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- Publisher
- Pubmed Central
- Copyright
- © 2021 European Academy of Neurology
- ISSN
- 1351-5101
- eISSN
- 1468-1331
- DOI
- 10.1111/ene.14913
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Abstract
National University of Singapore, Background and purpose: Although COVID- 19 predominantly affects the respiratory Singapore, Singapore system, recent studies have reported the occurrence of neurological disorders such as Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, UK stroke in relation to COVID- 19 infection. Encephalitis is an inflammatory condition of Health Services & Systems Research, the brain that has been described as a severe neurological complication of COVID- 19. Duke- NUS Medical School, Singapore, Singapore Despite a growing number of reported cases, encephalitis related to COVID- 19 infection Department of Neurology, National has not been adequately characterised. To address this gap, this systematic review and Neuroscience Institute, Singapore, meta- analysis aims to describe the incidence, clinical course, and outcomes of patients Singapore Neuroscience and Behavioural Disorders, who suffer from encephalitis as a complication of COVID- 19. Duke- NUS, Singapore, Singapore Methods: All studies published between 1 November 2019 and 24 October 2020 that Correspondence reported on patients who developed encephalitis as a complication of COVID- 19 were Isabel Siow, Yong Loo Lin School included. Only cases with radiological and/or biochemical evidence of encephalitis were of Medicine, National University of Singapore, 10 Medical Drive, Singapore included. 117597, Singapore. Results: In this study, 610 studies were screened and 23 studies reporting findings from 129,008 Email: [email protected] patients, including 138 with encephalitis, were included. The average time from diagnosis of Adeline Ng, Senior Consultant COVID- 19 to onset of encephalitis was 14.5 days (range = 10.8– 18.2 days). The average inci- Neurologist, Department of Neurology, National Neuroscience Institute, dence of encephalitis as a complication of COVID- 19 was 0.215% (95% confidence interval [CI] Singapore; Neuroscience and Behavioural = 0.056%– 0.441%). The average mortality rate of encephalitis in COVID 1 - 9 patients was 13.4% Disorders, Duke- NUS, 11 Jln Tan Tock Seng, Level 1, Singapore 308433, (95% CI = 3.8%– 25.9%). These patients also had deranged clinical parameters, including raised Singapore. serum inflammatory markers and cerebrospinal fluid pleocytosis. Email: [email protected] Conclusions: Although encephalitis is an uncommon complication of COVID- 19, when present, it results in significant morbidity and mortality. Severely ill COVID- 19 patients are at higher risk of suffering from encephalitis as a complication of the infection. K E Y WO R D S complication, coronavirus, COVID- 19, encephalitis I NTR O D U C TI O N respiratory system, recent studies have found that it has severe impact on the neurological system as well [1]. Work has begun in The coronavirus disease 2019 (COVID- 19) pandemic has caused the characterisation of some of these neurological complications an unprecedented burden on both economic and health care of COVID- 19, such as stroke and anosmia [2]. However, less com- systems globally. Although COVID- 19 primarily affects the mon neurological complications of COVID- 19 such as encephalitis Eur J Neurol. 2021;00:1–12. wileyonlinelibrary.com/journal/ene © 2021 European Academy of Neurology | 1 2 SIOW et al . [3], Guillain– Barré syndrome [4] and myelitis [5] are still not ade- The quality of included studies was assessed using the Joanna Briggs quately explored. Institute (JBI) checklist for prevalence studies and the JBI checklist for There have been increasing reports of the development of en- case series [17]. These tools rated the quality of selection, measure- cephalitis in severely ill COVID- 19 patients [6– 8]. These patients ment, and comparability for all studies and gave a score for cross- fare poorly, with significant morbidity and mortality rates [6,9]. sectional studies and case series. Two researchers assessed the quality The association of encephalitis with severe patient outcomes sug- of all included studies and discussed discrepancies until consensus was gests that systematic studies are required to determine the risk reached. Data were extracted on the following variables: study details, factors predisposing to its development. Currently, systematic sample size of study, method of diagnosis, age, gender, coexisting med- reviews that consolidate findings on encephalitis as a complica- ical conditions, clinical symptoms, laboratory investigations, time from tion of COVID- 19 are scarce, providing limited information on this COVID- 19 infection to onset of encephalitis, treatment details, and pa- condition [10– 13]. To address this important gap in the literature, tient outcomes. The outcome measure was mortality in hospital. a systematic review was conducted to more comprehensively Random effects meta- analyses were performed on variables and evaluate the epidemiology, clinical course, risk factors, and out- end points due to observed estimates and sampling variability across comes of patients who suffer from encephalitis as a complication studies. Pooled proportions were computed with the inverse variance of COVID- 19. method using the variance- stabilising Freeman– Tukey double arcsine transformation [18]. Confidence intervals (CIs) for individual studies were calculated using the Clopper– Pearson interval method. The I M AT E R IAL S AN D M E T H OD S statistics was used to present between- study heterogeneity, where I of 30% or less, between 30% and 50%, between 50% and 75%, and This review was conducted in accordance with the Preferred 75% or greater was considered to indicate low, moderate, substantial, Reporting Items for Systematic Reviews and Meta- Analyses and considerable heterogeneity, respectively [19]. Probability values (PRISMA) guidelines [14]. A search string was developed to iden - for the I statistics were computed by chi- squared distribution of tify original research studies reporting clinical features and treat- Cochran Q test. Missing values for mean were imputed using median. ment outcomes of patients with encephalitis as a complication of Statistical analysis was performed using R (R Foundation for Statistical COVID- 19 (Table S1). Encephalitis was defined as an inflammation Computing, Vienna, Austria; https://www.R- proje ct.org/) [20]. The of the brain [15]. For this analysis, studies reporting on any type of significance level was set at p < 0.05, and 95% CIs were reported. encephalitis were included, such as autoimmune encephalitis, acute disseminated encephalomyelitis (ADEM), and necrotising encepha - litis. All cases of encephalitis were diagnosed radiologically, such as RE S U LT S by computed tomography (CT) or magnetic resonance imaging (MRI) scans of the brain or by cerebrospinal fluid (CSF) analysis. The search The search strategy yielded 610 unique publications after removal of was applied to the following three electronic databases: PubMed, duplicates. After screening of titles and abstracts, 168 publications Embase, and CENTRAL (Cochrane Central Register of Controlled were reviewed in full text. A total of 23 original studies [3,6– 9,21– Trials). Searches were performed for each database on 24 October 38] were eventually included in our systematic review with a com- 2020. Limits were applied to the search to identify studies pub- bined population of 129,008 patients, including 138 who developed lished after 1 November 2019, as the first case of novel coronavirus encephalitis [Table 1]. was only reported in December 2019. This study was registered on Of the 23 studies, five studies each originated from the United PROSPERO (registration number CRD42020224776). All titles and States and Italy. Three studies each originated from Spain and abstracts were screened independently by two reviewers (I.S. and France, two studies each originated from Singapore and the United K.S.L.) against a set of predefined eligibility criteria. Potentially eligi- Kingdom, and one study each originated from Belgium, Pakistan, ble studies were selected for full- text analysis. Disagreements were and Turkey (Table 1). Sixteen studies were cross- sectional in na- resolved by consensus or appeal to a third senior reviewer (A.N.). ture (69.6%), and seven (30.4%) were case series. Of the 16 cross- All original studies reporting the clinical characteristics (symp- sectional studies, four studies attained a full score of 8 on the JBI toms and signs, laboratory investigations, and radiological findings) checklist for cross- sectional studies, eight studies attained a score of and treatment outcomes of COVID- 19 patients with encephalitis 7, and four studies attained a score of 6 (Table S3). Of the seven case complications were included in our systematic review. Case reports series, four studies attained a full score of 10 on the JBI checklist for and studies of small sample sizes (<3) were excluded per recommen- case series and three studies attained a score of 9 (Table S4). dations in accordance with methodologies of previously published meta- analyses [2,16]. Other exclusion criteria included non- English articles, non- original research papers, laboratory- based and epide- General analysis miological studies with no clinical characteristics reported, and non- human research subjects (Table S2). The PRISMA chart is detailed The two broad categories of encephalitis as a complication of in Figure 1. COVID- 19 were autoimmune encephalitis and infec tious encephalitis. ENCEPHALITIS AND COVID- 19 3 F I G UR E 1 Preferred Reporting Items for Systematic Reviews and Meta- Analyses study design Fourteen studies reported on the incidence of encephalitis as a com- Severity of COVID- 19 illness plication of COVID- 19. Combining results, the pooled incidence of encephalitis as a complication of COVID- 19 was 0.215% (95% CI = Twelve studies reported on the severity of COVID- 19 illness in pa- 0.056%– 0.441%). Notably, 10 of the 14 studies reported incidence tients who subsequently suffered from the complication of enceph- of less than 1% (Figure 2). However, among severely ill patients with alitis, whether severe of mild. Severe illness was defined as patients COVID- 19, the pooled incidence of encephalitis as a complication of who required intensive care unit (ICU) or high- dependence unit COVID- 19 was higher at 6.7% (95% CI = 4.3%– 9.4%; Figure S1). Ten (HDU) care. Mild illness included patients who were managed in the studies reported the time from diagnosis of COVID- 19 to onset of general ward with mild or no respiratory symptoms during their stay. encephalitis symptoms. P atients developed encephalitis an average Most patients had severe COVID- 19 illness prior to developing the of 14.5 days (SD = 10.8 - 18.2 days) after onset of COVID- 19 symp- complication of encephalitis, amounting to 83.8% (95% CI = 62.0%– toms (Table 2). 98.6%; Figure S2). 4 SIOW et al . TA B L E 1 Summary of studies Study Country Study design Encephalitis patients, n Age, mean Male, n (%) Abenza- Abildúa et al. Spain Case series 4 Benameur et al. United States Case series 3 43.0 2 (66.7) Cao et al. France Case series 5 56.0 4 (80.0) Dogan et al. TurkeyCross- sectional 3 43.3 3 (100.0) Guilmot et al. BelgiumCross- sectional 1 80.0 Helms et al. FranceCross- sectional 8 Iltaf et al. PakistanCross- sectional 3 >50 Kihira et al. United States Case series 2 53.5 1 (50.0) Koh et al. SingaporeCross- sectional 4 Kremer et al. FranceCross- sectional 8 60.8 7 (87.5) Liotta et al. United StatesCross- sectional 1 Luigetti et al. ItalyCross- sectional 1 Miró et al. SpainCross- sectional 16 Paterson et al. United Kingdom Case series 12 53 4 (33.3) Pilotto et al. (a) ItalyCross- sectional 14 Pilotto et al. (b) Italy Case series 25 65.9 15 (60.0) Radmard et al. United StatesCross- sectional 1 74 0 (0.0) Rifino et al. ItalyCross- sectional 5 60 4 (80.0) Romero- Sánchez et al. SpainCross- sectional 1 57 0 (0.0) Shah et al. United StatesCross- sectional 9 Umapathi et al. Singapore Case series 3 57 3 (100.0) Varatharaj et al. United KingdomCross- sectional 7 Zuccon et al. ItalyCross- sectional 2 Overall 138 59.4 68 (49.3) Demographics (84.6% of patients) and fever (63.6%) were the most common symp- toms experienced by patients. Cough (60.0%) and fatigue (50.0%) Demographic information of patients who suffered from encepha- were less common. Additionally, 23.8% of patients were asympto- litis as a complication of COVID- 19 was analysed. The mean age matic, that is, did not experience any COVID- 19 symptoms. Of the of patients who suffered from encephalitis as a complication of 11 studies that reported on symptoms of encephalitis, all reported COVID- 19 was 59.4 years (range = 43.0– 80.0 years). A similar that all the patients in the study experienced at least one symptom proportion of males and females suffered from encephalitis as a of encephalitis. Common symptoms of encephalitis included loss complication of COVID- 19, with 49.3% of such patients being male or decreased level of consciousness (77.1%), altered mental state (Table 1). Most of these patients had at least one comorbidity, (72.3%), seizures (38.2%), headaches (27.3%), and weakness (15.4%). amounting to 71.7%. The most common comorbidities were hy- Other less common symptoms that patients with encephalitis as a pertension (45.5% of patients), hyperlipidaemia (24.0%), and dia- complication of COVID- 19 suffered from were aphasia, ataxia, and betes mellitus (16.0%). Less commonly encountered comorbidities myoclonus (Table 4). included chronic kidney disease, chronic liver disease, and conges- tive cardiac failure (Table 3). Clinical parameters Symptoms Clinical parameters of COVID- 19 patients who suffered from en- cephalitis as a complication were also analysed. Six studies re- Thirteen studies reported on the clinical symptoms of patients, such ported results of serum analyses. D- dimer levels were raised, with as COVID- 19 symptoms and encephalitis symptoms. Of the eight an average of 13.4 mg/L (range = 6.9– 15.0 mg/L). Lactate dehydro- studies that reported on COVID- 19 symptoms, shortness of breath genase levels were raised, with an average of 358.7 U/L (range = ENCEPHALITIS AND COVID- 19 5 F I G UR E 2 Incidence of encephalitis in COVID- 19. Inverse Variance (IV) 322.8– 658.0 U/L). C- reactive protein levels were raised, with an av- Outcomes erage of 58.8 mg/L (range = 39.9– 216.6 mg/L). Interleukin 6 (IL- 6) levels were also raised, with an average of 1327.9 pg/ml (range = Thirteen studies reported on the mortality rate of patients who suf- 88.1– 3394.3 pg/ml; reference value < 6.5 pg/ml). Thirteen studies fered from encephalitis as a complication of COVID- 19. The pooled reported on CSF analyses. Protein levels were raised, with an aver- mortality rate of patients who suffered from encephalitis as a com- age of 64.8 mg/dl (range = 38.0– 115.0 mg/dl). Glucose levels were plication of COVID- 19 was 13.4% (95% CI = 3.8%– 25.9%; Figure 3). raised, with an average of 81.7 mg/dl (range = 59.0– 130.0 mg/dl). Cellularity was increased, with a red blood cell level of 328.8 cells/µl (range = 11.5– 1154.0 cells/µl) and white blood cell level of 14.8 cells/ D IS C U S S I ON µl (range = 6.0– 38.7 cells/µl). IgG levels were raised, with an aver- age of 83.2 mg/L (range = 5.0– 112.5 mg/L). Of the four studies that A comprehensive evaluation of the epidemiology and clinical out- reported on oligoclonal bands, three studies found that they were comes of patients who suffered from encephalitis as a complication absent in eight patients, whereas one study reported its presence in of COVID- 19 was performed. A key finding is that the incidence one patient (Table 5). of encephalitis in COVID- 19 patients is relatively low (<1%), but TA B L E 2 Time from COVID- 19 Encephalitis Days from COVID- 19 infection to infection to encephalitis onset Study patients, n encephalitis onset, mean (SD) Benameur et al. 3 11.7 (2.5) Cao et al. 5 20.0 (6.1) Dogan et al. 3 16.0 (2.2) Guilmot et al. 1 21.0 (0.0) Kihira et al. 2 10.5 (3.5) Koh et al. 4 24.0 (15– 65) Kremer et al. 8 19.1 (8.3) Pilotto et al. (b) 25 6.8 (10.1) Rifino et al. 5 16.4 (19.7) Umapathi et al. 3 45.3 (24.4) Overall 5914.5 (10.8– 18.2) 6 SIOW et al . TA B L E 3 Comorbidities No Encephalitis comorbidities, At least 1 Diabetes Hypertension, Hyperlipidaemia, Study patients, n n (%) comorbidity, n (%) mellitus, n (%) n (%) n (%) Benameur et al. 3 0 (0.0) 3 (100.0) 2 (66.7) Cao et al. 5 1 (20.0) 4 (80.0) 2 (40.0) Dogan et al. 3 2 (66.7) 1 (33.3) 1 (33.3) Kihira et al. 2 2 (100.0) 0 (0.0) Pilotto et al. (b) 25 3 (12.0) 22 (88.0) 4 (16.0) 12 (48.0) 6 (24.0) Rifino et al. 5 3 (60.0) 2 (40.0) 2 (40.0) Umapathi et al. 3 2 (66.7) 1 (33.3) 1 (33.3) Overall 46 13 (28.3) 33 (71.7) 4 (16.0) 20 (45.5) 6 (24.0) increases significantly to up to 6.7% in severely ill patients, defined who suffer from encephalitis as a complication are asymptomatic as patients requiring ICU or HDU care. Patients who suffer from carriers of COVID- 19 and only experience encephalitis symptoms encephalitis as a complication of COVID- 19 have much poorer out- [33– 35]. In a case series by Radmard et al., a 74- year- old female pre- comes compared to the general population of COVID- 19 patients, senting with altered mental status and no upper respiratory tract including admission to intensive care facilities, use of ventilators, and symptoms developed encephalitis and was subsequently found to high mortality rate. The mortality rate of patients with encephalitis be infected with COVID- 19 [33]. This brings into question whether as a complication of COVID- 19 is 13.4%, almost quadruple the 3.4% there is a need for COVID- 19 testing in encephalitis patients with in the general population of COVID- 19 patients [39]. It might thus be no COVID- 19 respiratory symptoms, as the management of such helpful to be vigilant of encephalitis as a complication of COVID- 19 patients in close proximity to other ill patients might result in viral as, although uncommon, it can have severe consequences [6]. transmission. Several risk factors for encephalitis as a complication of Common MRI brain findings seen in these cases include diffuse COVID- 19 were elucidated. Demographic risk factors such as old white matter hyperintensities and haemorrhagic lesions on fluid- age and underlying comorbidities may confer increased risk of com- attenuated inversion recovery and T2 sequences [24,25,33,35,37]. plications from COVID- 19 infection, including the development of Other less common MRI findings include cerebral oedema and ve- encephalitis [9,21,32]. Additionally, patients who are severely ill with nous thrombosis [3,9]. CT head findings were generally unremark- COVID- 19 are at a much- increased risk of suffering from the com- able [24]. Notably, some of these patients suffered from pre- existing plication of encephalitis [6,8,22]. The incidence of encephalitis as a chronic medical conditions such as diabetes mellitus and hyperten- complication of COVID- 19 is less than 1% in the general population sion [24,37] and it is possible that some degree of imaging findings of COVID- 19 patients, but rises greatly to 6.7% in those who are such as subcortical white matter hyperintensities and microbleeds severely ill. The physiological reserves theory might explain this phe- in the deep grey nuclei could have resulted from chronic conditions nomenon. The elderly with multiple comorbidities, or those who are such as hypertension. However, there are also a few reports of pa- severely ill with COVID- 19, are less able to compensate for physio- tients with encephalitis as a complication of COVID- 19 with normal logical derangements, increasing vulnerability to severe complica- brain imaging results [6]. This could be due to milder encephalitis tions such as encephalitis [40]. or imaging conducted prematurely before brain changes developed. Common symptoms of COVID- 19 include mild symptoms such Neuroimaging findings in patients with encephalitis as a complica- as cough, malaise, and fever as well as more severe symptoms such tion of COVID- 19 resemble those in the previous severe acute re- as shortness of breath [10]. Symptoms of encephalitis include loss spiratory syndrome coronavirus 1 (SARS- CoV- 1) and Middle East or decreased level of consciousness and altered mental state, focal respiratory syndrome outbreaks, suggesting possible similarities neurological signs such as weakness, and seizures [12]. Although in pathophysiology of central nervous system (CNS) involvement there are case reports of several patients developing encephalitis across these three coronaviruses [13]. Electroencephalography weeks after initial infection with COVID- 19 [37], most patients de- (EEG) in some patients showed patterns of general slowing [24]. velop both COVID- 19 symptoms and encephalitis symptoms during Although some patients developed seizures during their clinical the same period [30,32]. Notably, encephalitis is rarely the present- course [32,34], sharp waves and epileptiform activity were uncom- ing symptom of COVID- 19. Most often, patients present with respi - mon findings [24,33]. ratory symptoms and develop encephalitis an average of 14.5 days Interestingly, there have been increasing reports of severe later, during their hospital stay [7,21,25]. Therefore, it could be ben- encephalitis subtypes occurring even among young COVID- 19 eficial for physicians to monitor severely ill COVID- 19 patients more patients, such as ADEM [41,42]. ADEM is a postinfectious inflam- closely to mitigate the development of encephalitis as a complication matory demyelinating neurological condition that is more common of COVID- 19 should it occur [11]. However, a few COVID- 19 patients in children than adults [43]. It is a serious form of encephalitis with ENCEPHALITIS AND COVID- 19 7 TA B L E 4 Clinical symptoms COVID- 19 symptoms Encephalitis symptoms Altered mental Encephalitis Asymptomatic, Fever, Cough, SOB, Fatigue, Headache, Loss/decreased level of state, Seizure, Weakness, Study patients, n n (%) n (%) n (%) n (%) n (%) n (%) consciousness, n (%) n (%) n (%) n (%) Benameur et al. 3 0 (0.0) 2 (66.7) 2 (66.7) 3 (100.0) 3 (100.0) 1 (33.3) Cao et al. 5 0 (0.0) 4 (80.0) 3 (60.0) 4 (80.0) 3 (60.0) 3 (60.0) 1 (20.0) Guilmot et al. 1 1 (100.0) 1 (100.0) 1 (100.0) Kihira et al. 2 0 (0.0) 1 (50.0) 1 (50.0) 2 (100.0) 1 (50.0) Koh et al. 4 2 (50.0) 4 (100.0) 3 (75.0) 2 (50.0) Kremer et al. 7 1 (14.3) 6 (85.7) 3 (42.9) Paterson et al. 12 7 (58.3) Pilotto et al. (b) 25 19 (76.0) 9 (36.0) 1 (4.0) Radmard et al. 1 1 (100.0) 1 (100.0) Rifino et al. 5 2 (40.0) 5 (100.0) 2 (40.0) Romero- Sánchez 1 1 (100.0) et al. Shah et al. 9 Umapathi et al. 3 0 (0.0) 1 (33.3) 3 (100.0) 1 (33.3) 3 (100.0) 1 (33.3) 1 (33.3) Overall 78 5 (23.8) 7 (63.6) 6 (60.0) 11 (84.6) 4 (50.0) 3 (27.3) 27 (77.1) 34 (72.3) 13 (38.2) 6 (15.4) Abbreviation: SOB, shortness of breath. 8 SIOW et al . TA B L E 5 Clinical parameters Serum CSF Encephalitis D- dimer, CRP, IL−6, pg/ Protein, Glucose, Cells/ RBC, cells/ WBC, cells/ IgG, Oligoclonal a 3 Study patients, n mg/L LDH, U/L mg/L ml mg/dl mg/dl mm µl µl mg/L bands Benameur et al. 3 86.0 79.7 1154.0 38.7 High Cao et al. 5 88.1 Dogan et al. 3 6.9 658.0 216.6 3394.3 55.9 130.0 0.0 5.0 Absent Guilmot et al. 1 46.0 Kihira et al. 2 132.0 105.0 0.0 Absent Koh et al. 4 High High High 56.0 22.0 6.0 Kremer et al. 8 79.1 Normal 7.9 112.5 Present Luigetti et al. 1 115.0 Normal Paterson et al. 12 15.0 High Pilotto et al. (b) 25 322.8 39.9 60.1 76.2 6.4 Radmard et al. 1 High 38.0 59.0 32.0 12.0 Rifino et al. 5 High High High 45.0 9.8 High High Romero- Sánchez et al. 1 Normal Normal Normal Normal Umapathi et al. 3 52.5 73.0 11.5 3.5 Absent Overall 69 13.4 358.7 58.8 1327.9 64.8 81.7 6.3 328.8 14.8 83.2 Reference value < 6.5 pg/ml. ENCEPHALITIS AND COVID- 19 9 F I G UR E 3 Mortality of patients with encephalitis as a complication of COVID- 19. Inverse Variance (IV) much poorer outcomes compared to those in other subtypes of en- However, the preliminary success of these treatment modalities cephalitis, including poor functional recovery and a high mortality needs to be considered cautiously, as no large- scale randomised rate [43]. Worryingly, preliminary reports show that ADEM is not control trials regarding their efficacy have been published to date. exclusive to COVID- 19 patients with demographic risk factors, as More work needs to be carried out in this area to determine their young COVID- 19 patients and those with no comorbidities also de- suitability as treatment modalities for encephalitis as a complica- velop this complication [41,42]. These patients also often develop tion of COVID- 19. new white matter lesions seen on contrast- enhancement MRI [44]. There are three proposed mechanisms of the pathophysiology Further surveillance is warranted to improve management of these of encephalitis as a complication of COVID- 19: direct invasion of lethal subtypes of encephalitis. the nervous system, systemic inflammation, and molecular mimicry. Efficacious management protocols for encephalitis in First, direct invasion of the SARS- CoV- 2 virus into the brain paren- COVID- 19 are still being studied. Modes of management that chyma could cause the development of encephalitis. SARS- CoV- 2 have yielded positive patient outcomes include corticosteroids could enter the brain parenchyma via a transsynaptic propaga- [21], intravenous immunoglobulin [30], plasmapheresis [9] and tion or via haematogenous invasion. In transsynaptic propagation, monoclonal antibodies such as rituximab [45]. In a case series of SARS- CoV- 2 binds to the angiotensin II (ACE- II) receptor on the cell five patients by Cao et al., administration of corticosteroids (1 g/ membrane of peripheral nerve cells and enters cells via receptor- day intravenous methylprednisolone for 5– 10 days) resulted in mediated endocytosis. It then uses active axonal machinery to travel marked improvement of three patients, who showed dramatic retrogradely to the CNS [46]. One such route is via the olfactory ep- improvement of neurologic status within 1 week and were sub- ithelium, where SARS- CoV- 2 invades the olfactory primary sensory sequently discharged [21]. A combination of intravenous immu- neurons and travels to the cribriform plate of the ethmoidal bone. noglobulin and corticosteroids was successful in the treatment From there, it crosses into the anterior cranial fossa and may later of COVID- 19 patients with inflammatory CNS conditions such as spread throughout brain parenchyma to cause encephalitis [1]. In encephalitis, where 11 of the 12 patients studied recovered [30] haematogenous invasion, SARS- CoV- 2 crosses the blood– brain bar- Plasmapheresis was also shown to be effective in a case series of rier (BBB) to enter the brain parenchyma. SARS- CoV- 2 first invades six critically ill COVID- 19 patients with encephalitis, where five of vascular endothelial cells that express the ACE- II receptor. It then them recovered enough after commencement of plasmapheresis interacts with ACE- II on surrounding neurons, glial cells, and other to be discharged from the ICU to a normal ward [9]. Rituximab vascular cells, beginning a cycle of viral budding [1]. This causes dam- was also effective in the treatment of an elderly gentleman with age to both vascular and neuronal tissue, compromising the BBB and COVID- 19 encephalitis, causing marked improvement in neuro- allowing the SARS- CoV- 2 virus to enter the CNS [1]. Alternatively, psychiatric symptoms and mental status after administration [45]. haematogenous invasion could also occur through the infection of 10 SIOW et al . leukocytes [46]. Lymphocytes, monocytes, and granulocytes all ex - C ON C L U S I ON press the ACE- II receptor, making infection with SARS- CoV- 2 possi- ble. Once infected in blood vessels, these leukocytes cross the BBB, This systematic review and meta- analysis evaluated the epidemiol- entering the CNS and taking the SARS- CoV- 2 virus with them, where ogy, clinical course, and outcomes of patients who suffered from they can infect other cell types within the CNS to cause encephalitis encephalitis as a complication of COVID- 19. Although the incidence [46]. However, it has been suggested that direct invasion of SARS- of encephalitis in the general population of hospitalised COVID- 19 CoV- 2 virus into the CNS may be less likely to be the main mech- patients was low at 0.215%, the mortality rate of patients who suf- anism causing encephalitis in COVID- 19 [12,13], as most patients fered from encephalitis as a complication of COVID- 19 was high with encephalitis in COVID- 19 have had negative CSF polymerase at 13.4%. Severely ill COVID- 19 patients were much more likely chain reaction against SARS- CoV- 2, and symptoms of direct CNS in- to suffer from encephalitis as a complication. Further research volvement such as anosmia and ageusia have been very uncommon through collaborative international registries would help to com- [30,32– 34]. prehensively decipher the pathophysiology and prognosis of en- Another proposed mechanism for the pathophysiology of en- cephalitis in COVID- 19, improving the effectiveness of care. cephalitis as a complication of COVID- 19 is the systemic inflamma- tion caused by the SARS- CoV- 2 virus [47]. SARS- CoV- 2 infection A C K N O W L ED G EM EN TS causes activation of the innate immune system, causing release of We thank Toh Kim Kee for her assistance in designing the initial large amounts of inflammatory cytokines (interferon [IFN] α, IFNγ, search strategy. IL- 1β, IL- 6, IL- 12, etc.). This causes the phenomenon known as "cy- tokine storm," which results in systemic inflammatory response C O N FL I C T O F I N T E R E S T syndrome [47]. These inflammatory molecules are transported The authors declare no financial or other conflicts of interest. throughout the body, attacking all organ systems, including the ner- vous system. Resultant dysfunction of the nervous system could re- A U TH O R C O N TR I B U TI O N S sult in encephalitis [1]. Supportive evidence for this theory includes Isabel Siow: Conceptualisation (lead), methodology (lead), visuali- CSF analysis and serology, which show a proinflammatory state sation (lead), writing– original draft (lead), writing– review & editing [24,28,30]. Additionally, EEG results reveal diffuse patterns indic- (lead). Keng Siang Lee: Writing– original draft (supporting), writing– ative of extensive inflammation [13]. Further studies reporting CSF review & editing (supporting). John J. Y. Zhang: Writing– original and/or serum levels of such inflammatory cytokines may be useful draft (supporting), writing– review & editing (supporting). Seyed for elucidating underlying pathophysiological mechanisms. Ehsan Saffari: Data curation (lead), formal analysis (lead), software A third proposed mechanism for encephalitis as a complication (lead). Adeline Ng: Supervision (lead). of COVID- 19 is molecular mimicry [1]. In response to infection with the SARS- CoV- 2 virus, there is an expansion of host antibodies and E T H I C AL AP P R O VAL lymphocytes. Although these immune molecules are supposed to Research ethics approval was not applicable, as this submission did be specific for SARS- CoV- 2 viral antigens, some of them are cross- not involve human participants. All information was obtained from reactive and can attack self- antigens [1]. When cells in the vascular publicly available, published articles. endothelium and brain parenchyma are affected, diffuse damage to CNS results, which may cause the development of encephalitis [1]. D I S C L AI M E R S Notably, we found that the most common form of encephalitis in The views expressed in this article are entirely our own and not an COVID- 19 is autoimmune encephalitis [9,21,24,30,33]. There have official position of our institutions. also been reports of acute haemorrhagic necrotising encephalopathy [48] and Guillain– Barré syndrome [49] which are known to develop D ATA AVA I L A B I L I T Y S TAT E M E N T via molecular mimicry, further supporting the theory of molecular The data that support the findings of this study are openly available mimicry as the pathophysiology of encephalitis as a complication in PubMed. Additionally, the data that support the findings of this of COVID- 19. Overall, primary data from COVID- 19 patients with study are available from the corresponding author upon reasonable encephalitis remains limited, hence conclusions regarding the mech- request. anistic properties and pathophysiology of encephalitis in COVID- 19 cannot be drawn at present. O RC I D This study entails some limitations. First, as there are few robust Isabel Siow https://orcid.org/0000-0001-5989-1424 cross- sectional studies, we also included case series, which held sig- Keng Siang Lee https://orcid.org/0000-0003-2308-0579 nificant publication bias. Second, some studies did not report all our variables of interest, leading to incomplete data. However, as there R EF ER EN C E S is currently limited information on encephalitis as a complication of 1. Scoppettuolo P, Borrelli S, Naeije G. Neurological involvement in SARS- CoV- 2 infection: a clinical systematic review. 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Journal
European Journal of Neurology – Pubmed Central
Published: Jun 2, 2021