Cortical Tuber Count: A Biomarker Indicating Neurologic Severity of Tuberous Sclerosis Complex

Abstract

The relationship between the number of cortical tubers observed by magnetic resonance imaging (MRI) and the severity of cerebral dysfunction of tuberous sclerosis patients has been examined in a meta-analysis of the published literature. The literature review has identified five independent studies for examining the association. These studies consistently reveal that the cortical tuber count detected on MRI scans is increased among those with more severe cerebral disease. Severity of the cerebral dysfunction is measured by the seizure status and its control and by the developmental status and the level of mental retardation. Meta-analysis demonstrates that within a study population, the MRI-detected cortical tuber count is six times more likely to be above the median count for tuberous sclerosis patients with severe cerebral dysfunction (poor seizure control or moderate-severe retardation or both) than more mildly affected tuberous sclerosis patients. Similarly, across studies, moderately to severely affected patients are five times more likely to have greater than seven MRI-detected cortical tubers than those more mildly affected. These associations are both statistically significant and strong. The cortical tuber count is a biomarker that reasonably predicts the severity of cerebral dysfunction of tuberous sclerosis. Cortical tubers of tuberous sclerosis form in the early gestational period. The embryologic disruption determining the clinical severity of the cortical dysfunction of tuberous sclerosis is set in the early gestational period.

Analysis of Ictal EEGs of Epilepsy Associated with Tuberous Sclerosis

“…We found that these partial seizures had the following characteristics: (a) some patients had shifting epileptogenic foci with increasing age, (b) different types of patial seizures coexisted in the same period in an individual patient, (c) different partial seizures could occur sequentially in one seizure, and (d) the number of epileptogenic foci could increase during the clinical course. In spite of many studies about the relation between tubers and epilepsy (18)(19)(20)(21), it is still unclear which tubers become epileptogenic. It has been reported that cortical dysplasia is intrinsically epileptogenic because epileptogenic discharges were frequently recorded from cortical dysplastic lesions by means of electrocorticography (22).…”

“…Bebin et al (23) also described that there was a close relationship between the location of ictal seizure activities and the location of prominent neuroimaging abnormalities. Although some authors claim that cortical tuber count seems to be the best marker to predict the outcome of epilepsy in patients with tuberous sclerosis (21), this problem is still under discussion.…”

Differential Cellular Expression of Neurotrophins in Cortical Tubers of the Tuberous Sclerosis Complex

“…Tubers are highly correlated with epilepsy in TSC patients 52 and presurgical evaluations of TSC patients with medically intractable seizures have demonstrated that tubers are epileptic foci. 6 Changes in neurotrophin expression in tubers may have relevance to the epileptogenic properties of these lesions.…”

Genotype and cognitive phenotype of patients with tuberous sclerosis complex

“…[7][8][9][10][11][12][13] A bimodal intellectual quotient (IQ) distribution in the total TSC population has been suggested 7 and was recently refined as being observed only in the TSC2 population. 10 TSC patients with germline TSC1 and TSC2 mutations have only one fully functional TSC2 allele in all their cells, and this condition could lead to neurocognitive dysfunction through the mechanism of haplo-insufficiency, [14][15][16] similar to Fragile-X syndrome and Neurofibromatosis type 1.…”