key: cord-0840767-djjssotu
authors: Huo, Liang; Xu, Kai-Li; Wang, Hua
title: Clinical features of SARS-CoV-2-associated encephalitis and meningitis amid COVID-19 pandemic
date: 2021-02-16
journal: World J Clin Cases
DOI: 10.12998/wjcc.v9.i5.1058
sha: 6376047623bd6411c813b1a13285cd36e179a837
doc_id: 840767
cord_uid: djjssotu

BACKGROUND: Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic, numerous studies have been published on SARS-CoV-2-related encephalitis/meningitis, but it has not been established if there are specific clinical characteristics of encephalitis/meningitis associated with SARS-CoV-2 infection. AIM: To identify the specific clinical features of cases of encephalitis/meningitis associated with SARS-CoV-2 infection in the context of this virus infection pandemic and investigate their relationship with SARS-CoV-2 infection. METHODS: We searched PubMed, and included single case reports and case series with full text in English, reporting original data of coronavirus disease-19 (COVID-19) patients with encephalitis/meningitis and a confirmed recent SARS-CoV-2 infection. Clinical data were extracted. RESULTS: We identified 22 articles (18 single case reports and 4 case series) reporting on a total of 32 encephalitis/meningitis patients with confirmed SARS-CoV-2 infection. SARS-CoV-2 infection was confirmed through reverse transcriptase-polymerase-chain-reaction (RT-PCR) in 96.88% of cases. A total of 22 (68.75%) patients had symptoms of SARS-CoV-2 infection in about 1 wk (7.91 d) preceding the onset of neurologic symptoms. The most common neurological symptoms were consciousness disturbance (59.38%), seizure (21.88%), delirium (18.75%), and headache (18.75%). Four cases were confirmed by positive RT-PCR results in cerebrospinal fluid (CSF), one was confirmed by positive RT-PCR results in postoperative brain tissue, and one by the presence of SARS-CoV-2 antibodies in CSF. The mainly damaged targets identified by neuroimaging included the temporal lobe (15.63%), white matter (12.5%), frontal lobe (9.38%), corpus callosum (9.38%), and cervical spinal cord (9.38%). Eighty percent of patients had electroencephalograms that showed a diffuse slow wave. Twenty-eight (87.5%) patients were administered with specific treatment. The majority (65.63%) of patients improved following systemic therapy. CONCLUSION: Encephalitis/meningitis is the common neurological complication in patients with COVID-19. The appropriate use of definitions and exclusion of potential similar diseases are important to reduce over-diagnosis of SARS-CoV-2 associated encephalitis or meningitis.

Coronavirus disease-19 is an illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In December 2019, the first coronavirus outbreak was detected in China, which quickly spread around the world and became a global health emergency [1] . As of November 4, 2020, there were over 47690000 confirmed COVID-19 cases and 1210000 reported deaths in 216 countries worldwide, according to the World Health Organization (WHO) report.

The Centers for Disease Control has termed that many cases feature multisystem inflammatory syndrome in the setting of SARS-CoV-2 positive diagnostic testing [2] . SARS-CoV-2 may cause severe neurological complications, such as encephalopathy, encephalitis, stroke, acute disseminated encephalomyelitis, Guillain Barré syndrome, and skeletal muscle involvement [3] . Up to 85% of patients with SARS-CoV-2 have minor neurological symptoms [4] . Up to 20% of patients with SARS-CoV-2 require admission to the intensive care unit (ICU) because of neurological problems, and these patients have a higher mortality [5] . Neurological symptoms of SARS-CoV-2 include headache, decreased responsiveness, anosmia, myalgia, ageusia, hypogeusia, or dysgeusia [6, 7] .

Encephalitis refers to acute, diffuse, inflammatory lesions in the brain parenchyma caused by pathogens, including neuronal damage and nerve tissue lesions. The common symptoms of encephalitis include headache, fever, vomiting, convulsions, focal neurological deficits, and consciousness disorders [8] . Meningitis is an infection of

We identified 22 articles that were published between January 1, 2020 and September 13, including data from 30 isolated cases of confirmed COVID-19 patients complicated with encephalitis/meningitis. Tables 1 and 2 summarize the detailed demographic and clinical characteristics of patients with SARS-CoV-2-associated encephalitis/ meningitis [2, 9, .

Of the 32 individual patients with SARS-CoV-2-associated encephalitis or meningitis, 20 (62.5%) were male, and 12 (37.5%) were female, with a male-to-female ratio of 1.67:1. Their median age was 45.37 years (age range, 8-75 years). A total of 31 (96.88%) definite cases of SARS-CoV-2 infection were those confirmed by positive RT-PCR results, and one (11.4%) case was confirmed by the presence of SARS-CoV-2 antibodies. The time between reported viral syndrome and confirmed COVID-19 was 6 d (range, 2-15 d). A total of 22 (68.75%) patients had symptoms of SARS-CoV-2 infection in about 1 wk (7.91 d) preceding the onset of neurological symptoms ( Table 2) . Fever (n = 16, 55.17%), cough (n = 13, 44.83%), and dyspnea (n = 11, 37.93%) were the most frequently documented initial symptoms of SARS-CoV-2 infection, followed by diarrhea (n = 4, 13.79%). Median time between reported viral syndrome and onset of neurological symptoms was 7.91 d (range, 1-21 d). Consciousness disturbance (n = 19, 59.38%), seizure (n = 7, 21.88%), delirium (n = 6, 18.75%), and headache (n = 6, 18.75%) were the most frequently documented neurological symptoms of SARS-CoV-2-associated encephalitis/meningitis, followed by altered mental status (n = 3, 9.38%). A total of four (12.5%) definite cases of SARS-CoV-2associated encephalitis/meningitis were those confirmed by positive RT-PCR results in CSF, one (3.13%) was confirmed by positive RT-PCR results in postoperative brain tissue, and one (3.13%) was confirmed by the presence of SARS-CoV-2 antibodies in CSF.

The clinical and laboratory features of the patients with the SARS-CoV-2-associated encephalitis/meningitis are summarized in Tables 3 and 4 [2, 9, [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] 33, [37] [38] . Nineteen February 16, 2021 Volume 9 Issue 5 .38%), white matter (n = 3, 12.5%), cervical spinal cord (n = 3, 12.5%), thalami (n = 2, 9.38%), and cortex (n = 2, 6.25%).

In this group of SARS-CoV-2-associated encephalitis/meningitis patients, only 22 had chest radiogram performed, and of these, 81.82% (18/22) had positive findings. Surprisingly, 18.18% (4/22) of patients' chest radiograms were negative. Twenty-one (65.63%) patients underwent blood test analysis. Six (28.57%) patients had a low/normal white blood cell (WBC) count, ten (47.62%) had a high WBC count, four (19.05%) had lymphopenia, 14 (66.67%) had high C-reactive protein (CRP), ten (57.14%) had high D-dimer, and eight (38.1%) had high ferritin. Thirty-one (96.88%) patients underwent CSF analysis. Thirteen (13/22, 59 .09%) patients with CSF data had an increased protein level, nine (9/23, 39.13%) had an increased WBC level, and two (2/5, 40%) had increased intracranial pressure. One patient had a positive anti-NMDA antibody in CSF (Tables 3 and 4 ).

In this group of SARS-CoV-2-associated encephalitis/meningitis patients, 31 (96.88%) had neuroimaging performed, and of these 61.29% (18/31) had abnormal findings of brain damage. Approximately 38.71% (11/31) of patients had no significant findings. Ten (31.25%) patients received EEG to assess unexplained consciousness disturbance, myoclonus, seizure, headache, altered mental status, dysarthria, and responsiveness. Among these ten patients, eight (80%) had EEGs that showed a diffuse slow wave, and two (20%) had EEGs that showed a focal epileptic wave. These EEG findings suggest that CNS injury may be related to SARS-CoV-2 infection in these patients.

Twenty-eight (87.5%) patients were administered with specific treatment, of whom 22 (78.57%) received antibiotics, 14 (50%) received antiretroviral drugs, seven (25%) received corticoids, six (21.43%) received plasmapheresis treatment, six (21.43%) received intravenous immunoglobulin (IVIg), six (21.43%) received anticonvulsant medications, and one each received surgery, interleukin-1 receptor antagonist, and traditional Chinese medicine. Twenty-nine (90.63%) of patients had recorded outcomes; the prognosis was good in 21 (65.63%) patients and poor in five (15.64%), and three (9.38%) patients died (Tables 1 and 4 ).

SARS-CoV-2 involves multiple organs including the central and peripheral nervous system [15] . In a series of studies in Wuhan, 78 of 214 COVID-19 patients, recruited over 4 wk, developed neurological manifestations. These patients tended to be more severely affected, older, and with more complications, and for some, the neurological symptom was the first presentation of COVID-19 [32] . The widespread effects of COVID-19 include neurological disorders, but there have been no detailed clinical reports of their nature to date [33, 34] . Neurological complications caused by SARS-CoV-2 are similar to those caused by other coronaviruses, especially severe acute respiratory syndrome (SARS) in 2003 and Middle East acute respiratory syndrome in 2012. Cases described in those reports include encephalopathy, encephalitis, stroke, hemorrhage, acute disseminated encephalomyelitis, and Guillain-Barré syndrome [35, 36] . About 80% of COVID-19 patients have no or only mild symptoms, especially in children and young adults. Up to 20% patients with SARS-CoV-2 infection will develop some degrees of severe symptoms [15] . Severe patients were more likely to have neurological complications such as encephalitis, meningitis, stroke, and encephalopathy than nonsevere patients [10] . Most patients with SARS-CoV-2 infection were severe or critically ill, and they required ICU treatment and mechanical ventilation. Lung abnormalities were found in almost all patients with SARS-CoV-2-associated encephalitis [1] . Therefore, early diagnosis of viral encephalitis is essential to improve the prognosis of COVID-19 patients.

In this study, we systematically reviewed the clinical data of SARS-CoV-2associated encephalitis/meningitis that were identified in the context of the COVID-19 global pandemic. To our knowledge, this is the first largest comprehensive retrospective review of any published studies, including case or case series, that have been conducted to assess the role of SARS-CoV-2 infection in patients diagnosed with encephalitis/meningitis during the SARS-CoV-2 outbreak. We systematically described the epidemiological, clinical, radiology, laboratory, therapeutic, and prognostic outcomes. This latest review focuses on clinical characteristics that may help clinicians identify potential patients early and begin timely and appropriate February 16, 2021 Volume 9 Issue 5 treatment to improve the end result. Encephalitis/meningitis is the neurological complication in patients with SARS-CoV-2 infection [7] . During the ongoing pneumonia epidemic, a few isolated case (patients 4, 12, and 22) reports of SARS-CoV-2 associated encephalitis/meningitis, has been detected the SARS-CoV-2 in CSF [17, [37] [38] [39] . The medical team of Beijing Ditan Hospital confirmed the presence of SARS-CoV-2 in the CSF of COVID-19 patients through genome sequencing, thus clinically confirming SARS-CoV-2 viral encephalitis [19] . This provides a solid foundation for coronavirus encephalitis. Transcribrial spread of SARS-CoV-2 to the brain is also supported by the fact that hyposmia/anosmia is one of the earliest symptoms with which patients usually present [6] . Anosmia and abnormal brain function can help distinguish it from other encephalopathy [9] .

Currently, most of the patients with SARS-CoV-2 infection and neurological complications are elderly people, and most of them are more than 50 years old. This February 16, 2021 Volume 9 Issue 5 age group is more likely to have complications and develop into severe disease [40, 41] . In our review, however, COVID-19 patients with encephalitis or meningitis can be found in all age groups, and the main age group is over 30 years old (68.75%). The incidence of SARS-CoV-2-associated encephalitis or meningitis is relatively low in children and adolescents (31.25%), which may be related to the relatively mild illness of COVID-19 in children and adolescents. The cases were determined as SARS-CoV-2-associated encephalitis or meningitis according to WHO criteria (SARS-CoV-2 RNA PCR positive results from nasopharyngeal swab, CSF, or pathological specimen) [42] . Encephalitis is an infection or inflammation that involves the brain and surrounding tissues. Meningitis is an infection or inflammation that affects the meninges and spinal cord [43] . SARS-CoV-2-associated encephalitis/meningitis is always preceded by commoner clinical features about 1 wk ago (7.91 d, range 1-21 d), like fever (55.17%), cough (44.83%), dyspnea (37.93%), and diarrhea (13.79%). Most COVID-19 patients who develop encephalitis/meningitis complications are referred to ICU for hospitalization [1] . Symptoms of viral meningitis typically include fever, neck pain, photophobia, and/or photophobia. Symptoms of viral encephalitis may include abnormal brain function (altered mental state, personality change, and behavioral or verbal abnormalities), movement disorders, and focal neurological signs, like hemiplegia, facioplegia, or abnormal sensation. Seizures may occur in both viral meningitis and encephalitis [12] . Like other viruses, the main clinical symptoms of SARS-CoV-2-associated encephalitis/meningitis are consciousness disturbance (59.38%), seizure (21.88%), delirium (18.75%), and headache (18.75%). Laboratory indicators of COVID-19 showed lymphocytosis, elevated D-dimer, and altered ground glass opacity on chest imaging [41] . Among inflammatory markers in patients with SARS-CoV-2 associated encephalitis/meningitis, high WBC count (47.62%), high CRP (66.67%) and D-dimer (57.14%), and raised ferritin (38.1%) were reported in many cases.

To date, virus-induced immune response leading to inflammatory damage of the CNS and direct invasion are the two main pathophysiological mechanisms of SARS-CoV-2-associated encephalitis [43, 44] . SARS-CoV-2 enters cells by binding to ACE-2 receptors. The ACE-2 receptor is expressed not only in the lungs but also in the CNS [45, 46] . The combination of SARS-CoV-2 and ACE2 receptor may lead to increased secretion of inflammatory factors such as TNF-alpha, IL-1, and IL-6, which may be the cause of neuropsychiatric symptoms [47] . In the absence of evidence of direct viral invasion, SARS-CoV-2-associated encephalitis may be associated with immunemediated inflammatory mechanisms (patient 3) [15] . Although the human respiratory system is the target organ of human coronavirus, SARS-CoV-2 also has the ability to directly invade the nervous system [48] . It has been demonstrated in rodent models that SARS-CoV-2 invades the CNS and causes neuronal death [49] . Based on the known neurotropism of previous SARS-CoV strains, SARS-CoV-2 also can spread to the CNS directly, which could access the CNS via olfactory pathways or the bloodstream, causing meningitis and encephalitis [50, 51] .

By definition, SARS-CoV-2-associated encephalitis/meningitis is an inflammatory process, and supporting evidence includes the presence of COVID-19 patients with CSF pleocytosis and elevated protein [38] . Definitive evidence about direct neuroinvasiveness of SARS-CoV-2 would include SARS-CoV-2 RNA PCR positive tests in CSF, SARS-CoV-2-specific antibodies positive tests in CSF, or SARS-CoV-2 RNA or antigen positive tests in brain tissue obtained at autopsy or biopsy [52] . Although more and more cases of SARS-associated encephalitis have been reported, few (25%) actually meet the strict criteria for direct SARS-CoV-2-associated encephalitis. In the majority of reported patients with COVID-19-associated encephalopathy, CSF was reported as normal (Table 1) . Thus, detailed nervous system physical examination, auxiliary examination, and positive rate of SARS-CoV-2 detection in CSF are very important to provide direct neurotropic evidence of SARS-CoV-2 [53] .

In SARS-CoV-2-associated encephalitis, infection or inflammation can involve any part of the brain, especially the temporal lobe (15.63%), white matter (12.5%), frontal lobe (9.38%), and corpus callosum (9.38%). Neuroimaging abnormalities, in SARS-CoV-2-associated encephalitis, usually present with high T2/FLAIR signal hyperintensity in the subcortical white matter or other parts of brain injury. There are also many COVID-19 patients (38.71%) who do not have significant neuroimaging changes in encephalitis [54, 55] .

In the majority of patients (8/10, 80%) with SARS-CoV-2-associated encephalitis, the EEG manifestation was diffuse slow waves, and some patients present with a focal epileptic wave or generalized delta activity. Slow speed and theta activity in EEGs of COVID-19 patients are not necessarily direct evidence of encephalitis and may be related to depressants, drowsiness, muzziness, hypoxia, and other CNS depressive February 16, 2021 Volume 9 Issue 5 entities [56] . However, it is important to note that when EEGs show monomorphic biphasic high amplitude delta waves associated with occasional myoclonic muscular activity, this may suggest that brain damage is associated with the direct effect of COVID-19 itself [57] . Patients with encephalitis generally need ICU care and occasionally mechanical ventilation. More than 50% of patients with SARS-CoV-2-associated encephalitis/meningitis were treated with antibiotics and antiviral drugs (especially hydroxychloroquine, 42.86%). Some patients were also treated with IVIg and corticoids. Anticonvulsant medications were used in the patients with seizure. Dogan et al [26] reported plasma exchange in a series of six patients with SARS-CoV-2associated autoimmune meningoencephalitis.

In general, the presence of neurological disease in COVID-19 patients is associated with higher mortality, disturbance of consciousness, refractory epilepsy, and severe physical disability. However, we reviewed published case reports and found that most COVID-19 patients with encephalitis or meningitis (21/32, 65.63%) improved after systematic treatment. Three patients died and other patients remained in ICU.

In summary, given the high neurotropism potential of SARS-CoV-2, the lack of reports of COVID-19 patients complicated with encephalitis or meningitis is surprising [58] . Encephalitis/meningoencephalitis may cause direct damage to the brainstem respiratory center, which may be one of the reasons for the extremely high fatality rate in patients with COVID-19. Detailed biopsy or autopsy neuropathology studies should answer this question [59] . From the perspective of infectious diseases of the CNS, the cases of SARS-CoV-2-associated encephalitis that were reported lack direct evidence of SARS invading the nervous system, while the cases of COVID-19 patients who were tested for CSF while excluding other potential diagnoses were only accidental reports. Therefore, we should conduct appropriate investigations to exclude other identified brain infections and parainfluenza before attributing a condition to SARS CoV-2 [60] . The appropriate use of definitions and exclusion of potential similar diseases are important to reduce over-diagnosis of SARS-CoV-2-associated encephalitis or meningitis.

Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has quickly spread around the world and become a global health emergency. There were over 47690000 confirmed coronavirus disease-19 (COVID-19) cases and 1210000 reported deaths in 216 countries worldwide.

SARS-CoV-2 may cause severe neurological complications, such as encephalopathy and encephalitis. However, it has not been established if there are specific clinical characteristics of encephalitis/meningitis after SARS-CoV-2.

The objective of this study was to identify specific clinical features of cases of encephalitis/meningitis associated with SARS-CoV-2 infection in the context of this virus pandemic and investigate their relationship with SARS-CoV-2 infection.

We conducted a search of the medical literature using MEDLINE (accessed from PubMed) and Google Scholar from December 1, 2019 to September 13, 2020 through terms "COVID-19 and encephalitis, meningitis" and "SARS-CoV-2 and encephalitis, meningitis". Then we analyzed clinical features of COVID-19 patients complicated with encephalitis/meningitis in these articles.

We identified 22 articles that included a total of 32 encephalitis/meningitis patients February 16, 2021 Volume 9 Issue 5 with confirmed SARS-CoV-2 infection. Approximately 68.75% had symptoms of SARS-CoV-2 infection in about 1 wk preceding the onset of neurological symptoms. The most common neurological symptoms were consciousness disturbance, seizure, delirium, and headache. The mainly damaged targets identified by neuroimaging included the temporal lobe, white matter, frontal lobe, corpus callosum, and cervical spinal cord (9.38%). Eighty percent of patients had EEGs that showed a diffuse slow wave, and 65.63% of patients improved following systemic therapy.

Encephalitis/meningitis is the common neurological complication in patients with COVID-19. From the perspective of infectious diseases of the central nervous system, the cases of SARS-CoV-2-associated encephalitis that were reported lack direct evidence of SARS invading the nervous system, while the cases of COVID-19 patients who were tested for cerebrospinal fluid while excluding other potential diagnoses were only accidental reports. The appropriate use of definitions and exclusion of potential similar diseases are important to reduce over-diagnosis of SARS-CoV-2associated encephalitis or meningitis.

We should conduct appropriate investigations to exclude other identified brain infections and parainfluenza before attributing a condition to SARS-CoV-2. The appropriate use of definitions and exclusion of potential similar diseases are important to reduce over-diagnosis of SARS-CoV-2-associated encephalitis or meningitis.

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The authors would like to thank Professor Zheng LQ, at The Department of Medical Statistics, Library in Shengjing Hospital of China Medical University, for help with statistical analysis. Useful suggestions given by Professor Wang HQ of Perking University Aerospace School of Clinical Medicine are also acknowledged.