I read with great interest the article by Garg et al1 on “Encephalopathy in patients with COVID‐19: A review.” The authors performed a review of published reports on coronavirus disease‐2019 (COVID‐19)‐associated encephalitis and encephalopathy. They are to be congratulated for their timely, comprehensive, and insightful paper. Several aspects of cerebrospinal fluid analysis in patients with COVID‐19 having neurological manifestations, however, need to be further discussed.

First, reliable cerebrospinal fluid (CSF) biomarkers to confirm the involvement of the central nervous system (CNS) in COVID‐19 are still lacking. Previous reports, which mainly focused on the detection of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) RNA in CSF samples of patients with COVID‐19 having neurological manifestations using reverse transcriptase‐polymerase chain reaction (RT‐PCR) tests, have reported inconsistent results. The majority of the studies have reported negative findings,2-6 whereas some have successfully detected SARS‐CoV‐2 RNA in CSF.7, 8 These SARS‐CoV‐2 CSF PCR results should be interpreted with caution due to several reasons. The results were mainly based on case reports and case series, which may compromise on generalization. Also, the dynamics of SARS‐CoV‐2 in CSF are not fully understood and hence, no validated CSF assays are currently available. Furthermore, there are concerns about “false negative” SARS‐CoV‐2 PCR results, which have been observed to occur in up to 40% of throat sample tests.9 As such, a negative RT‐PCR may not necessarily mean that SARS‐CoV‐2 is absent in the CSF. High‐quality studies that are adequately powered to address these issues are urgently needed.

Second, whereas lack of identification of SARS‐CoV‐2 RNA in CSF may be indicative of the limitations of the currently available tests, it may also mean that the neurological manifestations could be mediated indirectly, through immune‐related mechanisms. It is noteworthy that most of the above studies did not provide data on anti‐SARS‐CoV‐2 antibodies within the CSF. Recently, several studies have successfully demonstrated the presence of these antibodies in the CSF of patients with COVID‐19. Andriuta et al10 detected antibodies against S1 protein, S2 protein, and nucleoprotein of the SARS‐CoV‐2 in the CSF of two patients who presented with encephalopathy. Similarly, Benameur et al11 demonstrated the presence of IgM for SARS‐CoV‐2 S1 and envelop proteins in three patients with COVID‐19 having encephalitis. Interestingly, PCR analysis for viral RNA in the CSF of the patients in both studies yielded negative results. This observation is consistent with CSF findings from other viral encephalities such as the Japanese encephalitis12 and dengue fever,13, 14 where antibodies against these viruses were isolated in CSF samples in the absence of viral RNA. These preliminary findings suggest that anti‐SARS‐CoV‐2 antibodies in CSF may be better indicators than viral RNA for CNS involvement in patients with COVID‐19, and should be subject to further investigations to determine validated assays and their specificity and sensitivities.

我饶有兴趣地阅读了 Garg 等人1发表的关于“COVID-19 患者脑病：综述”的文章。作者对已发表的有关 2019 年冠状病毒病 (COVID-19) 相关脑炎和脑病的报告进行了综述。他们的论文及时、全面、富有洞察力，值得祝贺。然而，有神经系统表现的 COVID-19 患者脑脊液分析的几个方面还需要进一步讨论。

首先，仍然缺乏可靠的脑脊液（CSF）生物标志物来确认中枢神经系统（CNS）参与COVID-19。之前的报告主要集中于使用逆转录酶聚合酶链反应（RT-PCR）检测在具有神经系统表现的COVID-19患者的脑脊液样本中检测严重急性呼吸综合征冠状病毒2（SARS-CoV-2）RNA，报告了不一致的结果。大多数研究报告了阴性结果，2-6，而一些研究成功地在脑脊液中检测到了 SARS-CoV-2 RNA。7, 8由于多种原因，应谨慎解释这些 SARS-CoV-2 CSF PCR 结果。结果主要基于病例报告和病例系列，这可能会影响概括性。此外，SARS-CoV-2 在 CSF 中的动态尚未完全了解，因此，目前尚无经过验证的 CSF 检测方法。此外，人们还担心 SARS-CoV-2 PCR 结果出现“假阴性”，据观察，高达 40% 的咽喉样本检测中都会出现这种情况。9因此，RT-PCR 阴性不一定意味着脑脊液中不存在 SARS-CoV-2。迫切需要有足够动力来解决这些问题的高质量研究。

其次，虽然脑脊液中缺乏 SARS-CoV-2 RNA 的鉴定可能表明当前可用测试的局限性，但这也可能意味着神经系统表现可以通过免疫相关机制间接介导。值得注意的是，上述大多数研究并未提供脑脊液内抗 SARS-CoV-2 抗体的数据。最近，多项研究成功证明了 COVID-19 患者的脑脊液中存在这些抗体。Andriuta 等人10在两名脑病患者的脑脊液中检测到了针对 SARS-CoV-2 S1 蛋白、S2 蛋白和核蛋白的抗体。同样，Benameur 等人11证明，三名患有脑炎的 COVID-19 患者体内存在 SARS-CoV-2 S1 的 IgM 和包膜蛋白。有趣的是，两项研究中患者脑脊液中病毒 RNA 的 PCR 分析均得出阴性结果。这一观察结果与其他病毒性脑病（例如日本脑炎12和登革热13, 14 ）的脑脊液发现结果一致，其中在没有病毒 RNA 的情况下，在脑脊液样本中分离出了针对这些病毒的抗体。这些初步研究结果表明，CSF 中的抗 SARS-CoV-2 抗体可能是比病毒 RNA 更好的 COVID-19 患者中枢神经系统受累指标，并且应接受进一步研究以确定经过验证的检测方法及其特异性和敏感性。