Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

renal cell carcinoma (suspected or confirmed)

1st line – kidney-sparing resection or total nephrectomy

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ACUTE
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renal cell carcinoma (suspected or confirmed)
1st line – 

kidney-sparing resection or total nephrectomy

If there is a suspicion of underlying carcinoma, kidney-sparing resection or total nephrectomy may be needed; the aim is to perform as limited a resection as possible. See Renal cell carcinoma (Management).

Treatment should be guided by specialist advice.

intracranial aneurysm

1st line – surgical/radiologic intervention

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ACUTE
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intracranial aneurysm
1st line – 

surgical/radiologic intervention

These lesions are very uncommon but, when present, may appear as elongated or segmental outpouchings from intracranial vessels. Flow voids on magnetic resonance angiogram (MRA) may appear as enlargements or inhomogeneous signal intensity, if there is a mural clot.

Treatment can be through interventional radiologic means, such as with intra-arterial coiling procedures, or by neurosurgical intervention through open craniotomy and aneurysm clipping procedures. See Cerebral aneurysm (Management).

ONGOING

neurologic

1st line – anticonvulsant

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ONGOING
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neurologic
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infantile spasms
1st line – 

anticonvulsant

The anticonvulsant vigabatrin is particularly effective for treating infantile spasms associated with TSC, and is recommended as first-line therapy.[1][14][50][51]

A meta-analysis of vigabatrin efficacy reported a cessation rate of 95% in children with TSC.[52] The duration of treatment is undefined, but has been suggested to be 6 to 12 months. Adverse effects of vigabatrin include potential retinal toxicity associated with peripheral vision loss, which may correlate with total cumulative dose. Vigabatrin should only be used when the potential benefits outweigh the potential risk of vision loss; appropriate monitoring should be carried out.[1][53]

Adrenocorticotropic hormone (ACTH), synthetic ACTH, or prednisone may be added as second-line therapy if spasms do not abate within 2 weeks.[1] ACTH, corticosteroids, topiramate, lamotrigine, valproate, and levetiracetam may be used as alternatives to vigabatrin, but are less effective.[52]

Exacerbation of generalized seizures, including infantile spasms, has been noted with the use of carbamazepine, oxcarbazepine, and phenytoin.[24]

Adjunctive oral cannabidiol has been reported to reduce seizures in TSC patients with a history of infantile spasms.[55]​​​ Use of oral cannabidiol is off-label for children younger than 1 year.

Treatment should be guided by specialist advice.

See Infantile spasms for more information.

Primary options

vigabatrin: 25 mg/kg orally twice daily initially, increase in increments of 25-50 mg/kg/day every 3 days according to response, maximum 150 mg/kg/day

More

Consider – ketogenic diet or low glycemic index treatment

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ONGOING
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neurologic
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infantile spasms
Consider – 

ketogenic diet or low glycemic index treatment

Treatment recommended for SOME patients in selected patient group

A ketogenic diet (which is high in fat and low in carbohydrate) or low glycemic index treatment may be an effective nonpharmacologic therapy for patients with infantile spasms that are refractory to vigabatrin and hormonal therapies.[1] The ketogenic diet must be started in the hospital, under close medical supervision, with appropriate monitoring.

1st line – anticonvulsant

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ONGOING
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neurologic
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seizures
1st line – 

anticonvulsant

Anticonvulsant drug therapy should be based upon the specific seizure type(s), epilepsy syndrome(s) present, the patient's age, and adverse-effects profiles.[1][49]​​[50]​​​​​

The long-term use of agents with potential sedating and mood-altering properties (benzodiazepines, barbiturates, levetiracetam) needs to be balanced against their potential utility.

Any anticonvulsant can be utilized judiciously.[24]

See Focal seizures, Generalized seizures in adults, and Generalized seizures in children for more information.

Exacerbation of generalized seizures, particularly myoclonic (infantile spasms) and atypical absence types, has been noted with the use of carbamazepine, oxcarbazepine, and phenytoin.[24] These agents, however, are particularly beneficial in patients with focal seizures.

Cannabidiol oral solution is approved by the Food and Drug Administration for the treatment of seizures associated with TSC in patients 1 year and older. In one double-blind randomized controlled trial, adjunctive cannabidiol significantly reduced TSC-associated seizures compared with placebo.[1][56]

Treatment should be guided by specialist advice.

Consider – everolimus

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ONGOING
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neurologic
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seizures
Consider – 

everolimus

Treatment recommended for SOME patients in selected patient group

Adjunctive everolimus has been shown to reduce seizure frequency and to be well tolerated.[1][80]​ It is approved by the Food and Drug Administration as an adjunctive treatment for patients aged 2 years and older with refractory focal-onset seizures, with or without secondary generalization, associated with TSC. It reduces seizure frequency by at least 25%.[49] [ Cochrane Clinical Answers logo ] ​

Primary options

everolimus (oncologic): consult specialist for guidance on dose

Consider – ketogenic diet or low glycemic index treatment

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ONGOING
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neurologic
|
seizures
Consider – 

ketogenic diet or low glycemic index treatment

Treatment recommended for SOME patients in selected patient group

The ketogenic diet (which is high in fat and low in carbohydrate) or low glycemic index treatment may be an effective nonpharmacologic therapy for patients with TSC with intractable epilepsy. The diet must be started in the hospital, under close medical supervision, with appropriate monitoring.

Consider – early evaluation and provision of surgical interventions

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ONGOING
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neurologic
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seizures
Consider – 

early evaluation and provision of surgical interventions

Treatment recommended for SOME patients in selected patient group

Surgical options include focal and multifocal cortical resection, corpus callosotomy, and vagus nerve stimulation (VNS).[24][54][58][59]

Each intervention will require careful and phased presurgical evaluation. Prolonged electroencephalogram (EEG) monitoring via noninvasive telemetry and invasive intracranial telemetry, augmented by advanced neuroimaging techniques (MRI, magnetic resonance spectroscopy, single photon emission computed tomography, positive emission tomography [PET] scan), will be necessary to identify both the epileptogenic foci and the most appropriate neurosurgical intervention.

Focal and multifocal cortical resection of epileptogenic tubers and regions of cortical dysplasia has been successful, despite theoretical concerns regarding the activation of alternative foci.[54]

Corpus callosotomy has been most successful as an adjunctive treatment for atonic and tonic seizures. The procedure may help limit the generalization of focal-onset seizures, but does not eliminate their genesis.[24] Therefore seizure reduction is not always expected; rather, an alteration to a better-tolerated seizure semiology (focal) is anticipated.

Vagus nerve stimulation in patients with TSC offers the potential for long-term reduction in seizure frequency as a palliative procedure, and is a less invasive intervention.[59]

1st line – periodic neuroimaging

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ONGOING
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neurologic
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subependymal giant cell astrocytoma
1st line – 

periodic neuroimaging

Subependymal giant cell astrocytoma (SEGA) lesions may be identified in prepubescent children. These have a propensity to enlarge, but not invariably so. The challenge clinically is identifying when to surgically resect these lesions before they become symptomatic.

Periodic neuroimaging to follow sequential growth rate and size, at 1- to 3-year intervals depending upon symptoms and clinical-radiographic findings, is recommended until age 25 years.[1][Figure caption and citation for the preceding image starts]: Large subependymal giant cell astrocytoma on MRI (A-axial T2)Courtesy of Dr Francis J. DiMario Jr [Citation ends].com.bmj.content.model.Caption@2a45f81d[Figure caption and citation for the preceding image starts]: Large subependymal giant cell astrocytoma on MRI (B-sagittal T1)Courtesy of Dr Francis J. DiMario Jr [Citation ends].com.bmj.content.model.Caption@28b9b4b

2nd line – surgical resection or mTOR inhibitor

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ONGOING
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neurologic
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subependymal giant cell astrocytoma
2nd line – 

surgical resection or mTOR inhibitor

If untreated, some lesions may grow into the ventricular system or into the adjacent frontal lobes and optic chiasm.

When lesions are confined to within the ventricles and are less than 2 to 3 cm in size, total extirpation is likely without difficulty. Medical therapy with sirolimus or everolimus may be used to induce tumor remission or size reduction before resection.[1][49]​​[61]​​​​ Larger lesions or those with extension into the surrounding and adjacent parenchyma will more often result in a residual tumor and a need for continued surveillance.[81]

Guidelines support the use of mTOR inhibitors as an alternative to surgery for patients with mild to moderate symptoms, or for patients with large symptomatic subependymal giant cell astrocytoma (SEGA) for whom surgery is not suitable or who prefer medical treatment.[1][14][49]​​[61][62]​​​​ Sustained, clinically significant responses (≥50% reduction in SEGA volume relative to baseline) to everolimus have been reported.[49][82][83] [ Cochrane Clinical Answers logo ] ​​​​​​

Sirolimus is a reasonable alternative to everolimus for treating SEGA, although it is not approved by the Food and Drug Administration for this indication.

Treatment should be guided by specialist advice.

Primary options

everolimus (oncologic): consult specialist for guidance on dose

Secondary options

sirolimus: consult specialist for guidance on dose

Consider – ventriculoperitoneal shunting

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ONGOING
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neurologic
|
subependymal giant cell astrocytoma
Consider – 

ventriculoperitoneal shunting

Treatment recommended for SOME patients in selected patient group

Very large lesions may require cerebrospinal fluid diversion during surgery, as these lesions are quite vascular and intracranial bleeding during surgery is a possibility.[1]

skin lesions

1st line – topical sirolimus or laser therapy or excision

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ONGOING
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skin lesions
|
angiofibroma or collagen plaque
1st line – 

topical sirolimus or laser therapy or excision

Annual skin examinations are recommended for children with TSC.[1][14] Facial angiofibromas and collagen plaques typically increase in both size and number over time, and such changes may be rapid.[Figure caption and citation for the preceding image starts]: Facial angiofibromasCourtesy of Dr Francis J. DiMario Jr [Citation ends].com.bmj.content.model.Caption@7fabd3f9

Topical sirolimus is effective for treating facial angiofibromas (a proprietary formulation is FDA-approved for this indication for patients 6 years and older), and may improve other skin lesions, in patients with TSC.[1][14][49] [ Cochrane Clinical Answers logo ] ​​​​ Smaller and flatter skin lesions appear to respond better to topical sirolimus than do bulky lesions. Long-term therapy is likely to be needed to maintain benefit. Topical sirolimus is well tolerated, with no measurable systemic absorption and generally mild adverse effects.[1][49]

Oral everolimus also has beneficial effects on skin lesions, but the risk of adverse effects is greater than with the use of topical sirolimus. Many patients show improvement in skin lesions while taking a systemic mTOR inhibitor for other manifestations of TSC.[1][49]​​

Laser therapy is also an effective option for treating angiofibromas, especially if early intervention is needed, or for lesions that protrude or do not improve with topical treatment.[1] Treatment may need to be repeated over time to maintain control of new growth. Surgical resection and dermabrasion are further options for larger lesions (>2 mm).[1]

Primary options

sirolimus topical: (0.2%) children ≥6 years of age and adults: apply to the affected area(s) twice daily for 12 weeks then re-evaluate need for continuing treatment, maximum 600 mg (2 cm)/day (children 6-11 years of age) or 800 mg (2.5 cm)/day (children ≥12 years of age and adults)

1st line – clipping

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ONGOING
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skin lesions
|
ungual fibroma
1st line – 

clipping

Associated nail deformity, local irritation, and the potential to bleed are reasons for intervention.[Figure caption and citation for the preceding image starts]: Ungual fibromaCourtesy of Dr Francis J. DiMario Jr [Citation ends].com.bmj.content.model.Caption@4a86e939

The parent or caregiver can do the clipping. At times, professional intervention may be required, depending upon size, location, and patient cooperation.

2nd line – surgery

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ONGOING
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skin lesions
|
ungual fibroma
2nd line – 

surgery

If simple clipping is unsatisfactory, the primary treatment is a surgical resection.

renal

1st line – antihypertensive drug therapy

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ONGOING
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renal
|
hypertension secondary to renal complications
1st line – 

antihypertensive drug therapy

Hypertension should be assessed at least annually. Treatment of hypertension secondary to renal complications with an inhibitor of the renin-aldosterone-angiotensin system should be guided by specialist advice.[1]

1st line – surveillance

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ONGOING
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renal
|
<3 cm angiomyolipomas (AMLs)
1st line – 

surveillance

Treatment is expectant surveillance for the initial years after identification. Magnetic resonance imaging of the abdomen should be performed every 1 to 3 years.[1]

1st line – mTOR inhibitor

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ONGOING
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renal
|
≥3 cm AMLs
1st line – 

mTOR inhibitor

When an asymptomatic, growing AML becomes larger than 3 cm in diameter, treatment with an mTOR inhibitor is recommended as first-line therapy.[1][14][49]​​[62]​​​​

A trial of everolimus may be considered for adults (and possibly younger patients, although it is not approved for use in children). Everolimus has been reported to be effective in reducing AML volume and to be safe over approximately 4 years.[65][66]

Sirolimus has also shown some efficacy for treating AMLs and is a reasonable alternative, although it is not approved for this indication.[67]

Treatment should be guided by specialist advice

Primary options

everolimus (oncologic): consult specialist for guidance on dose

Secondary options

sirolimus: consult specialist for guidance on dose

2nd line – embolization

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ONGOING
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renal
|
≥3 cm AMLs
2nd line – 

embolization

Elective and selective embolization of the artery supplying a lesion 6 to 8 cm in size can result in lesion infarction and involution.

Larger lesions can be treated in the same way, but may require selective kidney-sparing resection.[1]

Consider – mTOR inhibitor

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ONGOING
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renal
|
≥3 cm AMLs
Consider – 

mTOR inhibitor

Treatment recommended for SOME patients in selected patient group

Everolimus may be considered for adults (and possibly younger patients, although it is not approved for use in children) as part of a multidisciplinary approach including embolization.[1]

Sirolimus has also shown some efficacy for treating AMLs and is a reasonable alternative, although it is not approved for this indication.[67]

Treatment should be guided by specialist advice.

Primary options

everolimus (oncologic): consult specialist for guidance on dose

Secondary options

sirolimus: consult specialist for guidance on dose

3rd line – kidney-sparing resection

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ONGOING
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renal
|
≥3 cm AMLs
3rd line – 

kidney-sparing resection

Partial kidney-sparing resection may be performed if embolization is unsuccessful after repeated attempts, or if symptoms of hemorrhage, flank pain, or impaired renal function develop.[2]

Consider – mTOR inhibitor

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ONGOING
|
renal
|
≥3 cm AMLs
Consider – 

mTOR inhibitor

Treatment recommended for SOME patients in selected patient group

Everolimus may be considered for adults (and possibly younger patients, although it is not approved for use in children) as part of a multidisciplinary approach including surgical resection.[1]

Sirolimus has also shown some efficacy for treating AMLs and is a reasonable alternative, although it is not approved for this indication.[67]

Treatment should be guided by specialist advice

Primary options

everolimus (oncologic): consult specialist for guidance on dose

Secondary options

sirolimus: consult specialist for guidance on dose

1st line – dialysis

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ONGOING
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renal
|
renal failure secondary to AMLs or polycystic renal disease
1st line – 

dialysis

Dialysis will be necessary if renal failure occurs.

Renal transplantation will ultimately be needed.

cardiovascular

1st line – antiarrhythmics

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ONGOING
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cardiovascular
|
arrhythmias secondary to rhabdomyoma
1st line – 

antiarrhythmics

Treatment does not differ from usual treatment of arrhythmias, and should be guided by specialist advice.

Most often rhabdomyomas regress postpartum, but persistence can infrequently continue to produce preexcitation arrhythmias or outflow obstruction if large globular lesions protrude into the ventricular outflow tracts.[2] Nonetheless, even large lesions are typically asymptomatic and do not require intervention.

Echocardiography should be carried out every 1 to 3 years for asymptomatic patients with cardiac rhabdomyomas, and more frequently for symptomatic patients, until regression is documented.[1]

pulmonary

1st line – mTOR inhibitor

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ONGOING
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pulmonary
|
lymphangioleiomyomatosis
1st line – 

mTOR inhibitor

Sirolimus is approved by the Food and Drug Administration for treating lymphangioleiomyomatosis (LAM), and is recommended as first-line therapy for patients with abnormal lung function.[1] Sirolimus improved spirometric measurements and gas trapping, and stabilized lung function, in patients with LAM.[70][71]

Everolimus may be used off-label for treating LAM; if the patient is already taking everolimus for other indications, continued treatment with everolimus and monitoring with serial pulmonary function tests, rather than switching to sirolimus, is recommended.[1][14][70]

Treatment with mTOR inhibitors does not appear to increase the incidence of respiratory infections in patients with LAM, and may even be protective.[72]

Treatment should be guided by specialist advice.

Primary options

sirolimus: consult specialist for guidance on dose

Secondary options

everolimus (oncologic): consult specialist for guidance on dose

Consider – oxygen and bronchodilator

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ONGOING
|
pulmonary
|
lymphangioleiomyomatosis
Consider – 

oxygen and bronchodilator

Treatment recommended for SOME patients in selected patient group

Palliative intervention with supplemental oxygen and bronchodilator therapy may have limited benefit in selected cases.[74]

2nd line – lung transplant

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ONGOING
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pulmonary
|
lymphangioleiomyomatosis
2nd line – 

lung transplant

Lung transplantation is generally required for end-stage lymphangioleiomyomatosis. However, even transplanted lungs may be at risk for recurrence due to benign cellular metastases from renal angiomyolipomas.[75]

cognitive and behavioral

1st line – early educational support

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ONGOING
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cognitive and behavioral
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impaired cognitive function or autism
1st line – 

early educational support

A checklist for TSC-associated neuropsychiatric disorders (TAND) has been developed and validated.[21][22] TAND checklist Opens in new window Yearly monitoring for the features of TAND and their impact on daily life is recommended, with more frequent monitoring if appropriate.[1] Further detailed evaluations are suggested if initial screening identifies a concern.

Repeated detailed screening is suggested at a number of 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); and then as needed.[1][14]

Early intervention and special education programs will need to be provided to support the individual child. Ongoing reassessment and program adjustment through school, in conjunction with a vocational needs assessment and community support systems placements, should be planned. Psychological and social support should be provided to families and caregivers.[1]

Consider – specialist referral and treatment

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ONGOING
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cognitive and behavioral
|
impaired cognitive function or autism
Consider – 

specialist referral and treatment

Treatment recommended for SOME patients in selected patient group

There are currently no TSC-specific interventions for any manifestations of TSC-associated neuropsychiatric disorders (TAND). Early specialist referral is required, and evidence-based nonpharmacologic and pharmacologic treatment strategies for specific disorders (e.g., autism spectrum disorder, ADHD, and anxiety disorders) should be used, personalized to the TAND profile of each patient.[1][76]

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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