Growing evidence demonstrates the association of encephalitis, meningoencephalitis or encephalomyelitis, with SARS-CoV-2 infection. This study aims to determine the profile and possible mechanisms behind CNS inflammatory diseases in the context of Covid-19. We conducted a systematic review of case reports on Covid-19-related encephalitis, meningoencephalitis, acute necrotizing encephalitis, and acute disseminated encephalomyelitis in adults, published before January 2021. A total of 182 cases (encephalitis = 109, meningoencephalitis = 26, acute disseminated encephalomyelitis = 35, acute necrotizing (hemorrhagic) encephalitis = 12) were included. While cerebrospinal fluid (CSF) pleocytosis and increased protein level was present in less than 50%, magnetic resonance imaging (MRI) and electroencephalogram (EEG) were abnormal in 78 and 93.2% of all cases, respectively. Viral particles were detected in cerebrospinal fluid of only 13 patients and autoantibodies were present in seven patients. All patients presented with altered mental status, either in the form of impaired consciousness or psychological/cognitive decline. Seizure, cranial nerve signs, motor, and reflex abnormalities were among associated symptoms. Covid-19-associated encephalitis presents with a distinctive profile requiring thorough diagnosis and thereby a comprehensive knowledge of the disease. The clinical profile of brain inflammation in Covid-19 exhibits majority of abnormal imaging and electroencephalography findings with mild/moderate pleocytosis or proteinorrhachia as prevalent as normal cerebrospinal fluid (CSF). Oligoclonal bands and autoantibody assessments are useful in further evaluating neuro-covid patients, as supported by our pooled evidence. Despite the possibility that direct viral invasion cannot be easily estimated, it is still more likely that immune-mediated or autoimmune reactions play a more important role in SARS-CoV-2 neuroinflammation.
Since the rise of Covid-19, the virus has overwhelmed almost every country around the world. As of March 3, 2021, there have been more than 100 million confirmed cases and two million deaths, turning the infection into a global concern (Johns Hopkins University 2020). Previous studies have demonstrated that the most frequent symptoms are fever, cough, dyspnea (Zhang et al. 2020), along with less frequent extrapulmonary symptoms such as renal and liver dysfunction, gastrointestinal complications, cardiovascular complications, and neurological manifestations (Behzad et al. 2020). A wide spectrum of neurological complications has been reported, involving both the central nervous system (CNS) and peripheral nervous system (PNS), such as Guillain–Barre syndrome, acute cerebrovascular disease, anosmia, ageusia, and encephalopathy (Widyadharma et al. 2021).
Encephalitis is defined as the inflammation of brain parenchyma. Its characteristic features are altered consciousness or personality change, which are consistent with the other types of encephalopathy. However, fever, focal neurologic signs, seizures, cerebrospinal fluid (CSF) pleocytosis, and imaging or electroencephalogram (EEG) findings are the aspects that distinguish encephalitis from the rest (Venkatesan and Geocadin 2014). Since the beginning of the ongoing pandemic, there has been an increasing number of reports on Covid-19 associated encephalitis which appear in various forms, for instance, limbic or brainstem encephalitis, meningoencephalitis, acute demyelinating encephalomyelitis (ADEM), cerebellitis, acute necrotizing encephalitis (ANE), acute hemorrhagic necrotizing encephalitis (AHNE), and acute hemorrhagic leukoencephalitis (AHLE). Until now, the proposed underlying mechanisms are either based on the immune response or direct viral infection (de Sousa et al. 2020).
Considering the controversy about the mechanism responsible for Covid-19 related encephalitis, and the burden the pandemic has caused, we have reviewed the clinical characteristics of Covid-19 patients who have complications in the abovementioned forms.
Data sources and search strategy
A comprehensive search was conducted in PubMed/MEDLINE, Embase and Scopus using the keywords “encephalit*” OR “meningoencephalit*” OR “encephalomyelit*” OR “leukoencephalit*” OR “necrotizing encephal*” OR “ADEM” OR “AHNE” OR “ANE” OR “AHLE” AND “Covid-19” OR “SARS-CoV-2” OR “2019-nCoV” OR “coronavirus 2019” OR “ncov 2019” OR “covid2019” in title, abstract and keywords, along with corresponding terms from MeSh and Emtree. Reference lists of included studies and relevant reviews were manually searched to ensure literature saturation. The search was conducted on December 8, 2020 and updated on January 15, 2021.
Eligibility criteria and quality assessment
All English publications describing cases of confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with concomitant encephalitis, meningoencephalitis, encephalomyelitis, acute demyelinating or necrotizing encephalitis were included. Two authors separately screened titles and abstracts and solved any disagreement through consensus.
Animal and in-vitro studies, reviews, opinions, reports with poor case definition or without a definite SARS-CoV-2 diagnosis were excluded. Cases under 18 years old were excluded regarding widely distinct criteria and characteristics of disease in children. Studies reporting on a same case were identified and data was retrieved from the most detailed report.
The quality appraisal of studies was conducted using the tool developed by Murad et al. for methodological assessment of case reports and case series (Murad et al. 2018). Items related to drug adverse effects was omitted due to inapplicability. The search and selection process is demonstrated in Figure 1, in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Page et al. 2021).
Data extraction and classification
One hundred and thirty one full-texts were scanned by two reviewers simultaneously and the following data was extracted: First author, doi., country, type of work, number of cases, age, sex, severity of respiratory disease, neurological symptoms and findings, delay from initial symptoms to neurological symptoms, laboratory parameters of CSF, inflammatory markers of serum, imaging and EEG results, comorbidities, treatment, outcomes, and final diagnosis stated by author(s).
Severity of respiratory disease was evaluated according to National Institutes of Health (NIH) classification (2020). Cases intubated due to neurological involvement without evidence of respiratory distress were not considered as critical respiratory involvement, to avoid misinterpretation of relations (Table 1). Neurological symptoms were categorized in eight groups based on neurological assessment guidelines and approximate localization in the CNS (Fritz and Musial 2016; Shahrokhi and Asuncion 2021). Impaired Consciousness ranges from drowsiness to stupor and coma; Psychiatric and cognitive defects include impaired orientation, attention, memory, decision making, perception, language, and personality changes. Cranial nerve signs include sensory, motor or reflex defects corresponding to one or more cranial nerves; the most common examples are dysarthria, abnormal pupillary reflex, ageusia, and anosmia (Fritz and Musial 2016). Limb weakness, hyperreflexia, or hyporeflexia were classified as impaired reflex and tonicity, and other categories include seizure, dysautonomia, sensory, or movement defects.
|No. of patients||26||35||12||109|
|Severity a no. (%)|
|Mild/asymptomatic||5 (19.2)||6 (17.1)||3 (25)||27 (24.8)|
|Moderate||4 (15.4)||3 (8.6)||0 (0)||34 (31.2)|
|Severe||7 (26.9)||2 (5.7)||0 (0)||13 (11.9)|
|Critical||10 (38.5)||23 (65.7)||7 (58.3)||27 (24.8)|
|Undetermined||0 (0)||1 (2.9)||2 (16.7)||8 (7.3)|
|No. (%)||6 (23.1)||18 (51.4)||9 (75)||63 (57.8)|
Neuro-delay, Delay from onset of disease symptoms to onset of neurological symptoms; ADEM, Acute Disseminated Encephalomyelitis; AHLE, Acute Hemorrhagic Leukoencephalitis; ANE, Acute Necrotizing Encephalitis; AHNE, Acute Hemorrhagic Necrotizing Encephalitis. aSeverity of respiratory disease was evaluated according to National Institutes of Health (NIH) classification (2020).
Synthesis of results
All extracted data was handled in a spreadsheet and classified based on severity of respiratory disease, brain inflammation type, presence of positive CSF polymerase chain reaction (PCR) result and CSF pleocytosis.
Means and frequencies were computed by two authors and any disagreement was resolved through discussion. Frequency and percentages for each variable was calculated within cases that reported measuring the parameter.
A total of 1149 studies were identified through database searching. After removal of duplications and reviews, 497 studies were screened. One hundred and eighty seven full-texts was reviewed for eligibility and 89 publications reporting on a total of 182 patients were included; consisting of 65 case reports, 14 case series and 10 retrospective/multicenter studies (Appendix 1).
All patients were confirmed cases of SARS-CoV-2 infection, with suspected brain inflammation. All cases had clinical presentation suggesting of neurological involvement. One hundred and sixty cases underwent lumbar puncture, from which 144 cases tested for presence of SARS-CoV-2 in CSF. A total of 13 patients had positive CSF PCR result.
Common reported comorbidities included hypertension (19.2%), diabetes mellitus and dyslipidemia (11.5%), obesity (4.9%), and asthma (2.7%). One patient was coinfected with herpes simplex virus (HSV) and one patient with human immunodeficiency virus (HIV). Two patients presented with underlying Alzheimer disease, one patient with neurodegeneration and one with anxiety. Other underlying conditions: Renal failure, immunosuppression following transplant, apnea, hypothyroidism, gammopathy, single seizure history, etc.
Patients were categorized in four groups: encephalitis, meningoencephalitis, acute demyelinating disease (including ADEM, AHLE), and necrotizing encephalitis (ANE, AHNE).
Twenty six patients reported in 14 published papers were diagnosed with meningoencephalitis (Table 1). Twelve patients (46.1%) had underlying hypertension or cardiovascular disease, 9 (34.6%) had diabetes, dyslipidemia, or metabolic disturbance, and 2 patients (7.7%) were obese.
From 23 performed lumbar punctures, CSF pleocytosis was present in nine patients: one patient with bacterial profile of encephalitis and evidence of concomitant bacterial infection had marked pleocytosis of predominantly polymorph cells. Other eight patients (34.8% of examined cases) demonstrated mild or moderate lymphocyte-dominant pleocytosis with an average of 34.5 cells/ . CSF PCR for SARS-CoV-2 was positive in three patients. CSF glucose was elevated in 13 and decreased in 2 patients. Diagnostic imaging and EEG was carried out in 23 and 4 cases, respectively. Normal magnetic resonance imaging (MRI) was reported in six patients and six patients presented new MRI findings suggestive of meningoencephalitis: hyperintensity of frontal, parietal, or medial temporal white matter with sulci, gyral, or leptomeningeal enhancement, subarachnoid hemorrhage and one case of ventriculitis. Seven patients had only chronic and/or vascular abnormalities without evidence of recent brain inflammation. Head computed tomography (CT) scan was normal in 2 cases, had chronic atrophy in six and new lesions in 2. EEG was performed for four patients and showed isolated generalized slowing in three of them and one case also presented focal epileptic discharges (Table 2).
|Clinical Parameters||Total (n = 182)||Meningoencephalitis (n = 26)||ADEM/AHLE (n = 35)||ANE/AHNE (n = 12)||Encephalitis (n = 109)|
|LP performed no.||160||23||26||7||104|
|Pleocytosis no. (%)||73 (45.6)||8 (34.8)||9 (34.6)||2 (28.6)||54 (51.9)|
|WBC mean (SD)a||28 (41.2)||34.50 (21.7)||37.56 (62.8)||12.5 (10.6)||25.93 (41.1)|
|Proteinorrhachia no. (%)||86 (52.5)||12 (52.2)||13 (50)||5 (71.4)||56 (51.4)|
|Protein mean (SD)a||87.21 (44.2)||87.5 (57.35)||86.25 (51.6)||137.2 (75.9)||82.38|
|SARS-CoV-2 PCR tested||145||21||27||5||92|
|Inflammatory markers (%)b||56.8%||82.6%||44.8%||40%||54.1%|
|Imaging and EEG|
|MRI performed no.||173||20||35||12||106|
|CT performed no.||41||11||7||5||18|
|EEG performed no.||59||4||12||2||41|
|Generalized slowing (%)||40.7||75||66.7||100||29.3|
|Other findings (%)||52.5||25||33.3||0||61|
Pleocytosis is defined as and high proteinorrhachia as of cerebrospinal fluid. LP, lumbar puncture; PCR, polymerase chain reaction; MRI, magnetic resonance imaging; CT, computed tomography; EEG, electroencephalogram; WBC, white blood cell; ADEM, Acute disseminated encephalomyelitis,AHLE, Acute Hemorrhagic Leukoencephalitis; ANE, Acute Necrotizing Encephalitis; AHNE, Acute Hemorrhagic Necrotizing Encephalitis. aMean and standard deviation of values above normal limit. bProportion calculated within individually reported values.
Specific clinical manifestations such as neck stiffness and photophobia were described in four patients. Declined consciousness was the most common clinical finding including 6 cases of delayed post-sedation consciousness recovery. Delay of neurological presentations was the least in prevalence and length among all four groups. Prevalence of all CNS symptoms in patients with meningoencephalitis is summarized in Table 3.
|Signs and symptoms no. (%)||Meningoencephalitis (n = 26)||ADEM/AHLE (n = 35)||AHNE/ANE (n = 12)|
|Impaired consciousness||21 (80.8)||24 (68.6)||12 (100)|
|Psychiatric or cognitive deficit||14 (53.8)||11 (31.4)||6 (50)|
|Seizure||4 (15.4)||1 (2.9)||2 (16.7)|
|Autonomic instability||1 (3.8)||2 (5.7)||0 (0)|
|Sensory defect||1 (3.8)||6 (17.1)||1 (8.3)|
|Movement and gait defect||5 (19.2)||16 (45.7)||5 (41.7)|
|Cranial nerve signs||5 (19.2)||15 (42.9)||2 (16.7)|
|Abnormal reflex and tonicity||2 (7.7)||21 (60)||0 (0)|
ADEM, Acute Disseminated Encephalomyelitis; AHLE, Acute Hemorrhagic Leukoencephalitis; ANE, Acute Necrotizing Encephalitis; AHNE, Acute Hemorrhagic Necrotizing Encephalitis.
Acute disseminated encephalomyelitis
Twenty three studies described a total of 35 patients with acute disseminated encephalomyelitis (ADEM), including 11 cases of acute hemorrhagic leukoencephalitis (AHLE), a severe form of ADEM.
From all CSF samples obtained 35% showed pleocytosis, among which only one had a marked number of cells (>100/ ). Increased CSF total protein was reported in 50% of cases and CSF SARS-CoV-2 PCR was positive in one case. Five cases were reported with elevated CSF IgG level. CSF-specific oligoclonal bands were detected in two cases, whereas it was absent or mirror in eight patients.
All patients presented with abnormal MRI, suggesting of ADEM or AHLE. Lesions were typically located in cerebral white matter and white matter tracts (e.g. corpus callosum), pons, cerebral peduncles and rarely included deep gray matter. Radiological evidence of spinal cord involvement was reported in six patients and cranial nerve lesions were seen in 3 cases. Head CT showed hypodensity of corresponding lesions in four patients. EEG demonstrated diffuse slowing in all cases performed, of which four patients also presented localized or asymmetric abnormality (Table 2).
After reduced level of consciousness, the most common presentations were hyperreflexia/hyporeflexia and limb weakness. Other neurological manifestations include cranial nerve signs, motor and gait defect, psychiatric/cognitive abnormality and sensory loss. A total of seven patients presented with delayed consciousness and neurological involvement after weaning off sedation. Seizures and dysautonomia was only reported in cases of AHLE (Table 3).
Acute (hemorrhagic) necrotizing encephalitis
Twelve patients reported in 10 studies were diagnosed with acute necrotizing encephalitis (ANE), including 5 cases with hemorrhage, defined as acute hemorrhagic necrotizing encephalitis (AHNE). Underlying diseases was reported in one case with chronic hypertension and one case with type 2 diabetes mellitus.
From only seven CSF examinations, five had increased protein level and two had both increased protein and pelocytosis. Positive SARS-CoV-2 PCR of CSF was reported in one patient. Three cases reported increased CSF IgG level and CSF-specific oligoclonal bands were reported in one out of four cases examined. All patients had abnormal MRI findings demonstrating necrotizing or hemorrhagic lesions, predominantly in thalami, deep gray matter of basal ganglia, and medial temporal lobes. Head CT contained hypoattenuation of similar regions as well as swelling or hemorrhage. EEG was recorded in two cases with diffuse slowing.
Altered mental status in the form of impaired consciousness and orientation was the most common clinical profile, rarely accompanied by speech, memory or motor defects. Seizures, cranial nerve signs, and sensory loss were present in less than half of patients (Table 3).
A total number of 49 studies reported on 109 patients with encephalitis in the context of SARS-CoV-2 infection. These cases are not categorized under any of the mentioned categories, yet are identified as probable or definite encephalitis.
Lumbar puncture was performed at least once in 104 patients, among which 54 showed pleocytosis. Out of 92 cases tested, only 8 cases had positive CSF SARS-CoV-2 PCR result.
Abnormal brain MRI was described in 75 patients with a highly variable pattern and extent, predominantly including temporal, medial temporal and frontal regions. Hyperintensity of parietal lobes, deep white matter, claustrum, and pons and pulvinar areas was also described in several cases as well as white matter tracts and basal ganglia. Few cases were reported with microhemorrhages or subtle ischemic lesions in various areas. While 24 cases presented with symmetrical changes of hemispheres, others had asymmetrical or unilateral pattern of lesions. Head CT scan was abnormal in 27.8% and EEG in 90.2% of patients examined with mostly unspecific findings (Table 2).
Cognitive, psychiatric, consciousness, and motor disturbance were the most frequent neurological presentations, followed by cranial nerve signs and seizures (Table 4). Fourteen patients developed neurological symptoms, mostly in the form of delayed consciousness, after extubation or weaning off sedation.
|Signs and symptoms no. (%)||Limbic encephalitis (n = 7)||Brainstem encephalitis (n = 3)||Cerebellitis (n = 3)||Othera (n = 96)|
|Impaired consciousness||2 (28.6)||1 (33.3)||0 (0)||65 (67.7)|
|Psychiatric or cognitive deficit||5 (71.4)||1 (33.3)||0 (0)||71 (74)|
|Seizure||4 (57.1)||0 (0)||0 (0)||24 (25)|
|Autonomic instability||0 (0)||0 (0)||0 (0)||3 (3.1)|
|Sensory defect||0 (0)||1 (33.3)||0 (0)||4 (4.2)|
|Movement and gait defect||1 (14.3)||2 (66.7)||3 (100)||47 (49)|
|Cranial nerve signs||3 (42.9)||2 (66.7)||2 (66.7)||30 (31.3)|
|Abnormal reflex and tonicity||1 (14.3)||1 (33.3)||0 (0)||9 (9.4)|
aPatients categorized under this group compromise a range of cerebral involvement that is rather dispersed and cannot be classified based on localization of lesions. They are presented with cortical, subcortical or deep brain inflammation without specific signs of lower regions involvement. Limbic system lesions co-existed with other parts of cerebral parenchyma lesion in imaging, however, since the presentations were not specific, they could not be classified as isolate limbic encephalitis.
Diagnosis of encephalitis was subcategorized in 13 cases, as stated by authors: Seven patients identified as limbic encephalitis, of which two patients fulfill the criteria of definite autoimmune limbic encephalitis, and three had asymmetrical medial temporal involvement. Three patients identified as brainstem encephalitis, including one case of Bickerstaff brainstem encephalitis. Three patients were categorized as cerebellitis. The latter contains patients without obvious signs of altered mental status; however, we propose that similar mechanisms may be responsible for involvement of cerebellum, and if not a subtype of encephalitis, it could be considered as a highly overlapping disorder in the case of viral infections (Venkatesan and Murphy 2018).
Twelve cases from the total of 109 encephalitis patients were suspected of AIE. The diagnosis of definite AIE could be made in seven patients based on detection of autoantibodies in CSF or serum, including four patients with anti NMDAR, one anti GD1a, one anti CASPR2, and one unclassical anti MOG antibody encephalitis. Five other patients are considered as probable AIE based on suggestive imaging findings, CSF-specific oligoclonal bands and/or raised CSF IgG index (Table 5). All other patients with encephalitis and negative CSF PCR could be considered as possible autoimmune encephalitis.
|Author||Álvarez Bravo and Ramió i Torrentà (2020)||Ayatollahi et al. (2020)||Dono et al. (2020)||Franke et al. (2021)||Grimaldi et al. (2020)||Guilmot et al. (2020)||Llorente Ayuso et al. (2020)||Monti et al. (2020)||Mulder et al. (2021)||Panariello et al. (2020)||Pinto et al. (2020)||Zuhorn et al. (2020)|
|AIE criteria||Anti NMDAR antibody||Imaging||OCB||anti-NMDAR antibody||CSF IgG||anti-CASPR2 antibody||anti-GD1a antibody and clinical profile||anti-NMDAR antibody||CSF OCB and antineural IgG||anti-NMDAR antibody||anti-MOG antibody||Imaging|
|Category||Encephalitis||Encephalitis||Encephalitis||Encephalitis||Encephalitis, cerebellitis||Limbic encephalitis||Bickerstaff encephalits||Encephalitis||Encephalitis||Encephalitis||Encephalitis, vasculopathy||Encephalitis|
|Neurological findings||Psychomotor agitation, paranoia and hallucination, cognitive and memory disorder, dysarthria with dysprosody, seizures, impaired consciousness, and face and limb movement abnormality.||Impaired consciousness, seizure, disorientation, impaired memory, weakness and hyperreflexia, urinary retention, abnormal movement, and myoclonus, behavioral changes.||Impaired consciousness, status epilepticus, and jerky myoclonus||Downbeat nystagmus, orofacial myoclonus, and delirium.||Action tremor, cerebellar syndrome, and myoclonus.||Hallucination, memory disturbance, behavioral changes, dysarthria, and seizure.||Delirium and impaired consciousness, disorientation, oscillopsia, downbeat nystagmus, and ataxia.||Psychiatric symptoms, sizure, impaired consciousness, and orofacial dyskinesia||Agitation, hallucination, memory and emotion disturbance, behavioral changes, mutism, hyperkinesia and hyperreflexia, dysautonomina, and abnormal tonicity.||Behavioral changes, hallucination and other psyciatrc symptoms, impaired consciousness, dysphagia, dyskinesia, and dysautonomia.||Limb incoordination and weakness, aphasia, and attention deficit||Agressiveness, disorientation, impaired consciousness, delirium, and concentration problem.|
|CSF WBC||44 (90% lymphocyte)||20 (100% lymphocyte)||26||8||4||0||0||76, 25, 16||31, 11||960 cells including RBC||13, 8||9 (88% lymphocyte)|
|EEG findings||Epileptic discharges in the left frontotemporal region||Moderate bilateral nonepileptiform abnormalities||Sharp waves, spike-and-slow waves and fast activity in left fronto-temporal||NR||Background slowing||NR||Normal||Diffuse delta activity, anterior periodic theta activity||Non-specific slowing with left hemisphere predominance||Theta wave, unstable nonresponsive to visual stimuli||NR||NR|
|Imaging findings||Hyperintensity in left hippocampus||MRI hyperintensity in claustrum, CT normal||Hyperintesity in bilateral parietal cortex, left temporal cortex, and right cingulate cortex||NR||MRI normal, putaminal and cerebellum hypermetabolism on PET||NR||MRI hyperintensity in caudal vermis and right flocculus, contrast enhancement in the floor of the fourth ventricle, CT normal||MRI normal||MRI normal, PET higher uptake in striatum||NR||MRI hyperintensity in centrum semiovale with extension to hemispheres, perivascular enhancement.||MRI hyperintensity in caudal vermis and right flocculus, ontrast enhancement in the floor of the fourth ventricle, CT normal|
|Conclusion||Definite AIE||Probable AIE||Probable AIE||Definite AIE||Probable AIE||Definite AIE||Definite AIE||Definite AIE||Probable AIE||Definite AIE||Unclassical anti-MOG encephalitis||Probable AIE|
AIE, autoimmune encephalitis; NMDAR, N-methyl-d-aspartate receptor; OCB, oligoclonal bands; CSF, cerebrospinal fluid; CASPR2, contactin associated protein 2; MOG, myelin oligodendrocyte glycoprotein.
Encephalitis is known to be associated with various viral infections such as Herpesviridae family and enteroviruses. Demyelinating pathologies such as ADEM are best known to be triggered by infection in children rather than adults and necrotizing encephalopathies are mostly described in cases of influenza virus (Venkatesan and Murphy 2018).
Neurological manifestations in the context of Covid-19 infection are increasingly reported during one year of global pandemic. In an early survey of hospitalized Covid-19 patients in China, the prevalence of CNS symptoms was estimated to be 25% (Mao et al. 2020). Later, various observational studies reported different proportions of neurological involvement in hospitalized population; including 8.8% in a study of 490 patients (Meppiel et al. 2020). The incidence of encephalitis reported in a retrospective study of 841 patients was 0.1% and loss of consciousness was found to be correlated with disease severity (Romero-Sánchez et al. 2020).
The first case of SARS-CoV-2-induced encephalitis is an unpublished hospital record of status epilepticus, with negative imaging and positive CSF PCR result (Xiang et al. 2020), bringing up the possibility of direct CNS infection (This case is not included in this manuscript). However, numerous cases with negative CSF PCR as well as delayed neurological involvement shed light on the possibility of immune-mediated post-infectious or para-infectious encephalitis.
There are potential mechanisms of neuroinflammation in SARS-CoV-2 infection:
Immune-mediated inflammation and migration of inflammatory agents to CNS; as evidenced by encephalitis concomitant with cytokine storm (Pilotto et al. 2021).
Direct neuronal invasion via cribriform plate and olfactory bulb or other cranial nerves; as supported by olfactory invasion and manifestations (Lu et al. 2020).
For cases with critical respiratory disease, another possible explanation is septic, metabolic or intubation-related encephalopathy. It is currently impossible to rule out any of these hypotheses, and it is most likely that they are all existing simultaneously or in correlation (Panciani et al. 2020).
In-vitro studies and evidence of neurotropism in other members of the coronavirus family provide potential explanations for direct neuronal infection (Bullen et al. 2020; Desforges et al. 2019; Jensen et al. 2020). A molecular analysis of anti SARS-CoV-2 human antibodies demonstrated the cross-reaction of antibodies against viral spike protein and nucleoprotein, with several human antigens, including neurofilament proteins, which is known to be involved in neurodegeneration (Vojdani et al. 2020). High antigenic similarity between SARS-CoV-2 and various human proteins is as well documented in epitope mapping of this virus (Lucchese and Flöel 2020; Marino Gammazza et al. 2020).
Postmortem analyses of deceased Covid-19 patients demonstrate a range of hemorrhagic lesions to lymphocytic infiltrations. An interesting autopsy report presented ADEM-like hemorrhagic pathology with unclassical myelin loss (Reichard et al. 2020). Another postmortem study reported positive RT-PCR result in frozen brain parenchyma but negative in CSF, along with blebbing pattern of viral particles across the brain endothelium; supporting the hematogenous hypothesis and also explaining the paucity of PCR-positive CSF samples (Paniz-Mondolfi et al. 2020).
Herein, we reviewed clinical characteristics of brain inflammation or invasion, in the form of encephalitis, meningoencephalitis, encephalomyelitis and necrotizing/hemorrhagic lesions.
Ninety one percentage of patients reviewed in this paper presented with negative CSF PCR, and almost 54% showed neurological involvement in a delayed timespan from systemic or respiratory disease.
Altogether and in agreement with previous hypotheses, we suggest that immune-mediated inflammation of CNS is, if not the only cause, an important contributor to encephalitis spectrum outcomes of Covid-19.
Nevertheless, there are several limitations in interpretation of these findings that needs to be addressed: First, sensitivity and specificity of PCR in cerebrospinal fluid is still largely unknown and a proper tool for this specific examination is not yet developed. Most authors only reported one CSF examination, and it is likely that they have missed the window in which the virus is detectable. It is also possible that viral particles in CSF are in undetectable trace amounts (Virhammar et al. 2020 In addition, PCR was performed with different tools and protocols among various studies and there is a potential bias in pooling these results into one proportion. Second, high rate of false negative CSF PCR is demonstrated in many types of viral encephalitis and it could be the case in SARS-CoV-2 (Costa and Sato 2020). Third, there may be a reporting bias towards publishing cases with positive CSF PCR result, potentially overestimating the prevalence. Therefore, concluding on the probability of direct invasion based on the frequency of viral particles in CSF lacks enough accuracy. On the other hand, it is not always possible to exclude AIE based on clinical presentations or imaging; oligoclonal bands and antineural antibodies panel were examined in a small proportion of cases. It is likely that the prevalence of autoantibodies is considerably higher than estimated. Finally, a definite diagnosis of viral encephalitis could only be made via detection of viral particles in CSF or specific intrathecal antibodies. In a pandemic age, full laboratory analysis of each patient with an atypical manifestation is not readily accessible; therefore, a clinical diagnosis was made in most cases, based on presentations, imaging and molecular analysis, and a lack of evidence for an alternative cause. Although these data are promising to guide further studies and an initial description of a new disease, it should be noted that interpretation of findings could be biased when lacking a definite diagnosis.
Neurological symptoms of viral encephalitis vary from psychiatric/cognitive alterations in HSV to motor and cranial defect in West Nile and Mumps viruses (Venkatesan and Murphy 2018). Clinical picture of encephalitis in Covid-19 patients are widely heterogenous and involves all categories of neuropsychiatric evaluations. Similar to Herpesviridae family, we found considerable frequency of neuropsychiatric and cognitive abnormalities, specially aphasia, agitation and altered behavior in cases reported with neurologic Covid-19 manifestations. Impaired level of consciousness, ranging from mild confusion to lethargy and stupor, was reported in a vast number of publications. Most frequent motor disturbances were ataxia, paresis, myoclonus and tremor, along with gait and balance defects. Generalized or focal seizures and status epilepticus was described in 31 patients among all categories. Similar to many other viral etiologies of encephalitis, cranial nerve signs are frequently reported in Covid-19 patients, with or without CNS involvement. Cranial signs predominantly include hyposmia, hypogeusia, dysarthria, and dysphagia. Mechanism and location of cranial nerves inflammation is yet to be further investigated and its relation to other CNS or PNS involvements may be enlightening. Other types of neurologic manifestation such as sensory disturbance, dysautonomia, and dysreflexia were rarely reported. Furthermore, several cases were described as delayed consciousness, unresponsive wakefulness or delirium following sedation or intubation, including 6 cases in a single series of meningoencephalitis patients (Dogan et al. 2020).
According to Venkatesan and Geocadin (2014), CSF pleocytosis, seizures, abnormal EEG, and imaging findings are minor criteria suggesting acute encephalitis in addition to altered mental status as the major criterion. Different pathogens have few variations in clinical profile of CNS inflammation, making each criterion less or more helpful to stablish a diagnosis. Regarding data reviewed in this study, approximately 73% of patients with encephalitis and 65% of cases with meningoencephalitis had positive MRI findings. As expected, MRI abnormality was present in all patients with ADEM or ANE, and CT was suggestive of neuroinflammation in only half of all cases. EEG was performed in only one third of all patients and was predominantly abnormal with a variety of patterns, including periodic discharges, epileptic activity, spike waves, and localized or diffuse slowing. CSF pleocytosis (WBC count ≥ 5/ ) was only detected in 54% of cases with encephalitis and less than half of cases with meningoencephalitis, ADEM, or ANE. Among 13 cases with positive CSF SARS-CoV-2 PCR, we did not notice any commonalities, except the dominant prevalence of temporal lobe lesions, which was in accordance with the rest of the patients.
Preponderance of negative CSF PCR and pleocytosis highlights the role of imaging and EEG in fulfilling the criteria for viral encephalitis, or even developing new criteria for diagnosis of encephalitis in Covid-19 patients with neurological manifestations. Management of encephalitis highly depends on its cause or pathogen and it requires extensive research to identify the best treatment option and an accurate management protocol for central neuroinflammation in Covid-19 patients. Still, it can be enlightening to sum up reported experiences and their possible outcomes: Among herein-reviewed cases, the most commonly chosen treatment option was intravenous corticosteroids, occasionally in companion with intravenous immunoglobulins, plasma exchange and antiepileptic medications (Delamarre et al. 2020; Dogan et al. 2020). Several studies reported considerable improvement after corticosteroid treatments (Pilotto et al. 2020a,b); however, it cannot be ruled out that the disease is self limiting in nature. Further studies on the effect of immunosuppression, antiviral drugs and other management options are warranted.
Our pooled evidence suggests that Covid-19-related encephalitis presents with a delayed presentation of mostly psychiatric, consciousness, motor and/or cranial symptoms. CSF profile consists of either normal cell count or mild to moderate pleocytosis, absent or only mild proteinorrhachia and predominantly normal glucose level. Regarding the growing evidence of molecular mimicry between SARS-CoV-2 and human neural antigens, and the evidence of autoantibody formation in cases reviewed in this paper, we propose that OCB and autoantibody examinations would have diagnostic value and can guide further studies on the molecular basis of SARS-CoV-2-related encephalitis.
EEG and MRI are useful tools to evaluate brain involvement and immunosuppressive therapy should be considered for further research on treatment of SARS-CoV-2 encephalitis.
Acute demyelinating, hemorrhagic or necrotizing encephalopathies are frequently reported in adults with Covid-19 and must be considered in approaching neuro-Covid patients. MRI seems to be the most sensitive approach for diagnosis, with white matter lesions in cases of ADEM and deep gray matter abnormalities in ANE/AHNE.
Considering high transmission rate of SARS-CoV-2 and health care facility crisis in the pandemic and post-pandemic era, it is crucial to evolve comprehensive guidelines and considerations to approach neuroinflammation in the context of Covid-19. Evidences of immune and autoimmune mechanisms of CNS involvement, bring up the possibility that neuroinflammation may occur as a long-term consequence of Covid-19 and must be screened and evaluated among recovered patients in months and years after infection.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
Appendix 1: All included publications
|First author||Country||Type of work||Included cases||Category of disease|
|Abdi (Abdi et al. 2020)||Iran||Case report||1||ADEM|
|Al-Olama (Al-Olama et al. 2020)||United Arab Emirates||Case report||1||Meningoencephalitis|
|Álvarez Bravo (Álvarez Bravo and Ramió i Torrentà 2020)||Spain||Case report||1||Autoimmune encephalitis|
|Arca (Arca and Starling 2020)||United States||Case report||1||Meningoencephalitis|
|Assunção (Assunção et al. 2021)||Brazil||Case series||1||ADEM|
|Ayatollahi (Ayatollahi et al. 2020)||Iran||Case report||1||Encephalitis|
|Babar (Babar et al. 2020)||United States||Case report||1||Encephalitis|
|Benameur (Benameur et al. 2020)||United States||Case series||1||Encephaitis and myelitis|
|Bernard–Valnet (Bernard–Valnet et al. 2020)||Switzerland||Case series||2||Meningoencephalitis|
|Bodro (Bodro et al. 2020)||Spain||Case series||2||Encephalitis|
|Cao (Cao et al. 2020)||France||Case series||5||Encephalitis|
|Casez (Casez et al. 2021)||France||Case report||1||Encephalitis|
|Chaumont (Chaumont et al. 2020)||France||Case report||1||Meningoencephalitis|
|Corrêa (Corrêa et al. 2021)||Brazil||Case report||1||Encephalomyeloradculitis|
|Delamarre (Delamarre et al. 2020)||France||Case report||1||ANE|
|Delorme (Delorme et al. 2020)||France||Case series||3||Encephalitis|
|Dharsandiya (Dharsandiya et al. 2020)||India||Case report||1||Meningoencephalitis|
|Dixon (Dixon et al. 2020)||United Kingdom||Case report||1||ANE|
|Dogan (Dogan et al. 2020)||Turkey||Case series||6||Meningoencephalitis|
|Dono (Dono et al. 2020)||Italy||Case report||1||Encephalitis|
|Duong (Duong et al. 2020), Huang (Huang et al. 2020)||United States||Case report||1||Meningoencephalitis|
|Efe (Efe et al. 2020)||Turkey||Case report||1||Encephalitis|
|El-Zein (El-Zein et al. 2020)||United States||Case report||1||Meningoencephalitis|
|Etemadifar (Etemadifar et al. 2020)||Iran||Case report||1||Encephalitis|
|Fadakar (Fadakar et al. 2020)||Iran||Case report||1||Cerebellitis|
|Fitouchi (Fitouchi et al. 2020)||France||Case report||1||ADEM|
|Franke (Franke et al. 2021)||Germany||Case series||1||Encephalitis|
|Freire–Álvarez (Freire–Álvarez et al. 2020)||Spain||Case report||1||ADEM|
|Ghosh (Ghosh et al. 2020)||India||Case report||1||AHNE|
|Green (Green et al. 2020)||United Kingdom||Case report||1||ADEM|
|Grimaldi (Grimaldi et al. 2020)||France||Case report||1||Autoimmune encephalitis and cerebellitis|
|Guilmot (Guilmot et al. 2020)||Belgium||Multicenter/retrospective study||1||Autoimmune limbic encephalits|
|Hafizi (Hafizi et al. 2020)||United States||Case report||1||Meningoencephalitis|
|Haider (Haider et al. 2020)||United States||Case report||1||Encephalitis|
|Handa (Handa et al. 2020)||India||Case report||1||AHLE|
|Hosseini (Hosseini et al. 2020)||United Kingdom||Case series||2||1 encephalitis
1 limbic encephalitis
|Jeffrey (Sachs et al. 2020)||United States||Case report||1||ADEM|
|Jensen (Jensen et al. 2020)||United Kingdom||Case series||1||Brainstem encephalitis|
|Kamal (Kamal et al. 2020)||United Arab Emirates||Case report||1||Encephalitis|
|Karapanayiotides (Karapanayiotides et al. 2020)||Greece||Case report||1||AHLE|
|Karimi (Karimi et al. 2020)||Iran||Case report||1||Encephalitis|
|Khan (Khan and Khan 2020)||Pakistan||Case report||1||Meningoencephalitis|
|Khoo (Khoo et al. 2020)||United Kingdom||Case report||1||Encephalitis|
|Koh (Koh et al. 2020)||Singapore||Multicenter/retrospective study||4||2 encephalitis
1 ADEM, 1 AHLE
|Kremer (Kremer et al. 2020)||France||Multicenter/retrospective study||7||2 encephalitis, 2 limbic encephalitis
|Kulick–Soper (Kulick–Soper et al. 2020)||United States||Case report||1||AHNE|
|Kumar (A. Kumar et al. 2020)||United States||Case report||1||ADEM|
|Kumar (N. Kumar et al. 2020)||India||Case report||1||ANE|
|Langley (Langley et al. 2020)||United Kingdom||Case report||1||ADEM|
|Le Guennec (Le Guennec et al. 2020)||France||Case report||1||Encephalitis|
|Llorente (Llorente Ayuso et al. 2020)||Spain||Case report||1||Bickerstaff brainstem encephalitis|
|Mardani (Mardani et al. 2020)||Iran||Case report||1||Meningoencephalitis|
|McCuddy (McCuddy et al. 2020)||United States||Case series||3||ADEM|
|Meppiel (Meppiel et al. 2020)||France||Multicenter/retrospective study||21||Encephalitis|
|Moghimi (Moghimi et al. 2021)||Iran||Case series||8||Meningoencephalitis|
|Monti (Monti et al. 2020)||Italy||Case report||1||Encephalitis|
|Moriguchi (Moriguchi et al. 2020)||Japan||Case report||1||Meningoencephalitis|
|Muccioli (Muccioli et al. 2020)||Italy||Case report||1||Encephalitis|
|Mulder (Mulder et al. 2021)||Sweden||Case report||1||Encephalitis|
|Nersesjan (Nersesjan et al. 2021)||Denmark||Multicenter/retrospective study||2||1 encephalitis
|Novi (Novi et al. 2020)||Italy||Case report||1||ADEM|
|Panariello (Panariello et al. 2020)||Italy||Case report||1||Encephalitis|
|Parsons (Parsons et al. 2020)||Italy||Case report||1||ADEM|
|Paterson (Paterson et al. 2020)||United Kingdom||Multicenter/retrospective study||8||4 ADEM, 4 AHLE|
|Perrin (Perrin et al. 2020)||France||Case series||3||AHLE|
|Picod (Picod et al. 2020)||France||Case report||1||Encephalitis|
|Pilotto (Pilotto et al. 2021)||Italy||Multicenter/retrospective study||13||Encephalitis|
|Pilotto (Pilotto et al. 2020b)||United Kingdom||Case report||1||Encephalitis|
|Pilotto (Pilotto et al. 2020a)||Italy||Multicenter/retrospective study||15||10 encephalitis,
2 limbic encephalits
|Pinto (Pinto et al. 2020)||United Kingdom||Case report||1||Encephalitis and vasculopathy|
|Povlow (Povlow and Auerbach 2021)||United States||Case report||1||Cerebellitis|
|Poyiadji (Poyiadji et al. 2020)||United States||Case report||1||AHNE|
|Rifino (Rifino et al. 2020)||Italy||Multicenter/retrospective study||5||Encephalitis|
|Romero–Sanchez (Romero–Sánchez et al. 2020)||Spain||Multicenter/retrospective study||1||Encephalitis|
|Sattar (Sattar et al. 2020)||United States||Case report||1||Encephalitis|
|Sohal (Sohal and Mansur 2020)||United States||Case report||1||Encephalitis|
|Umapathi (Umapathi et al. 2020)||Singapore||Case series||3||2 encephalitis, 1 ADEM|
|Utukuri (Utukuri et al. 2020)||United States||Case report||1||ADEM|
|Vandervorst (Vandervorst et al. 2020)||Belgium||Case report||1||Encephalitis|
|Virhammar (Virhammar et al. 2020)||Sweden||Case report||1||ANE|
|Wang (Wang et al. 2020)||China||Case report||1||Encephalitis|
|Wong (Wong et al. 2020)||United Kingdom||Case report||1||Rhombencephalitis and myelitis|
|Ye (Ye et al. 2020)||China||Case report||1||Encephalitis|
|Yong (Yong et al. 2020)||Singapore||Case report||1||AHLE|
|Zambreanu (Zambreanu et al. 2020)||United Kingdom||Case report||1||Limbic encephalits|
|Zhang (Zhang et al. 2021)||United States||Case report||1||ADEM|
|Zoghi (Zoghi et al. 2020)||Iran||Case report||1||ADEM|
|Zuhorn (Zuhorn et al. 2020)||Germany||Case report||1||Encephalitis|
ADEM, acute disseminated encephalomyelitis; AHLE, acute hemorrhagic leukoencephalitis; ANE, acute necrotizing encephalitis; AHNE, acute hemorrhagic necrotizing encephalitis.
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