Medical Care
A multidisciplinary team approach is useful to address the many organ systems that may be affected by tuberous sclerosis. Periodic monitoring is necessary, ranging from 1-3 years, depending on the internal tumors and their manifestations. Treatment plans should be determined on an individual basis.
Sirolimus and everolimus have now become approved treatments for this condition. In a 2016 study, sirolimus (Rapamycin) was used in a 1% formulation applied twice daily continuously. [33] The authors found good improvement when started at an earlier age. Irritation was the main adverse effect.
Recommendations for epilepsy include the following:
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Review current antiepileptic medications.
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For new and unexplained behavior problems, mood changes, sleep disturbance, or nonconvulsive status, perform urgent brain scanning (MRI preferred to CT scanning) if symptoms and signs suggest raised intracranial pressure or if focal neurological symptoms or signs are present; perform EEG if applicable.
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Everolimus is an mTOR inhibitor that has been shown to reduce epileptic fits in over 55% of children treated. This has cytoreductive effects in subependymal giant cell astrocytoma and renal angiomyolipoma.
Solid renal lesions with a low fat content on ultrasound should be carefully investigated by an expert.
Recommendations for assessment of renal disease include the following:
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Measure blood pressure annually.
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Test renal function (eg, urea, electrolyte, and plasma creatinine levels) regularly in adults and children with polycystic kidney disease.
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Perform renal ultrasonography and repeat annually if a lesion has been documented or if otherwise indicated.
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Refer the patient to a specialist clinic if frank hematuria occurs or if treatment of the renal lesion is being contemplated.
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mTOR inhibitors have changed the landscape of management, with the EXIST-2 study showing clear reduction in renal masses with everolimus 10 mg daily. [34] This appears to be well tolerated. There has been a rebound increase in a few patients upon cessation of the drug.
Investigate for pervasive developmental disorders at age 2 years (eg, Childhood Autism Test [CHAT]) and again at school entry (ie, age 4-5 y). Perform an Alzheimer's Disease Information Questionnaire (ADIQ) if developmental delay is suspected.
Screening for psychiatric and behavioral disturbances may require testing at school entry and again at age 7 years, at secondary school transition, and during mid adolescence (age 15 y). Refer the patient to a mental health specialist as required.
If developmental delay is suspected, assess the patient's intellectual and cognitive profile at key stages in order to identify problems early and act accordingly (age 2-3 y, age 7-8 y). Access the need to place children and adults with learning disabilities and neuropsychological impairments in the care of specialists; also assess the need to refer patients to a community learning disabilities team. [35]
Infantile spasms may be treated and relapses may be less with high-dose vigabatrin. This can be given long term to prevent relapses. [36]
A 2020 double-blinded, randomized controlled trial has shown the superiority of topical rapamycin (0.1%) and calcitriol (0.0003%) combination compared with rapamycin monotherapy in the treatment of facial angiofibromas. [37] The combination resulted in a faster resolution of erythema, greater reduction in papule elevation, and better durability.
Calcitriol, the active form of vitamin D, has been shown to reduce the calcification in an in vitro model and was able to restore and rectify the defects in genes related to tuberous sclerosis complex (TSC). [38]
Studies on bumetanide therapy in TSC have shown marked improvement in all relevant behavioral domains, as was confirmed by parent questionnaires. [39] Bumetanide also has a favorable effect on hyperexcitability and sensory processing, thereby improving neuropsychiatric outcomes.
Experimental studies using rhabdomyosarcoma cells with ciclopirox olamine (CPX) have shown inhibition of mTORC1. [40] This inhibitory role contributed to its anticancer activity. CPX inhibition of mTORC1 was attributed to activation of AMP-activated protein kinase (AMPK)–TSC/raptor pathways.
Studies have identified macropinocytosis and phospholipid metabolism as novel mechanisms of metabolic homeostasis in mTORC1-hyperactive cells, which is targeted by ritanserin. [41] Hence, ritanserin may be a novel therapeutic strategy for use in mTORC1-hyperactive tumors, including pancreatic cancer.
Dysregulation of vitamin A–metabolizing enzymes has been observed in TSC gene mutations. [42] Retinoic acid normalizes RARβ levels and limits cell migration but only has a negligible effect on proliferation. The combination of retinoic acid with a reduced dosage of rapamycin has beneficial effects compared with a higher dosage of rapamycin monotherapy, as well as reducing the adverse effects of rapamycin.
Cutaneous delivery experiments using porcine skin have demonstrated that optimized micelle solutions and hydrogels (0.2%) were stable at 4°C for at least 6 and 3 months, respectively, and they increased sirolimus cutaneous bioavailability compared with the control (ointment 0.2%). [43]
mTOR inhibitors (rapamycin and its analogues ) are the preferred drug in the treatment of CNS lesions, with good efficacy and safety profile. A 2019 meta-analysis reported an increased incidence of stomatitis (grades 1 and 2) compared with earlier reported rates of upper respiratory tract infections and nasopharyngitis. [44]
A 2019 retrospective multicenter study has shown that mTOR inhibitor treatment with everolimus is safe for patients younger than 2 years. [45] Cardiac manifestations, subependymal giant cell astrocytoma size, and early epilepsy have shown the best response to everolimus.
Epilepsy in TSC can occur in 70-90% of children, with high degrees of resistance to conventional medication. EPISTOP was a multicenter clinical trial that proposed preventive antiepileptic therapy to modify the natural history. [46] Prophylactic vigabatrin therapy started after the first EEG abnormality was found to be safe and effective in reducing the severity of seizures.
A report from 2021 showed the effectiveness of cannabidiol in TSC-associated seizures. [47] The 25-mg/kg/day dosage had a better safety profile than the 50-mg/kg/day dosage.
Topical sirolimus has proven to be an effective and safe option for the treatment of facial angiofibromas in tuberous sclerosis. [48]
A single session of carbon dioxide laser ablation has been shown to increase percutaneous delivery of topical rapamycin in the treatment of angiofibromas. [49]
Comparative studies have shown superior antitumor activity of the inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor mizoribine, compared with mycophenolate mofetil. [50] These results provide preclinical support for placing mizoribine over other IMPDH inhibitors as an alternative to mTOR inhibitors for the treatment of TSC-associated tumors and other tumors featuring uncontrolled mTORC1 activity.
Studies in knockout mice have shown that oral administration of solid lipid curcumin particle (SLCP), a novel curcumin formulation, activates AMPK activity and inhibits mTOR activity in the brain tissue of Tsc2+/- mice. [51] It was found to rectify the electrophysiological abnormality and memory loss in the mice.
Everolimus is generally well tolerated with very few cutaneous adverse effects. Case reports have shown the rare occurrence of a child developing erythema nodosum while undergoing everolimus therapy. [52]
Surgical Care
The facial angiofibromas cause the most psychological distress for patients and benefit from laser treatment. The argon and pulsed-dye lasers are more effective on vascular lesions, while the carbon dioxide laser is effective in lesions with increased fibrous content. Either laser or diathermy can remove ungual fibromas.
In the case of treatment-resistant seizures in TSC patients, surgery has been shown to improve quality of life and augment neurodevelopmental potential. [53] Novel diagnostic, ablative, and neuromodulatory techniques have been developed that may help patients who were previously considered inoperable.
Consultations
Assess whether any of the following is needed:
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Special education (with appropriate documentation)
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Further vocational training or new work placement (refer to the local disablement resettlement officer if required)
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Social care options (eg, supported or sheltered employment, daycare, supported leisure activities, supported/staffed sheltered housing, residential care)
Investigate family members, when indicated, including a family history, a clinical examination (including skin evaluation with UV light), funduscopy, brain CT scanning or MRI, and genetic counseling.
Long-Term Monitoring
Neurodevelopmental testing as age-appropriate screening for behavioral and neurodevelopmental dysfunction at the time of tuberous sclerosis diagnosis is essential. Reassess children with abnormal test results periodically. Repeat assessment around the time that a child enters school and then reassess periodically in response to educational and behavioral concerns.
A tuberous sclerosis associated neuropsychiatric disorders (TAND) checklist is currently used for quick screening of behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial manifestations in patients with tuberous sclerosis complex (TSC)—THE TAND CHECKLIST. [54]
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Facial angiofibromas in a young man with tuberous sclerosis complex.
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Dysplastic periungual fibroma involving the great toe in a patient with tuberous sclerosis.
Tables
Major Features |
Minor Features |
Hypomelanotic macules (≥3, at least 5 mm in diameter) |
Confetti skin lesions |
Angiofibromas (≥3) or fibrous cephalic plaque |
Dental enamel pits (>3) |
Ungual fibromas (≥2) |
Intraoral fibromas (≥2) |
Shagreen patch |
Retinal achromatic patch |
Multiple retinal hamartomas |
Multiple renal cysts |
Cortical dysplasiasa |
Nonrenal hamartomas |
Subependymal nodules |
|
Subependymal giant cell astrocytoma |
|
Cardiac rhabdomyoma |
|
Lymphangioleiomyomatosis (LAM) plus |
|
Angiomyolipomas (≥2)b |
|
a Includes tubers and cerebral white matter radial migration lines. b A combination of the two major clinical features (LAM and angiomyolipomas) without other features does not meet criteria for a definite diagnosis. |
|
