Brain involvement is very common in people with TSC and is often the disorder's most pressing concern, having been linked to seizures, cognitive impairment, behavioral disorders, and other neurological complications. Fortunately, despite the fact that approximately 80 percent and possibly a higher percentage of people with TSC have brain involvement, it does not always have debilitating effects.
The brain is one of the most complex organs in the body and is the nervous system's control center. Normally the brain functions as a unified whole, with certain regions specializing in particular functions. However, when this complex structure is altered, the brain may fail to function normally.
There are three main anatomical features associated with TSC that alter the structure of the brain: cortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs). Cortical tubers form in and around the cerebral cortex, the brain's outermost layer. SENs and SEGAs form deeper within the brain, typically along the ependymal lining (walls) of the ventricles, the cavities containing cerebrospinal fluid.
Like TSC lesions that affect other parts of the body, brain lesions associated with the disorder are composed of masses of abnormally shaped, dysfunctional cells. Tubers are composed of cells that fail to differentiate into functional neurons and glial cells during early stages of brain development. The resulting cell masses form before birth and are not thought to increase in size or number over time. In contrast, SENs and SEGAs are benign tumors composed of abnormal cells called neuroastrocytes, which remain in an interior region of the brain called the germinal layer, under the ependymal lining. As tumors, SENs and SEGAs can grow in both size and number over time.
Tubers, SENs, and SEGAs often play a key role in the diagnosis of TSC. Brain images such as those produced by computed tomography (CT) scans and magnetic resonance imaging (MRI) enable neurologists to identify these lesions and confirm the diagnosis of TSC. All three types of lesions are considered major features in the diagnostic criteria of TSC.
Three Types of Brain Manifestations
Cortical tubers, from which tuberous sclerosis complex derives its name, are found in more than 80 percent of people with TSC. These benign lesions are found most often in the brain's outermost layer, the cerebral cortex. However, they can also be found in other regions of the brain and in other parts of the central nervous system, including the cerebellum and, rarely, the brain stem and spinal cord. Cortical tubers range in size from a few millimeters to several centimeters in diameter, and people with TSC may have anywhere from 0 to more than 20. Cortical tubers arise during early brain development and are present from birth. They are not thought to change in size or number over time.
Cortical tubers are characterized by the undifferentiated and dysfunctional cells that comprise them. These cells, which have characteristics of both neurons and glial cells, form dense masses that disrupt the highly organized interconnected layers of the cerebral cortex. More importantly, it is thought that they disrupt the functional connections between various parts of the brain, contributing to neurological problems such as epileptic seizures, and learning and behavioral issues. How they might do this is not entirely clear. However, studies have shown a positive correlation between the number of tubers—or, more recently, the volume of brain space occupied by tubers—and the frequency of these neurological problems. The location of tubers may also play a role. (For more information, see Brain: Seizures, Brain: Learning and Brain: Mental Health.)
Subependymal Nodules (SENs)
Like cortical tubers, subependymal nodules (SENs) are seen in approximately 80 percent of people with TSC. Typically these benign tumors arise along the ependymal lining (walls) of the lateral ventricles, the spaces that contain cerebrospinal fluid. They vary greatly in size and number, ranging from 2-10 mm in diameter and usually numbering more than one.
And like cortical tubers, SENs form early in brain development and are made up of highly disorganized and dysfunctional cells. However, while tubers have cells with both neuronal and glial characteristics, SENs are composed only of glial cells. SENs also differ from the relatively static tubers in that their growth can outpace that of the surrounding tissue, causing them to protrude into the cavities of the ventricles. While only 15 percent of SENs grow larger than 1 cm in diameter, those that do become classified as SEGAs and are cause for concern.
Subependymal Giant Cell Astrocytoma (SEGA)
Subependymal giant cell astrocytomas (SEGAs) are large SENs. They too are benign tumors composed of undifferentiated, dysfunctional glial cells. However, because of their large size and their potential for continued growth, especially in children and adolescents, these lesions pose a significant risk. For reasons that are not well understood, the propensity for SEGAs to develop decreases dramatically after adolescence.
In rare cases, SEGAs grow large enough to obstruct the flow of cerebrospinal fluid through the lateral ventricles. This is more likely when they occur in particularly narrow passages such as the foramen of Monro, which carries fluid between the lateral ventricles and the third ventricle. Obstruction of this flow can cause a condition known as hydrocephalus, in which cerebrospinal fluid builds up causing the ventricles to expand, and pressure within the cranium to increase. Without intervention to relieve the pressure, hydrocephalus can cause permanent damage to the brain or, in rare cases, death.