Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disease of cell differentiation and proliferation affecting multiple organs with hamartomas or abnormal neuronal migration. It was first described by Bourneville in 1880, and the incidence of tuberous sclerosis in the population is reported to be 1/6000 to 1/10,000.^1,2 Cortical tubers and subependymal nodules (SEN) are the hallmark pathological findings in children. TSC is caused by aberrant neuronal migration and differentiation. Radial glial fibers guide migration of neurons during development from the 3rd to 5th month of gestation, and if there is a disruption in one tract, hamartomas may develop. This process of abnormal differentiation also explains the occurrence of hamartomas outside the CNS.³

Tubers and other migrational defects typically arise in the cerebrum rather than the cerebellum or brainstem, although subcortical involvement occurs rarely. It is unknown whether seizures originate from dysplastic neurons or neurons in surrounding cortex. Tubers form during gestation, and all brain tubers do not change in number or location during postnatal life. Pathological examination of cortical tubers reveals sclerotic white patches within the gyri and few neurons. Most neurons are large and bizarrely shaped with 2–3 nuclei located peripherally and prominent nucleoli. Fibrillary astrocytic proliferation and large glial cells are also present.⁴

Magnetic resonance imaging (MRI) scans are better in defining tubers than computerized tomography (CT) scans. Tubers occur at the cortical gray white interface and are most frequent in the parietal and frontal lobes. Calcification is less common in tubers than in subependymal nodules (SEN). Myelination helps distinguish tubers from white matter and, tubers therefore become more evident in older children. T2 weighted imaging and fluid attenuation inversion recovery imaging (FLAIR) is more accurate for viewing tubers compared to T1 imaging.⁵ In children, tubers are hypointense on T1 weighted imaging and hyperintense on T2 weighted imaging and FLAIR. FLAIR also provides better resolution of small subcortical tubers but is not useful for SEN due to CSF flow artifact caused by the inflow of noninverted CSF especially at the foramen of Monroe. White matter radial lines occur in 20–30% of patients and consist of hyperintense linear lesions perpendicular to cortex that extend to the periventricular white matter on T2 weighted imaging.⁵

SEN do not cause seizures and are located in the anterior lateral ventricles. They are hamartomas composed of round or oval cells with whorls of fibrillary glial tissue and deposition of amyloid or calcification within the nodule and usually lie around the foramen of Monroe adjacent to the ventricle.⁶ SENs are less than 1 cm and rarely enhance. On MRI, SENs are better seen on T1 weighted images as the lesions are isointense to white matter and hyperintense to gray matter. SENs calcify with age and are well visualized on CT scans in adults.^5,7

SEN may enlarge over time and may transform into a subependymal giant cell astrocytoma (SEGA).

SEGAs are benign tumors occurring in 10% of patients with TSC.⁸ SEGAs typically occur at the Foramen of Monroe. They may obstruct the ventricle in older patients and lead to increased intracranial pressure. There is minimal correlation between the lesion’s histology and clinical aggressiveness and it is not known why growth takes place. SEGAs are pathologically similar to SEN; however, on neuroimaging, SEGAs are larger, usually greater than 10 mm in diameter⁸ and enhance with contrast. MRI is the procedure of choice for their diagnosis and follow-up as serial scans do not produce radiation exposure.

TSC is inherited through autosomal dominance with variable penetrance. Therefore, many parents may carry the gene but do not show symptoms due to high phenotypic variability.⁹ It is important to perform a Wood’s lamp examination, ophthalmologic exam, renal ultrasound or even a CT or MRI scan on parents for purposes of genetic counseling; when a parent carries the gene, the risk of conceiving another affected child is 50% compared to having a child with a spontaneous mutation where subsequent risk is 1:10,000, the same as the general population. In addition, there is a high sporadic mutation rate of 60%.^10,11,12

There are presently two confirmed genetic TSC loci on chromosome 9 (TSC 1 on 9p34.3) and chromosome 16 (TSC 2 on 16p13.3).^13,14 Most patients with a family history for TSC have the TSC 1 mutation¹⁵ that produces hamartin and is associated with less severe symptoms. A smaller proportion carries the TSC 2 mutation that produces tuberin. Both genes are tumor suppressor genes and negative growth regulators.¹³ The interaction between the 2 proteins, the tuberin–hamartin complex, is important in controlling cell growth.¹⁶ Genetic blood markers are available to screen for potential TS patients although there is a high false negative rate of 15%.¹⁷

The clinical manifestations of TSC are varied and affect multiple organ systems. The most common symptoms consist of cutaneous findings (96%), seizures (84%), mental retardation (45%), and autism (50%).¹⁸ In later life, renal manifestations and SEGAs produce the greatest morbidity and mortality. In terms of dermatological symptoms, ash leaf spots or hypopigmented macules are often present at birth or early infancy and best viewed with Wood’s lamp. This lesion is nonspecific as it occurs in asymptomatic individuals; thus only 3 or more findings are considered significant. Shagreen patches may also appear at birth on the trunk or buttocks. They are typically flesh colored and have a raised surface similar to an orange peel. Other dermatological lesions such as ungual fibromas in the nail beds and facial angiofibromas in the malar distribution become more prevalent in adolescence.

Cardiac rhabdomyomas usually present at birth and diminish in size with age. Arrhythmias are rare. Echocardiograms can exclude this diagnosis; Ophthalmologic lesions such as retinal hamartomas or mulberry lesions rarely impair vision and remain static. Renal angiomyolipomas, cysts, and carcinomas may worsen with age; polycystic kidneys have been reported in children.¹⁹ Angiomyolipomas may rupture with maturity and ultrasound surveillance is indicated for lesions larger than 4 cm. Renal cysts may cause hypertension and renal insufficiency.²⁰ Pulmonary lesions occur rarely in women with TSC and may produce spontaneous pneumothoraces.²¹

Neurological manifestations occur in 85% of patients with TSC and are the predominant cause of morbidity in children. These include behavioral issues (attention deficit, psychosis) seizures, autism, mental retardation, sleep abnormalities, hydrocephalus, or visual disturbances from SEGA-induced third ventricular obstruction. SEGAs are usually removed surgically; an ongoing trial is assessing the efficacy of rapamycin to shrink tumor growth.

Epilepsy is the most common presenting feature in TSC (while more common, skin lesions are rarely the presenting lesion) and occurs in 80–90% of patients; onset is usually before age 2 years.²² Epilepsy in TSC is often intractable and only 14% of patients achieve spontaneous remission.²³ However, many trials were performed prior to the use of newer anticonvulsants.²⁴

Seizures may occur in the neonatal period.²⁵ While all seizure types may occur in TSC, the most common presentation is infantile spasms (IS) that occurs in 1/3 of TSC patients. TSC accounts for 25% of all patients presenting with IS.²⁶ Most TSC children with IS eventually develop Lennox–Gastaut or complex partial seizures (CPS).^26,27

A high proportion of patients with TSC present with IS in the first year of life while older children more commonly present with partial epilepsy.²⁸ Seizure onset after 12 months is typically associated with partial seizures as the sole type.²⁹ In addition, TSC patients with partial seizures typically evidence better development than TSC patients with IS. Fukshima (2001) found that 64% of partial seizures are controlled with medications.²⁷ Partial seizures can coexist or predate the occurrence of IS suggesting that IS may result from rapid secondary generalization. Rapid secondary bilateral synchrony mimics primary generalized seizures if there is rapid spread of seizures propagating from a frontal tuber through the anterior commissure.^30,31

It has been suggested that high tuber counts, especially in the frontal lobes, increase the likelihood of intractable seizures and mental retardation (MR). However, this observation is controversial as normal IQs are documented in women with high tuber counts on MRI. 5–10 tubers correlated to an increased likelihood of MR although there is no minimum tuber count associated with MR or increased seizures.³² In addition, there is no correlation between the number of tubers on FLAIR imaging and IQ.

Newer imaging studies may show more tubers than the neuroimaging techniques in past which might also negate this finding. A study by Wong & Khong³³ looked at MRI scans and found that neither tuber count nor location had any influence over MR, autism, epilepsy, IS or age of seizure onset less than 1 year. Only the presence of cortical tubers in parietal and occipital region correlated with IS. Another study by Doherty found that autism occurred more commonly in patients with occipital lobe tubers, and that an increased tuber count was associated with IS and TSC2 mutations.³⁴ However, seizure control and MR were not associated with tuber count.

In addition, there is a correlation with tubers and cortical dysplasias. For example, there is a series of patients who had a solitary lesion removed during surgery and pathology findings of tuberous sclerosis were found rather than cortical dysplasia. In these patients, there are no skin stigmata for TSC.³⁵ Another study reported changes in MR imaging with time in a child with TSC and hemimegalencepahly.³⁶ TSC forms a histopathological spectrum with cortical dysplasias, which makes this close association possible. One study revealed hippocampal abnormalities on MRI in a series of tuberous sclerosis patients.³⁷

Mental retardation occurs in 60% of patients with TSC^38,39,40 and is often associated with seizures, especially ones that begin before age 2 years. Chou⁴¹ demonstrated that MR was associated with poor seizure control, especially for generalized tonic clonic seizures. However, 1/3 of patients with seizures show normal cognition. Winterkorn et al⁴² found that 57% of TSC patients had normal IQ/DQ scores and that MR was associated with intractable seizures and the presence of the TSC2 mutation.

Goh⁴³ reviewed 50 patients with TSC and IS and found that 64% of patients had IQs less than 70. There was an association with increased duration of IS, prolonged time from treatment initiation until the cessation of IS, and poor control of seizures after IS. Fukushima²⁷ documented 50 patients with TSC who presented with IS and were monitored for 10 years; Patients who developed other seizure types, especially generalized seizures, tended to have lower IQ scores. Dyspraxia, speech delay, visuospatial disturbances, dyscalculia or memory problems may also occur⁴³ especially in patients with high tuber counts.⁴⁴

Aggression and psychosis occur in 13% of patients with no history of IS.^45,46 25–50% of patients with TSC manifest autism⁴⁷ but it is unclear whether autism in TSC is the direct result of mutation in the TSC gene or a secondary effect of factors such as the associated structural brain abnormalities or epileptic encephalopathy.⁴⁸ Autism may result from tubers in anterior or posterior brain areas,⁴⁰ the temporal lobes or cerebellum.⁴⁹ Alternatively, autism may result from an interaction of seizures, tuber location, cognitive impairment, or linkage between the TSC and an autism susceptibility genes.⁵⁰

The diagnosis of TSC is based on clinical criteria established through a consensus conference (see Table 32–1).⁵¹ Increased weight was given to histologically confirmed lesions rather than to nonspecific findings. In addition, many of the findings, especially dermatological, may be apparent only at certain developmental stages. Patients may need to be reexamined to see if criteria are met. When both lymphagniomyomatosis and renal angiomyolipomas are present, other features of tuberous sclerosis must be present before entertaining a definitive diagnosis (Table 32–1).