Department of Clinical and Experimental epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 2BG, UK.
School of Cancer Sciences, University of Southampton, Southampton, UK.
Brain Pathol. 2021 Jan;31(1):133-143. doi: 10.1111/bpa.12891. Epub 2020 Sep 9.
Sudden unexpected death in epilepsy (SUDEP) is mechanistically complex and one probable cause is seizure-related respiratory dysfunction. Medullary respiratory regulatory nuclei include the pre-Bötzinger complex (pre-BötC) in the ventrolateral medulla (VLM), the medullary raphé nuclei (MR) and nucleus of solitary tract in the dorsomedial medulla (DMM). The region of the VLM also contains intermingled tyrosine hydroxylase (TH) catecholaminergic neurones which directly project to the pre-BötC and regulate breathing under hypoxic conditions and our aim was to evaluate these neurones in SUDEP cases. In post-mortem cases from three groups [SUDEP (18), epilepsy controls (8) and non-epilepsy controls (16)] serial sections of medulla (obex + 2 to + 13 mm) were immunolabeled for TH. Three regions of interest (ROI) were outlined (VLM, DMM and MR) and TH-immunoreactive (TH-IR) neurones were evaluated using automated detection for overall labeling index (neurones and processes) and neuronal densities and compared between groups and relative to obex level. C-fos immunoreactivity was also semi-quantitatively evaluated in these regions. We found no significant difference in the density of TH-IR neurones or labeling index between the groups in all regions. Significantly more TH-IR neurones were present in the DMM region than VLM in non-epilepsy cases only (P < 0.01). Regional variations in TH-IR neurones with obex level were seen in all groups except SUDEP. We also identified occasional TH neurones in the MR region in all groups. There was significantly less c-fos labeling in the VLM and MR in SUDEP than non-epilepsy controls but no difference with epilepsy controls. In conclusion, in this series we found no evidence for alteration of total medullary TH-IR neuronal numbers in SUDEP but noted some differences in their relative distribution in the medulla and c-fos neurones compared to control groups which may be relevant to the mechanism of death.
癫痫相关性猝死（SUDEP）的发病机制十分复杂，其可能的原因之一是与癫痫发作相关的呼吸功能障碍。延髓呼吸调节核团包括腹外侧延髓（VLM）中的 Pre-Bötzinger 复合体（pre-BötC）、延髓中缝核（MR）和背内侧延髓中的孤束核（DMM）。VLM 区域还包含混杂的酪氨酸羟化酶（TH）儿茶酚胺能神经元，这些神经元直接投射到 pre-BötC，并在低氧条件下调节呼吸，我们的目的是评估这些神经元在 SUDEP 病例中的变化。在来自三组的死后病例中[SUDEP（18 例）、癫痫对照组（8 例）和非癫痫对照组（16 例）]，对延髓（脊髓颈膨大+2 至+13mm）的连续切片进行 TH 免疫标记。在三个感兴趣区域（ROI）中勾勒出轮廓（VLM、DMM 和 MR），并使用自动检测评估 TH 免疫反应性（TH-IR）神经元的总标记指数（神经元和过程）和神经元密度，并在组间进行比较，并与脊髓颈膨大水平进行比较。在这些区域中还半定量评估了 c-fos 免疫反应性。我们发现，在所有区域中，各组之间的 TH-IR 神经元密度或标记指数均无显著差异。在非癫痫病例中，DMM 区域的 TH-IR 神经元数量明显多于 VLM（P<0.01）。除了 SUDEP 之外，在所有组中都可以看到随着脊髓颈膨大水平的变化而出现的 TH-IR 神经元的区域变化。我们还在所有组中都发现了 MR 区域中的偶尔 TH 神经元。在 VLM 和 MR 中，SUDEP 患者的 c-fos 标记明显少于非癫痫对照组，但与癫痫对照组无差异。总之，在本系列研究中，我们没有发现 SUDEP 患者延髓总 TH-IR 神经元数量改变的证据，但注意到与对照组相比，它们在延髓中的相对分布和 c-fos 神经元存在一些差异，这可能与死亡机制有关。
