Neurological manifestations of Tuberous Sclerosis

Tuberous sclerosis complex is an autosomal dominant neuorcutaneous disorder characterized by the presence of hamartomatous lesions in multiple organs [1]. Approximately two-thirds of the cases are sporadic. Tuberous sclerosis classically demonstrates the clinical triad of mental retardation, epilepsy and facial angiofibromas (Vogt triad) [1, 2]. Tuberous sclerosis is considered to be caused by mutation of two genes kwon as TSC1 and TSC2. TSC1 is located on long arm of chromosome 9 and encodes for protein hamartin, TSC2 is located on short arm chromosome 16 and encodes for protein tuberin. TSC1 and TSC2 are tumor suppressor genes are responsible for regulate the cell function and growth. When they are altered by mutation it disturbs the regulation of cell growth which results in formation of tumors involving multiple organs. TSC2 gene is found continuous with PKD gene and thought to be why sometimes multiple renal cysts are found in tuberous sclerosis [2]. Common intracranial manifestations of tuberous sclerosis are cortical tubers, subependymal nodules, Subependymal giant cell astrocytomas and white matter abnormalities [2]. Cortical tubers and Subependymal nodules are estimated to be present 95%-100% of the time and white matter abnormalities 40 – 100%. Other rare manifestations include mild dilatation of lateral ventricles, cerebellar atrophy, infarctions due to occlusive vascular disorders, cerebral aneurisms, dysgenesis of corpus callosum, microcephaly and macrocephaly [2]. Cortical tubers are the most commonly found lesion in cerebrum and 90% found involving frontal lobes [3]. These are characterized by loss of normal six layer structure of cerebral cortex with presence of dysmorphic neurons and large astrocytes [2]. Cortical tubers are variable in size and they occur most often in grey white junction although they can occur anywhere in the parenchyma from the cortex to white matter [2]. Tubers can be present in the cerebellum less frequently and appear more wedge in shape. Unlike cortical tubers they are thought to be non epileptogenic [3]. Calcification and central cystic degeneration of cortical tubers also reported. Cystic change does not indicate a malignant transformation. Cortical tubers considered to be closely related to epilepsy, cognitive disability and neurological behavioral abnormalities [2]. MRI is more sensitive than CT scan for detecting cortical tubers. Cortical tubers are hyperintense on T2W and FLAIR sequences and are hypointense on T1W studies. After administration of intravenous contrast 10% of the tubers show enhancement. In neonates and infants the cortical tubers can be less conspicuous on T2W studies due to their poor meylination and will be only demonstrated on T1W studies [2]. Subependymal nodules are hamartomatous lesions in the subependymal tissue. They are also composed of dysplastic astrocytes and neuronal cell components. On gross histology they give the appearance “candle guttering” because the nodules line the ventricular surface [4]. They are more prominent in the lateral ventricles but can present at any ventricular level. Subependymal nodules project into cerebrospinal fluid within ventricles and often associated with calcification (88%). Unenhanced CT scan shows multiple calcified Subependymal nodules along the ventricular walls bilaterally. At MR imaging Subependymal nodules are hyperintense on T1W and iso- to hyperintense on T2W and the calcification associated with nodules will be hypointense on both sequences [2]. Subependymal giant cell astrocytomas (SGA) are characterize by proliferative astrocytes and giant cells and reported in 1.7% to 26% of tuberous sclerosis patients. The diagnosis is made with its size and the typical location at foramen of Monro. Clinically they present with increased intracranial pressure due to obstructive hydrocephalus [2,4]. CT and MRI are helpful in evaluating invasiveness of the lesion. SGA are larger than 1cm in size, they demonstrate more intense enhancement and they are not or partially calcified compared with Subependymal nodules [2]. White matter abnormalities that identified in tuberous sclerosis can be further classified as, a.Superficial white matter abnormalities which are almost always associated with cortical tubers. On MRI imaging they are hyperintense on T2W and hypointense on T1W sequences. b.Radial white matter bands. They indicate altered development along the migratory pathway of neurons and glial cells. Theses lesions depicts high signal on T2W studies and iso or low signal intensity to normal white matter. They commonly involve the cerebral white matter bilaterally and predominantly frontal. c.Cyst like white matter lesions which are typically seen in deep white matter near lateral ventricles. At MRI imaging they show similar signal intensity to CSF in all sequences.[2] MRI with Fluid attenuated inversion recovery sequences have shown to be useful in detecting even small tubers but do not differentiate “silent” from epileptogenic tubers. Recent studies had shown that Diffusion weighted studies help identification of epileptogenic tubers. These tubers give higher ADC values because of increase extracellular water content as a result of edema [5].