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In previous studies we demonstrated that inflammation plays an important role in the epileptogenesis of cortical tubers 13, 35. In the present study we detected increases in inflammatory markers in type B and C tubers. Type A were not significantly differ- ent to controls. This observation may argue against the hypothesis that inflammation alone may underlie the epileptogenicity of the tuber. Accordingly, several studies suggest increase neuronal excitability through different mechanisms, including also a deregula- tion of astrocyte-mediated glutamate uptake and release, as well as through changes in the function of both glutamate and GABA receptors 36
Furthermore, hypomyelination is a common feature of FCD type II, although it is not fundamental to make the distinction between FCD type IIA and IIB 24 25. Notwithstanding, the underlying etiology is less well understood. With our set of data a lack of myelin could also be confirmed. After all, the oligodendroglial cell count did not delineate significant changes compared with controls. Findings in TSC mouse models indicate that there is a marked difference in brain myelination when TSC1 is lost in neu- rons, suggesting that the reduction in myelination is secondary to mTORC1 activation in neurons, rather than reflecting a primary oligodendroglial abnormality. Also, previous studies sreported that the number of oligodendroglial cells remain intact and that there is axonal loss 25, 14. Another study suggested that, at least in FCD type IIB there is also a maturational problem 24. However, the different methodological approaches may have led to these controversial results.
All together certain features of our assessment (neuronal loss, gliosis, calcifica- tion, myelin loss and inflammation) are considered regressive changes in pathology in TSC cortical tubers 14, 34, albeit our associations with the available clinical data suggests differently. In our cohort of type A tuber only a limited set of AEDs were prescribed and none of these patients underwent hemispherotomy as surgical strategy. We have to acknowledge that these parameters are certainly not a reflection of electrophysiological properties but they might act as surrogate markers for a milder phenotype. However, in our cohort, the number of patients with type A tuber was too small to evaluate the possible prognostic value on postsurgical seizure outcome or other clinical parameters, which deserves further investigation in prospective studies, using the proposed histo- logical tuber classification.
Another striking feature was the negative association between age at surgery and histology, with type C tuber occurring more often in very young children. This finding could be related to the time point of tuber formation leading to such severe pathologi- cal changes already in the early stages of cerebral development 37. Considering this, calci- fication, inflammation and increased gliosis in type C tubers may not exclusively indicate regressive changes but also a distinct pathogenesis. Furthermore, the relatively short duration of active epilepsy before surgery is consistent with a more severe phenotype with higher seizure burden and possible comorbid developmental problems. However, our cohort might be too small to detect subtle differences in clinical characteristics in relation to surgical outcomes.
We collected clinical data with special attention to MRI characterization. We were unable to detect an association between the previously proposed classification of tuber types on MRI and our histological assessments 11. Nevertheless, we identified a correlation between so-called “FCD-like features” and histological type B and C tubers.