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Neuropathology of SUDEP

View Article: PubMed Central - PubMed

ABSTRACT

Objective:: To seek a neuropathologic signature of sudden unexpected death in epilepsy (SUDEP) in a postmortem cohort by use of immunohistochemistry for specific markers of inflammation, gliosis, acute neuronal injury due to hypoxia, and blood-brain barrier (BBB) disruption, enabling the generation of hypotheses about potential mechanisms of death in SUDEP.

Methods:: Using immunohistochemistry, we investigated the expression of 6 markers (CD163, human leukocyte antigen–antigen D related, glial fibrillary acid protein, hypoxia-inducible factor-1α [HIF-1α], immunoglobulin G, and albumin) in the hippocampus, amygdala, and medulla in 58 postmortem cases: 28 SUDEP (definite and probable), 12 epilepsy controls, and 18 nonepileptic sudden death controls. A semiquantitative measure of immunoreactivity was scored for all markers used, and quantitative image analysis was carried out for selected markers.

Results:: Immunoreactivity was observed for all markers used within all studied brain regions and groups. Immunoreactivity for inflammatory reaction, BBB leakage, and HIF-1α in SUDEP cases was not different from that seen in control groups.

Conclusions:: This study represents a starting point to explore by immunohistochemistry the mechanisms underlying SUDEP in human brain tissue. Our approach highlights the potential and importance of considering immunohistochemical analysis to help identify biomarkers of SUDEP. Our results suggest that with the markers used, there is no clear immunohistochemical signature of SUDEP in human brain.

No MeSH data available.


Related in: MedlinePlus

BBB impairment in SUDEP and control cases(A–C) Medulla, (D–F) hippocampus, and (G–H) amygdala. (A) Semiquantitative evaluation of immunoglobulin G (IgG) marker in the medulla. (B) Fewer IgG-immunopositive neurons and astrocytes were present in ventrolateral medulla (VLM; a) and the floor of the fourth ventricle (IVth V; c) in a sudden unexpected death in epilepsy (SUDEP; b) than in a nonepileptic sudden death (NESD; d) case. (C) Semiquantitative evaluation of albumin marker in the medulla. (D) Semiquantitative evaluation of IgG marker in the hippocampus. Expression of IgG marker in SUDEP cases in CA1 and parahippocampal gyrus (PH-G ) was significantly lower than in NESD controls (*both p ≤ 0.001). (E) Lower expression of IgG marker in the hippocampus of a SUDEP (a–d) than in a NESD (e–h) case in mosaic-like pattern of expression in the dentate gyrus (DG; a, e), pyramidal neurons in CA1 (b, f), subiculum (Sub; c, g) and PH-G (d, h). (F) Semiquantitative evaluation of albumin marker in the hippocampus. (G) Semiquantitative evaluation of IgG marker in the amygdala. (H) Fewer IgG-immunopositive cells were present in lateral nuclei (LN) in the SUDEP (a) than in the NESD (b) case and in accessory basal nuclei (ABN; c and d, respectively). Scale bar for B, E, H = 100 µm. AN = arcuate nucleus; BBB = blood-brain barrier; BN = basal nuclei; IO =inferior olive; PT = pyramidal tracts; ST = solitary tract.
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Figure 2: BBB impairment in SUDEP and control cases(A–C) Medulla, (D–F) hippocampus, and (G–H) amygdala. (A) Semiquantitative evaluation of immunoglobulin G (IgG) marker in the medulla. (B) Fewer IgG-immunopositive neurons and astrocytes were present in ventrolateral medulla (VLM; a) and the floor of the fourth ventricle (IVth V; c) in a sudden unexpected death in epilepsy (SUDEP; b) than in a nonepileptic sudden death (NESD; d) case. (C) Semiquantitative evaluation of albumin marker in the medulla. (D) Semiquantitative evaluation of IgG marker in the hippocampus. Expression of IgG marker in SUDEP cases in CA1 and parahippocampal gyrus (PH-G ) was significantly lower than in NESD controls (*both p ≤ 0.001). (E) Lower expression of IgG marker in the hippocampus of a SUDEP (a–d) than in a NESD (e–h) case in mosaic-like pattern of expression in the dentate gyrus (DG; a, e), pyramidal neurons in CA1 (b, f), subiculum (Sub; c, g) and PH-G (d, h). (F) Semiquantitative evaluation of albumin marker in the hippocampus. (G) Semiquantitative evaluation of IgG marker in the amygdala. (H) Fewer IgG-immunopositive cells were present in lateral nuclei (LN) in the SUDEP (a) than in the NESD (b) case and in accessory basal nuclei (ABN; c and d, respectively). Scale bar for B, E, H = 100 µm. AN = arcuate nucleus; BBB = blood-brain barrier; BN = basal nuclei; IO =inferior olive; PT = pyramidal tracts; ST = solitary tract.

Mentions: Immunoreactivity for immunoglobulin G (IgG; medulla, hippocampus, amygdala) and albumin (medulla, hippocampus) was observed in the cytoplasm of neurons, astrocytes, and small cells with the morphology of oligodendroglia in all studied groups and regions of interest, indicating a compromised BBB. In the medulla and amygdala, there was no difference overall between SUDEP cases and either control group in the immunoreactivity score (figure 2, A–C, G, and H).


Neuropathology of SUDEP
BBB impairment in SUDEP and control cases(A–C) Medulla, (D–F) hippocampus, and (G–H) amygdala. (A) Semiquantitative evaluation of immunoglobulin G (IgG) marker in the medulla. (B) Fewer IgG-immunopositive neurons and astrocytes were present in ventrolateral medulla (VLM; a) and the floor of the fourth ventricle (IVth V; c) in a sudden unexpected death in epilepsy (SUDEP; b) than in a nonepileptic sudden death (NESD; d) case. (C) Semiquantitative evaluation of albumin marker in the medulla. (D) Semiquantitative evaluation of IgG marker in the hippocampus. Expression of IgG marker in SUDEP cases in CA1 and parahippocampal gyrus (PH-G ) was significantly lower than in NESD controls (*both p ≤ 0.001). (E) Lower expression of IgG marker in the hippocampus of a SUDEP (a–d) than in a NESD (e–h) case in mosaic-like pattern of expression in the dentate gyrus (DG; a, e), pyramidal neurons in CA1 (b, f), subiculum (Sub; c, g) and PH-G (d, h). (F) Semiquantitative evaluation of albumin marker in the hippocampus. (G) Semiquantitative evaluation of IgG marker in the amygdala. (H) Fewer IgG-immunopositive cells were present in lateral nuclei (LN) in the SUDEP (a) than in the NESD (b) case and in accessory basal nuclei (ABN; c and d, respectively). Scale bar for B, E, H = 100 µm. AN = arcuate nucleus; BBB = blood-brain barrier; BN = basal nuclei; IO =inferior olive; PT = pyramidal tracts; ST = solitary tract.
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Figure 2: BBB impairment in SUDEP and control cases(A–C) Medulla, (D–F) hippocampus, and (G–H) amygdala. (A) Semiquantitative evaluation of immunoglobulin G (IgG) marker in the medulla. (B) Fewer IgG-immunopositive neurons and astrocytes were present in ventrolateral medulla (VLM; a) and the floor of the fourth ventricle (IVth V; c) in a sudden unexpected death in epilepsy (SUDEP; b) than in a nonepileptic sudden death (NESD; d) case. (C) Semiquantitative evaluation of albumin marker in the medulla. (D) Semiquantitative evaluation of IgG marker in the hippocampus. Expression of IgG marker in SUDEP cases in CA1 and parahippocampal gyrus (PH-G ) was significantly lower than in NESD controls (*both p ≤ 0.001). (E) Lower expression of IgG marker in the hippocampus of a SUDEP (a–d) than in a NESD (e–h) case in mosaic-like pattern of expression in the dentate gyrus (DG; a, e), pyramidal neurons in CA1 (b, f), subiculum (Sub; c, g) and PH-G (d, h). (F) Semiquantitative evaluation of albumin marker in the hippocampus. (G) Semiquantitative evaluation of IgG marker in the amygdala. (H) Fewer IgG-immunopositive cells were present in lateral nuclei (LN) in the SUDEP (a) than in the NESD (b) case and in accessory basal nuclei (ABN; c and d, respectively). Scale bar for B, E, H = 100 µm. AN = arcuate nucleus; BBB = blood-brain barrier; BN = basal nuclei; IO =inferior olive; PT = pyramidal tracts; ST = solitary tract.
Mentions: Immunoreactivity for immunoglobulin G (IgG; medulla, hippocampus, amygdala) and albumin (medulla, hippocampus) was observed in the cytoplasm of neurons, astrocytes, and small cells with the morphology of oligodendroglia in all studied groups and regions of interest, indicating a compromised BBB. In the medulla and amygdala, there was no difference overall between SUDEP cases and either control group in the immunoreactivity score (figure 2, A–C, G, and H).

View Article: PubMed Central - PubMed

ABSTRACT

Objective:: To seek a neuropathologic signature of sudden unexpected death in epilepsy (SUDEP) in a postmortem cohort by use of immunohistochemistry for specific markers of inflammation, gliosis, acute neuronal injury due to hypoxia, and blood-brain barrier (BBB) disruption, enabling the generation of hypotheses about potential mechanisms of death in SUDEP.

Methods:: Using immunohistochemistry, we investigated the expression of 6 markers (CD163, human leukocyte antigen–antigen D related, glial fibrillary acid protein, hypoxia-inducible factor-1α [HIF-1α], immunoglobulin G, and albumin) in the hippocampus, amygdala, and medulla in 58 postmortem cases: 28 SUDEP (definite and probable), 12 epilepsy controls, and 18 nonepileptic sudden death controls. A semiquantitative measure of immunoreactivity was scored for all markers used, and quantitative image analysis was carried out for selected markers.

Results:: Immunoreactivity was observed for all markers used within all studied brain regions and groups. Immunoreactivity for inflammatory reaction, BBB leakage, and HIF-1α in SUDEP cases was not different from that seen in control groups.

Conclusions:: This study represents a starting point to explore by immunohistochemistry the mechanisms underlying SUDEP in human brain tissue. Our approach highlights the potential and importance of considering immunohistochemical analysis to help identify biomarkers of SUDEP. Our results suggest that with the markers used, there is no clear immunohistochemical signature of SUDEP in human brain.

No MeSH data available.


Related in: MedlinePlus