兽研摘要
背景
猫垂体卒中的手术治疗此前尚未有文献描述。
目的
描述3例猫垂体卒中的临床病程及随访情况。
方法
病例基于经蝶骨垂体切除术后组织病理学确诊的伴有出血性病变的垂体肿块进行筛选。通过回顾病历和影像学记录，回顾性获取体格检查、诊断性检查结果、治疗及随访病程的详细信息。
结果
两只猫表现为急性发作的神经系统症状（病例1和病例2），一只猫表现为亚急性内分泌功能障碍（病例3）。所有病例均成功接受了经蝶骨垂体切除术，随后进入重症监护住院治疗并顺利出院。病例1、2和3的切除垂体腺组织病理学检查均确认为垂体卒中。所有3例均存在与垂体卒中相符的影像学表现，但仅病例3采用了出血敏感序列成像，提供了病灶内出血的明确证据。病例1生存时间至少716天，因肿瘤复发接受了第二次经蝶骨手术，随后失访。病例2生存时间至少1，098天，在撰写本稿时仍存活。病例3在365天时影像学（MRI）发现肿瘤复发，并在经蝶骨垂体切除术后612天于放射治疗过程中死亡。
结论与临床意义
垂体卒中是一种罕见疾病，也可影响患有大型垂体腺瘤的猫。总体而言，这些猫获得了可接受的临床恢复和术后生存，支持经蝶骨垂体切除术作为受卒中影响的猫垂体肿瘤治疗选择的可行性。值得注意的是，即使在存在残留垂体组织的情况下也观察到了良好的结局，如后来发生垂体肿瘤复发的猫所示。
关键词：卒中，猫，垂体切除术，颅内出血，颅内梗死，垂体，经蝶骨
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引言
在人类医学中，垂体卒中（PA）的特征是突发严重头痛、意识水平改变和视力损害，源于垂体出血和/或梗死引起的鞍内压突然升高。该病通常发生于已有无功能性垂体大腺瘤的患者，但也可见于垂体腺健康的个体，或受炎症或感染影响的患者（1）。诊断基于临床怀疑并结合影像学检查，其中磁共振成像（MRI）是首选方法。与PA相符的表现包括出血、坏死或水肿的征象，常与垂体神经内分泌肿瘤相关（2）。治疗选择包括早期经蝶骨减压，或对无神经眼科体征或症状轻微且稳定的患者采取保守治疗（3）。
在兽医文献中，尤其是猫，PA鲜有描述。在已记录的猫病例中，观察到烦躁不安、急性失明、定向障碍和抑郁发作。诊断基于影像学表现结合组织病理学。在这些病例中，未进行手术干预，猫均被安乐死（4–6）。
本报告描述了首批成功接受经蝶骨垂体切除术（THX）并康复的猫垂体卒中病例。最初，所有病例均基于影像学检查诊断为垂体肿块。所有3例在高级影像学上均显示垂体不均匀，提示出血、梗死或坏死。随后，基于较大的P/B比值、神经或内分泌表现，它们接受了垂体切除术。垂体卒中的 definitive 诊断基于组织病理学检查。垂体卒中是对于急性发作神经系统症状的患者应给予更多考虑的鉴别诊断，如上所述，以优化诊断准确性，从而改善受影响患者的结局。本病例报告中描述的病例经手术干预后获得了迅速的神经功能恢复和良好的长期结局。
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病例描述
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病例1
一只11岁已绝育雌性家养短毛猫就诊，有2年食欲减退和进行性体重下降2 kg（从6.7 kg降至4.7 kg）的病史，以及2周急性行为异常的病史。临床症状包括沿墙壁向两个方向无目的地踱步、烦躁不安以及对其他猫有攻击性。该猫还主动寻求与主人接触。该猫的一般体格检查和神经系统检查均无异常；上述行为变化在就诊期间未能得到证实。根据血清甲状腺素（T4）浓度29 nmol/L（15–45）、促甲状腺激素浓度< 0.03 mcg/L（< 0.03 mcg/L）、胰岛素样生长因子-1（IGF-1）浓度268 mcg/L（< 598）和促肾上腺皮质激素（ACTH）浓度64 pg/mL（–358）（7, 8），未诊断出内分泌疾病。
计算机断层扫描（CT）显示垂体明显增大，尺寸为8.7 mm（高）× 15.1 mm（长）× 10 mm（宽），垂体高度与脑面积（P/B）比值为0.96。尽管尚无经验证的猫P/B比值参考值，但垂体高度超过了用于定义猫垂体增大的4.0 mm阈值（9），且P/B比值远高于犬的临界值0.31（10）。此外，病变内还存在高衰减和低衰减区域，提示肿块内有出血性和梗死性改变（图1A、B）。考虑到肿瘤的大小以及文献报道的猫经蝶窦垂体切除术（THX）的良好结局，本病例选择手术干预作为治疗方案。
[图：术前影像学。病例1：增强后计算机断层扫描（CT）背侧（A）和横断面（B）重建显示]
手术前一天，该猫住院进行术前稳定。以8 ml/h的维持速率给予静脉输液治疗（IVFT）。使用美洛昔康0.1 mg/kg每日一次（SID）提供镇痛。放置鼻饲管以实现营养摄入（Royal Canin Convalescence Support）。
在THX之前，该猫预先经静脉（IV）给予盐酸美沙酮0.70 mg（0.15 mg/kg），并使用咪达唑仑1.08 mg（0.22 mg/kg）IV和丙泊酚15 mg（3.1 mg/kg）IV平稳诱导。使用4号气管插管进行插管，随后立即进行手动通气（EtCO2 4–5 kPa）。使用七氟烷、瑞芬太尼0.2–0.3 mcg/kg/min IV恒速输注（CRI）和丙泊酚0.5–1 mg/kg IV按效应推注维持麻醉。使用利多卡因14.4 mg（3.06 mg/kg）对切口部位进行局部浸润。监测包括有创和无创动脉血压、二氧化碳描记法、心电图（ECG）、FiO2、脉搏血氧测定法和肺量测定法。使用Bairhugger和加温垫维持体温。术中心动过缓按效应使用阿托品3–5 mcg/kg IV和格隆溴铵5 mcg/kg IV治疗。术中低血压按效应使用多巴胺3–6 mcg/kg/min IV CRI治疗。通过维持CO2水平< 4.0 mmHg来降低颅内压。
THX按照先前关于猫该手术的出版物所述进行（9）。使用10号手术刀片在中线切开软腭，并用自固定Gelpi牵开器向侧方牵开。将黏膜骨膜与蝶骨和翼突钩分离。随后，识别蝶骨嵴，以确定钻孔的位置。使用钻头在蝶骨上创建一个10 mm的窗口。向头侧穿孔进入含气的蝶窦，确定了位于该点尾侧的窝的位置。然后继续向尾侧直接朝垂体方向进行入路。使用骨蜡（Ethicon, Somerville, NJ, USA）控制骨出血。在骨的松质部分，使用骨蜡实现止血。开口长度约为10 mm，宽度约为8 mm。垂体头侧呈红蓝色，提示肿瘤，尾侧呈白色，提示正常组织。使用双极电凝凝固硬脑膜，并使用11号刀片切开。将明显的异常组织小心地从周围组织中游离并分多块切除，所有碎片均置于单个福尔马林容器中送检，包括一些肉眼外观正常的垂体组织。清空垂体窝，可触及鞍背。垂体窝内填充明胶海绵（Spongostan可吸收止血明胶海绵（Ethicon, Somerville, NJ, USA），约8 × 6 mm。将骨蜡（Ethicon, Somerville, NJ, USA）应用于蝶骨缺损处和黏膜骨膜。尾侧放置单根聚二氧环己酮缝线（PDS II 6-0, Ethicon, Somerville, NJ, USA），使黏膜骨膜良好对合。骨蜡覆盖约50%。软腭分两层关闭；鼻黏膜使用聚乳糖910（Vicryl 4-0, Ethicon, Somerville, NJ, USA）以简单连续模式缝合，口腔黏膜使用聚乳糖910（Vicryl 4-0, Ethicon, Somerville, NJ, USA）以简单间断模式缝合。恢复平稳顺利。
该猫被收入重症监护室进行术后监测。每4小时进行一次常规体格检查（呼吸频率（RR）、心率（HR）、体温、黏膜及毛细血管再充盈时间（CRT））。每日两次（BID）测量血浆钠、钾、葡萄糖及血细胞比容（Ht）水平。每2小时监测并计算尿量及液体平衡。静脉输液治疗（IVFT）维持速率为8 ml/h（Sterofundin B/G），并据此进行调整。为维持营养摄入，该猫接受了食管饲管。以恒定速率输注（CRI）方式给予Royal Canin Convalescence Support。镇痛使用丁丙诺啡[20 mcg/kg，每日3次（TID），静脉注射]，并开始以阿莫西林-克拉维酸（20 mg/kg，TID，静脉注射）进行抗生素预防。该猫接受氢化可的松静脉注射[1 mg/kg，每日4次（QID）]的激素替代治疗，去氨加压素滴眼液TID，左右眼（OD和OS）交替使用，以及口服甲状腺素（15 mcg/kg，BID）。该猫存在严重心动过缓（100–130 bpm）和低血压，轻度低钠血症[135 mmol/L（146–158 mmol/L）]，并伴有严重贫血[Ht：0.14 L/L（0.28–0.47 L/L）]，为此该猫接受了输血，将Ht纠正至0.19。在此期间，观察到双侧瞳孔散大，双眼直接及间接瞳孔反射消失，威胁反应消失。同时未检测到眼内异常。由委员会认证的兽医眼科专家检查确认双侧失明，认为最可能与此前的外科手术有关。Schirmer泪液试验（STT）还发现干性角结膜炎（KCS），双眼（OU）泪液分泌量均为0 mm/min。8天后，该猫情况稳定并出院，在家进行适当的后续护理。终身激素替代治疗包括口服醋酸可的松维持剂量（0.35 mg/kg，BID）、口服L-甲状腺素（15 mcg/kg，BID）。尿崩症通过BID给予去氨加压素滴眼液管理，右眼（Oculus Dexter，OD）和左眼（Oculus Sinister，OS）交替使用，在1周和4周后测量血浆电解质水平，并据此调整剂量。一旦血浆电解质水平达到正常，滴眼液治疗再继续一周，之后即可停用。视觉障碍在该猫余生中保持不变。
3个月后，重复进行头颅CT扫描以监测垂体瘤复发。垂体组织内的变化与少量残留的垂体/肿瘤组织相符，尽管这些发现尚无定论。建议在6–12个月后以及此后每年进行临床随访，并在认为有指征时重复CT影像检查。
初次手术后第705天，通过重复影像检查（CT）诊断为复发，尺寸如下：7.8 mm（高）× 9.7 mm（长）× 6.7 mm（宽），垂体/脑比值（P/B）为1.0。该猫接受了第二次经蝶窦垂体切除术（THX）。THX后，该猫在ICU停留11天后出院。该猫出院后失访，登记生存时间为716天。
对切除组织的组织病理学和免疫组化（IHC）评估显示垂体卒中及嗜碱性肿瘤，初次IHC中ACTH和GH染色均明显缺失。第二次手术获得的肿瘤组织显示更为均一的嗜碱性肿瘤细胞群，同样ACTH和GH无免疫反应性。
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病例2
一只12岁去势雄性欧洲短毛猫因神经系统症状就诊。该猫厌食1个月，出现急性后肢无力发作及精神状态下降。一般检查显示该猫安静、反应灵敏，但整体状况明显下降。神经系统检查发现双侧直接瞳孔反射轻度延迟，而角膜反射和眼睑反射完整。鼻部敏感性明显降低。该猫前肢视觉反应延迟，触觉本体感觉缺失。左前脚本体感觉正常，而右前脚明显延迟，尽管该腿包扎有导管绷带敷料。颈部背屈可诱发左眼明显的腹侧斜视及双眼垂直性眼震。无内分泌病征象，如糖尿病（DM）或多尿/多饮（PUPD）。
同时进行了心脏超声检查，显示无结构性心脏异常或功能损害。对脑脊液（CSF）和血浆进行了弓形虫病评估。CSF分析显示IgG 94.16（< 50）、IgM 4.45（< 9）及总蛋白1.01 g/L。血浆血清学显示IgG 203.39（< 50）、IgM 18.54（< 9）。IGF-1（399 ng/mL，< 598）、基础血清皮质醇[12.5 ng/mL（2–50 ng/mL）]均在参考范围内，FeLV/FIV检测为阴性。当时未进行CSF总有核细胞计数、细胞学及抗原滴度检测。
进行了MRI检查，发现一个大的圆形垂体肿块[12.2 mm（高）× 10.8 mm（长）× 11.2 mm（宽）]，P/B比为1.25。该肿块压迫丘脑和脑干（向尾侧移位），并观察到双侧侧脑室和第四脑室中度至明显的充血。T2加权和T1加权图像显示肿块内低信号区域，提示病灶内出血（图1C–E）。颈椎脊髓显示明显的脊髓空洞症。与病例1一样，由于垂体肿块较大且该手术后 reported 的良好结局，选择THX作为首选治疗。
手术前一天，猫住院进行术前稳定。进行了全血细胞计数和常规生化分析。注意到应激性白细胞象，总蛋白和白蛋白轻度升高。ACTH在正常范围内[215 pg/mL（15–358 pg/mL）]。猫接受了氢化可的松1 mg/kg、阿莫西林-克拉维酸静脉注射[20 mg/kg每日三次（TID）]、马罗匹坦静脉注射（1 mg/kg每日一次）、奥美拉唑静脉注射（1 mg/kg每日一次）和加巴喷丁（15 mg/kg一次）。放置了饲管和颈静脉导管。手术当天，在初次就诊时获得阳性血清学和CSF滴度后3.5周，在第二家实验室重复进行了弓形虫血清学检查。合并IgG和IgM滴度为1:256（参考值< 1:64）。
手术前，猫接受了美沙酮盐酸盐1.66 mg（0.25 mg/kg）静脉注射和右美托咪定13.4 mcg（2 mcg/kg）静脉注射的预麻醉，提供了轻度镇静。猫用丙泊酚按效应诱导。用3.5号气管导管插管。使用异氟烷、舒芬太尼0.5–1 mcg/kg/min静脉恒速输注和氯胺酮10 mcg/kg/min静脉恒速输注维持麻醉。使用利多卡因13.2 mg（2 mg/kg）对切口部位进行局部浸润。监测遵循病例1中概述的相同方案，并增加了动脉血气分析。术中心动过缓按效应使用阿托品5 mcg/kg静脉注射和格隆溴铵1–10 mcg/kg静脉注射治疗。术中低血压按效应使用多巴酚丁胺0.55–8 mcg/kg/min静脉恒速输注治疗。通过维持CO2水平< 4.0 mmHg和使用甘露醇（0.25 g/kg over 20 min）来降低颅内压。
THX按病例1所述进行。打开垂体窝后，迅速遇到膨出的垂体腺。组织呈现不均匀外观。从窝中取出明显的异常组织（黏液样和灰色），分多块放入福尔马林容器中送检。外科医生观察到宏观完全切除。在整个手术过程中，使用18 cm 1.9 mm 30°前向望远镜检查入路和窝内容物，确认完全切除（图2A、B）。手术侧关闭按病例1所述进行。
[图：术中内窥镜。病例2：（A）垂体肿块（蓝色星号）膨出的术中内窥镜图像]
进行了术后头部直接CT扫描，并与术前MRI比较，确认先前可视化的肿块消失。剩余脑实质无异常。丘脑和脑干有明显减压。
手术后，猫迅速恢复且无并发症。随后，猫被送入ICU，住院6天。术后用药、监测和激素替代治疗按方案并如病例1所述进行。每4小时测量一次血糖水平，整个住院期间保持在< 9 mmol/L，未使用胰岛素。这表明DM缓解。此外，猫接受克林霉素12.5 mg/kg每日两次，指征为弓形虫血浆滴度阳性。STT识别出KCS，双眼值为5至6 mm/min。在此期间，猫表现出渴感缺失和厌食，为此猫通过食管饲管每日5次接受营养。此外，猫出现中度高热（40.4 °C），3天后无需额外治疗即消退。6天后，猫被认为稳定，按病例1所述方案出院并在家进行适当术后护理。
切除肿瘤组织的组织病理学和IHC检查显示IHC染色呈嗜碱性和ACTH阳性特征，以及垂体卒中。
手术后两周，猫由转诊兽医检查。食物和水摄入随时间显著增加，但总体猫仍处于轻度嗜睡状态。进一步一般体格检查无异常，尽管KCS持续存在。在撰写手稿时猫仍存活。尽管据报道嗜睡状态从未完全消退，但没有出现新的或复发的神经体征，导致无病间期为1,098天。鼓励主人在术后6个月和12个月对猫的垂体窝进行随访高级诊断成像，随后每年进行影像复查。然而，他们拒绝了，随访主要通过电子邮件联系进行。
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病例3
一只9岁已去势雄性家养短毛猫因食欲增加、体重增加（从5.1 kg增至5.7 kg）、因肌肉萎缩导致运动困难及多饮多尿转诊至原兽医处就诊。通过检测到糖尿及持续性血糖升高确诊糖尿病（DM）。开始胰岛素治疗，剂量为4.5 IU胰岛素（Caninsulin®，Intervet，Boxmeer，荷兰）每日两次皮下注射（SC）。多饮多尿改善但未完全缓解。随后，该猫出现自发性皮肤脆弱，导致怀疑脆性皮肤综合征，该综合征可由皮质醇过多症引起。观察到ACTH刺激试验反应过度，超声检查显示双侧肾上腺增大。
CT和MRI发现一个圆形垂体肿块，尺寸如下：10 mm（高）× 10 mm（长）× 11 mm（宽），P/B比为1.12。T2加权MRI图像以低信号出血区域为特征（图1F）。T2加权SWAN图像显示低信号伴 Blooms 伪影，高度提示出血（图1G、H）（11）。基于肿瘤体积大及存在内分泌疾病，手术被选为该猫的治疗方案。
在推定诊断为垂体依赖性皮质醇过多症（PDH）后，该猫开始使用trilostane（Vetoryl，Dechra Regulatory B.V.，Bladel，荷兰）。在2个月期间，剂量从5 mg增至10 mg再增至30 mg，每日两次。未检测血清IGF-1或生长激素（GH），因此，在手术干预前未排除该猫的生长激素过多症（HS）。
手术前一天，该猫住院并按照病例1所述进行手术准备。每小时测量血糖浓度，并相应调整胰岛素。
手术前，该猫以盐酸美沙酮1.71 mg（0.3 mg/kg）静脉注射和右美托咪定11.4 mcg（2 mcg/kg）静脉注射进行前驱麻醉，提供轻度镇静。该猫以丙泊酚诱导至效应。使用3.5号气管插管进行插管。使用异氟烷和右美托咪定持续速率输注（CRI）0.6–1.0 mcg/kg/h维持麻醉。切口部位使用利多卡因11.4 mg（2 mg/kg）局部浸润。监测遵循病例1所述相同方案，并增加动脉血气分析。此外，每10分钟监测血浆葡萄糖浓度，并相应调整胰岛素CRI。通过维持CO2水平< 4.0 mmHg降低颅内压。按病例1所述进行经蝶窦垂体切除术（THX）。在THX过程中，完整切除垂体腺，包括外科医生肉眼观察到的明显异常腺垂体。取出的病变组织包含出血性和灰色黏液样区域，收集用于组织学检查。手术过程中，使用18 cm 1.9 mm 30°前斜视内窥镜对手术入路和蝶鞍内容物进行内窥镜探查（图2C、D）。内窥镜提供了垂体窝内容物的更好可视化，使位于钻孔周边的肿瘤组织得以切除（图2D）。内窥镜确认窝内无残留垂体组织。按病例1所述关闭手术侧。
术后进行头部CT，显示垂体腺缺失。然而，右侧脑实质尾部区域（约4 × 4.5 × 3.2 mm）出现对比增强，提示垂体腺可能未完全切除。
该猫恢复迅速。垂体切除术后该猫收入ICU，并按照病例1所述标准化方案进行治疗。住院期间，在麻醉后初期恢复良好后观察到双眼瞳孔散大。明显的失明在给予丁丙诺啡和氢化可的松后立即被注意到，并伴有极度兴奋。次日经眼科专家检查后，该猫被诊断为角膜溃疡和视力受损。双眼（OU）直接和间接瞳孔反射均缺失，然而，威胁反射和眩光反射均存在。同时给予阿片类药物被认为是当时瞳孔反射缺失的可能促进因素，尽管无法确定。双眼泪液分泌量在参考范围内。眼底镜检查未见异常。视力损害被认为最可能继发于手术创伤，可能为皮质性，因为当时瞳孔散大及可能的后续瞳孔反射不足被归因于对阿片类药物的反应；然而，确切病因无法明确确定。该猫在手术后7天出院，糖尿病完全缓解。随着时间的推移，在手术后数月内，视力似乎部分改善。瞳孔散大持续存在，但不如术后住院期间那么严重。
垂体组织的组织病理学和IHC分析证实存在嗜碱性和ACTH阳性肿瘤，合并垂体卒中。
垂体切除术后，对库欣病的缓解情况进行了监测。术后直接促肾上腺皮质激素评估显示血浆促肾上腺皮质激素浓度显著下降（经蝶手术前：877 pg/ml，经蝶手术后1小时：298 pg/ml，经蝶手术后3小时：176 pg/ml，经蝶手术后5小时：156 pg/ml）。术后多次测量基础尿皮质醇/肌酐比值。出院后、3周、8周、6个月和1年时的尿皮质醇/肌酐比值分别为8.9、28.5、6.7和11.5。所有测量浓度均在参考范围内（2–36）（7）。术后约12个月和18个月进行了磁共振成像随访，其中12个月磁共振成像首次注意到局部肿瘤复发，肿块测量约5 x 6 x 4 mm，位于垂体窝左后侧。当时，未注意到涉及内分泌或神经系统疾病的临床症状。18个月时，肿瘤肿块在磁共振成像图像上缓慢进展，测量为6 x 7 x 7 mm，术前糖尿病或高皮质醇症的体征未复发。
由于术后12个月磁共振成像检测到垂体窝内存在肿瘤肿块，且术后18个月磁共振成像显示缓慢进展，该猫在稿件审阅过程中接受了根治性意图的体外放射治疗。虽然第二次手术是可能的，鉴于目前无内分泌疾病、猫的暴躁性格以及放射治疗的本地可用性，选择了这种微创治疗。该猫在经蝶手术后612天因无关合并症在家中死亡。未进行尸检。
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组织学
组织病理学检查由委员会认证的兽医病理学家（GG）进行。所有病例均进行了常规苏木精和伊红染色，并结合促肾上腺皮质激素、生长激素和α-促黑素细胞刺激素的免疫组织化学染色。
病例1（图3A–D）显示为嗜碱性腺瘤，而在两次连续手术中获得的两个组织样本中，免疫组织化学促肾上腺皮质激素、生长激素和α-促黑素细胞刺激素染色均为阴性。然而，与原发性肿瘤相比，复发性肿瘤组织显示更单一的肿瘤细胞群体。
[图：组织病理学。3只猫垂体肿块的组织病理学研究。病例1：（A）垂体肿块的组织学 w]
病例2（图3E–G）也被诊断为嗜碱性腺瘤。促肾上腺皮质激素免疫组织化学显示大量细胞胞质内呈强、相对粗颗粒状阳性。肿瘤细胞群体内生长激素染色为阴性，整个组织中仅偶见散在阳性染色的原有腺垂体细胞。α-促黑素细胞刺激素染色显示微弱背景染色，可能大部分为非特异性。
病例3（图3H–J）显示为嗜碱性腺瘤，促肾上腺皮质激素免疫反应性呈轻度弥漫性染色，少数散在细胞中生长激素染色强，可能代表原有（正常）腺垂体细胞。
所有3例均表现出明显的出血区域，常伴有含色素巨噬细胞的多灶性积聚，最符合含铁血黄素细胞，以及胆固醇裂隙，表明急性和慢性出血。
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讨论
本报告描述了3例经经蝶手术治疗的猫垂体腺瘤，据作者所知，这是猫中该病成功手术管理的首次描述。所有3只猫均在我们机构因怀疑存在垂体肿块而接受评估。其中2只的主诉为急性发作的神经系统症状；第三只已确立垂体依赖性高皮质醇症的诊断，并存在神经功能缺损。所有3例均通过垂体组织病理学检查回顾性鉴定为垂体腺瘤。回顾性评估了肿块的诊断影像学特征，以寻找垂体腺瘤的标志物供未来参考。所有3例从初次就诊到最近随访的临床过程示意图概述见补充图1。
关于急性起病的中枢神经系统体征，需要强调的是，病例2在脑脊液和血清学中均显示刚地弓形虫（T. gondii）IgG滴度阳性。值得注意的是，脑脊液IgM滴度为阴性。在健康和临床受累猫的脑脊液中均可检测到弓形虫特异性抗体，这可能反映血清被动转移或局部鞘内产生（12）。脑脊液IgM滴度阴性结合配对的血清IgM滴度阳性，不支持显著的鞘内抗体产生，更符合近期全身性感染或潜伏感染再激活（12, 37）。在实验研究中，患有慢性弓形虫病的猫在免疫系统受损时可出现IgM/IgG滴度升高的短暂复发（37）。鉴于就诊时的年龄以及欧洲猫中约45%的 reported 血清阳性率，既往暴露更有可能（13）。此外，脑脊液采样时进行的MRI未显示脑膜炎征象，而急性中枢神经系统弓形虫病可能出现此征象。应考虑卒中事件本身继发的血脑屏障破坏可能允许血清免疫球蛋白进入脑脊液，进一步使脑脊液抗体滴度的解读复杂化。遗憾的是，脑脊液是在转诊前采集的，因此无法获得包括细胞学评估、有核细胞计数和弓形虫PCR在内的完整检查。脑脊液蛋白浓度和有核细胞计数升高可能提示中枢神经系统炎症过程；然而，这些发现也可出现在PA中，因为它可引起化学性无菌性脑膜炎（14）。如果没有同一实验室间隔4周获得的配对血清或脑脊液滴度显示IgG和IgM显著升高，或脑脊液弓形虫PCR阳性，则无法建立中枢神经系统弓形虫病的确定性诊断（37）。因此，病例2的弓形虫滴度结果应谨慎解读。尽管如此，在收到实验室结果后立即开始了针对性抗菌治疗（克林霉素）。存在极大的垂体肿块（P/B比值为1.25）以及手术后显著改善，提示肿块与观察到的临床异常之间存在因果关系。尽管临床症状理论上可归因于任一病理，但仅垂体的极度增大在作者看来就需要减压手术。然而，不能完全排除并发弓形虫病的潜在贡献，且感染对疾病临床过程和结局的影响无法确定。
PA是一种通过结合急性起病的神经系统体征与提示垂体出血或梗死的特征性影像学和病理学发现来诊断的综合征（15–19）。在人类文献中，其通常以突发严重头痛（95%−100%）为特征，随后出现视力损害、呕吐、意识水平改变和眼肌麻痹。这些症状源于垂体出血和/或梗死引起的鞍内压突然升高（18, 20, 21）。此外，激素缺乏（即垂体功能减退）在人类中也常见报道，研究显示高达80%的患者出现一种或多种垂体前叶激素缺乏（15, 22）。在犬类文献中，PA被描述为行为改变、视力损害、共济失调、烦躁不安、癫痫发作、前庭功能障碍（头倾斜、眼球震颤、前庭性共济失调）和胃肠功能障碍的体征（19, 23）。在猫中，已观察到烦躁不安发作、视力缺陷、定向障碍和抑郁（4–6）。我们的2个临床病例（病例1和病例2）的主要就诊体征为烦躁不安伴贴墙行为、精神状态下降、本体感觉缺陷和后肢共济失调，而病例3仅表现为DM，无神经系统异常。特别是这些病例中突然起病的神经系统和行为改变，回顾性分析引起了对PA的怀疑。在我们的病例中，手术干预前是否存在视力损害值得商榷。初次就诊时，病例1未显示明显的视力下降，病例2表现出轻度延迟的瞳孔反射和延迟的视觉本体感觉，尽管在该猫的表现中没有进一步的失明证据。值得注意的是，由于未表现出PA的临床体征，病例3代表一种亚临床形式，其诊断仅在切除垂体的组织病理学检查后才得以确定。
垂体卒中可通过先进诊断影像学在CT或MRI上识别，其中MRI为首选检查方式。垂体卒中的潜在病理生理过程可为缺血性梗死（即无出血成分）、出血性梗死、混合性出血性梗死伴血凝块，或单纯血凝块（15, 24）。这有助于解释为何垂体影像学检查很少显示单纯性梗死或出血，而多表现为混合性特征。在犬中，急性垂体卒中的典型CT特征包括局灶性高密度区，可解释为瘤内出血，常合并低密度梗死成分（25）。梗死区域在平扫影像上通常无异常表现。静脉注射对比剂后，周边环形强化也可能提示垂体卒中（26）。这与猫病例中的发现一致（5, 6）。
除检测是否存在出血外，鞍区/鞍上肿块的MRI表现还取决于发病时间（26）。出血性病变在T1和T2加权成像上急性期初期可表现为低信号，而亚急性期病变则变为高信号（26）。这在犬垂体卒中的一项研究中亦有体现，大多数犬就诊时处于急性期，导致垂体病变在T2W上呈低信号表现（23）。也有证据表明T2在超急性期显示高信号，而亚急性期持续呈低信号（1, 22）。在T2加权MRI序列中，磁敏感加权血管成像（SWAN）对检测出血产物尤为敏感。在SWAN上，出血通常表现为低信号伴所谓的Blooming伪影，使即使极少量的血液产物也能被显示（11）。此外，静脉注射钆对比剂后周边环形强化在垂体卒中病例的MRI上经常可见（1, 23）。除设备特异性细节外，主流观点认为垂体卒中的影像学证据以垂体腺瘤内含混合性低信号和高信号区域为特征，与瘤内出血和/或梗死相一致。
本手稿中呈现的3例病例在诊断影像学上显示了多项与垂体卒中一致的发现。首先，需要认识到尽管MRI被认为是确诊垂体卒中的金标准，但在我们的一些病例中选择了CT而非MRI。初始诊断影像学检查是在转诊至我院之前进行的，取决于当地设备可用性和转诊临床医生的偏好。在那一阶段，垂体卒中可能尚未被纳入鉴别诊断。由于垂体位于血脑屏障之外，增强CT可以识别垂体增大，并且仍可提示腺体内出血性病变。在病例1中，由于组织病理学确诊了垂体卒中，CT上病变内高密度和低密度区的存在支持了这些影像学发现可能与垂体卒中相符的解释。同样，病例2的MRI发现（肿块内低信号区）表明与垂体卒中相符。最有力的证据来自病例3，其中磁敏感敏感MRI序列在经蝶手术前显示了与病变内出血高度一致的发现。有趣的是，尽管影像学证据显示垂体出血，该患猫仍未出现神经学和行为学异常。
除与垂体卒中相符的影像学发现外，所有3只猫均表现出显著的高P/B比值，与猫肢端肥大症（HS）——该物种最常见的垂体肿瘤类型——中通常报道的比值相比。虽然垂体增大在诊断为HS的猫中很常见，但据报道这些动物的P/B比值为0.58（9）。因此，病例1、2和3中观察到的P/B比值分别为0.96、1.25和1.12，反映了显著的垂体增大。有趣的是，鞍上延伸是人类和犬垂体卒中的常见发现（19, 23, 27）。鉴于这些发现，这些猫选择手术治疗的理由是存在的；在垂体严重增大引起临床症状（神经学或内分泌功能亢进）的病例中，通常首选以手术切除为形式的治愈性治疗（28）。
虽然在本手稿描述的3只猫中，大型垂体肿块的存在是手术的主要指征，但这些病例引发了关于猫垂体卒中（PA）识别和管理的有趣思考。尽管PA经典上被视为一种临床综合征，但人类研究表明，高达25%的垂体腺瘤在诊断成像（MRI）上显示坏死和/或出血区域，而临床症状仅出现在2%-12%的垂体腺瘤患者中（29, 30）。这引发了怀疑，即在猫和犬的垂体腺瘤中，出血和/或梗死可能比目前认识的更频繁发生，通常不引起明显的临床症状。尽管在人类医学中已被充分认识，但这在兽医文献中此前尚未描述（27）。病例3似乎代表了这样一种情况：诊断成像显示与亚急性出血相符的发现（图1G, H），结合组织学检查的出血证据，但缺乏明显的中枢神经系统体征。作为兽医，我们必须保持警惕，伴侣动物中头痛和轻度视力损害的早期迹象容易被忽视。
PA的最佳治疗方法在人类医学中仍存在争议。治疗决策主要基于临床症状的严重程度，特别是神经眼科缺陷和意识障碍（15, 31）。已提出如Jho及其同事（27）的分级系统来支持决策，特别是是否需要立即手术干预而非择期手术或保守管理。权衡这种紧迫性的理由在于结果的时效性。尽管在PA中垂体增大可能是暂时的，但在垂体卒中分级系统较高等级中提倡及时手术减压，因为这些患者倾向于更早接受手术，而所有等级均报告了良好的总体结果（27）。
在当前兽医医学中，治疗选择同样受临床症状严重程度的影响，尽管迄今为止决策主要是在保守管理和安乐死之间。大多数报告的病例，通常是犬，要么基于临床症状和放射学诊断进行保守管理，要么在治疗不成功时安乐死并提交病理确认（19, 23）。同样，先前报告的猫PA病例应主人要求被安乐死（4-6）。猫和犬中缺乏手术治疗病例的报告，可能部分是由于相对缺乏手术治疗的途径（28）。迄今为止，PA的手术治疗仅描述过一次，在一只犬患者中（32）。在我们的报告中，手术治疗被选为治疗选择，基于神经症状（病例1和2）或内分泌病（病例3）的存在，结合影像学上发现的垂体大小。先前研究已证明在患有产激素肿瘤的猫中THX后具有良好的长期结果（9, 33），本报告进一步表明，在并发PA的猫垂体肿瘤中也可能实现类似良好的结果。
尽管在我们的病例中手术是首选，但保守管理，包括糖皮质激素和/或抗惊厥药物联合高渗剂，在选定患者中仍是相关选择，并在先前提到的病例系列中证明有效（19, 23）。重要的是，这些研究报告了良好的短期结果，而PA的潜在原因（即垂体肿块）在评估预后和治疗选择时仍是需要考虑的重要因素。单一较大的犬PA队列接受保守管理或放射治疗，其总体出院存活率为58%，令人沮丧（23）。即使肿块的减压可能被视为不成比例的侵入性干预，与垂体肿块发展相关的潜在内分泌疾病，如PDH或HS，本身可能通过手术干预治愈（9, 27, 28）。然而，鉴于伴侣动物PA治疗的报告非常少，作者认为保守治疗也可被视为PA的可能治疗方法。
放射治疗同样被用于患有PA的犬（19, 23）。然而，放射治疗在PA急性期的效果仍存在争议。在人类医学中，放射治疗与卒中发展有关，可能是由于放射引起的肿瘤内血管壁损伤（3, 16, 26）。它不用于急性PA的治疗，因为减小肿瘤大小的效果起效缓慢。放射治疗已被描述为犬、猫和人类选定垂体肿瘤的有用方法（28），并在垂体疾病的整体治疗中占有一席之地。
在探讨这些治疗方案时，从紧急手术减压到择期手术、保守治疗或放疗，建立一个结构化的治疗决策框架将是有益的。Jho及其同事开发的重体腺卒中分级系统在这方面可能是一个有价值的工具；然而，它需要针对兽医患者进行调整。在人类系统中，较高的分级（以视觉障碍定义）通常反映其鞍上延伸的影响。然而，猫和狗的解剖结构与人类显著不同：在这些物种中，视交叉位于鞍结节更偏头侧的位置。因此，尽管偶尔观察到视觉障碍，但重体腺卒中更常见的表现包括提示颅内疾病的细微至明显的行为变化（即头顶墙、性格改变、靠墙寻求支撑、恐惧），以及步态和本体感觉的改变（包括前庭征象）和精神状态的变化(19, 23, 25)。此外，人类重体腺卒中分级系统是基于一大群患者的结局制定的(27)。在兽医医学中，尚无可用于验证等效系统的病例数量。总而言之，通过一些调整和转化知识，可以开发一个猫重体腺卒中分级系统（图4）。该 proposed 系统使用临床症状的严重程度作为重体腺卒中占位效应所致颅内压增高程度的替代指标。它还考虑了影响干预紧迫性的合并症：“修饰性合并症”需要在手术前更好地稳定病情，从而降低快速手术干预的需求，而“放大性合并症”则可能提示优先选择快速干预。
[图：猫重体腺卒中分级系统。基于以下内容开发了一个 proposed 的猫重体腺卒中分级系统]
使用该 proposed 分级系统，病例1将被归类为3级，行为异常和烦躁不安被解释为可能的头痛，这定义了该级别。在该病例中，没有影响临床判断的放大因素或修饰因素，使其处于紧急手术干预与择期手术或保守管理之间的中间位置。然而，鉴于重体肿块的极大尺寸，作者认为择期手术治疗是合适的选择。病例2在该量表上代表4级，因为存在行走障碍；精神状态下降 moreover 应计为放大因素，进一步支持快速手术干预。病例3代表2级患者，因为没有神经系统异常。然而，鉴于并发PDH，猫脆弱皮肤综合征和由重体肿块引起的糖尿病作为放大因素，将患者在该谱系上向上移动，支持快速手术干预。
本报告中3例病例中有2例在术后出现视觉障碍。在病例1和3中，THX后识别出双侧瞳孔散大和视觉障碍，而在就诊时未检测到视觉缺陷。虽然KCS是THX后更常记录的 ocular 并发症，如病例1和2中所观察到的，但视觉障碍在接受该手术的猫和狗中并不常见报道(9, 34, 35)。可以想象，与人类相比，更偏头侧的位置使视交叉在THX期间更接近手术野，使其更容易受到医源性损伤(36)。病例1中威胁反应和瞳孔反射均缺失，且无可检测的眼内异常，可能与视神经或视交叉损伤一致。病例3确实显示瞳孔反射缺失，同时双眼存在威胁反应和 dazzle 反射，眼底镜检查未发现异常。瞳孔散大随时间变得不那么明显，视力随时间部分恢复。最可能的解释与病例1相同；眼外视神经炎，可能与THX相关。病例3最初分类为皮质盲可能归因于猫同时出现的突然行为变化，以及威胁反应和 dazzle 反射的存在。瞳孔散大归因于阿片类药物给药，然而，停止阿片类药物治疗后瞳孔散大持续存在。阳性威胁反射也可能由气流和随后的角膜反射引起，并且当时可能被过度解读。在两例中，眼底镜检查均未显示视神经炎的证据，但视盘无眼内变化并不能排除眼外视神经炎。视神经和视交叉相对位于重体窝的头侧，然而，在大肿瘤中，手术切除仍可能引起局部损伤，因为大肿块可向头侧扩展，因此，摘除需要向头侧操作肿瘤。重体窝头侧边界（鞍结节以外）的可视化较差，意外操作钻孔头侧的结构是可能的。进一步改进术中可视化技术包括内窥镜可能防止医源性创伤并改善这些病例的结局。
建议对所有3例病例每隔6至12个月进行重复随访影像学检查，以识别肿瘤复发的情况。该间隔基于既往接受THX的猫垂体瘤队列数据。Meij等（34）的一项研究报告了一例PDH猫在19个月后肿瘤复发，该复发是基于高肾上腺皮质激素症的临床和生化体征诊断的。此外，有研究报告5例生长激素过度分泌症猫的中位复发时间为248天（范围84–1,232天）（33）。在病例1中，术后3个月进行的CT成像显示垂体窝内存在可能与少量残留垂体组织相符的改变，尽管这些发现尚无定论。鉴于术后约2年影像学上肿瘤复发的明确证据，初次手术干预后仍可能存在显微镜下残留组织。猫2的主人拒绝进一步成像。在病例3中，术中检查垂体窝未见异常组织存在，但术后直接CT扫描确实显示一小片对比增强区域，提示可能存在残留垂体组织。术后1年CT扫描显示垂体窝内肿块复发，尽管此次UCCRs中未见PDH复发的证据，且该猫仍无临床症状。这说明了在实现肿瘤完全切除与保留正常下丘脑组织之间难以平衡，因为该区域手术野的可视化本质上受限。内镜探查目前在该机构于THX后常规进行，似乎可增强垂体窝的可视化，并可能有助于识别残留垂体组织，但其应用仍是未来研究的领域。
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结论与未来展望
对于表现为急性发作神经系统症状的猫，尤其是当垂体影像学检查有证据显示鞍区肿块增大时，应将PA列为鉴别诊断。所呈现的病例表明，THX可为患有PA的猫带来良好结局。对于未来研究，有必要在先进影像学上对PA进行更系统的评估，以更好地确定与垂体瘤相关的出血和梗死的发生频率。此外，外科、影像学和病理学学科之间更紧密的协作将有助于对该综合征作出更一致的诊断。
致谢
作者特别感谢C. Valtolina博士（EBVS®急诊与重症监护专科医师）、ICU团队以及参与这些病例诊断的内科医师对猫成功疗程所做的贡献。我们还感谢E.A.W.S. Weerts博士（EBVS®兽医病理学专科医师）参与组织病理学评估，以及C. Planas Padrós博士（EBVS®欧洲兽医诊断影像专科医师，DipECVDI）在本文稿准备过程中对诊断图像的审阅。
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根据当地法规和机构要求，涉及动物的研究无需伦理批准，因为这是一份回顾性病例报告；治疗中遵循了标准诊疗。根据当地法规和机构要求，在入院时已获得动物主人对将其动物参与回顾性研究的书面知情同意。已获得参与者对发表本病例报告的书面知情同意。
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Abstract
Background
Surgical treatment of feline pituitary apoplexy has not been previously described.
Objectives
To describe the clinical course and follow-up of 3 cases of feline pituitary apoplexy.
Methods
Cases were selected based on histopathological confirmation of pituitary masses with haemorrhagic lesions, following transsphenoidal hypophysectomy. Details of physical examination, diagnostic test results, treatment and follow-up course were retrospectively acquired by review of medical and imaging records.
Results
Two cats were presented with acute onset of neurologic signs (case 1 and 2), and one cat showed subacute endocrinological dysfunction (case 3). All cases underwent successful transsphenoidal hypophysectomy, followed by intensive care hospitalization and successful discharge. Pituitary apoplexy was identified by histopathological examination of the excised pituitary glands in cases 1, 2, and 3. Imaging findings compatible with pituitary apoplexy were present in all 3 cases, although only case 3 was imaged with a hemorrhage-sensitive sequence, providing unequivocal evidence of intralesional hemorrhage. Case 1 had a survival time at least 716 days, underwent a second transsphenoidal surgery because of tumor recurrence and was subsequently lost to follow-up. Case 2 had a survival time of at least 1,098 days and is still alive at the time of writing this manuscript. In case 3, tumor recurrence was identified radiologically (MRI) at 365 days, and it died during a course of radiation therapy 612 days after transsphenoidal hypophysectomy.
Conclusion and clinical importance
Pituitary apoplexy is a rare condition that also affects cats with large pituitary adenomas. Overall, the cats experienced acceptable clinical recovery and postoperative survival, supporting the feasibility of transsphenoidal hypophysectomy as a therapeutic option for cats with pituitary tumors affected by apoplexy. Notably, a favorable outcome was observed even in the presence of remnant pituitary tissue, as illustrated by the cat that later developed pituitary tumor recurrence.
Keywords: apoplexy, cat, hypophysectomy, intracranial hemorrhage, intracranial infarction, pituitary, transsphenoidal
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Introduction
In human medicine, pituitary apoplexy (PA) is characterized by a sudden onset of severe headaches, altered levels of consciousness and visual impairment originating from a sudden increase in intrasellar pressure, caused by hemorrhage and/or infarction of the pituitary gland. This condition generally arises in patients with pre-existing non-functional pituitary macroadenomas, but it can also develop in individuals with healthy pituitary glands, or patients affected by inflammation or infection (1). Diagnosis is based on clinical suspicion, in combination with imaging, where magnetic resonance imaging (MRI) is the preferred option. Findings consistent with PA include signs of hemorrhage, necrosis or oedema, often in association with a pituitary neuroendocrine tumor (2). Therapeutic options consist of either early transsphenoidal decompression or conservative approach for patients without neuro-ophthalmic signs or with mild and stable symptoms (3).
In veterinary literature, and especially in cats, PA is scarcely described. In the feline cases that have been documented, episodes of restlessness, acute blindness, disorientation, and depression have been observed. Diagnoses were based on radiological findings in combination with histopathology. In these cases, no surgical intervention was performed, and the cats were euthanized (4–6).
This report describes the first cases of cats with pituitary apoplexy, which underwent successful transsphenoidal hypophysectomy (THX) and recovery. Initially, all cases were diagnosed with a pituitary mass, based on radiological examination. All 3 cases showed a heterogeneous pituitary gland on advanced imaging, indicative of hemorrhage, infarction or necrosis. Subsequently, they underwent hypophysectomy, indicated by the large P/B ratios, neurological or endocrinological manifestations. The definitive diagnoses of pituitary apoplexy were based on histopathological examination. Pituitary apoplexy is a differential diagnosis that should be given greater consideration in patients with an acute onset of neurological signs, as outlined above, to optimize diagnostic accuracy and thereby improve outcomes for affected patients. Surgical intervention in the cases described in this case report led to a swift neurological recovery and positive long-term outcome.
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Case descriptions
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Case 1
An 11-year-old neutered female Domestic Shorthaired cat was presented with a 2-year history of hyporexia and progressive weight loss of 2 kg (from 6.7 to 4.7 kg), as well as a 2-week history of acute behavioral abnormalities. Clinical signs included aimless pacing along walls in both directions, restlessness and aggression toward other cats. The cat was also actively seeking contact toward the owners. General physical and neurological examinations of this cat were unremarkable; the aforementioned changes in behavior could not be verified during the consultation. No endocrine disease was diagnosed, based on serum thyroxine (T4) concentrations of 29 nanomole/L (nmol/L) (15–45), thyroid-stimulating hormone concentrations < 0.03 microgram/L (mcg/L) (< 0.03 mcg/L), insulin-like growth factor-1 (IGF-1) concentrations of 268 mcg/L (< 598) and adrenocorticotropic hormone (ACTH) concentrations of 64 picogram/mL (pg/mL) (–358) (7, 8).
Computed tomography (CT) demonstrated a markedly enlarged pituitary gland measuring 8.7 mm (H) × 15.1 mm (L) × 10 mm (W) and a pituitary height-to-brain area (P/B) ratio of 0.96. Although no validated feline reference value for the P/B ratio is available, the pituitary height exceeded the 4.0 mm threshold used to define pituitary enlargement in cats (9), and the P/B ratio was well above the canine cut-off of 0.31 (10). Additionally, intralesional hyperattenuating and hypoattenuating areas were also present, suggestive of haemorrhagic and infarctive changes within the mass (Figures 1A, B). Considering the size of the tumor and the favorable outcomes reported for THX in cats, surgical intervention was elected as the treatment of choice in this case.
[图：Preoperative imaging. Case 1: Post contrast computed tomography (CT) dorsal (A) and transverse (B) reconstructions showi]
The day prior to surgery, the cat was hospitalized for pre-operative stabilization. Intravenous fluid therapy (IVFT) was administered at a maintenance rate of 8 ml/h. Analgesia was provided with meloxicam 0.1 mg/kg one time daily (SID). A nasal feeding tube was placed to enable nutrition intake (Royal Canin Convalescence Support).
Prior to THX, the cat was pre-medicated with 0.70 mg (0.15 mg/kg) methadone hydrochloride intravenously (IV) and induced smoothly with 1.08 mg (0.22 mg/kg) midazolam IV and 15 mg (3.1 mg/kg) propofol IV. It was intubated with an endotracheal tube size 4, directly followed by manual ventilation (EtCO2 4–5 kPa). Anesthesia was maintained using sevoflurane, remifentanil 0.2–0.3 mcg/kg/min IV Constant Rate Infusion (CRI) and propofol 0.5–1 mg/kg IV bolus on effect. Local infiltration of the incision site using lidocaine 14.4 mg (3.06 mg/kg). Monitoring consisted of invasive and non-invasive arterial blood pressure, capnography, electrocardiogram (ECG), FiO2, pulsoximetry and spirometry. Body temperature was supported using Bairhugger and a warming matrass. Intra-operative bradycardia treated on effect with atropine 3–5 mcg/kg IV and glycopyrrolate 5 mcg/kg IV. Intra-operative hypotension treated on effect with dopamine 3–6 mcg/kg/min IV CRI. Reduction of intracranial pressure by maintaining CO2 levels < 4.0 mmHg.
THX was performed as described in a previous publication on this procedure in cats (9). The soft palate was incised in the midline using a No. 10 scalpel blade and retracted laterally with a self-retaining Gelpi retractor. The mucoperiosteum was separated from the sphenoid bone and the hamular processes. Subsequently, the sphenoid ridge was identified, to determine the position of the burr hole. A 10 mm window was created in the sphenoid bone, using a burr. Rostral perforation into the air-filled sphenoid sinus identified the position of the fossa, located caudally to this point. The approach was then continued caudally directly toward the pituitary gland. Bleeding from the bone was controlled with bone wax (Ethicon, Somerville, NJ, USA). In the cancellous portion of the bone, haemostasis was achieved with bone wax. The opening measured approximately 10 mm in length and 8 mm in width. The pituitary gland appeared red-blue rostrally, suggestive of tumor, and white caudally, suggestive of normal tissue. The dura mater was coagulated using bipolar electrocautery and incised using a No. 11 blade. The apparent abnormal tissue was carefully dissected free from surrounding tissue and removed in multiple fragments, which were all submitted in a single formalin container, including some macroscopically normal-appearing pituitary tissue. The fossa was emptied and the dorsum sellae was palpable. The fossa was filled with a gelatine foam sponge (Spongostan Absorbable Hemostatic Gelatin Sponge (Ethicon, Somerville, NJ, USA), approximately 8 × 6 mm. Bone wax (Ethicon, Somerville, NJ, USA) was applied to the sphenoid defect and mucoperiosteum. Caudally, a single suture of polydioxanone (PDS II 6-0, Ethicon, Somerville, NJ, USA) was placed with good apposition of the mucoperiosteum. Bone wax coverage was approximately 50%. The soft palate was closed in two layers; nasal mucosa was sutured using polygalactin 910 (Vicryl 4-0, Ethicon, Somerville, NJ, USA), in a simple continuous pattern, and the oral mucosa was sutured using polyglactin 910 (Vicryl 4-0, Ethicon, Somerville, NJ, USA) in a simple interrupted pattern. The recovery was smooth and uneventful.
The cat was admitted to the intensive care unit for postoperative monitoring. General physical examination (respiratory rate (RR), heart rate (HR), temperature, mucus membranes and capillary refill time (CRT) was performed every 4 h. Plasma sodium, potassium, glucose and haematocrit (Ht) levels were measured 2 times daily (BID). Urine production and fluid balance was monitored and calculated every 2 h. The IVFT maintenance rate was 8 ml/h (Sterofundin B/G) and corrections were administered accordingly. To maintain nutrition intake, the cat had received an esophageal feeding tube. Royal Canin Convalescence Support was administered at a CRI. Analgesia was provided with buprenorphine [20 mcg/kg 3 times daily (TID) IV] and antibiotic prophylaxis was initiated with amoxycillin-clavulanate (20 mg/kg TID IV). The cat received hormone replacement therapy with hydrocortisone IV [1 mg/kg 4 times daily (QID)], desmopressin ocular drops TID, alternating the right eye (OD) and left eye (OS), and oral thyroxine (15 mcg/kg BID). The cat was severely bradycardic (100–130 bpm) and hypotensive, had mild hyponatremia [135 mmol/L (146–158 mmol/L)] and was severely anemic [Ht: 0.14 L/L (0.28–0.47 L/L)], for which the cat received a blood transfusion, correcting the Ht to 0.19. During this period, bilateral mydriasis was observed, with absent direct and consensual pupillary reflexes and an absent menace response in both eyes. Meanwhile there were no detectable intraocular abnormalities. Examination by a board-certified veterinary ophthalmologist confirmed bilateral blindness, considered most likely to be related to the surgical procedure. A Schirmer Tear Test (STT) also identified keratoconjunctivitis sicca (KCS), measuring a tear production of 0 mm/min in both eyes (OU). After 8 days, the cat was stable and discharged for appropriate aftercare at home. Life-long hormone replacement therapy consisted of a maintenance dose of oral cortisone acetate (0.35 mg/kg BID), oral L-thyroxine (15 mcg/kg BID). Diabetes insipidus was managed by administering desmopressin eyedrops BID, alternating right eye (Oculus Dexter, OD) and left eye (Oculus Sinister, OS), measuring plasma electrolyte levels after 1 and 4 weeks, and adjusting the dose accordingly. Once normal plasma electrolyte levels were achieved, treatment with the ocular drops was continued for an additional week, after which they could be discontinued. The visual impairment remained unchanged for the remainder of the cat's life.
After 3 months, a CT scan of the skull was repeated to monitor for recurrence of pituitary tumor. Changes within the pituitary tissue were compatible with a minute amount of residual hypophyseal/neoplastic tissue, although these findings were not conclusive. Clinical follow up, with repeat CT imaging if deemed indicated, was recommended after 6–12 months and annually thereafter.
At 705 days after the initial surgery, recurrence was diagnosed through repeat imaging (CT), with the following dimensions: 7.8 mm (H) × 9.7 mm (L) × 6.7 mm (W) and a pituitary/brain ratio (P/B) of 1.0. The cat underwent a second THX. Following THX, the cat remained in the ICU for 11 days before being discharged. The cat was lost to follow-up after discharge at a registered survival time of 716 days.
The histopathological and immunohistochemical (IHC) evaluation of the excised tissue showed pituitary apoplexy and a basophilic tumor that demonstrated marked absence of both ACTH and GH staining in the IHC in the first instance. Tumor tissue obtained during the second surgical procedure showed an even more homogenic basophilic tumor cell population, with again, no immunoreactivity for ACTH and GH.
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Case 2
A 12-year-old neutered male European Shorthaired cat was presented with neurologic signs. The cat exhibited anorexia for 1-month, acute episodes of weakness in the hind limbs, and decreased mentation. General examination showed a quiet and responsive cat with a markedly reduced general condition. The neurologic examination revealed a minimally delayed direct bilateral pupillary reflex, while corneal and palpebral reflexes were intact. There was a marked reduced sensitivity of the nose. The cat showed delayed visual and absent tactile proprioception in the thoracic limbs. Proprioception was normal on the left front limb, while markedly delayed on the right front limb, although this was the leg wrapped with a catheter bandage dressing. Dorsiflexion of the neck elicited marked ventral strabismus in the left eye and vertical nystagmus in both eyes. There were no signs of endocrinopathy like diabetes mellitus (DM) or polyuria/polydipsia (PUPD).
A sonographic examination of the heart was performed as well, which showed no structural cardiac abnormalities or function impairment. Cerebrospinal fluid (CSF) and plasma were assessed on Toxoplasmosis. CSF analysis revealed IgG 94.16 (< 50), IgM 4.45 (< 9) and total protein 1.01 g/L. Plasma serology showed IgG 203.39 (< 50), IgM 18.54 (< 9). IGF-1 (399 ng/mL, < 598), basal serum cortisol [12.5 ng/mL (2–50 ng/mL)] were within reference range and FeLV / FIV testing was negative. CSF total nucleated cell count, cytology and antigen titres were not performed at the time.
MRI was performed, which identified a large round pituitary mass [12.2 mm (H) × 10.8 mm (L) × 11.2 mm (W)] with a P/B ratio of 1.25. The mass compressed the thalamus and brainstem (caudal displacement), and moderate-marked congestion of both lateral ventricles and the fourth ventricle were observed. T2-weighted and T1-weighted images demonstrated hypointense areas within the mass, suggestive of intralesional hemorrhage (Figures 1C–E). The spinal cord of the cervical spine showed a marked syringomyelia. Like case 1, THX was selected as the treatment of choice because of the large size of the pituitary mass and the favorable outcomes reported following this procedure.
The day prior to surgery, the cat was hospitalized for preoperative stabilization. Complete blood cell count and routine biochemical analysis were performed. A stress leucogram was noted, and mild increase in total protein and albumin. ACTH was within normal limits [215 pg/mL (15–358 pg/mL)]. The cat received hydrocortisone 1 mg/kg, amoxicillin-clavulanate intravenously IV [20 mg/kg 3 times daily (TID)], maropitant IV (1 mg/kg SID), omeprazole IV (1 mg/kg SID) and gabapentin (15 mg/kg once). A feeding tube and jugular catheter were placed. On the day of surgery, a repeat Toxoplasma gondii serology was performed at a second laboratory, 3.5 weeks after the positive serology and CSF titres obtained at initial presentation. The combined IgG and IgM titer was 1:256 (reference < 1:64).
Prior to surgery, the cat was premedicated with methadone-hydrochloride 1.66 mg (0.25 mg/kg) IV and dexmedetomidine 13.4 mcg (2 mcg/kg) IV, providing a mild sedation. The cat was induced with propofol on effect. It was intubated with an endotracheal tube size 3.5. Anesthesia was maintained using isoflurane, sufentanil 0.5–1 mcg/kg/min IV CRI and ketamine 10 mcg/kg/min IV CRI. Local infiltration of the incision site using lidocaine 13.2 mg (2 mg/kg). Monitoring adhered to the same protocol as outlined in case 1, with the addition of arterial blood gas analysis. Intra-operative bradycardia treated on effect with atropine 5 mcg/kg IV and glycopyrrolate 1–10 mcg/kg IV. Intra-operative hypotension treated on effect with dobutamine 0.55–8 mcg/kg/min IV CRI. Reduction of intracranial pressure by maintaining CO2 levels < 4.0 mmHg, and administration of mannitol (0.25 g/kg over 20 min).
THX performed as described in case 1. Upon opening the pituitary fossa, the bulging pituitary gland was rapidly encountered. The tissue showed a heterogenous aspect. Apparent abnormal tissue (mucoid and gray) was removed from the fossa in multiple fragments and submitted in a formalin container. The surgeon observed macroscopic complete excision. Throughout the surgical procedure, the approach and fossa contents were examined using a 18 cm 1.9 mm 30° forward telescope, confirming complete extirpation (Figures 2A, B). Closure of the surgical side was performed as described in case 1.
[图：Intraoperative endoscopy. Case 2: (A) Intraoperative endoscopic image of the pituitary mass (blue star) bulging through ]
A direct post-operative CT scan of the head was performed and compared to the preoperative MRI, confirming absence of the previously visualized mass. The remaining brain parenchyma was unremarkable. There was a marked decompression of the thalamus and brainstem.
After surgery, the cat recovered swift and without complications. Subsequently, the cat was admitted to the ICU, where it had a hospitalization period of 6 days. Postoperative medication, monitoring, and hormone replacement therapy were followed as protocolized and described in case 1. Blood glucose level was measured every 4 h, which remained < 9 mmol/L throughout the hospitalization period, without the administration of insulin. This indicated a remission of DM. Furthermore, cat received clindamycin 12.5 mg/kg BID, indicated by positive Toxoplasma plasma titres. A STT identified KCS, with values between 5 and 6 mm/min. in both eyes. During this period, the cat exhibited adipsia and anorexia, for which the cat received nutrition through an esophageal feeding tube 5 times daily. Furthermore, the cat developed moderate hyperthermia (40.4 °C), which resolved without additional therapy after 3 days. After 6 days, the cat was considered stable and discharged with appropriate aftercare at home following protocol as described in case 1.
Histopathological and IHC examination of the excised tumor tissue showed a basophilic and ACTH positive profile on IHC staining and pituitary apoplexy.
Two weeks after surgery, the cat was examined by the referring veterinarian. The food and water intake increased significantly over time, but in general the cat was still in slight lethargic state. Further general physical examination was unremarkable although the KCS persisted. The cat is still alive at the time of writing of the manuscript. Although the lethargic state reportedly never fully resolved, there has been no development of new or recurrent neurological signs, resulting in a disease-free interval of 1,098 days. The owner was encouraged to have follow up advanced diagnostic imaging of the pituitary fossa performed on the cat at 6- and 12-months post-surgery followed by yearly imaging rechecks. However, they declined and follow up has been performed through predominantly email contact.
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Case 3
A 9-year-old neutered male Domestic Shorthaired cat was presented with increased appetite, weight gain (from 5.1 kg to 5.7 kg), locomotor difficulties due to muscle wasting and PUPD at the referring veterinarian. DM was confirmed with detection of glucosuria and persisting elevated blood glucose levels. Insulin therapy was initiated at a dose of 4.5 IU of insulin (Caninsulin®, Intervet, Boxmeer, The Netherlands) BID administered subcutaneously (SC). PUPD improved but did not completely resolve. Subsequently, the cat developed spontaneous skin fragility, leading to suspicion of Fragile Skin Syndrome, which can be caused by hypercortisolism. An excessive response to an ACTH stimulation test was observed, and ultrasonography revealed bilateral adrenal enlargement.
CT and MRI identified a rounded pituitary mass with the following dimensions: 10 mm (H) × 10 mm (L) × 11 mm (W), P/B ratio of 1.12. T2-weighted MRI images were characterized by hypointense regions of hemorrhage (Figure 1F). T2-weighted SWAN images demonstrated a hypointense signal with a blooming artifact, which is very indicative of hemorrhage (Figures 1G, H) (11). Based on the large tumor size and the presence of endocrinopathy, surgery was the elected treatment of choice in this cat.
With the presumptive diagnosis of pituitary-dependent hypercortisolism (PDH), the cat was started on trilostane (Vetoryl, Dechra Regulatory B.V., Bladel, the Netherlands). Over a period of 2 months, the dosage was increased from 5 mg to 10 mg to 30 mg, BID. Serum IGF-1 or growth hormone (GH) was not measured, therefore, hypersomatotropism (HS) was not ruled out in this cat prior to surgical intervention.
One day before surgery, the cat was hospitalized and was prepared for surgery as described in case 1. Blood glucose concentrations were measured every hour, and insulin was adjusted accordingly.
Prior to surgery, the cat was premedicated with methadone-hydrochloride 1.71 mg (0.3 mg/kg) IV and dexmedetomidine 11.4 mcg (2 mcg/kg) IV, providing a mild sedation. The cat was induced with propofol on effect. It was intubated with an endotracheal tube size 3.5. Anesthesia was maintained using isoflurane and dexmedetomidine CRI at 0.6–1.0 mcg/kg/h. Local infiltration of the incision site using lidocaine 11.4 mg (2 mg/kg). Monitoring adhered to the same protocol as outlined in case 1, with the addition of arterial blood gas analysis. Additionally, plasma glucose concentrations were monitored every 10 min, and insulin CRI was adjusted accordingly. Reduction of intracranial pressure was achieved by maintaining CO2 levels < 4.0 mmHg. THX was performed, as described in case 1. During the THX, the complete pituitary gland was removed including the apparent abnormal adenohypophysis, as macroscopically observed by the surgeon. The extracted affected tissue contained haemorrhagic and gray mucoid areas, which were collected for histological examination. During the procedure, the surgical approach and content of the fossa were examined endoscopically using a 18 cm 1.9 mm 30° forward angled telescope (Figures 2C, D). Endoscopy provided a better visualization of the pituitary fossa content, enabling resection of tumor tissue that lies in the periphery of the burr hole (Figure 2D). Endoscopy confirming absence of residual pituitary tissue in the fossa. Closure of the surgical side was performed as described in case 1.
Post-operative head CT was performed, demonstrating absence of the pituitary gland. However, contrast enhancement in the right caudal portion of the brain parenchyma (±4 x 4.5 x 3.2 mm), suggested possible incomplete resection of the pituitary gland.
The cat underwent a swift recovery. The cat was admitted to the ICU after hypophysectomy and was treated with the standardized protocol as described in case 1. During the hospitalization, mydriasis was observed in both eyes after initial good recovery from anesthesia. The apparent blindness was noted directly after buprenorphine and hydrocortisone administration, and was combined with extreme excitation. After examination by an ophthalmologic specialist the following day, the cat was identified with corneal ulcerations and impaired vision. Direct and consensual pupillary reflexes were absent in both eyes (OU), however, menace and dazzle reflexes were both present. Concurrent opioid administration was considered a possible contributing factor for the absence of pupillary reflexes at the time, although this could not be determined with certainty. Tear production was within reference range in both eyes. No abnormalities were seen during fundoscopy. The visual impairment was considered most likely secondary to surgical trauma, possibly cortical in nature as mydriasis and possible subsequent inadequate pupillary reflexes were attributed to the response to opioids at the time; however, the exact etiology could not be definitively determined. The cat was discharged 7 days after surgery, with complete resolution of DM. Over time, in the months following surgery, vision appeared to improve partially. Mydriasis persisted, although not as profound as it was during postoperative hospitalization.
Histopathological and IHC analysis of the pituitary tissue confirmed the presence of a basophilic and ACTH positive tumor, combined with pituitary apoplexy.
After hypophysectomy, remission of Cushing's disease was monitored. Direct post-operative ACTH evaluations demonstrated a marked decrease in plasma ACTH concentrations (pre-THX: 877 pg/ml, post THX T = 1 h: 298 pg/ml, post THX T = 3 h: 176 pg/ml, post THX T = 5 h: 156 pg/ml). Basal urinary cortisol/creatinine ratios (UCCR) have been measured multiple times after surgery. Respectively after discharge, 3 weeks, 8 weeks, 6 months and 1-year UCCRs were 8.9, 28.5, 6.7 and 11.5. All measured concentrations were within reference range (2–36) (7). MRI follow up was performed at approximately 12 and 18 months after surgery, in which local tumor recurrence was first noted on the 12 months MRI, with a mass measuring approximately 5 x 6 x 4 mm, located on the caudal left-hand side of the pituitary fossa. At that time, no clinical signs involving endocrinological nor neurological disease were noted. At 18 months, tumor mass slowly progressed measuring 6 x 7 x 7 mm on the MRI images, without recurrence of the preoperative signs of diabetes mellitus or hypercortisolism.
Due to this presence of tumor mass in the pituitary fossa detected on the 12-month post-surgery MRI and slow progression on the 18-month post-surgery MRI, the cat underwent curative intent external beam radiotherapy (RT) at the time of the reviewing process of the manuscript. Although a second surgical procedure was possible, with the current absence of endocrinological disease, the fractious nature of the cat and the local availability of RT, this minimally invasive therapy was chosen. The cat died at home during the treatment period due to unrelated comorbidities at 612 days post THX. No postmortem examination was performed.
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Histology
Histopathological examination was performed by a board-certified veterinary pathologist (GG). Routine haematoxylin and eosin (H&E) staining, in combination with immunohistochemical staining for ACTH, GH, and alpha-melanocyte-stimulating hormone (α-MSH), was performed in all cases.
Case 1 (Figures 3A–D) demonstrated a basophilic adenoma, while it stained negative for ACTH, GH and alpha-MSH on immunohistochemistry in both tissue samples obtained during the two consecutive surgeries. However, the recurrent tumor tissue showed a more monotonous population of neoplastic cells compared to the primary tumor.
[图：Histopathology. Histopathological studies from pituitary masses on 3 cats. Case 1: (A) Histology of the pituitary mass w]
Case 2 (Figures 3E–G) was also diagnosed as a basophilic adenoma. ACTH immunohistochemistry revealed strong, relatively coarse granular cytoplasmic positivity in a large number of cells. GH staining was negative within the neoplastic cell population, with only occasional scattered positively staining pre-existing adenohypophyseal cells present throughout the tissue. Alpha-MSH staining demonstrated faint background staining, likely largely nonspecific.
Case 3 (Figures 3H–J) demonstrated a basophilic adenoma with mild diffuse staining ACTH immunoreactivity and strong GH staining in a small number of scattered cells, likely representing pre-existing (normal) adenohypophyseal cells.
All 3 cases exhibited marked areas of hemorrhage, frequently paired with multifocal accumulation of pigment-laden macrophages, most consistent with siderophages, as well as cholesterol clefts, indicative of both acute and chronic hemorrhage.
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Discussion
This report describes 3 cases of feline PA treated by THX, and represents, to the authors' knowledge, the first description of successful surgical management of this condition in the cat. All 3 cats were assessed at our institution under the suspicion of presence of a pituitary mass. In 2, the presenting complaint was an acute onset of neurological signs; in the third, a diagnosis of PDH had been established and neurological deficits were present. PA was retrospectively identified on histopathological examination of the pituitary glands in all 3 cases. Diagnostic imaging features of the masses were evaluated in retrospect, in search of markers for PA for future reference. A schematic overview of the clinical course of all 3 cases, from initial presentation to the most recent follow-up, is provided in Supplementary Figure 1.
In relation to the acute onset of central neurological signs, it is important to highlight that case 2 showed a positive titer IgG on both CSF and serology for Toxoplasma (T.) gondii. Notably, the IgM CSF titer was negative. T. gondii-specific antibodies can be detected in the CSF of both healthy and clinically affected cats, and may reflect either passive transfer from serum or local intrathecal production (12). The negative CSF IgM titer combined with the positive paired serum IgM titer does not support a significant intrathecal antibody production and is more consistent with a recent systemic infection or reactivation of a latent infection (12, 37). In experimental studies, cats with chronic toxoplasmosis can experience transient recurrence of IgM/IgG titer increases when the immune system is compromised (37). Given the age at presentation and the reported seroprevalence of approximately 45% in cats in Europe, prior exposure is more likely (13). Furthermore, the MRI performed at the time of the CSF sampling did not show signs of meningitis, as might be expected with acute CNS toxoplasmosis. It should be considered that blood-brain barrier disruption secondary to the apoplectic event itself may have allowed passage of serum immunoglobulins into the CSF, further complicating the interpretation of CSF antibody titres. Unfortunately, the CSF was collected prior to referral, and consequently the complete workup, including cytological evaluation, nucleated cell count, and T gondii PCR, was not available. An increase in CSF protein concentration and nucleated cell count could indicate a CNS inflammatory process; however, these findings can also occur in PA, as it can cause a chemical, sterile meningitis (14). Without paired serum or CSF titres from the same laboratory obtained at a 4-week interval demonstrating a significant rise in IgG and IgM, or a positive Toxoplasma gondii PCR on CSF, a definitive diagnosis of CNS toxoplasmosis cannot be established (37). Therefore, the T. gondii titer results from case 2 should be interpreted with caution. Nonetheless, targeted antimicrobial therapy (clindamycin) was initiated promptly following receipt of the laboratory results. The presence of an extremely large pituitary mass (P/B ratio of 1.25) and the marked improvement following surgery suggest a causal relationship between the mass and the observed clinical abnormalities. Although the clinical signs could theoretically be attributable to either pathology, the extreme size of the pituitary alone warranted decompressive surgery in the opinion of the authors. Nevertheless, a potential contribution of concurrent toxoplasmosis cannot be entirely excluded, and the impact of the infection on the clinical course of disease and outcome cannot be established with certainty.
PA is a syndrome diagnosed by combining an acute onset of neurological signs with characteristic imaging and pathological findings suggestive of hemorrhage or infarction of the pituitary gland (15–19). In human literature, it is commonly characterized by a sudden onset of severe headaches (95%−100%), followed by visual impairment, vomiting, altered levels of consciousness, and ocular palsy. These symptoms originate from a sudden increase in intrasellar pressure, caused by hemorrhage and/or infarction of the pituitary gland (18, 20, 21). Furthermore, hormonal deficiency (i.e., hypopituitarism), is also commonly reported in humans, with studies showing up to 80% of patients presenting with one or more anterior pituitary hormone deficiencies (15, 22). In canine literature, PA is described with signs of behavioral change, visual impairment, ataxia, restlessness, seizures, vestibular dysfunction (head tilt, nystagmus, vestibular ataxia) and gastrointestinal dysfunction (19, 23). In cats, episodes of restlessness, visual deficits, disorientation, and depression have been observed (4–6). The main presenting signs in our 2 clinical cases (cases 1 and 2) were restlessness with wall-hugging behavior, decreased mentation, proprioceptive deficits and hindlimb ataxia, while case 3 only presented with DM, without neurologic abnormalities. Especially the sudden onset of neurological and behavioral changes in these cases raised suspicion of PA, retrospectively. The presence of visual impairment prior to the surgical intervention in our cases is debatable. At initial presentation, case 1 did not show obvious reduction in vision, and case 2 exhibited a mildly delayed pupillary reflex and delayed visual proprioception, although there was no further evidence of blindness in the presentation of this cat. Notably, as no clinical signs of PA were demonstrated, case 3 represents a subclinical form, in which the diagnosis was made only following histopathological examination of the excised pituitary gland.
PA can be identified on advanced diagnostic imaging either on CT or MRI, where MRI is the modality of choice. The underlying pathophysiological process in PA can be ischemic infarction (i.e., with no haemorrhagic component), haemorrhagic infarction, mixed haemorrhagic infarction and clot, or a pure clot (15, 24). This helps to explain why pituitary imaging rarely shows pure infarction or hemorrhage, but rather mixed features. In dogs, characteristic CT features of acute PA include focal hyperdense areas, which can be interpreted as intratumoural hemorrhage, often combined with hypodense infarction components (25). The infarcted region usually shows no abnormalities on non-contrast imaging. Following IV contrast administration, peripheral rim enhancement may also be suggestive of PA (26). This is consistent with findings in feline cases (5, 6).
In addition to detecting the presence or absence of hemorrhage, the MRI appearance of the sellar/suprasellar mass depends on the time of onset (26). Haemorrhagic lesions on T1 and T2 weighted imaging can initially show low signal in the acute phase, while subacute lesions become hyperintense (26). This is also evident in a study on canine PA, where most dogs presented in the acute phase, rendering a hypointense T2W appearance of the pituitary lesion (23). There is also evidence that T2 demonstrates hyperintensity in the hyperacute phase, while hypointensity persists in the subacute phase (1, 22). Among the T2-weighted MRI sequences, Susceptibility-Weighted Angiography (SWAN) is particularly sensitive for the detection of haemorrhagic products. On SWAN, hemorrhage typically appears as a hypointense signal with a so-called blooming artifact, making even minimal amounts of blood products visible (11). Additionally, peripheral rim enhancement after IV gadolinium contrast administration is frequently observed on MRI in cases of PA (1, 23). Apart from modality-specific details, the prevailing opinion is, that imaging evidence of PA is characterized by a pituitary adenoma containing mixed hypo- and hyperintense areas, consistent with intratumoural hemorrhage and/or infarction.
The 3 cases presented in this manuscript demonstrated multiple findings consistent with PA on diagnostic imaging. First, it is important to recognize that although MRI is considered the gold standard for confirming PA, CT has been chosen instead of MRI in some of our cases. The initial diagnostic imaging was performed prior to referral to our clinic and depended on local availability and the preferences of the referring clinician. PA may not yet have been considered in the differential diagnoses at that stage. As the pituitary gland resides outside of the blood–brain barrier, contrast-enhanced CT can identify pituitary enlargement and can still be suggestive of haemorrhagic lesions within the gland. In case 1, as PA was confirmed on histopathology, the presence of intralesional hyperattenuating and hypoattenuating areas on CT support the interpretation that these imaging findings may have been compatible with PA. Similarly, the MRI findings of case 2 (hypointense areas within the mass) indicate compatibility with PA. The strongest evidence was provided by case 3, in which a susceptibility-sensitive MRI sequence revealed findings highly consistent with intralesional hemorrhage prior to THX. Interestingly, this patient remained free of neurological and behavioral abnormalities despite imaging evidence of pituitary hemorrhage.
In addition to the imaging findings compatible with PA, all 3 cats exhibited substantial high P/B ratios compared to those generally reported in cats with hypersomatotropism (HS), the most prevalent pituitary tumor type in this species. While pituitary enlargement is common in cats diagnosed with HS, the P/B ratio in those animals is reported to be 0.58 (9). The P/B ratios of 0.96, 1.25 and 1.12 observed in cases 1, 2, and 3, respectively, therefore reflect a substantial pituitary enlargement. Interestingly, suprasellar extension is a common finding in human and canine PA (19, 23, 27). Given these findings, the rationale for selection of surgical treatment in these cats existed; in cases in which there is a severely enlarged pituitary gland causing clinical signs, either neurological or endocrinological hyperfunction, curative intent treatment in the shape of surgical excision is generally preferred (28).
While the presence of a large pituitary mass was the primary indication for surgery in the 3 cats described in this manuscript, these cases raise interesting considerations regarding the recognition and management of feline PA. Although PA is classically regarded as a clinical syndrome, human studies have shown that up to 25% of pituitary adenomas display necrotic and/or haemorrhagic areas on diagnostic imaging (MRI), whereas clinical signs only occur in 2%−12% of patients with pituitary adenomas (29, 30). This raises the suspicion that also in feline and canine pituitary adenomas, hemorrhage and/or infarction may occur more frequently than is currently appreciated, often without causing overt clinical signs. Although well recognized in human medicine, this has not been previously described in veterinary literature (27). Case 3 appears to represent such an instance: diagnostic imaging showed findings compatible with subacute hemorrhage (Figures 1G, H), in combination with evidence of hemorrhage on histological examination, yet in absence of obvious central neurological signs. As veterinarians we must remain aware that early signs of headache and mild vision impairment are easily missed in companion animals.
The optimal therapeutic approach to PA remains controversial in human medicine. Treatment decisions are primarily based on the severity of clinical signs, in particular neuro-ophthalmic deficits and impaired consciousness (15, 31). Grading systems such as that of Jho and colleagues (27) have been proposed to support the decision-making, in particular whether immediate surgical intervention is warranted rather than elective surgery or conservative management. The rationale for weighing this urgency lies in the time-dependent nature of the outcome. Although pituitary enlargement can be temporary in PA, timely surgical decompression was advocated in the higher grades of the Pituitary Apoplexy Grading System, as these patients tended to undergo surgery earlier, while good overall outcomes were reported across all grades (27).
In current veterinary medicine, treatment choice is similarly influenced by the severity of clinical signs, although the decision has so far largely been between conservative management and euthanasia. Most reported cases, often dogs, are either managed conservatively based on clinical signs and radiological diagnosis, or euthanized and submitted for pathological confirmation when treatment is unsuccessful (19, 23). Similarly, previously reported cases of feline PA have been euthanized at the owners' request (4–6). It is likely that the lack of surgically managed cases reported in cats and dogs, is partially due to the relative lack of access to surgical treatment (28). To date, surgical treatment of PA has been described only once, in a canine patient (32). In our report, surgical therapy has been elected as the treatment of choice based on presence of either neurological complaints (case 1 and 2), or endocrinopathy (case 3), combined with the size of the pituitary found on imaging. Where previous studies have demonstrated a favorable long-term outcome following THX in cats with hormone-producing tumors (9, 33), this report further suggests that similarly favorable outcomes may also be achieved in cats with pituitary tumors complicated by concurrent PA.
Although surgery was preferred in our cases, conservative management, comprising of glucocorticoids and/or anticonvulsant medication combined with hyperosmotic agents, remains a relevant option in selected patients and has proven effective in the previously mentioned case series (19, 23). Importantly, these studies report a favorable short-term outcome, while the underlying cause of PA (i.e., pituitary mass) remains an important factor to be considered when evaluating prognosis and treatment options. The single larger cohort of dogs with PA treated with conservative management or radiation therapy, had a discouraging overall survival to discharge rate of 58% (23). Even when decompression of the mass effect might be considered a disproportionately invasive intervention, the underlying endocrine disease associated with the development of a pituitary mass, such as PDH or HS, may itself be cured by surgical intervention (9, 27, 28). Nevertheless, with the very few reports on treatment of PA in companion animals, the authors find that also conservative therapy could be considered as a possible therapeutical approach for PA.
Radiotherapy has likewise been employed in dogs with PA (19, 23). However, the effects of radiation therapy in the acute setting of PA remain controversial. In human medicine, radiotherapy has been linked to the development of apoplexy, likely due to the vascular wall damage within the tumor, caused by radiation (3, 16, 26). It is not used in the treatment of acute PA, as the effects on decreasing tumor size are slow in onset. Radiotherapy has been described as a useful approach for selected pituitary tumors in dogs, cats and humans alike (28), and has its place in the overall treatment of pituitary disease.
When navigating these treatment options, ranging from urgent surgical decompression to elective surgery, conservative management or radiotherapy, a structural framework for therapy decision-making would be beneficial. The Pituitary Apoplexy Grading System developed by Jho and colleagues could prove a valuable tool in this regard; however, it would need adaptation to the veterinary patient. In the human system, the higher grades (defined by visual impairment) typically reflect the effect of their suprasellar extension. However, the anatomy of cats and dogs differ significantly from that of humans: in these species the optic chiasm is located more rostral to the tuberculum sellae. Consequently, although visual impairment is occasionally observed, more common presentations of PA include subtle to overt changes in behavior indicative of intracranial disease (i.e., head pressing, changes in character, seeking support from walls, fear), as well as changes in ambulation and proprioception (including vestibular signs), and mentation (19, 23, 25). Furthermore, the human Pituitary Apoplexy Grading System is based upon the outcomes of a large cohort of patients (27). In veterinary medicine, the case numbers to validate an equivalent are not yet available. Altogether, with some adaptations and translational knowledge, a Feline Pituitary Apoplexy Grading System could be developed (Figure 4). The proposed system uses the severity of clinical signs as a proxy for the extent of increased intracranial pressure caused by the mass effect of the PA. It also accounts for comorbidities that affect the urgency for intervention: “modifying comorbidities” that necessitate a better stabilization prior to surgery, thus lowering the need for rapid surgical intervention, vs. “amplifying comorbidities” that may suggest that a swift intervention is preferred.
[图：Feline pituitary apoplexy grading system. A proposed grading system for feline pituitary apoplexy was developed based on]
Using this proposed grading system, case 1 would be classified as a grade 3, with the behavioral abnormalities and restlessness interpreted as possible headache, which defines this grade. In this case, there were no amplifiers or modifiers that would affect the clinical judgement, placing it in an intermediate position between urgent surgical intervention and elective surgery or conservative management. Given the extremely large size of the pituitary mass, however, the author's consider elective surgical therapy an appropriate choice. Case 2 would represent grade 4 on this scale, as there was ambulatory compromise; the decreased mentation would moreover count as an amplifier, further favoring rapid surgical intervention. Case 3 would represent a grade 2 patient, as there were no neurological abnormalities. However, given the concurrent PDH, feline fragile skin syndrome and diabetes mellitus arising from the pituitary mass act as amplifiers, shifting the patient upward on the spectrum and favoring rapid surgical intervention.
Visual impairment developed postoperatively in 2 of the 3 cases of this report. In case 1 and 3, bilateral mydriasis and visual impairment were identified following THX, whereas no visual deficits had been detected at presentation. While KCS is a more frequently documented ocular complication following THX, as observed in case 1 and 2, visual impairment is not commonly reported in cats and dogs undergoing this procedure (9, 34, 35). It is conceivable that the more rostral location places the optic chiasm in closer proximity to the surgical field during THX compared to humans, rendering it more vulnerable to iatrogenic injury (36). The absence of both the menace response and pupillary reflexes in case 1, without detectable intraocular abnormalities, could be consistent with injury to the optic nerves or optic chiasm. Case 3 did show lack of pupillary reflexes, combined with presence of both menace response and dazzle reflexes in both eyes and no abnormalities found on fundoscopy. Mydriasis became less pronounced over time and vision partially recovered over time. The most likely explanation would be the same as in case 1; extraocular optic neuritis, likely related to the THX. The initial classification of cortical blindness in case 3 was likely due to concurrent sudden behavioral changes of the cat, and the presence of both menace response and dazzle reflex. Mydriasis was attributed to the opioid administration, however, mydriasis persisted after ceasing opioid therapy. The positive menace reflex could also be caused by airflow and subsequent corneal reflexes and is likely overinterpreted at the time. In both cases, fundoscopy did not show evidence of optic neuritis, but lack of intraocular changes to the optic disc does not exclude extraocular optic neuritis. The optic nerves and optic chiasm reside relatively rostral to the pituitary fossa, however, in large tumors, surgical excision may still evoke local damage as large masses can expand rostrally and thus, extraction necessitates rostral tumor manipulation. The visualization on the rostral border of the pituitary fossa, beyond the tuberculum sellae, is poor, and inadvertent manipulation of structures rostral to the burr hole is possible. Further improvement of intraoperative visualization techniques including endoscopy may prevent iatrogenic trauma and improve outcomes in these cases.
Repeated follow-up imaging at 6- to 12-month intervals was recommended in all 3 cases to identify presence of tumor recurrence. This interval was based on data from previous cohorts of cats with pituitary tumors that underwent THX. A study by Meij et al. (34) reported tumor recurrence in a cat with PDH after 19 months, which was diagnosed based on clinical and biochemical signs of hyperadrenocorticism. Additionally, a median recurrence time of 248 days (range 84–1,232 days) was reported in 5 cats with hypersomatotropism (33). In case 1, the CT imaging performed 3 months postoperatively revealed changes within the hypophyseal fossa that were potentially consistent with a small amount of residual hypophyseal tissue, although these findings were not conclusive. Given the definitive evidence of tumor recurrence on imaging approximately 2 years after surgery, it remains possible that microscopic residual tissue persisted following the initial surgical intervention. The owner of cat 2 declined further imaging. In case 3, intraoperative inspection of the fossa showed no abnormal tissue present, but the direct postoperative CT scan did show a small area of contrast enhancement indicative of possible remnant pituitary tissue. CT scan at 1 year post surgery showed recurrence of a mass in the pituitary fossa, although this time, no recurrence of PDH was evident in the UCCRs and the cat remained without clinical signs. This illustrates the difficult balance between achieving complete tumor resection, while preserving normal hypothalamus tissue, as visualization of the surgical field in this region is inherently limited. Endoscopic inspection, which is now routinely performed following THX at this facility, appears to enhance visualization of the hypophyseal fossa, and may facilitate the identification of residual pituitary tissue, although its use remains an area for future research.
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Conclusion and future perspectives
PA should be considered a differential diagnosis in cats presenting with an acute onset of neurological signs, particularly when there is evidence of an enlarged sellar mass on pituitary imaging. The presented cases demonstrate that THX can offer a positive outcome in cats with PA. For future studies, a more systematic assessment of PA on advanced imaging is warranted to better determine the frequency of hemorrhage and infarction in association with pituitary tumors. Additionally, closer alignment between the surgical, imaging and pathology disciplines will lead to more consistent diagnoses of this syndrome.
Acknowledgments
The authors would like to acknowledge the contribution to the successful course of the cats made in particular by Dr. C. Valtolina (EBVS® Specialist in Emergency and Intensive Care), the ICU team and the internists involved in the establishment of diagnoses of these cases. We also thank Dr. E.A.W.S. Weerts (EBVS® Specialist in Veterinary Pathology) for his involvement in the histopathological evaluation, and Dr. C. Planas Padrós (EBVS® European Specialist in Veterinary Diagnostic Imaging, DipECVDI) for his review of the diagnostic images in preparation of this manuscript.
Funding Statement
The author(s) declared that financial support was not received for this work and/or its publication.
Footnotes
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Data availability statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics statement
Ethical approval was not required for the studies involving animals in accordance with the local legislation and institutional requirements because this is a retrospective case report; standard of care was followed in treatments. Written informed consent was obtained from the owners for the participation of their animals in retrospective studies at the time of hospital admission in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the participants for the publication of this case report.
Author contributions
MvS: Writing – review & editing, Writing – original draft. LvS: Supervision, Writing – review & editing, Data curation. GG: Data curation, Writing – review & editing. BM: Supervision, Data curation, Writing – review & editing.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The handling editor BL declared a past co-authorship with one of the authors BM.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fvets.2026.1779079/full#supplementary-material
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References
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Associated Data
Supplementary Materials
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Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.