy' above.)

-Monitoring for the development of seizures includes parental education to recognize seizures in infants as well as serial EEG. (See 'EEG monitoring' above.)

-For the treatment of infantile spasms and TSC, we suggest vigabatrin as initial therapy rather than hormonal therapy with corticotropin injection gel (adrenocorticotropic hormone [ACTH]) or oral glucocorticoids (Grade 2C). Vigabatrin is considered the most effective treatment in this population. We treat focal seizures and other seizure types with an appropriate antiseizure medication (ASM), following the principles used to select seizure treatment in the general population. (See 'Initial ASM therapy' above.)

-For patients with infantile spasms that do not abate within two weeks of vigabatrin treatment (along with resolution of the hypsarhythmia pattern if present on EEG), ACTH, synthetic ACTH, or prednisolone can be added (table 2). Options for failure of initial ASM therapy include everolimus and cannabidiol (pharmaceutical), as reviewed above. (See 'Failure of initial ASM therapy' above.)

-For patients with TSC who develop epilepsy that is refractory to ASMs, options include epilepsy surgery, the ketogenic diet, and vagus nerve stimulation. (See 'Refractory epilepsy' above.)

Brain lesions – Brain MRI with and without contrast should be obtained every one to three years for patients with TSC until age 25 years (table 1) to monitor for the development of subependymal giant cell astrocytomas (SEGAs), also known as subependymal giant cell tumors (SGCTs). (See 'Brain imaging' above.)

The main treatment options for brain tumors associated with TSC are laser interstitial thermal therapy (LITT), open surgical resection, and medical therapy with everolimus. The choice among these approaches will depend upon individual circumstances, and shared decision-making is advised. In most cases, we offer a trial of everolimus prior to laser treatment or open surgery. Some patients with acutely symptomatic SEGAs will require surgical resection. Other small, stable lesions may be followed expectantly with serial imaging (table 1), as described. For patients with multiple and/or enlarging lesions, the choice between LITT, surgery, and everolimus is individualized. (See 'Brain tumor treatment' above.)

TSC-associated neuropsychiatric disorders (TAND) – These disorders include intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, behavioral problems, psychiatric disorders, neuropsychologic deficits, school problems, and occupational difficulties. All patients with newly diagnosed or suspected TSC should be evaluated for TAND using the TAND checklist (table 1). Thereafter, screening for TAND should be performed at least annually, and more comprehensive formal evaluations should be obtained at key developmental time points. Management should be directed by the TAND profile of each patient and optimal treatment of individual disorders. (See 'Neuropsychiatric disorders' above.)

Prognosis – TSC is highly variable in severity. Some individuals may demonstrate only dermatologic features of the disease, while others may develop more serious neurologic or systemic manifestations. Complications in major organ systems are the predominant source of morbidity in adolescents and young adults with TSC, and they contribute to a modest increased incidence of early death. (See 'Prognosis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Sharon Plon, MD, PhD, James Owens, MD, PhD, and John B Bodensteiner, MD, who contributed to earlier versions of this topic review.

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Topic 16902 Version 58.0

References

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