伪狂犬病毒脑炎临床观察与脑脊液二代测序鉴定

Clinical experience and next-generation sequencing analysis of encephalitis caused by pseudorabiesvirus

目的通过对病因未明的脑炎患者的临床评估与脑脊液二代测序（NGS）病原体筛查，诊断伪狂犬病毒（PRV）脑炎，描述其临床特征。方法选择2016年12月至2017年12月基于北京协和医院神经科牵头的脑炎多中心临床登记研究，并根据北京脑炎协助组脑炎诊断标准入组病因未明的脑炎病例，进一步进行病因筛查，对疑似感染性脑炎而病因未明者行脑脊液二代测序。结果共收集到4例疑似PRV脑炎病例，均为从事生猪与生猪肉产销的人员。急性起病，表现为迅速进展的重症脑炎，癫痫大发作、意识障碍、呼吸障碍，需要ICU救治，3例呼吸机支持。2例合并双侧视网膜炎，神经影像学提示灰质受累为主的坏死性脑炎，受累部位包括边缘系统、基底节区与中脑，无明显出血改变。脑脊液压力升高，脑脊液白细胞升高（6～64）×10^6/L，脑脊液细胞学为淋巴细胞性炎症。对2例患者进行脑脊液NGS，检测到伪狂犬病毒，未检测到其他病原体，其他临床病原学检测结果阴性。阿昔洛韦、静脉免疫球蛋白与激素治疗部分有效，末次随访4例患者的改良Rankin评分分别为3、5、5和6分。结论伪狂犬病毒可感染人而导致脑炎、视网膜炎。对于病因不明的脑炎病例，如果流行病学、临床表现、脑脊液与影像学符合该病，应尽快进行脑脊液PRV核酸检测，及时诊断和治疗。

Objective To detect potential pathogens including pseudorabies virus in patients with encephalitis of unknown etiology in China and describe novel encephalitie entities. Methods Patients with clinically suspected infectious encephalitis were enrolled in a muhieenter study to identify the pathogens in PUMCH Encephalitis Program. Next-generation sequencing（NGS） of cerebrospinal fluid （CSF） was used in patients with encephalitis of unknown etiology enrolled from 2016 to 2017. The patients diagnosed as PRV encephalitis were studied to describe this novel entity. Results The four patients（3 male, 1 male, 38 -54 years old） had occupational exposure to raw park when working in the production or marketing of pork and at least one got injured during pork-cutting. Two of them were confirmed with NGS of CSF, and anti-PRV antibodies were positive in 3 patients whose serum was available for serological analysis. They all presented with an acute onset of fever, convulsion, loss of consciousness and respiratory failure within 1 to 4 days andrapidly deteriorated even on extensive treatment. All the patients needed ICU admission and 3 needed mechanical ventilation. Two patients also had bilateral retinitis. Neuroimaging revealed symmetric gray matter lesions including limbic system, basal ganglia and midbrain without obvious hemorrhage. Lumbar puncture revealed elevated intracranial pressure and lymphocytic pleoeytosis [ （6 -64）×10^6/L] of CSF. The patients failed to response to the treatment of acyelovir combined with intravenous immunoglobulin and steroids. Modified Rankin Score was 3, 5, 5 and 6 （died） for the 4 patients respectively on last follow- up. Conclusions PRV could be a cause of severe encephalitis. The patients with suspected pseudorabies encephalitis （PRE） need to be tested for PRV DNA timely. Severe encephalitis with bilateral involvement of limbic system, basal ganglion, thalamus and midbrain in patient with occupational exposure indicate this emerging infectious encephalitis.