1. Case Report # 1 Submitted by: 29 August, 2007 Faculty reviewer: Date accepted: Radiological Category:Principal Modality (1): Principal Modality (2): Neuroradiology MRI CT Brian Deuell, MS IV Sandra Oldham, M.D.

2. Case History A four year old male presented with seizures. The patient has a history of infantile spasms, but had been seizure free for two years before this presentation.

3. Radiological Presentations

11. Gray Matter Heterotopia Metastatic disease Tuberous sclerosis complex TORCH infection Which one of the following is your choice for the appropriate diagnosis? Test Your Diagnosis

12. MR of the head without contrast shows multiple nodules with increased T1 signal seen along the subependymal regions. There is a large area of encephalomalacia seen in the right frontal lobe consistent with a prior surgical procedure. The T2 weighted images show some increased signal in the left occipital lobe. CT of the head without contrast shows an area of encephalomalacia as described above. A parenchymal nodule is seen adjacent to the encephalomalacia. Multiple hyperdense subependymal nodules are seen in both lateral ventricles. Renal ultrasound shows multiple cystic lesions. In the upper pole of the right kidney a small echogenic focus with a hypoechoic center is seen Gray Matter Heterotopia Tuberous Sclerosis Complex Astrocytoma Infection Brain metastases Findings: Differentials: Findings and Differentials

13. Tuberous Sclerosis (TS) is a genetic disorder associated with a clinical triad of cutaneous lesions, seizures, and mental retardation. Proteins that regulate cellular proliferation are disrupted (hamartin and tuberin), predisposing the affected individuals towards formation of benign tumors containing disorganized arrays of tissue elements appropriate to that body site, called hamartomas. Hamartomas of TS are commonly seen radiographically in the brain, heart, kidneys, retina, lung, and retina. Lesions in the brain are classified as cortical/subcortical tubers, subependymal nodules, or subependymal giant cell astrocytomas. There is a high incidence of seizures with these lesions and many patients require seizure medications and/or resection of tuberous lesions. Subependymal Giant Cell Astrocytomas (SGCA) are a Grade I neoplasm of TS that most often occurs near the foramen of Monroe with intermediate signal on T1, high signal on T2-weighted images and intense contrast enhancement. Complications can include obstructive hydrocephalus. Discussion

14. Renal angiomyolipomas may be present in nearly half of patients with TS, and the major morbidities include hemorrhage and mass effect. Renal cysts are present in approximately one quarter of patients, and range from simple cysts to a small association with Polycystic Kidney Disease (PCKD). There is only a slight increase in incidence of Renal Cell Carcinoma (RCC). (6) Cardiac rhabdomyomas occur is as many as 50-60% of patients with TS (4). These hamartomas are benign and frequently regress with age, so asymptomatic patients require no surgery. Pulmonary lymphangiomyomatosis (LAM) results from abnormal growth of smooth-muscle like cells in the lungs, leading to cystic destruction of the interstitium, obstruction of the airways and lymphatics, and formation of fluid filled cystic structures. It occurs most often in women of childbearing age. Incidence in this population with TS is approximately 29-36% (5). Affected individuals may undergo lung transplant. Retinal phakomas may be seen on CT or MR scans, or fundoscopic surveillance Discussion

15. Radiologic evaluation for suspected cases or initial diagnostic evaluation should include a brain MRI, a renal ultrasound/CT/MRI, and a cardiac echo. An asymptomatic patient should have follow-up brain MRI every 1-3 years in children and less frequently in adults. They kidneys should be followed once every three years. Cardiac echo and Pulmonary CT are recommended only if symptoms arise in these organ systems. Non-radiologic follow up includes neurological testing, dermatologic screening, EEG if seizures occur, and fundoscopic exams. Asymptomatic first degree relatives are recommended for screening via brain CT/MRI and renal ultrasound/CT/MRI. Discussion

16. Gray Matter Heterotopia (GMH) can present with seizures and developmental delay and will show similar subependymal nodules on T1 weighted images. To distinguish this from TS, GMH may have a ribbon of tissue isointense with gray matter along neuronal migration paths. In addition, the lesions rarely calcify or enhance (as the lesions in TS do), and are isointense with gray matter. TORCH infections – congenital CMV may present with neurological deficits such as seizures and developmental delay, and periventricular calcifications can be seen, appearing similar to nodules of TS on certain modalities. However, there are usually other manifestations such as microcephaly, migration defects, and ventricular enlargement. Metastatic lesions present commonly as multiple, enhancing solid lesions at the gray-white matter junction with prominent surrounding edema. Discussion

17. Definite TSC: Either 2 major features or 1 major feature with 2 minor features Probable TSC: One major feature and one minor feature Possible TSC: Either 1 major feature or 2 or more minor features Major Features –Facial angiofibromas or forehead plaque –Non-traumatic ungual or periungual fibroma –Hypomelanotic macules (more than three) –*Shagreen patch (connective tissue nevus) –*Multiple retinal nodular hamartomas –*Cortical tuber –*Subependymal nodule –*Subependymal giant cell astrocytoma –*Cardiac rhabdomyoma, single or multiple –*Lymphangiomyomatosis –*Renal angiomyolipoma Discussion

18. Minor Features –Multiple randomly distributed pits in dental enamel –Hamartomatous rectal polyps –*Bone cysts –*Cerebral white matter migration lines –Gingival fibromas –*Non-renal hamartoma (histology) –Retinal achromic patch –"Confetti" skin lesions –*Multiple renal cysts Discussion

19. Tuberous Sclerosis Complex, s/p right frontal lobe resection with multiple subependymal tubers, retinal hamartoma, and renal cysts. Surgical pathology after resection of the patient’s large right frontal hamartoma confirmed early diagnostic suspicions by showing disorganization of the cortex, large neurons, calcifications, and abnormal astrocytes. Diagnosis

20. 1. Tuberous Sclerosis Alliance website www.tsalliance.org 2. Kasper, DL, et al (eds). Harrison’s Principles of Internal Medicine, 16e, New York., McGraw-Hill, 2005. 3. Schwartz, Robert A., et. al. Tuberous Sclerosis Complex: Advances in Diagnosis, Genetics, and Management. Journal of American Academy of Dermatology. Volume 57, Issue 2; August 2007. p. 189-202. 4. Ibrahim, C.P.H., et. al. Cardiac rhabdomyoma presenting as left ventricular outflow tract obstruction in a neonate. Interactive Cardiovascular and Thoracic Surgery 2:572- 574(2003) 5. Goncharova, Elena A., Pulmonary lymphangioleiomyomatosis (LAM): Progress and current challenges. Journal of Cellular Biochemistry. Published Online: 31 May 2007 6. Rakowski, S.K., et. al. Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors. Kidney International (2006) 70, 1777– 1782.www.tsalliance.org References