Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients.
Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients.
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DOI：
10.1186/s12974-021-02339-0
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发表时间：
2022-01-20
影响因子：
9.3
通讯作者：
in cooperation with the German Society for Cerebrospinal Fluid Diagnostics and Clinical Neurochemistry
中科院分区：
文献类型：
--
作者：
Jarius S;Pache F;Körtvelyessy P;Jelčić I;Stettner M;Franciotta D;Keller E;Neumann B;Ringelstein M;Senel M;Regeniter A;Kalantzis R;Willms JF;Berthele A;Busch M;Capobianco M;Eisele A;Reichen I;Dersch R;Rauer S;Sandner K;Ayzenberg I;Gross CC;Hegen H;Khalil M;Kleiter I;Lenhard T;Haas J;Aktas O;Angstwurm K;Kleinschnitz C;Lewerenz J;Tumani H;Paul F;Stangel M;Ruprecht K;Wildemann B;in cooperation with the German Society for Cerebrospinal Fluid Diagnostics and Clinical Neurochemistry
到目前为止，尚缺乏来自大规模多中心研究的关于COVID-19患者脑脊液（CSF）特征和神经系统受累的综合数据。系统分析COVID-19的CSF特征。回顾性分析了17所欧洲大学中心127例经PCR证实的COVID-19和神经系统症状患者的150次腰椎穿刺最常见的病理结果是血-脑脊液屏障（BCB）功能障碍（中位数QAlb 11.4 [6.72-50.8]），其存在于来自无预先/共存CNS疾病的患者（组I）的58/116（50%）样本中。QAlb在发病后> 14天（47.6%）甚至> 30天（55.6%）仍持续升高。54/118（45.8%）份样本的CSF总蛋白升高（中位数65.35 mg/dl [45.3-240.4]），与QAlb强相关。14/128（11%）份样本的CSF白色细胞计数（WCC）增加（主要是淋巴单核细胞;中位数10个细胞/μl，仅4例> 100）。43/115（37.4%）例样本中发现白蛋白细胞学分离（ACD）。26/109例患者的CSF L-乳酸升高（24%;中位数3.04 mmol/l [2.2-4]）。CSF-IgG在50/100（50%）中升高，但为外周源性，因为几乎所有病例的QIgG均正常，QIgA和QIgM也正常。在58/103例（56%）样本中，存在与全身炎症相容的4条寡克隆带（OCB），而仅在2/103例（1.9%）样本中发现CSF限制性OCB。SARS-CoV-2-CSF-PCR检测结果为阴性。35%的常规CSF结果正常。CSF（通常与BCB功能障碍相关）和血清中的细胞因子水平经常升高，部分在高水平下保持阳性数周/数月（939次检测）。值得注意的是，在2/19例（10.5%）患者中发现SARS-CoV-2-IgG抗体指数（AI）阳性，这与两例患者中异常高的WCC相关，其中一例患者的白细胞介素-6（IL-6）指数显著升高（另一例未检测）。抗神经元/抗神经胶质自身抗体在CSF和血清中大多不存在（1509次检测）。在既往/共存CNS疾病患者的样本中（第II组[N = 19];包括多发性硬化、JC病毒相关免疫重建炎性综合征、HSV/VZV脑炎/脑膜炎、CNS淋巴瘤、抗Yo综合征、蛛网膜下腔出血），CSF结果主要代表相应疾病。COVID-19伴神经系统症状的CSF特征主要表现为在无鞘内炎症的情况下BCB破坏，与脑脊液内皮病相符。持续的BCB功能障碍和细胞因子水平升高可能导致急性症状和“长期COVID”。SARS-CoV-2直接感染中枢神经系统，即使发生，似乎也很罕见。建议广泛的鉴别诊断考虑，以避免将可治疗的共存神经系统疾病误解为COVID-19的并发症。在线版本包含补充材料，可通过10.1186/s12974-021-02339-0获得。
Comprehensive data on the cerebrospinal fluid (CSF) profile in patients with COVID-19 and neurological involvement from large-scale multicenter studies are missing so far. To analyze systematically the CSF profile in COVID-19. Retrospective analysis of 150 lumbar punctures in 127 patients with PCR-proven COVID-19 and neurological symptoms seen at 17 European university centers The most frequent pathological finding was blood-CSF barrier (BCB) dysfunction (median QAlb 11.4 [6.72–50.8]), which was present in 58/116 (50%) samples from patients without pre-/coexisting CNS diseases (group I). QAlb remained elevated > 14d (47.6%) and even > 30d (55.6%) after neurological onset. CSF total protein was elevated in 54/118 (45.8%) samples (median 65.35 mg/dl [45.3–240.4]) and strongly correlated with QAlb. The CSF white cell count (WCC) was increased in 14/128 (11%) samples (mostly lympho-monocytic; median 10 cells/µl, > 100 in only 4). An albuminocytological dissociation (ACD) was found in 43/115 (37.4%) samples. CSF l-lactate was increased in 26/109 (24%; median 3.04 mmol/l [2.2–4]). CSF-IgG was elevated in 50/100 (50%), but was of peripheral origin, since QIgG was normal in almost all cases, as were QIgA and QIgM. In 58/103 samples (56%) pattern 4 oligoclonal bands (OCB) compatible with systemic inflammation were present, while CSF-restricted OCB were found in only 2/103 (1.9%). SARS-CoV-2-CSF-PCR was negative in 76/76 samples. Routine CSF findings were normal in 35%. Cytokine levels were frequently elevated in the CSF (often associated with BCB dysfunction) and serum, partly remaining positive at high levels for weeks/months (939 tests). Of note, a positive SARS-CoV-2-IgG-antibody index (AI) was found in 2/19 (10.5%) patients which was associated with unusually high WCC in both of them and a strongly increased interleukin-6 (IL-6) index in one (not tested in the other). Anti-neuronal/anti-glial autoantibodies were mostly absent in the CSF and serum (1509 tests). In samples from patients with pre-/coexisting CNS disorders (group II [N = 19]; including multiple sclerosis, JC-virus-associated immune reconstitution inflammatory syndrome, HSV/VZV encephalitis/meningitis, CNS lymphoma, anti-Yo syndrome, subarachnoid hemorrhage), CSF findings were mostly representative of the respective disease. The CSF profile in COVID-19 with neurological symptoms is mainly characterized by BCB disruption in the absence of intrathecal inflammation, compatible with cerebrospinal endotheliopathy. Persistent BCB dysfunction and elevated cytokine levels may contribute to both acute symptoms and ‘long COVID’. Direct infection of the CNS with SARS-CoV-2, if occurring at all, seems to be rare. Broad differential diagnostic considerations are recommended to avoid misinterpretation of treatable coexisting neurological disorders as complications of COVID-19. The online version contains supplementary material available at 10.1186/s12974-021-02339-0.
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