All patients should have a 3-generation family history obtained to determine if additional family members are at risk of diagnosis. Genetic testing is recommended for counseling purposes or when the diagnosis of tuberous sclerosis complex is suspected but cannot be clinically confirmed.
Evaluation for initial diagnosis and clinical monitoring requires attention to the following organ systems: (1) the skin, with natural or ultraviolet light, looking for facial angiofibroma, shagreen patches, fibrous cephalic plaques, periungual fibromas, and hypomelanotic spots; (2) the retina, by indirect ophthalmoscopy after mydriasis; (3) the brain, with MRI and EEG; (4) the kidneys, with MRI, assessment of glomerular filtration rate, and blood pressure; (5) the lungs, with imaging by high-resolution CT in adults, particularly women, in addition to pulmonary function tests; (6) the heart, with fetal echocardiogram if prenatal ultrasound reveals rhabdomyomas, echocardiogram in pediatric patients under 3 years of age, and routine ECGs in all patients (Goldman 2000); and (7) a detailed dental examination.
Studies with MR of the brain have found that T1-weighted imaging is best for identification of subependymal nodules, whereas fluid-attenuated inversion recovery pulse images are more sensitive than spin-echo sequences to cortical and subcortical tubers (Kato et al 1997). T2-weighted images may show subcortical white matter changes, and shadows from subependymal nodules may indent the walls of the ventricles. MR imaging demonstrates cyst-like structures that are commonly seen immediately adjacent to cortical tubers or within dysplastic lesions (Van Tassel et al 1997a).
Newer imaging modalities are becoming available for evaluating the disease burden and for noninvasive surgical planning. They have added significantly to our knowledge of the disease. Magnetization transfer imaging (MTI) can depict more tubers and white matter anomalies than conventional spin echo images in older children and adults. Dual inversion recovery MRI has been reported to depict cortical tubers as very bright signals in comparison to high-resolution T2 or FLAIR imaging. Computational morphometry MRI has been used to objectively quantify the brain lesions in tuberous sclerosis complex. This has revealed that the highest frequency of tubers is in the frontal lobes and the highest density is in the parietal lobe. Decreased bilateral gray matter volumes and white matter tracts have been reported to correlate with memory deficits in tuberous sclerosis complex. Proton magnetic resonance spectroscopy (MRS) studies have shown a pattern of decreased N-acetylaspartate/creatine and increased myoinositol/creatine ratios in tubers, reflecting decreased neurons and increased glial cells, respectively. Evidence of hypomyelination in tuberous sclerosis complex is also reflected by the low fractional anisotropy values of the perilesional white matter. Increased apparent diffusion coefficient (ADC) value has been noted in epileptogenic tubers and hamartomas and may be used to identify the epileptogenic cortical tuber. Diffusion tensor imaging (DTI) can potentially be used to detect and define the epileptic circuitry as it evolves with chronicity and increasing severity of epilepsy. Interictal 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) scanning in tuberous sclerosis complex has detected small cortical tubers similar to FLAIR images, but with a larger area of glucose hypometabolism. It has also been shown that the seizure activity often originates from the mildly hypometabolic regions adjacent to the cortical tubers rather than directly from the tuber. Alpha[11C]methyl-L-tryptophan positron emission tomography (AMT-PET) has been used in the identification of the epileptogenic zone (Luat et al 2007).
EEG is recommended at initial diagnosis of all patients, irrespective of a history of seizures. This should be followed by a 24 hour video EEG monitoring if there are any abnormalities on routine EEG or if there are any symptoms of neuropsychiatric disease.