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Tuberous sclerosis complex: Management and prognosis

Tuberous sclerosis complex: Management and prognosis
Author:
Stephanie Randle, MD, MS
Section Editors:
Helen V Firth, DM, FRCP, FMedSci
Alberto S Pappo, MD
Marc C Patterson, MD, FRACP
Deputy Editor:
John F Dashe, MD, PhD
Literature review current through: Dec 2022. | This topic last updated: Aug 30, 2022.

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, clinical features, and diagnosis" and "Renal manifestations of tuberous sclerosis complex" and "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults".)

MANAGEMENT — The management of TSC is directed at its neurologic and systemic manifestations, which include seizures, TSC-associated neuropsychiatric disorders, brain tumors, 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. 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, their families and caregivers [1].

Epilepsy — The most common and difficult aspect of management in TSC is the detection and treatment of seizures. (See "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis", section on 'Epilepsy'.)

EEG monitoring — 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]. In addition, all pediatric patients with TSC should have baseline electroencephalography (EEG) even if seizures are not evident. Children who have an abnormal EEG, particularly those with clinical features of TSC-associated neuropsychiatric disorders, should have a follow-up 24-hour video EEG to look for subclinical seizure activity or epileptiform discharges [2].

TSC guidelines 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]. The guidelines note that 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.

Preventive therapy in infants — Another approach involves frequent video EEG monitoring for all patients beginning at the time of TSC diagnosis along with preventive antiseizure treatment for those with epileptiform activity on EEG [3-5]. This strategy was tested in the multicenter EPISTOP study that enrolled infants with TSC and no history of seizures [6]. For patients with epileptiform activity detected on video EEG, one group (n = 25) received preventive treatment with vigabatrin started when epileptiform EEG activity was first detected before seizure onset, while the second group (n = 29) received conventional treatment with vigabatrin started only after the first clinical or electrographic seizure. Assignment was random for 27 patients but fixed according to local clinical practice for 27 others. In a pooled analysis of all 54 patients, the median time to the first clinical or electrographic seizure was longer for the preventive treatment group (587 days, 95% CI 397-infinity) compared with the conventional treatment group (124 days, 95% CI 114-200). At age 24 months, preventive treatment was associated with a reduced risk of clinical seizures, infantile spasms, and drug-resistant epilepsy. Patients in both groups had similar rates of adverse events, except for one death during epilepsy surgery in a patient in the conventional treatment group. Limitations to this study include small patient numbers and nonrandomized treatment assignment for half of the patients.

Seizure control — Appropriate selection of an antiseizure medication depends upon the type of seizure:

Many children with TSC have infantile spasms, which can be hard to control. For the treatment of infantile spasms and TSC, vigabatrin should be considered first line, as it has been shown to be the most effective treatment in this population [1]. Corticotropin (adrenocorticotropic hormone [ACTH], corticotropin injection gel) should be considered as an adjunctive or alternative to vigabatrin. (See "Infantile spasms: Management and prognosis", section on 'Vigabatrin for patients with tuberous sclerosis' and "Infantile spasms: Management and prognosis", section on 'Corticotropin (ACTH)'.)

We usually treat focal seizures with a narrow spectrum agent such as oxcarbazepine, although some clinicians use carbamazepine. For patients who become seizure-free for at least two years with antiseizure medication treatment, tapering off medication is a reasonable consideration, with 30 of 33 such patients remaining seizure free in one study [7]. Other seizure types can occur and may require different antiseizure medications.

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".)

Refractory epilepsy — Although epilepsy can be difficult to manage in TSC, one-third of patients achieve epilepsy remission, including nearly 20 percent of patients with a history of refractory epilepsy [7]. Unfortunately, approximately 60 percent of patients with TSC and epilepsy develop medically intractable epilepsy [7,8]. For such patients, treatment options include a ketogenic diet, vagus nerve stimulation, epilepsy surgery, everolimus, and cannabidiol.

Ketogenic dietary therapies – A 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 [9-12]. (See "Ketogenic dietary therapies for the treatment of epilepsy".)

Vagus nerve stimulation – Vagus nerve stimulation is a treatment option for patients who are not deemed surgical candidates or who have refractory seizures after epilepsy surgery [13-17]. 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. (See "Vagus nerve stimulation therapy for the treatment of epilepsy".)

Epilepsy surgery – Surgery is another treatment option for patients with TSC and drug-resistant epilepsy, especially when a glioneuronal hamartoma or tuber is identified as the primary epileptogenic focus [18-22]. A systematic review of 177 published cases reported that epilepsy surgery led to seizure remission in 57 percent of patients [23]. Seizure frequency was reduced in 90 percent of patients. Developmental delay and tonic seizures were potential risk factors for a less favorable outcome after surgery. 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 [24]. (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 [25]. Other EEG findings that may predict refractory epilepsy include higher hypsarhythmia severity scores, background disorganization, and absent normal sleep patterns [26].

Everolimus – Treatment with everolimus is an option for patients with refractory epilepsy associated with TSC. Everolimus is also used for the treatment of subependymal giant cell tumors associated with TSC who are not candidates for surgical resection. (See 'Everolimus' 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 antiseizure medication, with or without vagus nerve stimulation or ketogenic diet [27]. 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 in patients one year of age and older with TSC [28,29]. 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 [30]. The most common adverse events were diarrhea, seizure, and decreased appetite.

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'.)

Brain lesions — Central nervous system abnormalities characteristic of TSC include (see "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis", section on 'Brain lesions'):

Cortical glioneuronal hamartomas (also known as cortical tubers) (image 1)

White matter heterotopia

Subependymal nodules (image 2)

Subependymal giant cell tumors (SGCTs), also known as subependymal giant cell astrocytomas (SEGAs) (image 3)

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 SGCTs [1]. The international TSC guidelines recommend more frequent magnetic resonance imaging (MRI) brain scans for patients with asymptomatic SGCTs 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 is the test of choice for screening patients with TSC [31]. 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 to CT in order to minimize radiation exposure in syndromes such as TSC that predispose to cancer and require multiple imaging.

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

The duration of monitoring for new brain lesions is uncertain. In a series of 134 patients seen at a single center, no patient over the age of 20 required surgical resection of a SGCT [31]. In addition, it is atypical for a patient who has been screened every one to three years to present with a new SGCT after the age of 21. As a result, it may be appropriate to diminish the frequency of cranial MRI in young adults without evidence for SGCT. In comparison, a SGCT diagnosed at a younger age may not become symptomatic until many years later, and would require routine monitoring throughout life. International TSC guidelines are in general agreement with these conclusions; individuals without SGCTs by the age of 25 years do not need continued surveillance imaging, whereas those with asymptomatic SGCTs in childhood should continue to be monitored by MRI for life because of the possibility of growth [1].

Brain tumor treatment — There are two main treatment options for brain tumors associated with TSC [32-34]:

Surgical resection

Medical therapy with mTOR inhibitors such as everolimus

For patients with TSC who are good candidates, we suggest surgical resection for acutely symptomatic SGCTs, in agreement with international guidelines [1]. In certain cases, a cerebrospinal fluid shunt may also be necessary. The indications for surgery vary, but include the presence of hydrocephalus, increased intracranial pressure, new focal neurologic deficits, behavioral change, and/or increased seizure frequency attributable to the tumor [1,31,35,36].

In selected patients, however, mTOR inhibitor therapy (see 'Everolimus' below) may be preferred as initial treatment for symptomatic SGCTs. However, surgical or laser resection may be an option if medication management is not tolerated or desired. The choice between medical therapy and resection will depend upon individual circumstances, and shared decision-making is advised [1].

Despite their benign nature, some SGCTs show massive hemorrhage, rapid growth, and local recurrence following resection [37]. We suggest treatment with everolimus for patients with TSC and recurrent SGCTs that are symptomatic or growing. (See 'Everolimus' below.)

Either early surgical resection or medical therapy with an mTOR inhibitor (see 'Everolimus' below) can be effective for growing but otherwise asymptomatic SGCTs [1]. Limited retrospective evidence and clinical experience suggests that early surgery (eg, for a small but growing asymptomatic SGCT) may be of greater benefit than later surgery (eg, for a larger SGCT that has progressed to cause symptoms or hydrocephalus) [38,39]. In this regard, a retrospective series evaluated surgical resection of 64 SGCTs in 57 subjects with TSC (mean age 9.7 years) [40]. There were no surgical complications among 13 patients with SGCTs <2 cm size, whereas surgical complication rates were high among patients with SGCTs ≥2 cm, bilateral SGCTs, and children younger than three years of age. 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 [31].

The risk of malignant transformation is increased in patients with underlying tumor susceptibility syndromes such as the neurofibromatoses and TSC [41-43]. This realization has resulted in recommendations to avoid radiation therapy whenever possible in this group of disorders.

Everolimus — Everolimus is a macrolide immunosuppressant and a mechanistic target of rapamycin (mTOR) inhibitor, which has antiproliferative and antiangiogenic properties. The role of the hamartin-tuberin complex in cellular signaling mediated by the mTOR led to the evaluation of targeted inhibitors of this pathway as a treatment for brain tumors in patients with TSC [44-48]. (See "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis", section on 'Mechanism of tumor formation'.)

The evidence supporting the safety and efficacy of everolimus for refractory epilepsy and SGCTs is reviewed below. Other data suggest that mTOR inhibitors are useful for the treatment of renal angiomyolipomas, pulmonary lymphangioleiomyomatosis, and facial angiofibromas associated with TSC [49-51]. (See "Renal angiomyolipomas (AMLs): Management" and "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults", section on 'mTOR inhibitors' and 'Skin lesions' below.)

Everolimus for refractory epilepsyEverolimus significantly reduced seizures in patients with TSC and treatment-resistant epilepsy, as shown in the randomized, double-blind EXIST-3 trial [52].

The usual initial dose of everolimus to treat TSC-associated partial-onset seizures is 5 mg/m2 orally once daily; the dose should be adjusted in increments not exceeding 5 mg to attain trough concentrations of 5 to 15 ng/mL [53]. Everolimus is metabolized in the liver primarily by 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.

EXIST-3 was an 18-week trial that enrolled 366 subjects (ages 2 to 56 years; median age 10 years) with TSC and treatment-resistant seizures [52]. Subjects were maintained on their pre-study antiseizure medications 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. The following observations were made [52]:

The proportion of subjects 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). Seizure reduction with everolimus was noted among multiple seizure types.

The median reduction in seizure frequency was significantly greater for the low- and high-exposure everolimus groups (29 and 40 percent, compared with 15 percent for placebo).

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). 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 [54,55].

These results suggest that everolimus is an effective and safe adjunctive treatment option for patients with TSC and treatment-resistant epilepsy.

Everolimus for SGCTs – We suggest treatment with everolimus for patients with TSC and symptomatic subependymal giant cell tumors (SGCTs) who are not good candidates for surgical resection, such as patients with multiple or infiltrating SGCTs, and those with multisystem disease and/or comorbidities that may increase the risk of surgery. In addition, everolimus is an alternative to surgery for patients with asymptomatic but enlarging SGCTs.

The starting dose of everolimus for patients with SGCT is 4.5 mg/m2. The dose of everolimus is then titrated in increments not exceeding 5 mg to achieve a serum trough concentration of 5 to 15 ng/mL.

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 SGCTs to treatment with everolimus (n = 78) or placebo (n = 39) [46]. At a median follow-up of approximately 10 months, the proportion of patients experiencing a ≥50 percent reduction in volume of SGCTs was significantly greater for the everolimus group compared with placebo (35 versus 0 percent). In addition, the proportion of subjects with SGCT progression – defined as increase in SGCT volume, worsening of non-target SGCTs, appearance of new lesions, or new hydrocephalus – was significantly lower for the everolimus group (0 versus 15 percent).

In an earlier open-label study of 28 patients with TSC and SGCTs 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) [47]. 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.

Additional experience will be required to determine the long-term effectiveness of treatment with this approach [56]. Data from the extension phase of one small trial suggest that everolimus remains safe with sustained benefit over five or more years of treatment [57].

Adverse effects – The most frequent adverse reactions of everolimus are stomatitis, diarrhea, pyrexia, and respiratory tract infections. Long-term use of everolimus may be associated with an increased risk of diabetes [58].

Cognitive and behavioral problems — Although patients with TSC may have normal intelligence, cognitive disability is a common and primary feature of TSC. In addition, autism and autistic behaviors, including hyperactivity, inattention, and self-injurious behavior, are common in children with TSC who have seizures and can be a significant source of stress for parents and caregivers. (See "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis", section on 'Cognitive deficits' and "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis", section on 'Autism and behavioral problems'.)

International TSC guidelines recommend that all newly diagnosed patients should be evaluated for TSC-associated neuropsychiatric disorders (TAND), including possible aggressive behaviors, autism spectrum disorders, intellectual disabilities, psychiatric disorders, neuropsychological deficits, school problems, and occupational difficulties (table 1) [1]. Thereafter, all patients with TSC should be screened for TAND at least once a year, using a validated screening instrument such as the TAND checklist. 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 tumors, seizures, or renal disease.

Depending on patient age, the following assessments and interventions are recommended [59,60]:

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 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 [1,59].

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: Genetics, clinical features, and diagnosis", section on 'Dermatologic features'.)

International guidelines for TSC recommend performing a detailed skin examination at the time of diagnosis and annually thereafter (table 1) [1]. Good sun protection is recommended for individuals with TSC, since hypopigmented macules are susceptible to sunburn, and since ultraviolet-induced DNA damage may play a role in the development of facial angiofibromas [61,62]. 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 [61]. Many patients complain about the cosmetic impact of the facial angiofibromas and the lack of effective treatment.

Limited data suggest that topical mTOR inhibitors such as sirolimus (rapamycin) are effective for the treatment of facial angiofibromas [49,63-65], ungual fibromas [66], and hypomelanotic macules [67]; sirolimus topical gel received FDA approval in 2022 for the treatment of facial angiofibroma associated with TSC in patients age ≥6 years [68]. Patients, particularly teens, should be counseled that ointments marketed for acne are not effective; their use should be discouraged. Disfiguring lesions (particularly the forehead plaque) may improve with laser therapy and dermabrasion [69-71].

Dental and oral lesions — 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, and 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 [61].

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 jaw bone lesions should be treated with surgical excision or curettage.

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

Because of the potential for renal lesion development and growth, for all patients with TSC, renal surveillance with MRI is recommended at the time of diagnosis (table 1), with repeat testing every one to three years [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 is discussed in detail elsewhere. (See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults".)

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

International TSC guidelines note that for individuals with rhabdomyoma identified via prenatal ultrasound, fetal echocardiography may be useful to detect those with high a risk of heart failure after delivery [1]. Although most cardiac rhabdomyomas regress spontaneously, some can cause significant hemodynamic compromise. 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 [72].

Children with TSC, particularly those less than three years of age, should have baseline echocardiography and electrocardiography to evaluate for rhabdomyoma and arrhythmia, respectively (table 1). Adults with TSC and no cardiac history or symptoms do not require echocardiography. However, baseline electrocardiography 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 electrocardiogram (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.

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

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 administration recommends that patients on vigabatrin 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 as more appropriate even for children receiving vigabatrin [1].

Counseling — The diagnosis of a child with TSC has a major impact on the family [73]. Counseling should be provided for patients, families, and caregivers. It should include information on the inheritance of the disorder, genetic testing results, prognosis, and psychosocial adjustment. The progressive nature of the disease and its clinical manifestations and complications should be addressed. International TSC guidelines recommend that first-degree relatives of affected patients with TSC should be offered clinical assessment [1]. In addition, they should be offered genetic testing if a pathogenic variant has been identified in the index case.

The genetics of TSC, including potential recurrence risk in other offspring, should be explained to the parents of affected children. (See "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis", section on 'Genetics'.)

Specific counseling may be warranted for adolescents with TSC who face issues with self-esteem and the psychosocial impact of this condition.

Organizations such as the Tuberous Sclerosis Alliance (United States) and the Tuberous Sclerosis Association (United Kingdom) provide information about the disorder and general support. Referral of the family to a local chapter can be helpful.

PROGNOSIS — TSC is a progressive disorder, and the individual features tend to emerge at different times. 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: Genetics, clinical features, and diagnosis", section on 'Natural history'.)

Causes of death — 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 [74]. 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 [75]. The most common causes of mortality were neurologic disease (including 10 patients who died as a result of subependymal giant cell tumors 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 [75]. Several children with severe developmental delay and intractable 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 [76]. 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 subependymal giant cell tumor, 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

The management of tuberous sclerosis complex (TSC) is directed at its neurologic and systemic manifestations, which include seizures, TSC-associated neuropsychiatric disorders, brain tumors, skin lesions, renal disease, pulmonary disease, cardiac involvement, and an increased risk of malignant tumors (table 1). (See 'Management' above.)

The most common and difficult aspect of management in TSC is the control of seizures. Monitoring for the development of seizures includes parental education to recognize seizures in infants as well as serial electroencephalography. For the treatment of infantile spasms and TSC, vigabatrin should be considered first line, as it has been shown to be the most effective treatment in this population. Corticotropin (adrenocorticotropic hormone [ACTH], corticotropin injection gel) should be considered as an adjunctive or alternative to vigabatrin. We usually treat focal seizures with a narrow spectrum agent such as oxcarbazepine. Other seizure types can occur and may require different antiseizure medications. For patients with TSC who develop epilepsy that is resistant to standard antiseizure medications, options include adjunctive treatment with everolimus, the ketogenic diet, vagus nerve stimulation, and epilepsy surgery. (See 'Epilepsy' above.)

Brain imaging should be obtained every one to three years for patients with TSC until age 25 years to monitor for the development of subependymal giant cell tumors (SGCTs), which are also known as subependymal giant cell astrocytomas (SEGAs). For patients with TSC who are good candidates, we suggest surgical resection for acutely symptomatic SGCTs (Grade 2C). The indications for surgical resection include the presence of hydrocephalus, increased intracranial pressure, new focal neurologic deficits, behavioral change, and/or increased seizure frequency attributable to the SGCT. For patients with TSC and symptomatic SGCTs who are not good candidates for surgical resection, such as those with multiple or infiltrating SGCTs, and those with multisystem disease and/or comorbidities that may increase the risk of surgery, we suggest treatment with everolimus (Grade 2C). The starting dose and titration is described above in detail. (See 'Brain tumor treatment' above and 'Everolimus' above.)

All newly diagnosed patients should be evaluated for TSC-associated neuropsychiatric disorders (TAND), including possible aggressive behaviors, autism spectrum disorders, intellectual disabilities, psychiatric disorders, neuropsychological deficits, school problems, and occupational difficulties. 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; additional measures may include early intervention and individual education programs, special education services, other scholastic, social and vocational support, and psychiatric evaluation and treatment. (See 'Cognitive and behavioral problems' above.)

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

Patients with TSC should have periodic dental and oral inspections or examinations to assess for dental enamel defects (pits) and intraoral fibromas. (See 'Dental and oral lesions' above.)

TSC is frequently associated with renal lesions. The most common are angiomyolipomas and renal cystic disease. Additional manifestations include renal cell carcinoma, oncocytoma, interstitial disease, focal segmental glomerulosclerosis, and other renal lesions. The surveillance, diagnosis, and treatment of TSC-associated renal disease is discussed in detail separately. (See "Renal manifestations of tuberous sclerosis complex".)

Some individuals with TSC, most often women 18 years of age or older, develop pulmonary disease that is indistinguishable from the diffuse interstitial fibrosis known as lymphangioleiomyomatosis. The evaluation, diagnosis, and management of TSC-related pulmonary involvement is discussed in detail elsewhere. (See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults".)

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

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 an 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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