小动物临床前沿（神经学专刊 - 上册）· 脑部疾病
Brain Diseases
New Frontier of Veterinary Medicine
2022 SEP | 总第 12 期
- 111 -
图1：组织学病理诊断为GME的6岁雌性未绝育金毛寻回猎犬的丘脑间连结的T2W矢状面(A)和T2W横断面(B) 和FLAIR横断面(C)。注意T2W
和FLAIR图像上的弥漫性高强度信号影响到灰质(包括皮质和深灰质)和白质，累及前脑(颞叶)和脑干(图片由伦敦大学皇家兽医学院提供)。
病因不明性脑膜脑脊髓炎(MUO)指的是一组特
发性、非感染性中枢神经系统(CNS)疾病(Talarico
and Schatzberg, 2010; Coates and Jeffery, 2014)。
值得注意的是，术语MUO与MUA(aetiology病因学)
和MUE(病因学etiology)是同义的，并且所有术语在
整篇文献中相互混杂。这组特发性非感染性脑膜炎
脑脊髓炎(NIME)分为几个亚型，包括类固醇反应性
脑膜炎-动脉炎(steroid responsive meningitis-arteritis，SRMA)、嗜酸性粒细胞性脑膜脑炎(eosinophilic meningoencephalitis，EME)、肉芽肿性脑膜
脑脊髓炎(granulomatous meningoencephalomyelitis，GME)和坏死性脑炎(necrotizing encephalitis，NE；包括坏死性脑膜脑脊髓炎(necrotizing
meningoencephalomyelitis，NME)和坏死性白质脑炎
(necrotizing leucoencephalitis，NLE))。由于SRMA和
EME具有相当明显的诊断特征，因此引入MUO一词
来涵盖只能通过组织病理学证实的NIME三种特定亚
型，包括GME、NME和NLE (Granger et al., 2010;
Talarico and Schatzberg, 2010; Coates and Jeffery,
2014)。目前还没有关于犬类MUO的总体发病率的
统计数据，但早期的报告引用了GME在犬所有中枢
神经系统疾病中的不一的发病率5-25%(Braund,
1985; Tipold, 1995)。
通常，MUO的诊断是根据动物特征、神经学检
查结果、磁共振成像(MRI)发现和脑脊液(CSF)分析
相结合得出的(Munana and Luttgen, 1998; Adamo
et al., 2007; Granger et al., 2010; Talarico and
Schatzberg, 2010; Coates and Jeffery, 2014)，尽管
这些检查结果可能在不同的研究和病患之间存在很
大差异(Wong et al., 2010)。
这组疾病的诊断和治疗都使兽医面临挑战。如
果不开始恰当的治疗，这种疾病被认为是致命的
(Munana and Luttgen, 1998; Granger et al., 2010)，
最近的一些研究评估了不同的治疗方式和潜在的预
后因素。
病因学
MUO 的确切病因学和病理生理学目前尚不清
楚，最新的一些理论在最近的一些文献综述中进行了
讨论 (Coates and Jeffery, 2014)。虽然 MUO 很可能
有多因素发病机制，但遗传倾向性和触发过度免疫反
应的因素的结合被认为是最重要的 (Kipar et al.,
1998; Talarico and Schatzberg, 2010; Flegel et al.,
2011; Coates and Jeffery, 2014)。可疑的诱因包括环
境因素和各类感染性抗原 (Schatzberg et al., 2005;
Greer et al., 2010; Barber et al., 2012)。结 合 这 组 疾
病对免疫抑制治疗的普遍积极反应等信息，表明了诱
发 MUO 的因素是免疫介导性疾病 (Wong et al.,
2010)，因此，药物治疗的基石是免疫抑制治疗 (Kipar
et al.,1998; Talarico and Schatzberg, 2010; Coates
and Jeffery, 2014)。
临床表现
中年玩具品种犬和㹴犬易患 GME (Munana and
Luttgen, 1998; Adamo et al., 2007; Talarico and
Schatzberg, 2010); 而 NE 主要侵袭较小体型的玩具
品种和小型犬，包括巴哥犬、约克夏㹴、马尔济斯犬、
吉娃娃、北京犬、蝴蝶犬、西施犬、图莱亚尔绒毛犬和
布鲁塞尔格里芬犬 (Talarico and Schatzberg, 2010;
Cooper et al., 2014)。然而，任何品种和年龄的犬都
可 能 受 到 侵 袭 (Granger et al., 2010; Coates and
Jeffery, 2014)；最近的一项研究显示，25% 诊断患有
MUO 的犬是大型犬 (>15kg; Cornelis et al., 2016b)。
通过对 173 例 GME、53 例 MUO 和 69 例 NE 的
数据统计分析，发现 GME 和 NE 的年龄分布有显著差
异；有 NE 的犬主要小于 4 岁，而 GME 的峰值年龄为
4-8 岁 (Granger et al., 2010)。在一组 60 例患 NE 巴哥
犬中 (Levine et al., 2008)，诊断时的中位年龄为 18 个
月。在一组 5 例 NE 的吉娃娃 (Higgins et al., 2008) 中，
诊断时的中位年龄为 5 岁。在巴哥犬中，与深色雄性相
比，浅褐色雌性更常被诊断患有 NME (Greer et al.,
2010)。尽管普遍认为 GME 中雌性占多数 (Russo,
1979; Braund, 1985; Bailey and Higgins, 1986; Sorjonen, 1990; Munana and Luttgen, 1998)，在较近期的
研 究 中，雌 雄 比 例 没 有 统 计 学 差 异 (Talarico and
Schatzberg, 2010; Granger et al., 2010; Cornelis et al.,
2016a,b)。
曾经 GME 的组织学分布有描述三种模式：多灶
型或弥散型、局灶型和眼型 (Cuddon and Smith-Maxie, 1984;Braund,1985; Sorjonen, 1990)。每一种分布型
都与不同的临床表现有关，包括多灶型 GME 犬的急性
发作和快速渐进性发展，局灶型 GME 犬的发展更隐匿
或更缓慢渐进性，以及眼型 GME 犬的视觉功能障碍的
急 性 症 状 (Braund,1985; Sorjonen,1990; Zarfoss et
al.,2006;Talarico and Schatzberg, 2009; Coates and
Jeffery, 2014)。
神经外症状很少见，但发热偶尔会伴随于中枢
神经系统炎症(Talarico and Schatzberg, 2010)。常
见的实验室检查(血常规、生化、尿分析)往往在正常
参考范围内(Thomas and Eger, 1989; Sorjonen,
1990; Tipold, 1995)。
在神经学检查中，疾病定位分类如下：a) GME
以前脑、脑干或多灶型病变为主；b) MUO 以多灶型
( 前脑、脑干 ) 或多灶型为主；或 c)NE 以前脑为主
(Granger et al., 2010; Talarico and Schatzberg,
2010; Coates and Jeffery, 2014; Cornelis et al.,
2016a)。与小型犬相比，大型犬更容易出现可识别的
意识状态下降 (Cornelis et al., 2016b)。8% 被诊断为
GME 的 犬 表 现 出 提 示 脊 髓 病 的 神 经 功 能 缺 陷
(Granger et al., 2010)。脊髓病可定位于脊髓的任何
部位，临床表现从全身性本体感受性共济失调到轻瘫
或麻痹；常见发现有脊髓过度敏感 (Griffin et al.,
2008; Wong et al., 2010; Cornelis et al., 2017a)。
诊断发现
如前所述，MUO 是一种临床诊断，可基于动物
特征、神经学检查结果、颅内横断面影像异常和脑脊
液分析获得 (Munana and Luttgen,1998; Adamo et
al.,2007; Talarico and Schatzberg, 2010; Coates
and Jeffery,2014)。Granger 等人 (2010) 系统性地回
顾了 457 例已发表的 NIME 病例 ( 包括 MUO、GME
和 NE)，并制定了招募没有组织病理学诊断的 MUO
病例的指南。已确定以下四项纳入标准 : (1) 年龄大
于 6 个月的犬 ; (2) T2W MR 影像上表现为多发、单
发或弥漫性轴内高强度信号 ; (3) 脑脊液分析表现出
脑脊液细胞增多，且单核细胞 / 淋巴细胞 >50%; (4)
排除特定地理区域内常见的传染病 (Granger et al.,
2010)。如前所述，只有通过组织病理学检查才能获
得明确诊断 (Uchida et al., 2016)。
横断面影像
据报道，MRI 在检测大脑异常方面的敏感性为
94.4%，特异性为 95.5%，在肿瘤性和炎症性疾病的分
类方面也有同样高度的表现。相比之下，MRI 对脑血
管疾病分类的敏感性仅为 38.9% (Wolff et al., 2012)。
值得注意的是，在一项研究中，多达 7% 的犬 (2/25 例
，一例诊断为 GME，另一例诊断为 MUO) 在 T2W MR
图 像 中 没 有 显 示 异 常 (Talarico and Schatzberg,
2010; Granger et al., 2010)，如果没有组织病理学证
据，可能会导致类似病例不被纳入前瞻性研究或回顾
性 研 究。同 样 在 CT 成 像 方 面，研 究 显 示 高 达
14%(5/36 例 犬，未 指 定 具 体 诊 断 ) 未 发 现 异 常
(Granger et al., 2010)。总的来说，影像学在识别神经
系统检查怀疑的所有炎症性异常方面的敏感性仍然
很低 (<60%; Granger et al., 2010)。此外，在一项研究
中，只有 76% 的脑脊液炎性病变病例出现 MRI 异常
(19/25 例犬 ; Lamb et al., 2005)。虽然使用横断面成
像可能有助于区分不同类型的特发性脑膜脑炎
(Talarico and Schatzberg, 2010)，但目前没有关于使
用 MRI 鉴别组织病理学证实的 GME、NME 和 NLE 病
例的信息。
一项研究特别关注了 11 例组织病理学证实为
GME 的犬的 MRI 检查结果 (Cherubini et al.，2006)。
局灶型、多灶型或弥漫型的 T2W 和 FLAIR 高强度信
号分布于前脑、脑干或小脑 ( 图 1)。异常散在分布于
灰质和白质，在 T1 加权 (T1W) 图像上表现为不同强
度 信号，增强程度不同。T2W 图像通常提示白质内血
管源性水肿，脑膜强化通常不明显，即使有也很轻微
(Cherubini et al., 2006; Talarico and Schatzberg,
2010; Coates and Jeffery, 2014)。MR 影像病变的分
布 ( 位于灰质或白质 ) 与组织病理学结果一致
(Cherubini et al., 2006)。
报道的 NME 犬最常见的 MRI 异常是不对称、多
灶性和位于前脑的病变 ( 更严重的病变位于顶叶和枕
叶 );T2W、FLAIR 高强度信号 ; 通常影响皮质灰质和
皮质下白质，在 T1W 增强后图像上灰质 / 白质界限
丧失，实质病变的对比增强程度不同 (Flegel et al.,
2008; Young et al., 2009; Talarico and Schatzberg,
2010; 图 2）。然而，在一项研究中，分别有 4/18 例和
3/18 例发现小脑和脑干病变 (Young et al.， 2009)。脑
膜强化也可出现，伴有肿物效应和不同程度的脑室增
大 (Coates and Jeffery, 2014)。
在 NLE 中，发现了多处不对称的大脑白质和脑干
病变 (von Praun et al.， 2006)。这些病变在 T2W 和
FLAIR 上表现为典型的高强度信号，常包括多个囊性
坏死区域。在两项已报道的研究中，实质异常的对比
度增强很少 (Talarico and Schatzberg, 2010; Coates
and Jeffery, 2014)。第三项研究显示未见脑膜强化和
肿物效应，但伴有不同程度的脑室增大 (Coates 和
Jeffery, 2014; 图 3)。
已有报道 57 例犬患有不明病因性脑膜脊髓炎，
包括 3 例经组织病理学证实为 GME 的犬 (Cherubini
et al., 2006; Griffin et al., 2008; Wong et al., 2010;
Cornelis et al., 2017a)。57 例中有 36 例使用不同类型
的影像学检查结果。12 例犬单独进行了（X 线片）脊髓
造影或计算机断层扫描 (CT) 的脊髓造影；11 例犬未
发现异常，1 例犬腹侧硬膜外脊髓受压 (Wong et al.，
2010)。对 25 例犬进行了 MRI 检查，其中 3 例犬未发
现异常，6 例犬出现多灶性边界不清晰的髓内 T2W 高
强度信号，增强程度不一，在 16 例犬的髓内 T2W 高
强度信号和 T1W 等强度信号的异常中，脊髓实质病
变和 / 或覆盖脑膜的不同对比度增强 (Cherubini et
al., 2006; Wong et al., 2010; Cornelis et al., 2017a)。
其他成像方式，包括 NME 的正电子发射断层扫
描 (PET)， MUO 的氟脱氧葡萄糖 PET (FDG-PET) 和
单体素质子磁共振波谱 (1H MRS)，以及 GME 的经颅
超声检查结果，被研究作为诊断方式 (Eom et al.,
2008; Kang et al., 2010; Carvalho et al., 2012; Carrera et al., 2016)。然而，需要更大样本量的进一步研究
来评估这些成像方式的临床用途。
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