Laboratory Studies
Laboratory studies are performed as indicated clinically to identify genetic mutations associated with the disorder, monitor anticonvulsant treatment, identify idiosyncratic or dose-related adverse effects, and identify or monitor underlying renal or pulmonary disease.
Molecular genetic testing is now commercially available in the United States through several laboratories, including Athena Diagnostics, Ambry, GeneDX, and Invitae. Testing through Athena was extended to include screening for large deletions and other types of mutations to improve their diagnostic yield.
Under optimal circumstances, genetic testing identifies mutations in up to 75–80% of affected individuals. Therefore, a negative genetic diagnostic test result does not exclude a diagnosis of tuberous sclerosis.
Diagnosis should be possible in most cases using established clinical criteria. Molecular genetic testing is useful in uncertain or questionable cases, for prenatal diagnosis, and for screening family members of an affected individual. The utility of molecular diagnostic testing is limited by the cost (approximate self-pay costs of $3300 to provide deletion analysis and DNA sequencing for TSC1 and TSC2 index cases and $450 for confirmatory testing in family members). Costs are frequently not covered by private insurance carriers. Patient assistance programs may be available through various laboratories.
Imaging Studies
Three imaging procedures are usually undertaken: CT or MRI scans of the brain, renal ultrasounds, and echocardiograms. Some centers perform these evaluations annually, at least until adulthood. This is a topic of some controversy, as the natural history of TSC and the cost-effectiveness of these types of screening examinations are not known clearly. Some are concerned that routine screening can lull the clinician into a false sense of security, and thus into ignoring symptoms that arise between serial examinations. Suggested frequency of monitoring tests was documented by the 2012 International Tuberous Sclerosis Complex Consensus Conference. This includes brain MRI every 1–3 years until the age of 25 years; annual clinical assessment of renal function and blood pressure; abdominal MRI (for instance, at the same as brain MRI), CT or ultrasound; echocardiogram every 1–3 years in asymptomatic patients until regression of cardiac rhabdomyomas is documented, and 12-lead ECG every 3–5 years; and high-resolution chest CT every 5–10 years in asymptomatic females 18 years of age and older, and every 2–3 years in patients with lung cysts. [14]
CT or MRI scans of the brain
CT or MRI scans of the brain are performed to identify SEGAs before obstructive hydrocephalus occurs. They also identify the extent and number of cortical tubers present. [2] On occasion, they may reveal vascular dysplastic lesions such as aneurysms.
SEGAs are often large and difficult to resect by the time they produce clinical symptoms; even then, avoiding substantial complications such as blindness, hemiparesis, and shunt dependency may be impossible. Initially their manifestations may be quite subtle, such as a change in personality or behavior. They rarely exhibit significant growth after puberty, if they have not already shown evidence of this. These factors should be considered when planning serial neuroimaging examinations.
The author's own practice has been to perform MRI, rather than CT, scans every 2 years in asymptomatic patients, at least until puberty. In children, sedation usually is required for CT scan, as it is for MRI. MRI is superior to CT scan for detection of tubers, migrational anomalies, and vascular lesions. MRI does not involve radiation exposure, as does CT.
In addition to standard brain MRI protocols, fluid-attenuated inversion recovery sequences (FLAIR) should be obtained. [15] FLAIR is superior for identification of tubers. Contrast can be administered; however, both SEGAs and SENs typically enhance. Contrast enhancement is not in itself an indication that an SEN is going to grow, or that surgical intervention is necessary. MR angiography is useful if an aneurysm or vascular dysplastic lesion is noted.
Some authors have performed resections on SEGAs that exhibit an interval increase in size on serial imaging. Our own practice has been to obtain more frequent imaging studies when a lesion increases in size, provided no signs/symptoms of ventricular obstruction, new focal neurological deficit, or increased intracranial pressure are noted. Lesions may stabilize or stop growing spontaneously after increasing in size (see following images).
Enhancing subependymal nodules, including a probable giant cell astrocytoma in the region of the foramen of Monro. Subependymal nodules may increase in size over time from one scan to the next, and then stabilize. This lesion had not changed with serial imaging over 2 years. The patient remains asymptomatic and is monitored closely for any deterioration.
This presumed tuber was first noted in the left frontal region. It expanded in size, affecting adjacent structures across the midline and resulting in calcifications still evident in the right frontal region. The tuber then spontaneously involuted. About 20% of tubers may show changes in imaging characteristics over time, requiring close imaging follow-up. This patient remained asymptomatic from the mass effect, and his seizures resolved as the lesion involuted.
Renal ultrasounds
Renal ultrasounds are performed to assess change in AMLs or cysts, in the hope that this will allow operative intervention prior to development of renal failure.
Due to under-recognition and underestimation of AML occurrence and size, renal ultrasound is losing favor and is being replaced by abdominal MRI.
Small renal cysts and AMLs usually do not grow significantly until after puberty, and often not until the third or fourth decade of life.
In the author's practice, abdominal MRI is obtained every 2–3 years, concurrent with brain MRI. Studies are obtained more frequently if clinically indicated.
Echocardiograms
Echocardiography is performed as part of the baseline evaluation in a patient with newly diagnosed or suspected TSC. Identification of cardiac rhabdomyomas can aid in diagnosis. Depending on their location and size, rhabdomyomas can result in valvular dysfunction, outflow tract obstruction, ventricular hypokinesis, or arrhythmias.
In our practice, echocardiography is not repeated if no lesions are seen on baseline examination. If cardiac lesions are seen, echocardiography is repeated as indicated clinically.
Positron emission tomography
No current indication exists for routine positron emission tomography (PET) scanning in patients with TSC.
PET scans may be useful when patients are undergoing evaluation as candidates for epilepsy surgery. PET scanning with the tracer alpha-methyltryptophan may have particular utility in identifying epileptogenic tubers as part of the evaluation for epilepsy surgery.
Single-photon emission computed tomography
No current indication exists for routine single-photon emission computed tomography (SPECT) scanning in patients with TSC.
SPECT scans may be useful when patients are undergoing evaluation as candidates for epilepsy surgery.
Other Tests
Electroencephalogram
EEG should be performed in patients with TSC in whom seizures are suspected. Many neurologists will have low threshold for performing EEG to assess for subclinical seizures; there is also increasing consideration of whether early antiseizure treatment may impact neurodevelopmental outcome. Follow-up EEGs are performed as clinically indicated. A multicenter NIH-sponsored trial that aims to assess the impact of EEG surveillance and early treatment with vigabatrin of asymptomatic infants with TSC on developmental outcome and epilepsy is currently underway.
Some patients with TSC have a coexisting recognizable epilepsy syndrome such as West syndrome (ie, infantile spasms) or Lennox-Gastaut syndrome. If so, prolonged video-EEG telemetry may be useful to help in the following:
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Detecting syndrome-specific EEG findings
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Capturing and classifying each of the patient's multiple seizure types
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Educating parents on which of the patient's "events" are seizures and which are nonepileptic behavioral events (especially atypical absences)
Electrocardiogram
Baseline ECG is recommended for all patients newly diagnosed with TSC, since cardiac arrhythmias, although rare, may have sudden death as their presenting symptom.
In the author's practice, ECGs are performed at diagnosis and every 2-3 years thereafter until puberty.
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Enhancing subependymal nodules, including a probable giant cell astrocytoma in the region of the foramen of Monro. Subependymal nodules may increase in size over time from one scan to the next, and then stabilize. This lesion had not changed with serial imaging over 2 years. The patient remains asymptomatic and is monitored closely for any deterioration.
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Hydrocephalus from a subependymal giant cell astrocytoma in a patient with tuberous sclerosis. The patient presented with acute blindness and ataxia.
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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.
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Gingival fibromas (see arrows) in a patient with tuberous sclerosis. A stain outlines dental pits and craters. Gingival hyperplasia from other causes (eg, phenytoin use) is more diffuse and usually not nodular/focal in nature.
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Typical ash leaf macules; the reddish, nodular area at the upper lumbar area is a shagreen patch.
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Atrial rhabdomyoma as seen on cardiac CT scan in a patient with tuberous sclerosis.
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Nonobstructive ventricular rhabdomyomas in a patient with tuberous sclerosis.
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Ventricular rhabdomyomas may diffusely infiltrate the myocardium, as in this patient with tuberous sclerosis. The patient presented with cardiac failure and hydrops at birth. After a period of intensive supportive care and inotropic therapy, she now has essentially normal cardiac function and is on no medications.
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Multifocal pulmonary cysts characteristic of lymphangiomyomatosis. As many as 40% of women with tuberous sclerosis have pulmonary cysts on chest CT scan.
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Massive bilateral angiomyolipomas in a woman with tuberous sclerosis. She also has lymphangiomyomatosis.
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Pre-embolization angiography of the patient with angiomyolipomas shown the previous image. Dysplastic arterial vessels are demonstrated.
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Vessels to the angiomyolipoma shown in the previous image have been occluded with coils. This should produce regression of the lesion and prevention of hemorrhage. Functional intervening renal parenchyma is preserved.
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Enamel pitting in tuberous sclerosis. Pinpoint size pitting (A) and crater size pitting (B) are visible. Red dye is used to enhance recognition.
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Basilar artery aneurysm in a 2-year-old girl with tuberous sclerosis. The arrow shows the anterior aspect of the aneurysm where it abuts the clivus. The lesion was not present on MRI performed 11 months earlier.
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This presumed tuber was first noted in the left frontal region. It expanded in size, affecting adjacent structures across the midline and resulting in calcifications still evident in the right frontal region. The tuber then spontaneously involuted. About 20% of tubers may show changes in imaging characteristics over time, requiring close imaging follow-up. This patient remained asymptomatic from the mass effect, and his seizures resolved as the lesion involuted.
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This father and all 3 children have tuberous sclerosis complex. The children are now grown up and of normal intelligence, including the young lady at left who is cushingoid from therapy with adrenocorticotropic hormone for infantile spasms.
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The child whose CT scan is shown presented with medically intractable epilepsy thought to be due to partial hemimegalencephaly. She became seizure free after partial hemispherectomy. Pathology was consistent with a cortical tuber. She was subsequently found to have multiple ash leaf macules and diagnosed with tuberous sclerosis.
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Multiple tubers in a child with tuberous sclerosis, normal intelligence, and well-controlled seizures. High tuber count does not invariably mean poor neurological outcome.
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All tubers are not equal. This child has a smaller number of tubers than the patient shown in the previous image, but the tubers are larger in size. She too has normal intelligence and is seizure free on medication.
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Mammalian target of rapamycin (mTOR) activates the protein S6 kinase, which enhances cell growth and protein synthesis. It, in turn, is regulated by multiple factors, including insulin, amino acids, the drugs rapamycin and its congeners (eg, RAD001), and the TSC gene products via the GTPase-activating protein Rheb.
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Subependymal giant cell astrocytoma prior to stereotactic insertion of balloon catheter as seen on T2-weighted MRI.
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Modified angioplasty catheter used in creation of surgical tract for astrocytoma resection.
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Catheter placed in proximity to lesion, balloon inflated.
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Postoperative T2-weighted MRI in a patient with subependymal giant cell astrocytoma showing gross total resection of giant cell astrocytoma with minimal disruption of overlying cortex.
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Mean reduction in simple and complex partial seizures in patients with tuberous sclerosis complex (TSC) who were treated with vagus nerve stimulator at the author's institution at 6 and 12 months. Overall reduction in secondarily generalized seizures was 22% at 12 months (N = 17; 10 boys, 7 girls, aged 3-12 y).
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Regression of a giant cell astrocytoma after approximately 15 months oral rapamycin therapy in a 4-year-old patient with tuberous sclerosis.
