key: cord-0956418-c697sb76
authors: Koupaei, Maryam; Shadab Mehr, Negar; Mohamadi, Mohamad Hosein; Asadi, Arezoo; Abbasimoghaddam, Sajjad; Shekartabar, Amirhosein; Heidary, Mohsen; Shokri, Fazlollah
title: Clinical symptoms, diagnosis, treatment, and outcome of COVID‐19‐associated encephalitis: A systematic review of case reports and case series
date: 2022-04-18
journal: J Clin Lab Anal
DOI: 10.1002/jcla.24426
sha: 1a9a3891248f66b816908f994537e7a595224afa
doc_id: 956418
cord_uid: c697sb76

INTRODUCTION: Since COVID‐19 outbreak, various studies mentioned the occurrence of neurological disorders. Of these, encephalitis is known as a critical neurological complication in COVID‐19 patients. Numerous case reports and case series have found encephalitis in relation to COVID‐19, which have not been systematically reviewed. This study aims to evaluate the clinical symptoms, diagnosis, treatment, and outcome of COVID‐19‐associated encephalitis. METHODS: We used the Pubmed/Medline, Embase, and Web of Science databases to search for reports on COVID‐19‐associated encephalitis from January 1, 2019, to March 7, 2021. The irrelevant studies were excluded based on screening and further evaluation. Then, the information relating diagnosis, treatment, clinical manifestations, comorbidities, and outcome was extracted and evaluated. RESULTS: From 4455 initial studies, 45 articles met our criteria and were selected for further evaluation. Included publications reported an overall number of 53 COVID‐19‐related encephalitis cases. MRI showed hyperintensity of brain regions including white matter (44.68%), temporal lobe (17.02%), and thalamus (12.76%). Also, brain CT scan revealed the hypodensity of the white matter (17.14%) and cerebral hemorrhages/hemorrhagic foci (11.42%) as the most frequent findings. The IV methylprednisolone/oral prednisone (36.11%), IV immunoglobulin (27.77%), and acyclovir (16.66%) were more preferred for COVID‐19 patients with encephalitis. From the 46 patients, 13 (28.26%) patients were died in the hospital. CONCLUSION: In this systematic review, characteristics of COVID‐19‐associated encephalitis including clinical symptoms, diagnosis, treatment, and outcome were described. COVID‐19‐associated encephalitis can accompany with other neurological symptoms and involve different brain. Although majority of encephalitis condition are reversible, but it can lead to life‐threatening status. Therefore, further investigation of COVID‐19‐associated encephalitis is required.

in the systematic review. The results of various studies including participants' clinical manifestations, comorbidities, diagnosis, treatment, and outcome are reported in Tables 1 and 2 . Moreover, a summary of the case report and case series findings are reported in Table 3 .

From a total of 45 studies, 53 patients with COVID-19-associated encephalitis were enrolled from 18 countries. Forty-one (93.18%) studies were case reports and 4 (6.82%) were case series. The most significant number of studies was conducted in the USA (n = 10), followed by Italy (n = 6) and Iran (n = 5).

Demographic information of the individuals with COVID-19associated encephalitis can be found in Tables 1 and 2. The patients were 21 female and 32 male with mean age of 52.12 years ranged between 9 months and 89 years. The highest incidence of COVID-19-associated encephalitis was observed in people over 50 years of age (54.72%).

COVID-19 was most often diagnosed by RT-PCR (92.45%) and chest CT (37.73%). In addition, serological tests (11.32%) and simplexa assay (1.88%) were used to detect SARS-CoV-2 virus ( Table 3) .

Brain MRI (81.48%), CSF analysis (46.29%), electroencephalography (42.59%), and head CT (37.03%) were the most frequently used methods to diagnose encephalitis ( Table 3 ). The most common brain MRI patterns were hyperintensity in the white matter (44.68%), hyperintensity in the temporal lobe (17.02%), and hyperintensity of the thalamus (12.76%). In addition, hypodensity of the white matter (17.14%) and cerebral hemorrhages/hemorrhagic foci (11.42%) were the most common head CT scan patterns. 

The most common comorbidities were hypertension (29.16%), diabetes mellitus (14.58%), obesity (12.50%), and neurologic disorders (10.41%). The less common comorbidities were anemia (2.08%), hypercholesterolemia (2.08%), hypothyroidism (2.08%), vitiligo (2.08%), and asthma (2.08%).

A wide range of treatment options was used to treat COVID-19.

The most common of which were hydroxychloroquine (50%), acyclovir (20%), and ritonavir/lopinavir (16.66%), respectively.

Common encephalitis treatment modalities included IV methylprednisolone/oral prednisone (36.11%), IV immunoglobulin (27.77%), acyclovir (16.66%). In Table 3 , we summarize all of the drugs used.

In total, 58.69% of the patients with COVID-19-associated encephalitis discharged and 13.05% of them were still hospitalized. The pooled mortality rate of these patients was 28.26%.

The results of the critical appraisal (JBI checklist) of included studies are summarized in Table S1 . Overall, 45 articles were identified as having a low risk of bias (quality assessment score >7). Thus, it is recommended that more sensitive and specific tests be performed. 23 In this study, the most common methods used to diagnose en- The most common MRI findings included hyperintensity in the white matter, hyperintensity in the temporal lobe, and hyperintensity in the corpus callosum, respectively. Although the CT findings of patients with COVID-19-associated encephalitis usually are not remarkable, 24 our study showed that the most findings are hypodensity of the white matter (17.14%) and cerebral hemorrhages/hemorrhagic foci (11.42%).

Probably, some of the signs in the imaging are related to the subcortical white matter hyperintensities and microbleeds in the deep gray nuclei caused by underlying diseases. 12 The association between underlying diseases such as hypertension, diabetes, chronic obstructive pulmonary disease (COPD), cardiovascular disease, and cerebrovascular disease has been identified with COVID-19. People with the above underlying diseases are more likely than others to develop COVID-19 and the severity of the disease. 25 In the present study, patients with COVID-19-associated encephalitis had a higher percentage of hypertension (29.16%) and

diabetes mellitus (14.58%).

Angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, is abundant in various organs. 3 Diabetes can increase the serum ACE2. Thus, it is not surprising that diabetes is a common comorbidity in patients with COVID-19-associated encephalitis. 26 In this study, COVID-19-associated encephalitis was more common in people over 50 years of age (54.72%). It seems that elderly people with several underlying diseases are less able to physiological rearrangement, which makes them more prone to encephalitis. 27 Although various treatments have been used to treat COVID-19associated encephalitis, none of them can be used with certainty.

At the time of the COVID-19 epidemic, physicians should suspect SARS-CoV-2 as a differentiating factor when certain diseases and neurological symptoms occur. 21 Our survey showed that IV methylprednisolone/oral prednisone (36.11%), IV immunoglobulin (27.77%), and acyclovir (16.66%) were the common treatment options to treat encephalitis. The healing role of IV immunoglobulin in severe cases of COVID-19 has been confirmed in several studies. [28] [29] [30] [31] There are some limitations in this study. First, only case reports and case series were enrolled in this systematic review. Thus, the existence of publication bias should be considered. Second, since our search was limited to articles published in English, some relevant articles in other languages have missed. Third, some studies lacked sufficient data.

In this systematic review, various aspects of COVID-19-associated encephalitis including clinical symptoms, diagnosis, treatment, and outcome were studied. COVID-19-associated encephalitis is one of the complications of SARS-CoV-2, which may accompany with other neurological symptoms and make the patient's condition worse. It usually occur in severe cases and can increase the mortality rate.

Thus, it is recommended to pay special attention to neurological symptoms during the COVID-19 epidemic. Lack of proper attention causes problems such as delay in COVID-19 diagnosis, virus transmission, and increased mortality. Therefore, further studies on COVID-19-associated encephalitis are suggested.

The authors declare that they have no competing interests. 

All the data in this review are included in the study.

https://orcid.org/0000-0002-9839-5017

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