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Bychkova, E.; Dorofeeva, M.; Levov, A.; Kislyakov, A.; Karandasheva, K.; Strelnikov, V.; Anoshkin, K. Focal Cortical Dysplasia in Tuberous Sclerosis Complex. Encyclopedia. Available online: (accessed on 11 December 2023).
Bychkova E, Dorofeeva M, Levov A, Kislyakov A, Karandasheva K, Strelnikov V, et al. Focal Cortical Dysplasia in Tuberous Sclerosis Complex. Encyclopedia. Available at: Accessed December 11, 2023.
Bychkova, Ekaterina, Marina Dorofeeva, Aleksandr Levov, Alexey Kislyakov, Kristina Karandasheva, Vladimir Strelnikov, Kirill Anoshkin. "Focal Cortical Dysplasia in Tuberous Sclerosis Complex" Encyclopedia, (accessed December 11, 2023).
Bychkova, E., Dorofeeva, M., Levov, A., Kislyakov, A., Karandasheva, K., Strelnikov, V., & Anoshkin, K.(2023, June 20). Focal Cortical Dysplasia in Tuberous Sclerosis Complex. In Encyclopedia.
Bychkova, Ekaterina, et al. "Focal Cortical Dysplasia in Tuberous Sclerosis Complex." Encyclopedia. Web. 20 June, 2023.
Focal Cortical Dysplasia in Tuberous Sclerosis Complex

Patients with tuberous sclerosis complex present with cognitive, behavioral, and psychiatric impairments, such as intellectual disabilities, autism spectrum disorders, and drug-resistant epilepsy. It has been shown that these disorders are associated with the presence of cortical tubers. Tuberous sclerosis complex results from inactivating mutations in the TSC1 or TSC2 genes, resulting in hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway, which regulates cell growth, proliferation, survival, and autophagy. TSC1 and TSC2 are classified as tumor suppressor genes and function according to Knudson’s two-hit hypothesis, which requires both alleles to be damaged for tumor formation. However, a second-hit mutation is a rare event in cortical tubers. This suggests that the molecular mechanism of cortical tuber formation may be more complicated and requires further research.

tuberous sclerosis complex tuber TSC1 TSC2 epilepsy

1. Introduction

Tuberous sclerosis complex (TSC), also known as Bourneville–Pringle disease, is an autosomal-dominant disorder classified as phakomatosis, with an incidence of 1 per 6000–10,000 live births [1][2][3]. The products of the TSC1 and TSC2 genes, hamartin and tuberin, together with the TBC1D7 protein, form a complex that implements negative regulation of the mechanistic target of rapamycin (mTOR) signaling pathway, which is responsible for controlling cell growth and autophagy. Inactivating mutations in TSC genes provoke sustained activation of RHEB, a GTP-binding protein that activates the mechanistic target of rapamycin (mTOR). This, in turn, induces phosphorylation cascades, leading to cell growth, proliferation, and the suppression of autophagy [1][4].
The phenotypic manifestations of TSC are widely variable. These include heart, lung, kidney, skin, and brain malformations [1][3]. The absence of pathognomonic features complicates the diagnosis. Diagnosis can be made based on a combination of at least 2 major features or 1 major and 2 minor features. Major features comprise hypomelanotic macules (≥3, at least 5 mm in diameter), angiofibromas (≥3) or fibrous cephalic plaques, ungual fibromas (≥2), a shagreen patch, multiple retinal hamartomas, cortical dysplasias, subependymal nodules, subependymal giant cell astrocytoma, cardiac rhabdomyoma, lymphangioleiomyomatosis, and angiomyolipomas (≥2). Minor features comprise confetti skin lesions, dental enamel pits (>3), intraoral fibromas (≥2), a retinal achromic patch, multiple renal cysts, and nonrenal hamartomas. The presence of a pathological mutation in the TSC1 or TSC2 genes is sufficient for a diagnosis of TSC [1].
The presence of cortical tubers, subependymal nodes (SENs), or subependymal giant cell astrocytomas (SEGAs) in the cerebral cortex and/or subcortical white matter is a distinctive histopathological characteristic of TSC in the brain that occurs in 80–90% of cases [2]. Epilepsy is present in 80–90% of TSC cases and usually develops before the age of three [1][2][3]. It has been shown that disorders such as intellectual disabilities, autism spectrum disorders, and drug-resistant epilepsy, which occur in patients with TSC [2][5], are associated with the presence of cortical tubers [2][6][7]. The mechanism of epilepsy is a complex process that involves more than one signaling pathway, so it remains underdetermined.
Tubers are malformations of cortical development, represented by a disruption of the normal hexalaminar structure of the cerebral cortex, the formation of atypical neurons and glial cells, and a significant decrease in the number of normal neurons [2][8]. Abnormal cells are represented by dysmorphic neurons (DNs), giant cells (GCs), and gliotic and reactive astrocytes [2][3][9][10]. Hypomyelination, an abnormal vascular density, and inflammation are detected in the tuber tissue [11][12][13].
The TSC1 and TSC2 genes are classified as tumor suppressor genes and function according to Knudson’s two-hit hypothesis, which means that both alleles must be damaged for tumor formation. However, a second-hit mutation is a rare event in cortical tubers [14][15]. This suggests that the molecular mechanism of cortical tuber formation may be more complicated and requires further research.

2. Structural Features of Cortical Tubers

Tubers are areas of cortical dysplasia represented by several types of atypical, enlarged cells, including DNs, gliotic and reactive astrocytes, and GCs [2][9][10]. The normal hexalaminar structure of the neocortex is damaged within tubers. Classic features of focal cortical dysplasia, such as blurred boundaries of gray and white matter and cortex thickening, can be observed by MRI [11]. Microscopic structural changes in the brain, such as small areas of cortical dislocation, microtubers (small clusters of GCs, dysplastic astrocytes, and heterotopic neurons), and single, isolated GCs, are found in close proximity to the tubers [16][17][18]. These changes may contribute to the epileptogenicity of perituberal tissue. Cortical tubers should be considered a subtype of focal cortical dysplasia (FCD) type IIb because of their histological similarities: disruption of cortical lamination and the presence of morphologically abnormal cell types, specifically DNs and balloon cells (BCs), referred to as GCs in the case of TSC [19].
MRI is widely recognized as the reference method for defining CNS involvement in TSC. In infants, tubers appear as localized cortical thickening with moderate hyperintensity on T1-weighted images and hypointensity on T2-weighted images compared with normal unmyelinated tissue. After myelin maturation, tubers typically appear as areas of increased signal from the cerebral cortex and decreased signal from the subcortical white matter on T1-weighted sequences, along with increased signals from the cortex and subcortical white matter on T2-weighted sequences and fluid-attenuated inversion recovery (FLAIR) images [20][21].
Based on their MRI appearance, tubers have been classified into different types, including isointense on volumetric T1 images and subtly hyperintense on T2-weighted and FLAIR images (type A), hypointense on volumetric T1 images and homogeneously hyperintense on T2-weighted and FLAIR images (type B), and hypointense on volumetric T1 images, hyperintense on T2-weighted, and heterogeneous on FLAIR images characterized by a hypointense central region surrounded by a hyperintense rim (type C) [22]. Type C tubers correspond to cyst-like tubers, which are found in about 50% of TSC cases at an early age and are more common with TSC2 mutations [23][24]. Cyst-like tubers are expected to result from cellular degeneration or apoptosis. Gliosis is stronger in cystic tubers and the perituberal region than in conventional tubers. Cystic tubers are characterized by a more significant loss of subcortical white matter than classical tubers. It has been shown that an increase in the size of cystic tubers and the formation of cystic cavities in conventional tubers can occur in the postnatal period [23]. The presence of cystic tubers strongly correlates with more severe epilepsy [24]. Calcified tubers occur in 54% of patients with the diagnosis of TSC and progress with age [25]. The presence of calcified tubers correlates with more severe seizures and an early onset of the disease [11].
In cortical tubers, the following types of atypical cells are represented: DNs, GCs, and dysplastic astrocytes. DNs have an enlarged soma, atypical processes, a high content of neurofilaments, and Nissl bodies in the cytoplasm [11][26]. These abnormal cells express neurofilament proteins in their cell bodies. DNs can be located within all cortical layers as well as in subcortical white matter [8][27]. They are immunoreactive to p-S6, a downstream mTOR substrate, demonstrating cell-specific activation of the mTOR pathway [16][27], and are positive for neuronal markers such as NF200, DCX, and NeuN [28]. DNs and GCs show nuclear and cytoplasmic accumulation of p62, a stress-inducible intracellular protein that is known to regulate different signal transduction pathways and has been identified as a key target of autophagy [29].
GCs detected in TSC are histologically similar to BCs of FCD type IIb [29]. These are enlarged cells with an eosinophilic opalescent cytoplasm and one or more flattened and decentered nuclei [28][29]. GCs have a cell body that is 3 to 10 times greater in length compared to common neurons and glial cells [9]. They are mainly present in the deep layers of the affected cortical area and corresponding white matter as well as outside TSC lesions [29]. An immunohistochemical and electron microscopy analysis indicated the presence of two different subtypes displaying glial or neuronal features [9][28]. Electron microscopy revealed neuronal features, such as round nuclei with a prominent nucleolus, an organized reticulum and microtubules, lots of intermediate filament bunches, and synapses on processes, and glial features, such as a large, smooth cytosol devoid of organelles around the nucleus, an accumulation of organelles at the periphery of the cell, and numerous glial filaments and lysosomes [9][28]. An immunohistochemical analysis showed that some GCs express markers of mature neurons (neurofilaments, NeuN, synaptophysin, doublecortin, MAP2, neuron-specific enolase, neuropeptide Y) and those of immature neurons (doublecortin). Other GCs are positive for markers of glial cells (GFAP, β-crystallin, S-100) [9]. Markers of neural stem cells (SOX2, nestin, CD133) are also expressed by GCs.
Astrocytes are presented in tubers in a significantly larger amount than in the perituberal cortex and control brain tissue [10][30]. Two subpopulations of abnormal astrocytes have been distinguished within tubers—gliotic and reactive. Gliotic astrocytes are characterized by smaller sizes and lower levels of glutamate transmitters, glutamine synthetase, and inward-rectifier potassium channels, all of which represent proepileptogenic changes [10]. Reactive astrocytes have larger soma and the presence of thick and tortuous extensions and express GFAP and vimentin [10][28]. The expression of p-S6 in reactive astrocytes reveals mTOR activation, although compared with DNs and GCs, dysplastic astroglia represent only a smaller fraction of cells expressing the p-S6 protein [10][28]. Whether the different degrees of mTOR activation underlie the wide diversity in astrocyte functions and phenotypes in TSC is a major research challenge. The dynamics of the distribution of gliotic and reactive astrocytes may be responsible for the changes in epileptogenicity and the morphological dynamics of tubers over time [30]. Astrocytes demonstrate high levels of ICAM-1, NFkB, TNFa, and IL-1b and its signaling receptor IL-1RI, as well as greater expression of the enzymes inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) [10][30][31]. The expression of proinflammatory cytokines and inflammatory enzymes may further activate astrocytes within tubers and foster epileptogenesis.
Subcortical white matter loss is also detected in tubers, which may be explained by a loss of projections between abnormal neurons and the other brain regions. Significant myelin reduction has been shown in tubers, but it is not always accompanied by a decrease in the number of oligodendrocytes [11][32]. Near the base of the cortical tuber, clusters of cytomegalic neurons commonly form heterotopias that are accompanied by hypomyelination [33].
As in SENs and SEGAs, inflammation is present in tubers, albeit to a lesser degree [15]. The expression of HLA-DR, CCL2, and SerpinA3 indicates the activation of microglia within tuber tissue [34]. Microglia are often clustered around DNs and GCs and are associated with immune mediators, such as CD8-positive T-lymphocytes and the complement cascade. Cortical tubers show a large number of activated microglial cells expressing MHC class II antigens [12]. Microglia activation has a damaging effect on oligodendrocytes and neurons, leading to neuronal dysfunction, concomitant neurological diseases, and increased excitability [30]. Proinflammatory factors expressed by microglial cells and the increased synthesis of vascular endothelial growth factor (VEGF) caused by mTOR hyperactivation are associated with changes in vascular density within tuber tissue. This increases the blood–brain barrier permeability in tubers compared to the surrounding perilesional cortex, promoting lymphocyte infiltration [35].

3. Molecular Genetics

3.1. Impaired Inhibition of the mTOR Pathway by the TSC Complex

The mTOR pathway is inhibited by a protein complex consisting of hamartin, tuberin, and TBC1D7. Hamartin is encoded by TSC1 (chromosome 9q34.13), and tuberin is encoded by TSC2 (chromosome 16p13.3). TSC1, TSC2, and TBC1D7 assemble the TSC complex with a 2:2:1 stoichiometry. Two TSC2 molecules come together to form a pseudo-symmetric dimer through tail-to-tail interactions, while the TSC1 dimer makes multiple contacts with the tuberin dimer and stabilizes the conformation of the complex. Dimerization of the TSC1 protein leads to asymmetric formation of the TSC1–TSC2 tetramer and the recruitment of a single TBC1D7 molecule [36]. Hamartin and tuberin stabilize each other, which is confirmed by a significant decrease in the TSC1 protein with a homozygous TSC2 mutation and, vice versa, a decrease in the TSC2 protein with a homozygous TSC1 mutation [37][38].
The TSC1–TSC2–TBC1D7 complex regulates the activity of the mTOR protein kinase by inhibiting the regulatory protein RHEB. Regulation of the mTOR signaling pathway is carried out by a GAP domain in tuberin, which hydrolyzes GTP bound to RHEB, thereby inactivating the protein [39]. TSC1 is believed to enhance TSC2 function by activating TSC2 GAP activity, stabilizing TSC2, and/or maintaining the correct intracellular localization of the TSC complex [40]. RHEB is an activator of the mTORC1 complex consisting of the mTOR protein kinase, the LST8 protein associated with the mTORC1 catalytic domain, RPTOR, a regulatory protein, and two inhibitory proteins, DEPTOR and AKT1S1 [7]. MTORC1 participates in the regulation of many cellular processes, including protein synthesis, lipogenesis, ribosomal biogenesis, purine and pyrimidine nucleotide biosynthesis, DNA transcription, autophagy, and mitochondrial biogenesis [39][41]. MTORC1 can be allosterically inhibited by rapamycin, a macrolide [4][39].
As a result of a TSC1/TSC2 mutation, the GAP domain in TSC2 fails to perform its function, leading to impaired RHEB inhibition. The constitutive activity of RHEB leads to the hyperactivation of mTORC1. This leads to phosphorylation of the key effectors of protein synthesis, the p70S6 and 4E-BP1 kinases. The p70S6 kinase phosphorylates the ribosomal protein S6, resulting in the phosphorylation of transcription elongation factors, which facilitates translation and cell growth [4][39][41][42].
Figure 1. Effects of activation of the mTOR signaling pathway via TSC1 or TSC2 inactivation.
The disturbance of mTOR signaling plays a key role in a variety of neurological disorders, including TSC, FCD, hemimegalencephaly, epilepsy, and autism spectrum disorder [41][43]. A number of studies have identified somatic mutations in genes encoding canonical signaling proteins within the mTOR pathway, including PIK3CA, AKT3, TSC1, TSC2, and MTOR itself in the aforementioned disorders [43][44]. The mTOR signaling pathway plays vital roles in cortical development and the maintenance of cell homeostasis and energy metabolism and participates in the regulation of cell proliferation, differentiation, migration, and survival as well as in the formation and functioning of synapses [41][42]. This pathway is also involved in establishing the shape and size of neurons, dendritic arborization, spine morphology, axon outgrowth, and the regulation of excitatory and inhibitory neurotransmission [41]. MTORC1 was identified as a positive regulator of Notch signaling. By increasing Notch activation, newly formed neurons may prime multipotent progenitors to respond to gliogenic cytokines, resulting in a switch to astrogenesis [45][46]. The suppression of mTORC1 signaling during the transition from proliferation to neuronal differentiation of human neurons is a prerequisite for normal neuro- and gliogenesis [47]

3.2. Alternative Mechanisms for Brain Pathlogy in TSC

In addition to the pathogenetic role of mTOR hyperactivation, other mechanisms of tuber formation have been discussed. The alterations in cell signaling mechanisms critical for neuronal migration still remain unclear. One suggested mechanism of irregular migration is ineffective Reelin-Dab1 signaling. Reelin is a glycoprotein synthesized in the marginal zone during neurogenesis. It regulates neuronal migration by polarizing and stabilizing neuronal processes and ordering neuronal–glial connections. It functions by interacting with the VLDR and ApoER2 receptors, resulting in phosphorylation of their intracellular domain, Dab1. The phosphorylated Dab1 (pDab1) activates downstream pathways that regulate neuronal migration. The phosphorylation of Dab1 is regulated by the Src family kinase. Cullin 5 (Cul5), a core component of E3 ubiquitin-protein ligase complexes, is involved in the ubiquitin-mediated degradation of the pSrc kinase and pDab1. Cortical tubers from TSC2 Emx1-Cre CKO mice show increases in Reelin, Dab1, and Cul5, but pDab1 levels are significantly reduced, resulting in the impaired regulation of migration [48]. Examination of the layer-specific neuronal markers SMI32, Tbr1, Satb2, Cux2, ER81, and RORβ in tuber tissue has revealed a general decrease in the number of neurons, as well as impaired cortical lamination, revealing neurons expressing layer-specific markers that are randomly scattered throughout the tuber volume and perituberal cortex [8][49].

3.3. Biallelic Mutations in the TSC1 or TSC2 Genes Are Rarely Detected in Cortical Tubers

Knudson’s two-hit hypothesis has been shown to be valid for tumors in TSC, such as SEGA, renal angiomyolipoma, and facial angiofibroma [50][51][52]. According to this hypothesis, the inactivation of both alleles of a tumor suppressor gene is required for tumor formation. The first hit is an inherited or de novo germline mutation, and the second hit occurs in somatic cells, including a loss of heterozygosity or a point mutation, and leads to a complete loss of gene function [53][54]. Biallelic mutations in the TSC1 or TSC2 genes are rarely detected in tuber tissue samples, so the mechanism of the second hit in cortical tubers remains unclear [15][26][55]. Inactivation of the second allele of the tumor suppressor gene may be the result of epigenetic silencing; however, there are extremely few data on differential TSC1 and TSC2 methylation in cortical tubers to suggest that methylation may be responsible for the second hit [15][56]. There are also no mutations in tumor driver genes and mTOR pathway genes specific to TSC patients [15].
Given the rarity of detection of biallelic mutations in the TSC1 or TSC2 genes in tuber tissue samples, it is tempting to assume that the nature of TSC causative mutations makes Knudson’s two-hit hypothesis nonapplicable to the pathogenesis of at least some TSC-associated lesions, such as cortical tubers. In 2020, Feliciano suggested that a loss of both functional copies of TSC1 or TSC2 is perhaps not necessary to cause TSC and that haploinsufficiency or dominant negative mutations could also underlie the pathogenesis of cortical tubers [5]. Mutations in the TSC1 or TSC2 genes that cause a premature termination codon (PTC) were demonstrated to be associated with nonsense mediated decay (NMD) of the RNA, resulting in a reduced level of the mutant transcript, thus presenting loss of function mutations [57][58]. In TSC1, virtually all mutations are nonsense or small frameshift changes producing PTCs [57], thus rendering them loss of function mutations.
About one-third of TSC cases are inherited in an autosomal dominant manner; the other cases are the result of de novo germline or somatic mutations [7][42][59]. Somatic mutations are reported to cause FCD, hemimegalencephaly, as well as TSC lesions. Somatic mutations occur in postzygotic cells during embryogenesis, and if a somatic mutation occurs late in development, it may be present in a percentage of cells in only one tissue, which makes such mutations difficult to identify [43]. Damaging somatic mutations need to be present in a threshold percentage of cells to disrupt neuronal development and function. It was reported that somatic mutations present in as few as 1% of cells can cause cortical malformation [60]. To detect somatic mutations present in a particular cell fraction, DNA from bulk tissue or single cells must be sequenced. One of the possible reasons for the absence of biallelic mutations from the brain tissue of TSC patients is that tubers include different cell types, and only a small portion of the tuber is affected by a second hit. Tubers contain atypical cells with an increased mTORC1 activity level as well as normal neurons and glial cells.

3.4. Transcriptome and miRNA Expression in Cortical Tubers

Studies of the protein-coding transcriptome revealed the altered expression of the spectrum of genes in cortical tubers and the perituberal region compared to normal brain tissue [15][61][62]. Using a single-cell RNA-Seq analysis, it was shown that most of the genes that were overexpressed were specific to microglia, and the genes that were underexpressed were specific to neurons [62].
Increased expression of genes involved in the regulation of innate and adaptive immunity, the inflammatory response, the cytokine-mediated signaling pathway, and cell adhesion has been shown. The expression of immune and inflammatory molecules is believed to be increased by mTOR activation, since lower expression was observed in perituberal tissue. Elevated levels of cell adhesion and inflammatory molecules may contribute to increased permeability of the blood–brain barrier, the disorganization of cortical lamination, and epileptic activity in tubers [61].
Genes with reduced expression in cortical tubers are involved in the processes of neurogenesis, the regulation of glutamatergic and GABAergic synaptic transmission, as well as formation of inward-rectifier potassium channels. Neural cell adhesion molecules (NCAM) contribute to the interaction between neurons during brain development, neuronal migration, synaptogenesis, and synaptic plasticity. Contactin-3, an immunoglobulin-like NCAM, is downregulated in cortical tubers at the RNA and protein levels, especially during the early postnatal period, which is critical for brain development. The lack of contactin-3 may be involved in the development of neurodevelopmental and behavioral disorders in TSC [63].

4. The Origin of Cortical Tubers

4.1. Normal Cortical Development and Tuberogenesis

The human cerebral cortex develops from the neuroectoderm. Neuroepithelial cells (NECs) divide symmetrically, increasing their population pool. During neural tube formation, NECs transform into radial glia cells, and together, line the lateral ventricles, thus forming the ventricular zone [64]. These radial glia cells give rise to different types of brain cells, including neurons, astrocytes, oligodendrocytes, and ependyma, in a temporally regulated manner [5]. It is assumed that the population of radial glia cells is heterogeneous, comprising cells committed to neurons or macroglia as well as multipotent cells. About 10–20% of radial glia cells generate pairs of neurons. Radial glia cells also generate intermediate progenitor cells, which divide 1–3 times for self-renewal and generate pairs of neurons. Excitatory projection neurons migrate and constitute the cortical plate. Neurons are born in an inside-out order: at the early stage, neurons of the lower cortical layers are formed, followed by upper-layer neurons. Radial glia cells also provide a physical substrate for neuronal movement into the cortical layers.
Tubers are thought to originate during fetal development, starting at around the 19th week of gestation (GW) [18][28][43][65][66][67][68][69]. The formation of dysmorphic astrocytes and GCs in subcortical zones are probably initial events in tuberogenesis. Dysmorphic astrocytes have been detected in abortive material at 19–21 GW, mainly in the marginal zone and subpial granule cell layer. GCs can be detected in the deep white matter by 23–24 GW, and the expression of neuronal markers in the GCs can be observed after only 30 GW. Clusters of GCs appear in the cortical plate by 32–34 GW [18][28]

4.2. Models for Studying the Development of Cortical Tubers

To better understand the formation of cortical malformations, researchers utilize mouse models. Although cortical tubers are not present in mice, they do exhibit similar abnormalities, and conditional TSC1 and TSC2 mutations are used due to the lethality of biallelic germline mutations at the embryonic stage [70]. Conditional mutations are performed at different stages of brain development, which allows for speculation about the timing of the second mutational event.
The loss of both copies of TSC1 in dorsal NPCs of Emx1-Cre conditional knockout (CKO) mice resulted in a severe disruption of cortical lamination, an increased cell size, increased mTORC1 activity, astrogliosis, and hypomyelination. Astrocytes showed abnormalities in glutamate transport and potassium homeostasis, which plays a role in the development of seizure activity. It should be noted that heterozygous TSC1 models had no seizures or increased mTORC1 activation [70]. Rapamycin treatment suppressed seizure activity, myelination, and astrocyte defects and led to a reduction in the soma size of hypertrophic neurons [70][71].
TSC2 hGFAP-Cre CKO mice, with a conditional mutation in radial glial cells, exhibited defects of cortical lamination, postnatal cortex thickening, and macrocephaly, enlarged cells, astrogliosis, and hypomyelination. An increase in the number of progenitor cells and a decrease in the number of postmitotic neurons, especially early neurons, was observed, suggesting impaired progenitor cell differentiation [72].

5. Epileptogenicity of Cortical Tubers and Its Treatment

Epilepsy is the most common symptom, affecting 85–90% of patients diagnosed with TSC [1][7]. Epilepsy in TSC is quite heterogeneous, frequently involving a variety of seizure types, including partial seizures, generalized seizures, and infantile spasms. TSC-associated epilepsy is characterized by early-onset seizures, starting in the first year of life in 63% of patients, often by three months of age, but the first seizure can also occur in adolescence or early adulthood [7][42]. Refractory to standard antiepileptic drugs, epilepsy develops in two-thirds of individuals with TSC [1]. Surgical removal of tubers causes the reduction or elimination of seizures, which supports tubers’ contribution to seizure development [7]. It was observed that the tuber volume correlates with the severity of epilepsy and intellectual disability. The ratio of the tuber volume to the whole brain volume is supposed to be a more reliable indicator for the prediction of cognitive impairment [73].
EEG studies have made it possible to identify the seizure initiation zone. Epileptiform discharges appear to arise in the center of the epileptogenic tuber and spread to its periphery and to the perituberal cortex [74]. Some studies claim that the perituberal cortex has its own epileptogenic activity [1][74]. Tubers can be classified into three groups: drug-resistant epileptogenic tubers, drug-controlled epileptogenic tubers, and epileptogenically inert. All three types can be observed within the brain of a single patient. It is noteworthy that seizure-generating tubers and nonepileptogenic tubers can be indistinguishable morphologically [75].
The mechanism of tuber epileptic activity remains a topical issue of study, because it is essential for the development of effective treatment for patients with drug-resistant epilepsy. Hyperactivation of mTOR is directly related to epileptogenesis, which has been confirmed by the results of clinical studies (EXIST-3) [76] and the reduced number of epileptic seizures or their elimination following the use of mTOR inhibitors [7]. Persistent upregulation of the mTOR pathway is hypothesized to initiate changes in neuron physiology, dendritic morphology, and changes in dendritic spine density and structure that contribute to epileptogenesis [77]. Disorders of synaptic transmission of an excitatory neurotransmitter glutamate play a significant role in the mechanism of epileptogenesis. A critical factor that regulates neuronal excitability is the expression and function of synaptic receptors for the main excitatory neurotransmitter glutamate.


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