Prepared by Brian J. Fortman, MD; Brian S. Kuszyk, MD; and Norman Beauchamp, MD, Department of Radiology, The Johns Hopkins Hospital, Baltimore, MD.

CASE SUMMARY:

A 67-year-old man with a history of myocardial infarction and splenectomy for polycythemia rubra vera presented with the complaint of recurrent frontal headaches which had increased in frequency over the past 6 months. The pain was predominantly retro-orbital and was not relieved with analgesics. He had no focal neurologic signs and no other significant past medical history. A non-contrast CT of the head and gadolinium-enhanced MR of the brain were performed (figures 1-4).

IMAGING FINDINGS:

Non-contrast CT of the head showed multiple areas of high attenuation corresponding to densely calcified subependymal nodules, as well as a calcified nodule in the left cerebellar hemisphere (figure 1). There was a prominent heterogeneous nodule on the right, adjacent to the interventricular foramen of Monro. A cavum septum pellucidum and cavum vergae also were present. Gadolinium-enhanced MRI of the brain showed multiple areas of decreased signal intensity within the subependyma on T2-weighted images, compatible with calcification (figure 2). There was marked cortical irregularity and pachygyria in the left posterior temporal and parietal regions in addition to the lesion near the foramen of Monro (figure 3). This heterogeneous lesion showed significant enhancement with gadolinium. There also were subtle areas of gray matter heterotopia noted in the subcortical white matter (figure 3). The patient had previously undergone CT scanning and renal ultrasound during his hospitalization for splenectomy due to polycythemia vera (figures 4A,4B). Review of his renal ultrasound showed several focal areas of increased echogenicity within the kidneys. His abdominal CT revealed multiple focal areas of decreased attenuation in both kidneys measuring ­30 to ­50 HU, compatible with angiomyolipomas. A review of all previous chest radiographs found no evidence of pulmonary parenchymal disease.

DIAGNOSIS:

Tuberous sclerosis (Bourneville's disease)

DISCUSSION:

Tuberous sclerosis (TS), or Bourneville's disease, is an autosomal-dominant (AD) neurocutaneous syndrome with an approximate incidence of 1:10,000 to 50,000. The classic triad of mental retardation, seizures, and a papular facial nevus known as adenoma sebaceum is observed in less than 50% of patients. ¹ More commonly, TS presents as a forme fruste, a partial or arrested form of the disease. There is considerable genetic heterogeneity in TS, and several transmitted gene loci, as well as spontaneous mutations, have been postulated to occur. ^2,3

The variable phenotypic expressivity of TS, as well as the variety of organ systems affected, leads to a substantial number of cases first presenting in adolescence and early adulthood. It is atypical for a patient to present at 67 years of age with such classic findings of TS, though reports do exist. Our patient showed no cutaneous manifestations of the disease and had no history of seizures.

As the classic clinical triad of TS is seen in the minority of patients, it is now universally accepted that the radiologic hallmarks of this disorder are sufficient for diagnosis. Pathologic diagnoses are rarely obtained due to the hamartomatous nature of most lesions. This patient demonstrated the classic central nervous system (CNS) manifestations of TS as seen on CT and MRI. Multiple calcified subependymal nodules along with cortical tubers, subtle white matter abnormalities, and an enhancing heterogeneous lesion adjacent to the foramen of Monro are diagnostic. Other lesions that may occur near the foramen of Monro include central neurocytoma, colloid cyst, and subependymoma.

The characteristic location and enhancement of this lesion, along with the other CNS findings, make a giant cell astrocytoma highly likely. Most, if not all, patients with subependymal giant cell astrocytomas (SGCAs) are believed to have TS. ⁴ SGCAs are histologically benign but may enlarge with time and cause obstructive hydrocephalus.

The patient's renal findings also are typical of TS. Angiomyolipomas occur in 40 to 80% of cases. These characteristically appear as hyperechoic foci on ultrasound and multiple foci of fat attenuation on CT. Such lesions have no malignant potential and are often clinically silent, although some surgeons recommend resection of lesions greater than 5 cm due to the risk of hemorrhage. When multiple and bilateral, these lesions often are the initial finding, which suggests a subclinical case of TS when renal US or abdominal CT is performed for other indications. The presence of renal involvement with the TS complex increases the patient's risk of developing renal cell carcinoma, and prudent screening with computed tomography is recommended. Other systemic manifestations of TS include cutaneous macules, cardiac rhabdomyomas, pulmonary lymphangiomyomatosis, pancreatic and splenic hamartomas, sclerotic bone lesions, and vascular aneurysms or stenosis. ⁴

The differential diagnosis for multiple calcified subependymal nodules is essentially limited to tuberous sclerosis or congenital "TORCH" infections such as cytomegalovirus or, less commonly, toxoplasmosis. In our case, MRI of the brain revealed lesions which are typical of cortical tubers. The prominent enhancing nodule adjacent to the foramen of Monro is the classic appearance of a subependymal giant cell astrocytoma. These findings, along with the patient's subtle gray matter heterotopias are typical cerebral manifestations of TS. Both CMV and toxoplasmosis could lead to migrational abnormalities and heterotopias; however, in our patient, the enhancing nodule near the foramen of Monro and the absence of findings such as microcephaly and chorioretinitis make this much less likely. The presence of bilateral renal angio-myolipomas confirms the of TS in this patient. The patient declined a neurosurgical consult at that time and elected close follow up to monitor for the development of hydrocephalus.

The diagnosis of TS in this patient is not only important for his future medical treatment, but is also relevant to the patient's family. Even if this patient represents the proband within the family, it is likely that at least one of his children will have subclinical disease or carry the TS gene. For this reason, medical screening and genetic counseling is advised for families of newly diagnosed TS patients. Ongoing research continues to better define the genetic heterogeneity of TS and may lead to gene-guided therapy for patients with TS and other phakomatoses in the future. Several organizations and societies now exist in the United States and abroad to offer support and information to patients and families affected by TS.