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Epileptogenic but MRI-normal perituberal tissue in Tuberous Sclerosis Complex contains tuber-specific abnormalities.

Sosunov AA, McGovern RA, Mikell CB, Wu X, Coughlin DG, Crino PB, Weiner HL, Ghatan S, Goldman JE, McKhann GM - Acta Neuropathol Commun (2015)

Bottom Line: Perituberal giant cells and astrocytes together formed characteristic "microtubers".A parallel analysis of tubers showed that many contained astrocytes with features of both protoplasmic and gliotic cells.Microtubers represent a novel pathognomonic finding in TSC and may represent an elementary unit of cortical tubers.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Recent evidence has implicated perituberal, MRI-normal brain tissue as a possible source of seizures in tuberous sclerosis complex (TSC). Data on aberrant structural features in this area that may predispose to the initiation or progression of seizures are very limited. We used immunohistochemistry and confocal microscopy to compare epileptogenic, perituberal, MRI-normal tissue with cortical tubers.

Results: In every sample of epileptogenic, perituberal tissue, we found many abnormal cell types, including giant cells and cytomegalic neurons. The majority of giant cells were surrounded by morphologically abnormal astrocytes with long processes typical of interlaminar astrocytes. Perituberal giant cells and astrocytes together formed characteristic "microtubers". A parallel analysis of tubers showed that many contained astrocytes with features of both protoplasmic and gliotic cells.

Conclusions: Microtubers represent a novel pathognomonic finding in TSC and may represent an elementary unit of cortical tubers. Microtubers and cytomegalic neurons in perituberal parenchyma may serve as the source of seizures in TSC and provide potential targets for therapeutic and surgical interventions in TSC.

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Microtubers in perituberal tissue. (a) Microtubers differ in the shape of astrocytes: type I (asterisk) has astrocytes with long processes, whereas type II (star) has astrocytes with regular lengths of processes. Inset, enlarged boxed area outlined in (a), GS+ giant cell (arrow) in type II microtuber. (b, c) Immunostaining for plasma membrane glycoprotein CD44 emphasizes the difference in the shapes of astrocytes in type I (b) and type II (c) microtubers. Note that fibrous-like astrocytes in type I microtubers do not have small leaf-like processes and main branches are clearly outlined (b1), in contrast CD44+ astrocytes in II type microtubers, display an abundance of miniature leaf-like processes located on main branches, which produces the characteristic bushy-like view of the cell (c1). (d) Type I microtuber with vimentin (VIM) immunoreactive giant cell (arrow). Note that astrocytes (arrowheads) with long process express VIM, a typical feature of reactive astrocytes. (e) Microtuber composed of a p-S6+ giant cell (arrow) surrounded only by a few astrocytes with high levels of GFAP. Confocal microscopy, double immunostaining, counterstaining with Nissl. a’, b’,b1’, c’, and c1’represent split images of a, b, b1, c, and c1, respectively. b1, c1, d1, and e1 –enlarged boxed area outlined in b, c, d, and e respectively. scale bars: 150 μm in a; 55 μm in b,c, and d; 80 μm in e.
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Fig2: Microtubers in perituberal tissue. (a) Microtubers differ in the shape of astrocytes: type I (asterisk) has astrocytes with long processes, whereas type II (star) has astrocytes with regular lengths of processes. Inset, enlarged boxed area outlined in (a), GS+ giant cell (arrow) in type II microtuber. (b, c) Immunostaining for plasma membrane glycoprotein CD44 emphasizes the difference in the shapes of astrocytes in type I (b) and type II (c) microtubers. Note that fibrous-like astrocytes in type I microtubers do not have small leaf-like processes and main branches are clearly outlined (b1), in contrast CD44+ astrocytes in II type microtubers, display an abundance of miniature leaf-like processes located on main branches, which produces the characteristic bushy-like view of the cell (c1). (d) Type I microtuber with vimentin (VIM) immunoreactive giant cell (arrow). Note that astrocytes (arrowheads) with long process express VIM, a typical feature of reactive astrocytes. (e) Microtuber composed of a p-S6+ giant cell (arrow) surrounded only by a few astrocytes with high levels of GFAP. Confocal microscopy, double immunostaining, counterstaining with Nissl. a’, b’,b1’, c’, and c1’represent split images of a, b, b1, c, and c1, respectively. b1, c1, d1, and e1 –enlarged boxed area outlined in b, c, d, and e respectively. scale bars: 150 μm in a; 55 μm in b,c, and d; 80 μm in e.

Mentions: In contrast to the highly gliotic tubers, the perituberal gray matter was populated mainly with protoplasmic astrocytes displaying high levels of GS and low levels of GFAP (Figure 2a,b). To detect abnormal cells typical for tubers within perituberal tissue, we used several markers specific for neurons and glial cells and known to be increased in giant cells and cytomegalic neurons [14,15], as well as p-S6, to look for mTOR activation [16]. In every section from every specimen of perituberal tissue, we found aberrant cells characteristic of tubers: giant cells, gliotic astrocytes, and cytomegalic neurons.Figure 2


Epileptogenic but MRI-normal perituberal tissue in Tuberous Sclerosis Complex contains tuber-specific abnormalities.

Sosunov AA, McGovern RA, Mikell CB, Wu X, Coughlin DG, Crino PB, Weiner HL, Ghatan S, Goldman JE, McKhann GM - Acta Neuropathol Commun (2015)

Microtubers in perituberal tissue. (a) Microtubers differ in the shape of astrocytes: type I (asterisk) has astrocytes with long processes, whereas type II (star) has astrocytes with regular lengths of processes. Inset, enlarged boxed area outlined in (a), GS+ giant cell (arrow) in type II microtuber. (b, c) Immunostaining for plasma membrane glycoprotein CD44 emphasizes the difference in the shapes of astrocytes in type I (b) and type II (c) microtubers. Note that fibrous-like astrocytes in type I microtubers do not have small leaf-like processes and main branches are clearly outlined (b1), in contrast CD44+ astrocytes in II type microtubers, display an abundance of miniature leaf-like processes located on main branches, which produces the characteristic bushy-like view of the cell (c1). (d) Type I microtuber with vimentin (VIM) immunoreactive giant cell (arrow). Note that astrocytes (arrowheads) with long process express VIM, a typical feature of reactive astrocytes. (e) Microtuber composed of a p-S6+ giant cell (arrow) surrounded only by a few astrocytes with high levels of GFAP. Confocal microscopy, double immunostaining, counterstaining with Nissl. a’, b’,b1’, c’, and c1’represent split images of a, b, b1, c, and c1, respectively. b1, c1, d1, and e1 –enlarged boxed area outlined in b, c, d, and e respectively. scale bars: 150 μm in a; 55 μm in b,c, and d; 80 μm in e.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4383198&req=5

Fig2: Microtubers in perituberal tissue. (a) Microtubers differ in the shape of astrocytes: type I (asterisk) has astrocytes with long processes, whereas type II (star) has astrocytes with regular lengths of processes. Inset, enlarged boxed area outlined in (a), GS+ giant cell (arrow) in type II microtuber. (b, c) Immunostaining for plasma membrane glycoprotein CD44 emphasizes the difference in the shapes of astrocytes in type I (b) and type II (c) microtubers. Note that fibrous-like astrocytes in type I microtubers do not have small leaf-like processes and main branches are clearly outlined (b1), in contrast CD44+ astrocytes in II type microtubers, display an abundance of miniature leaf-like processes located on main branches, which produces the characteristic bushy-like view of the cell (c1). (d) Type I microtuber with vimentin (VIM) immunoreactive giant cell (arrow). Note that astrocytes (arrowheads) with long process express VIM, a typical feature of reactive astrocytes. (e) Microtuber composed of a p-S6+ giant cell (arrow) surrounded only by a few astrocytes with high levels of GFAP. Confocal microscopy, double immunostaining, counterstaining with Nissl. a’, b’,b1’, c’, and c1’represent split images of a, b, b1, c, and c1, respectively. b1, c1, d1, and e1 –enlarged boxed area outlined in b, c, d, and e respectively. scale bars: 150 μm in a; 55 μm in b,c, and d; 80 μm in e.
Mentions: In contrast to the highly gliotic tubers, the perituberal gray matter was populated mainly with protoplasmic astrocytes displaying high levels of GS and low levels of GFAP (Figure 2a,b). To detect abnormal cells typical for tubers within perituberal tissue, we used several markers specific for neurons and glial cells and known to be increased in giant cells and cytomegalic neurons [14,15], as well as p-S6, to look for mTOR activation [16]. In every section from every specimen of perituberal tissue, we found aberrant cells characteristic of tubers: giant cells, gliotic astrocytes, and cytomegalic neurons.Figure 2

Bottom Line: Perituberal giant cells and astrocytes together formed characteristic "microtubers".A parallel analysis of tubers showed that many contained astrocytes with features of both protoplasmic and gliotic cells.Microtubers represent a novel pathognomonic finding in TSC and may represent an elementary unit of cortical tubers.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Recent evidence has implicated perituberal, MRI-normal brain tissue as a possible source of seizures in tuberous sclerosis complex (TSC). Data on aberrant structural features in this area that may predispose to the initiation or progression of seizures are very limited. We used immunohistochemistry and confocal microscopy to compare epileptogenic, perituberal, MRI-normal tissue with cortical tubers.

Results: In every sample of epileptogenic, perituberal tissue, we found many abnormal cell types, including giant cells and cytomegalic neurons. The majority of giant cells were surrounded by morphologically abnormal astrocytes with long processes typical of interlaminar astrocytes. Perituberal giant cells and astrocytes together formed characteristic "microtubers". A parallel analysis of tubers showed that many contained astrocytes with features of both protoplasmic and gliotic cells.

Conclusions: Microtubers represent a novel pathognomonic finding in TSC and may represent an elementary unit of cortical tubers. Microtubers and cytomegalic neurons in perituberal parenchyma may serve as the source of seizures in TSC and provide potential targets for therapeutic and surgical interventions in TSC.

Show MeSH
Related in: MedlinePlus