犬臨床和病理診斷肉芽腫性腦膜腦脊髓炎之回溯性調查與中樞神經引流淋巴結免疫染色表現

Canine antemortem and postmortem diagnosed granulomatous meningoencephalomyelitis: a retrospective study and immunohistochemical findings of CNS draining lymph nodes

吳芝菁(Chih-Ching Wu)

指導教授 ： 張雅珮 ； 蘇璧伶

國立臺灣大學/獸醫專業學院/臨床動物醫學研究所/碩士(2016年)

https://doi.org/10.6342/NTU201610128

摘要

犬肉芽腫性腦膜腦脊髓炎（granulomatous meningoencephalomyelitis，GME）是犬中樞神經一種常見的發炎性疾病。GME好發於壯年至中年的玩具與小型犬種，GME特徵病理變化為中樞神經白質為主，發炎細胞以血管為中心同心圓式聚集，病理變化可以彌散發生在灰白質內，也可能形成明顯的肉芽腫團塊。目前GME的致病機轉仍不明，但懷疑是一種與T型淋巴球為主的遲發過敏反應相關的自體免疫疾病。由於GME需經過組織病理學檢查確診，因此多為死後診斷，或需經腦採樣取得檢體，後者目前臨床使用的普遍性不高，實用性較低，因此在生前診斷GME仰賴病患符合幾項特徵：好發族群、腦脊髓液與進階神經影像變化，並排除其他感染性疾病，皆符合者稱為生前診斷GME患者。
GME若不經積極治療預後不佳，且病程可能進展快速，文獻指出約有15%患犬發病後尚未接受治療即死亡。為了瞭解GME的危險因子，並比較臺大附設動物醫院常用的以類固醇為基礎的3種免疫抑制療法（cytosine arabinoside、mycophenolate mofetil、cyclsporin)，本研究收集臺大附設動物醫院自2007年至2014年經生前或死後確診的GME病患資料共77隻，分析其影響生存時間的危險因子；因GME進入慢性病程後需長期用藥，因此藥物累積性副作用、飼主對長期用藥的偏好與經濟考量、病患對藥物適應程度等多種因素都可能影響藥物選擇與使用，為減少這些因素的影響，故採取無進展生存期（progression free survival，PFS）作為評估3種免疫治療的替代終點。危險因子分析結果發現，延後治療（神經症狀出現21到42天）、就診時神經症狀包含癲癇、無法行走、有叢集或重積癲癇的病史以及治療期間發生脊椎旁壓痛等，皆為生存時間的顯著危險因子。當用多因子統計法同時考量其他影響PFS的因素後，cyclosporin在延長PFS上較另外兩種免疫抑制劑表現佳。在早期復發的病患中，若能使用多種免疫抑制療法，則可顯著增長其存活時間。
然而在積極治療下，仍有36%病患存活期無法超過一年，10%病患在入院一個月內死亡。為了從不同的角度研究此疾病，本研究第二部分對引流中樞神經的深頸淋巴結進行前導研究，以組織化學染色方式分析GME患犬深頸淋巴結的淋巴球形態與分佈，結果發現GME患犬淋巴結出現Ｔ淋巴球增多與Ｂ淋巴球大量減少，懷疑此變化與患犬中樞神經發炎反應有關，值得更進一步研究周邊免疫系統在調控或維持中樞神經發炎中是否扮演部分角色。

關鍵字

犬肉芽腫性腦膜腦脊髓炎 ； 中樞神經引流淋巴結 ； 免疫抑制藥物 ； 危險因子

並列摘要

Canine granulomatous meningoencephalomyelitis (GME) is a common canine inflammatory central nervous system (CNS) disease. It was yet unknown the etiology of GME and the theory suggesting its association with the T-cell delayed-type hypersensitivity is generally accepted.
If left untreated, the prognosis of GME is poor. In order to identify the risk factors and to evaluate treatment efficacy between 3 different adjunctive immunosuppressants (cytosine arabinoside, mycophenolate mofetil, and cyclosporin) on canine antemortem or postmortem diagnosed GME, a retrospective study reviewing medical records of canine GME patients in National Taiwan University Veterinary Hospital between January 2008 and December 2014 was performed. A total of 77 dogs were included. Since the clinical conditions became more diverted with time under various confounding factors, progression free survival (PFS) was used as a surrogate endpoint instead of overall survival time (OST) for treatment efficacy comparison. Risk factors of OST and PFS were calculated separately. Delayed admission after the onset of neurologic signs (21-42 days), seizure, mentation change at presentation, non-ambulation, history of status epilepticus or cluster seizure, latent onset of spinal pain had significant influence on overall survival time (OST). With other significant risk factors of PFS calculated in a multivariate model, cyclsporin had the best efficacy among these 3 immunosuppressants. Multiple immunosuppressive therapy significantly increased OST in patients experiencing early relapses.
Despite deploying collaborative immunosuppressive therapy, 36% of patients failed to achieve 1-year-survival and 10% died within 1 month. In hopes of approaching this disease from another angle, a primitive study on the CNS draining lymph nodes (LN) was undertaken. Immunohistochemical labeling reveals that those LNs had a marked expanded T-cell colony and diminished B-cell compartment, implicating a connection between the CNS and peripheral immune organs might exist in GME cases.

並列關鍵字

canine granulomatous meningoencephalomyelitis ； CNS draining lymph node ； cyclosporin ； cytosine arabinoside ； mycophenolate mofetil ； risk factor

參考文獻

1. Barnoon I, Shamir M, Aroch I, Bdolah‐Abram T, Srugo I, Konstantin L, et al. Retrospective evaluation of combined mycophenolate mofetil and prednisone treatment for meningoencephalomyelitis of unknown etiology in dogs: 25 cases (2005–2011). J Vet Emerg Crit Car. 2016;26(1):116-124.

2. Lowrie M, Smith PM, Garosi L. Meningoencephalitis of unknown origin: investigation of prognostic factors and outcome using a standard treatment protocol. Vet Rec. 2013;172(20):527.

3. Tipold A. Diagnosis of Inflammatory and Infectious Diseases of the Central Nervous System in Dogs: A Retrospective Study. J Vet Intern Med. 1995;9(5):304–314.

4. Munana KR, Luttgen PJ. Prognostic factors for dogs with granulomatous meningoencephalomyelitis: 42 cases (1982-1996). J Am Vet Med Assoc. 1998 ;212(12):1902–1906.

5. Braund KG. Granulomatous meningoencephalomyelitis. J Am Vet Med Assoc. 1985;186(2):138–141.