Tuberous sclerosis complex

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By Hema R Murali MBBS and Narayana S Murali MD

Multispecialty involvement is indicated in the management, and regional tuberous sclerosis complex clinics in the United States specialize in this. The website for the Tuberous Sclerosis Alliance is a comprehensive resource for physicians and patients alike.

Drug treatment. Seizures are frequently refractory to treatment. While recommending both low-dose ACTH and vigabatrin, the American Academy of Neurology recommended low dose ACTH preferentially over vigabatrin as the drug of choice for short-term treatment in tuberous sclerosis complex-related infantile spasms, based on Level C studies (Go et al 2012). The TSC Consensus Meeting for SEGA and Epilepsy Management in 2012, however, recommended vigabatrin as the first drug of choice for infantile spasms and focal seizures secondary to tuberous sclerosis (Curatolo 2012). Vigabatrin was approved in the United States in 2009 for the adjunctive treatment of refractory complex partial seizures and as treatment of infantile spasms (Tolman 2009). Literature review suggests 25 to 50 mg/kg per day may be a good starting point. Typically, 100 to 150 mg/kg per day of vigabatrin is used.

Approximately 1 in 3 individuals on vigabatrin suffer visual field loss, revealing a progressive “dose-adverse response” relationship. Patients on vigabatrin need close monitoring for visual field defects with any of the several known ocular techniques. These could include electroretinography, multifocal electroretinography, electrooculography, field-specific visual evoked potentials, and optical coherence tomography. Some of these techniques require sedation or anesthesia and certain centers have adopted regular ophthalmology evaluations instead. Insomnia, agitation, and constipation occur in fewer patients.

In view of both the frequent association and potentially devastating developmental outcome of infantile spasms in tuberous sclerosis complex, diagnosis and management of infantile spasms solely based on clinical grounds has been suggested, even in the absence of classical EEG findings (Thiele 2004). A published meta-analysis has identified a 95% response rate in this clinical setting (Hancock 1999). Also, prophylactic management of patients based on early EEG changes has been shown to improve cognition and seizure control with lesser need for polypharmacy in the long run (Jozwiak 2011). Asleep and awake EEG monitoring is recommended every month for the first 6 months and then every 6 to 8 weeks unless there are other abnormalities (Curatolo 2012).

In some centers, valproate or topiramate have been added to vigabatrin if the spasms were refractory to monotherapy with vigabatrin. ACTH, parenterally as a gel, and oral prednisone have been used in management of infantile spasms. There has been an inordinate increase in the cost of ACTH since 2008, preventing its use in many cases.

There is no head-to-head study for the preferred antiepileptic medication for localization-related epilepsy. Studies suggest that carbohydrate restriction alone (ie, modified Atkin’s® or low glycemic index diet) may have similar benefits to that of the classical ketogenic diet.

Growing evidence suggests that mTOR inhibitors may be helpful in the management of epilepsy for patients with tuberous sclerosis complex and may lead to improvement in cognition. These include rapamycin (sirolimus), everolimus, and temsirolimus, a prodrug for sirolimus. These agents work by dissociating mTORC1 from its cofactor Raptor, thereby inactivating it. An open label trial of everolimus for epilepsy in tuberous sclerosis complex is currently underway in the United States. An initial publication from this trial suggests that everolimus is effective in intractable epilepsy in patients with tuberous sclerosis complex, by a duration-dependent mechanism, in about 12 weeks of initiating medication (Krueger et al 2013b).

Surgery in epilepsy. Patients with focal seizures should be considered for epilepsy surgery (Bebin et al 1992). Surgical treatment of patients with tuberous sclerosis complex and intractable epilepsy is most effective when a single tuber or epileptogenic area can be identified. The source of the seizures can be identified and resected even if other tubers or diffuse EEG abnormalities are present. It has been shown that the seizure activity often originates from the mildly hypometabolic regions adjacent to the cortical tubers rather than directly from the tuber in humans. Multiple newer modalities of imaging are available to identify the epileptogenic focus. In patients with unlocalized epilepsy patterns, seizure control may be obtained by corpus callosotomy (Guerreiro et al 1998; Koh et al 2000). Early epilepsy surgery has been advocated as a means for better prognosis in intractable epilepsy (Wu et al 2010). Epilepsy surgery should be considered for all tuberous sclerosis complex patients with seizures refractory to medical treatment (Madhavan et al 2007).

Multimodality management of subependymal giant cell astrocytomas (SEGAs).SEGAs need to be managed with serial MRI every 1 to 3 years in the first 2 decades of life, even if they are asymptomatic. Monitoring every 6 months is recommended for SEGAs greater than 1 cm in size. Neuroimaging should be continued in patients with evidence of SEGAs prior to 25 years of age, but the frequency can be decreased beyond this period (Krueger et al 2013a). Signs of increased intracranial pressure, positional headache, irritability, and loss of seizure control should be recognized as possible indicators of a symptomatic subependymal giant cell astrocytoma and urgent neuroimaging should be performed in such an instance. Gross total resection is the procedure of choice for management and is usually curative (Jozwiak et al 2013). However, if the tumor cannot be completely resected or if regrowth occurs, rapamycin or everolimus are indicated in management. Surgery is indicated for asymptomatic SEGAs as well, if there is ventriculomegaly, or increase in size of the lesion on imaging. Everolimus can be considered as an alternative in this situation. Regrowth is known to occur on discontinuation of mTOR inhibitors (Krueger et al 2010). Everolimus has been used in children as young as 12 months of age with excellent benefit in SEGA size and seizure control (EXIST-1 trial) (Kotulska et al 2013).

Neuropyschiatric issues. Early psycho-educational or neuropsychological assessment is important to identify problems in cognitive development and to develop appropriate teaching strategies. Problems with inattention, hyperactivity, aggression, or autistic features may necessitate psychological or psychiatric consultation. The transition from special education resources in the classroom to vocational rehabilitation opportunities in young adulthood should be carefully monitored (DeVries et al 2005). Periodic assessment is advised at each developmental age in childhood to tailor appropriate support services through the school, and psychosocially. Abrupt behavioral changes in patients should precipitate an evaluation for SEGA, epilepsy, and renal failure. A tuberous sclerosis-associated neuropsychiatric disorders (TAND) checklist has been validated under a pilot study. It has been suggested as a starting point to address the significant burden of disease associated with tuberous sclerosis in a scheduled and organized manner (Leclezio et al 2015).

Management of renal complications. Blood pressure and renal function (with glomerular filtration rate) have to be monitored annually. Measurement of serum cystatin C concentration can be used to evaluate glomerular filtration rate. It is critical to manage the severe hypertension associated with renal cysts appropriately, as surgical decompression alone to relieve parenchymal compression is inadequate. Caution must be exercised in use of ACTH/prednisone in the above setting, especially with coexistent polycystic kidney disease. A renin-aldosterone-angiotensin system inhibitor is advised as first line therapy. Angiotensin converting enzyme inhibitors should be avoided in patients on mTOR inhibitors. Zonisamide and topiramate used as antiepileptics increase risk of nephrolithiasis.

Lifelong renal MRI is recommended every 1 to 3 years in all age groups because renal angiomyolipomas may enlarge rapidly, even in children (Ewalt et al 1998). It is recommended that newly diagnosed cases of tuberous sclerosis have renal MRI scanning for early detection of polycystic kidney disease associated with contiguous gene deletions spanning the TSC2/PKD1 genes. Asymptomatic, growing renal angiomyolipomas less than 3 cm in diameter should be treated with an mTOR inhibitor. Large renal angiomyolipomas can be managed by embolization. The success of transarterial therapeutic embolization, even in angiomyolipomas as large as 4cm or greater (Ewalt et al 2005; Kothary et al 2005), makes surgery a less preferred option, especially for central lesions.

Surveillance with annual to triennial renal imaging is recommended even after therapeutic embolization as recurrence of renal angiomyolipomas is common (Kothary et al 2005). A recent large, double-blinded, placebo-controlled multicenter trial (EXIST-2) revealed clear benefit from everolimus in angiomyolipomas and sporadic lymphangioleiomyomatosis (Bissler et al 2013). Patients with renal or pulmonary failure require meticulous medical care and may be candidates for organ transplant.

Management of pulmonary complications. An important recommendation is that women with tuberous sclerosis complex have a noncontrast, high-resolution chest CT once at 18 years of age, then every 5 to 10 years if asymptomatic, and at any time if inexplicable or persistent respiratory symptoms occur (Krueger et al 2013a). A single CT image slice at the level of the carina has been suggested by some experts as a reasonable screening method with low radiation exposure (Cudzilo et al 2013). A baseline pulmonary function test is indicated in women at age 18. Annual pulmonary function tests are also indicated in patients with lymphangioleiomyomatosis. A serum vascular endothelial growth factor type D (VEGF-D) level may be helpful to establish a baseline for future lymphangioleiomyomatosis development or progression. Counseling on smoking risks and estrogen use in oral contraceptive preparations, which can compound the impact of lymphangioleiomyomatosis, should also occur. Talc pleurodesis and pleurectomy are avoided in patients who are candidates for lung transplantation in the future. Patients should be vaccinated for influenza and pneumococcus (Franz et al 2010). Sirolimus may be considered on an individual basis in patients with rapid decline in lung function or symptoms, after careful evaluation of the risk-to-benefit ratio in an experienced center (Johnson et al 2010). Everolimus has been proven to be effective in a large trial for sporadic lymphangioleiomyomatosis (Bissler et al 2013).

Lymphangioleiomyomatosis-associated chylous pleural effusions have been shown to decrease or even resolve with sirolimus therapy. Also, pulmonary function seems to stabilize or improve with sirolimus treatment of lymphangioleiomyomatosis, and this response seems to be durable for at least 2 years (Taveira-DaSilva et al 2011).

Management of cardiac complications. A follow-up echocardiogram should be performed every 1 to 3 years in asymptomatic patients until regression of cardiac rhabdomyomas is documented. In addition to a baseline 12-lead ECG, an ECG is recommended at minimum every 3 to 5 years to monitor for conduction defects. Cardiac symptoms including congestive cardiac failure and arrhythmias may require symptomatic treatment, including medications, ablative procedures, pacemakers, resective surgery for obstructive tumors and, rarely, heart transplant (Demkow et al 1995). Screening abdominal sonography and chest radiography should be performed every 2 to 3 years before puberty and every year after puberty, for vascular aneurysms (Jost et al 2001).

In patients with symptomatic retinal hamartomas with persistent and recurrent vitreous hemorrhage, pars plana vitrectomy is a therapeutic strategy (Mennel et al 2007). Surveillance of lesion growth by periodic imaging has been advised, although no conclusive guidelines exist yet. Annual eye examination is advised in asymptomatic patients.

There are reports and studies of benefits of topical rapamycin with or without tacrolimus for angiofibromas in children and adults (Tanaka et al 2013). Annual skin survey is recommended to assess for symptomatic or rapidly changing lesions. Dental assessments are advised every 3 to 6 months.

Everolimus is the only orally available mTOR inhibitor, which is typically titrated up from a dose of 4.5 mg/m2 body surface area to achieve a drug level in the range of 5 to 15 ng/ml. The most common side effects on mTOR inhibitors were stomatitis and upper respiratory tract infections. Other side effects included rash, gastrointestinal symptoms, increased total cholesterol, decreased fibrinogen levels, decreased white blood cell counts, anorexia, and urinary tract infections. This medication has been used for up to 4 years in tuberous sclerosis patients.

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited