Tuberous sclerosis (synonyms: epiloia, Bournville's disease) is an autosomal dominant multisystem disease that usually presents in childhood with a characteristic facial rash (adenoma sebaceum) and seizures or learning difficulties. Other organs (e.g. heart and kidney) are less commonly involved. Because the condition has very variable clinical expression, and two-thirds of cases are thought to be new mutations, it is important to examine and screen relatives. Central nervous system lesions in tuberous sclerosis are due to a developmental disorder of neurogenesis and neuronal migration. Management may involve many specialists and close co-operation between specialists is essential.
2 Incidence and prevalence
The incidence of tuberous sclerosis (TS) is uncertain but the point prevalence is between 1 in 10 000 and 1 in 6000 (Hunt and Lindenbaum, 1984).
3 Genetic factors
The sites of genetic mutation in tuberous sclerosis are now well established. There is locus heterogeneity with one gene on chromosome 9q34 (TSC1) and a second gene on chromosome 16p13.3 (TSC2). The TSC2 gene has been cloned. Most of the TSC2 mutations are subtle, and somatic and germline mosaicism could explain the phenotypic heterogeneity and possibly non-penetrance. The protein produced by the gene has been termed ‘tuberin’. The TS gene may be a tumour suppressor gene which would account for the high incidence of tumours in TS patients, and allelic losses of the tuberous sclerosis genes in the tumours have also been found (Short et al. 1995).
4 Clinical features and imaging diagnosis
Adenoma sebaceum (facial angiofibromas) is the most common outward manifestation of this disorder. Other skin changes include hypopigmented macules, café-au-lait spots and ‘shagreen patches’. Facial angiofibromas are most commonly seen over the cheeks and nasolabial folds. The rash can extend to the chin and forehead. The angiofibromas are rather greasy and can be mistaken for acne. Hypopigmented macules are frequently shaped like an ash leaf, are 1–3 cm in diameter, and are most easily identified by shining ultraviolet light over the skin. Subungal fibromas are found in approximately 50 per cent of cases. Seizures are common and can be partial (focal), multifocal, or generalized. Seizure type is commonly related to the site of cortical tubers. The cortical dysplastic lesions are hamartomatous and may calcify.
Sometimes clinically, and even histologically, it can be difficult to differentiate cortical dysplasia from well-defined ganglionic tumours. The most common tumours associated with tuberous sclerosis are subependymal giant-cell astrocytomas. However, immunohistochemical staining may be negative for glial acidic fibrillary protein (GFAP) and there can be evidence of neuronal differentiation, with positivity with neuronal specific enolase (NSE). Tuberous sclerosis can also be associated with gangliogliomas and pleomorphic xanthoastrocytomas.
These are categorized as WHO grade 1 astrocytomas and typically alter little in size over several years. MRI with gadolinium enhancement is the investigation of choice for patients with neurocutaneous syndromes. Subependymal nodules and cortical and white matter tubers characteristic of tuberous sclerosis are readily identified by MRI.
Patients with tuberous sclerosis are at a higher risk of renal disease associated with angiomyolipomas of the kidneys and renal cysts. The gene that accounts for 85 per cent of polycystic kidney disease is situated on chromosome 16p13.3, adjacent to the tuberous sclerosis gene (TSC2), and children with large deletions of this region can present with tuberous sclerosis and severe childhood-onset polycystic kidney disease (Harris et al. 1995).
Renal cysts and angiomyolipomas become increasingly common with the passage of time and can progressively enlarge, as demonstrated by serial renal imaging (O'Hagan et al. 1996). Although bilateral renal angiomyolipomas are commonly found, chronic renal failure in the absence of cystic disease is uncommon.
The imaging appearances of tuberous-sclerosis-related cystic disease of the kidney resemble those of autosomal dominant polycystic kidney disease; however, the histopathological findings are quite different, with hypertrophic, hyperplastic lining to the renal cysts. Hepatic angiomyolipomas are commonly asymptomatic but can occur and present with abdominal pain followed by malaise and possibly hepatomegaly. The tumour is hyperechoic on ultrasound and has low density (<20 Houndsfield units) by CT and increased vascularity on angiography. There is also an increase in the number and size of retinal hamartomas and cardiac rhabdomyomas with increasing age.
The diagnostic criteria are outlined in Table 1 (Osbourne and Fryer 1991).
One major or two minor criteria:
- Definite shagreen patch
- Ungal fibroma
- Retinal hamartomas
- Adenoma sebaceum
- Bilateral multiple renal angiomyolipomas
- Subependymal glial nodules on CT/MRI
- Atypical shagreen patch
- Hypomelanocytic macules
- Gingival fibromas
- Bilateral polycystic kidneys
- Single renal angiomyolipoma
- Cardiac rhabdomyoma
- Histological evidence of a cortical tuber
- Honeycomb lung on X-ray
- Infantile spasms
- Forehead fibrous plaques
- Giant cell astrocytoma
- A first-degree relative with tuberous sclerosis
The epilepsy can be severe and resistant to the usual anticonvulsant medications. Carefully selected patients with refractory epilepsy may be suitable for neurosurgical intervention. The success of surgery depends on the clear identification of an epileptogenic focus and identification of a structural abnormality at a corresponding site. Children may be found to have learning difficulties and may require special schooling or assistance (Curatolo 1996).
If headaches or focal neurological signs develop, CT or MRI scanning of the head is advisable. This may identify cortical tubers or tumours. If a symptomatic cerebral tumour is identified, the best plan of management is to debulk the tumour and follow up by serial MRI scanning annually or if new neurological symptoms develop.
The place of radiation therapy is uncertain. Radiation can reduce the size of these tumours but, because of the excellent long-term survival and the frequency of late radiation-induced side-effects, such as radiation-induced dementia and leucoencephalopathy, the optimal time for radiation therapy remains uncertain. Occasionally anaplastic variants can occur and in this situation early radiation therapy is probably advisable. Close monitoring of renal function in tuberous sclerosis is advisable as chronic renal insufficiency is a cause of morbidity and mortality.
Families should have access to genetic counselling and genetic testing for TSC1 and TSC2. Genetic counselling includes explanation of the risk of a disorder being inherited, the consequences of that risk, the probability of developing or transmitting the disease, and the ways in which transmission can be prevented. Parents and other family members should be examined clinically, including examination under Wood's light (ultraviolet light) and ophthalmoscopic examination of the eyes for retinal phakomas. Chest radiography, CT or MRI brain scan, and renal ultrasound should also be performed.
CT scans of parents and sibs of apparently sporadic cases will sometimes demonstrate asymptomatic cortical tubers. Even mildly affected parents can have severely affected children. Once any genetic tests or investigative tests have been performed, further counselling about the results is usually necessary.
6 Prognosis and complications of treatment
Severe infantile spasms and other severe forms of epilepsy have a poor prognosis because this is usually a sign of severe brain disease and treatment of the seizures is frequently ineffective and status epilepticus is common. There is a high mortality rate in infants with infantile spasms, either due to the seizures or as a result of complications occurring during treatment for status. In the absence of severe epilepsy and significant cognitive impairment, prognosis is good, with most patients having a normal life span. If cerebral tumours develop, these are slow growing and have an excellent prognosis if complete removal can be performed. In most cases, however, partial resection is all that is possible and the median survival is approximately 10–20 years (Nagib et al. 1984). Adenoma sebaceum can be treated with laser therapy.
7 Recovery and rehabilitation
Children will require a great deal of medical support when epilepsy is prominent, and school or learning support during periods when seizures are quiescent. Advice regarding anticonvulsant medication and pastimes to avoid should be openly discussed with the patient and family members. Counselling and support helps re-integration into school and society (Curatolo 1996).