Encephalitis > Volume 4(1); 2024 > Article
Sawalha, Alkilani, and Abdelaziz: The association between autoimmune encephalitis mediated by N-methyl-ᴅ-aspartate receptor autoantibodies and COVID-19: a systematic review


Neurological complications related to coronavirus disease 2019 (COVID-19) infection have been increasingly reported. One of the most serious neurological complications is encephalitis, which could be due either to direct viral invasion or an immune-mediated inflammatory reaction. In this study, we conducted a systematic review of reported cases of autoimmune encephalitis mediated by N-methyl-ᴅ-aspartate receptor antibodies in conjunction with or after diagnosis of COVID-19 infection.


The coronaviruses are one of the RNA virus families characterized by positive charge, envelopment, and a single strand [1]. The novel coronavirus disease 2019 (COVID-19) was reported for the first time in Wuhan, China, in December 2019 [2]. Shortly after that, reports emerged on the effect of COVID-19 on all body systems, including but not limited to the nervous system. Several case reports and systematic reviews have described neurological manifestations of COVID-19, including Guillain-Barré syndrome and seizures. However, one of the rarely reported observations of COVID-19 infection is its association with the onset of autoimmune encephalitis [3]. We conducted this review to outline the association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and N-methyl-ᴅ-aspartate receptor (NMDA-R) antibody encephalitis.


Search strategy

We searched the Cochrane Library 2023, MEDLINE (December 2019 to August 2023), EMBASE (December 2019 to August 2023), PubMed (December 2019 to August 2023), Scopus, and Web of Science databases according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [4]. There were no restrictions of language or date during our electronic search for case reports or case series.
The following search strategy was utilized with the following keywords and their synonyms (in all fields): ([SARS-CoV-2] OR COVID OR COVID-19 OR coronavirus) AND (Encephalitis OR [limbic encephalitis]) AND ([Anti-N-Methyl-D-Aspartate Receptor Encephalitis] OR [NMDA] OR [Autoimmune limbic encephalitis] OR [anti-NMDA receptor autoantibody] OR [Receptors, N-Methyl-D-Aspartate]).
Case series and case reports of COVID-19 with evident autoimmune encephalitis mediated by NMDA-R autoantibodies were confirmed by cerebrospinal fluid (CSF) analysis. After exclusion of duplicates, all articles were evaluated through title and abstract screening by three independent reviewers, followed by a detailed and accurate reading of all full-text articles.

Inclusion criteria

The inclusion criteria for the articles were as follows: (1) Described patients with neurological signs or symptoms concerning autoimmune encephalitis attributed to COVID-19; (2) COVID-19 infection proven via SARS-CoV-2 polymerase chain reaction testing with nasopharyngeal or oropharyngeal swab; (3) Published in a peer-reviewed journal.
Cases of autoimmune encephalitis that occurred after COVID-19 vaccination were excluded. Only cases that occurred with a direct relationship to COVID-19 infection were included.

Study selection and data extraction

All reviewers performed data extraction for patient demographics, COVID-19 testing from a nasal swab and CSF, respiratory or other body system involvement in COVID-19 infection, the time between COVID-19 infection and the onset of autoimmune encephalitis symptoms, CSF analysis, treatment used, and outcome. Symptoms included an altered mental status, seizures (generalized or focal), sleep disturbances, abnormal movements (including dystonia or chorea), cognitive dysfunction, mood symptoms, and psychosis. We defined the outcome using one of the following terms: good, recovering, and poor. A good outcome was defined as discharged home and/or use of the following descriptive terms in the study: “no morbidity” or “good recovery.” If the patient was discharged to a rehabilitation facility, then the outcome was defined as “recovering” and/or if any of the following terms were used: “started to improve” or “recovering.” A poor outcome was defined as continued worsening of the condition despite adequate treatment and period of observation. If the onset of autoimmune encephalitis symptoms and signs started within 5 days of the onset of COVID-19 respiratory or systemic symptoms, they were labeled as simultaneous onset.
Normal white blood cell (WBC) count results in CSF values were stratified by age. For adult patients, the normal WBC value is <5 cells/mm3. For people from the age of 5 years to puberty, the normal value is 0–10/mm3, while people from the age of 1–4 years have a normal value of 0–20/mm3. Finally, for patients younger than 1 year, the normal value is 0–30/mm3 [5]. A normal protein count in the CSF was defined as equal to or less than 45 mg/dL.


Our search strategy identified 19 peer-reviewed case reports of confirmed COVID-19 infection and autoimmune encephalitis mediated by NMDA-R autoantibodies. The total number of patients involved was 19 (Figure 1).
The number of adult patients (age, >17 years) included was 13, and the mean age was 35.8 years (range, 18–65 years). The number of pediatric patients was six, and the mean age was 5.6 years (range, 1–11 years). There was equal inclusion of both sexes, with 53% of patients being female (n = 10) (Table 1 [6-24]).
CSF testing for COVID-19 was performed in three patients only, one of whom was positive. In addition, 58% of patients (n = 11) had respiratory infection manifestations (including upper or lower respiratory tract involvement). In patients with no respiratory infection manifestations prior to the onset of neurological manifestations, COVID-19 infection was discovered incidentally by nasal or oropharyngeal swab test (Figure 2). Of the 11 patients who had no systematic involvement of COVID-19, three had fever.
It was found that 70% of the patients (n = 7) who had respiratory manifestations with COVID-19 infection had a simultaneous onset of the neurological manifestations of autoimmune encephalitis. Two patients had onset after 2 weeks, and one had onset of neurological manifestations after 1 week (Figure 3).
Among patients with confirmed NMDA-R antibodies in the CSF, six had a positive serum test for NMDA-R autoantibodies. One patient demonstrated co-expression of NMDA-R antibodies and anti-glutamic acid decarboxylase 65 (GAD 65) antibodies.
The CSF analysis of WBCs was normal in 100% of pediatric cases (n = 6) and five of the 13 adult patients (38%). The average CSF WBC count in patients with elevated WBCs was 97.8/mm3 (range, 7–500/mm3). Unfortunately, most of the articles did not mention if the WBCs were predominantly composed of lymphocytes or polymorphonuclear cells.
All pediatric patients and five adult patients (38%) had a normal protein count. The average protein count in patients with elevated protein in the CSF was 218.6 mg/dL (range, 48–770 mg/dL).
The most prevalent neurological manifestation was an altered mental status (n = 17, 89%), which is defined by a reduced level of consciousness or disorientation. This condition was followed by focal or generalized seizures (n = 12, 63.1%). Around half of the patients had psychosis (n = 9), and 36.8% had cognitive dysfunction (Figure 4).
In total, 58% of the patients had a normal brain magnetic resonance imaging (MRI) scan at the time of presentation with neurological manifestations (n = 11). The most common abnormality noted on brain MRI was hyperintensity on T2 sequences involving the hippocampus (32%, n = 6), with bilateral involvement (n = 4) being more common than unilateral involvement (n = 2). This abnormality was followed by diffuse subcortical hyperintensity on T2 sequences (n = 2, 11%).
The majority of the patients experienced a good outcome (n = 14, 74%). The therapeutic interventions used were high-dose intravenous (IV) methylprednisolone, IV immunoglobulins (IVIG), rituximab, and plasmapheresis. Three patients had a poor outcome, and two patients had a “recovering” outcome.


Our systematic review indicates that COVID-19 infection is not only a respiratory illness, but that neurological complications also may occur. Autoimmune encephalitis is a rare disorder; however, the cases included in our review are indicative of a potential association between COVID-19 infection and autoimmune encephalitis mediated by NMDA-R autoantibodies. None of the female patients in our study had ovarian teratoma, which is an established risk factor for NMDA-R autoimmune encephalitis.
Our analysis showed that commonly used CSF markers of inflammation (WBC count and protein) are not helpful in the diagnosis of autoimmune encephalitis, and this trend was more pronounced in the pediatric population in which none of them had an elevated WBC count or protein count. This finding was based on the first lumbar puncture analysis findings, which can be a limitation as those numbers could change in the subsequent CSF analyses [25]. Immunoglobulin G synthesis and oligoclonal band analysis were not assessed, which is another limitation in the CSF analysis in this review because these substances are sensitive markers for inflammation [26].
Serum analysis of NMDA-R autoantibodies was not carried out in all patients; however, our data are in concordance with the current evidence of serum NMDA-R autoantibodies as a limited marker for autoimmune encephalitis. This trend illustrates the importance of NMDA-R autoantibodies in CSF to confirm the diagnosis [27].
Brain MRI also had its limitations in assisting with the diagnosis of autoimmune encephalitis, especially in the acute phase, with almost half of the patients having normal brain MRI. The most common finding was the involvement of the hippocampal region of the temporal lobes, which is one of the most common sites of involvement in NMDA-R autoimmune encephalitis [28].
An altered mental status was the most common neurological manifestation (n = 17, 89%), followed by seizures. Half of the patients experienced acute psychosis, and about one-third of patients demonstrated cognitive dysfunction. The neurological manifestations did not correlate with MRI-specific findings.
None of the inflammatory biomarkers (WBCs or protein count), MRI findings, or clinical symptoms correlated with the need for aggressive immunotherapy or the outcome, which could be indicative of the temporary presence of COVID-19 infection in the initiation and augmentation of encephalitis mediated by NMDA-R autoimmune encephalitis.
The distributions of the ages and genders of the affected patients were the same between adults and pediatric patients, which emphasized the pathogenic role of COVID-19 infection in this disorder.
The exact pathological role of COVID-19 infection in autoimmune encephalitis is not yet established. While some patients did not have respiratory symptoms and their positivity for COVID-19 was a coincidence, the majority of the patients had respiratory symptoms, and most neurologic manifestations started within 5 days of the onset of respiratory symptoms. Nonstructural protein mimicry of the SARS-CoV-2 virus with NMDA-R subunit epitopes was suggested as the underlying cause of the autoimmune response against NMDA-R in the brain. However, this link has not yet been proven [29]. T-helper 17 (Th17) and interleukin-6 involvement in the pathophysiology of COVID-19 infection has been linked to the pathophysiology of neuropsychiatric symptoms that may arise with COVID-19 infection [30,31]. The proinflammatory response produced by activated Th17 can disrupt the blood-brain barrier and could lead to autoimmune neurological manifestations [32].
Our systematic review is unable to provide a strong association between the SARS-CoV-2 virus and the emergence of NMDA-R. Due to the limited availability of autoimmune antibody testing around the world and the variations in testing modalities, some cases likely were missed. The approach to encephalopathy may also vary among providers. Patients who had a normal brain MRI or CSF analysis upon presentation could have had an abnormal MRI or CSF results on repeated testing. No such data were available from the outpatient follow-up visits.
The prognosis was favorable for most patients. There was no correlation between the outcome and the degree of inflammation found in the CSF, MRI findings, or therapeutic interventions used. However, all patients received IV methylprednisolone, IVIG, rituximab, or plasmapheresis as solo therapy or combined treatment. This review highlights the potential association between COVID-19 infection and autoimmune encephalitis mediated by NMDA-R antibodies and indicates the importance of early immunotherapy upon diagnosis. Further research is also needed to follow up on the patients affected by this syndrome to determine the rate of recurrence and if this is a monophasic syndrome caused by COVID-19 infection or a chronic syndrome.


Our systematic review highlights the potential association between COVID-19 infection and autoimmune encephalitis mediated by NMDA-R antibodies. It also suggests the importance of early immunotherapy upon diagnosis. Further research is needed to establish the prevalence of neurological complications of COVID-19 and to further investigate its biological background.


Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

Author Contributions

Conceptualization, Investigation, Visualization: all authors; Data curation, Methodology, Project administration: AS; Formal analysis: AS, HA; Writing–original draft: AS, HA; Writing–review & Editing: all authors

Figure 1.

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flowchart of study selection for this review

Figure 2.

The number of patients who had a fever at the time of presentation among COVID-19-infected individuals

The graph illustrates the comparison between patients who had respiratory involvement with COVID-19 infection and those who did not.
COVID-19, coronavirus disease 2019.
Figure 3.

The time of onset of neurological manifestations after COVID-19 infection respiratory involvement according to the number of patients

COVID-19, coronavirus disease 2019.
Figure 4.

Neurological manifestations in N-methyl-ᴅ-aspartate receptor autoantibody-positive patients (n = 19)

Table 1
Patients’ demographics and chronological summary of hospital course
Study  Year Age (yr) Sex MRI brain findings COVID-19 systemic symptomsa) Fever at the time of presentation of neurological symptoms Time from COVID-19's first systematic symptoms to the onset of the neurological manifestations CSF WBC count (/mm3) CSF glucose (mg/dL) CSF protein (mg/dL) Main clinical features Treatment Outcome
Adauto Luizaga et al. [6] 2022 2 M Normal None Absent NA Choreoathetotic movements in all extremities IVMP Good
Language deficits IVIG
Cognitive dysfunction
Allahyari et al. [7] 2021 18 F Diffuse subcortical edema Respiratory Present Simultaneous 27 55 241 Altered mental status IVIG Good
Álvarez Bravo [8] 2020 30 F Hippocampal Respiratory Present Simultaneous 44 54 Altered mental status IVMP Poor
Unilateral Focal and generalized seizures IVIG
Psychosis: psychomotor agitation, paranoid ideation, and visual hallucinations Rituximab
Ariza-Varón et al. [9] 2022 48 F Hippocampal Respiratory Present Simultaneous Normal Normal Altered mental status IVMP Good
Burr et al. [10] 2021 2 F Normal None Present NA 7 56 25 Altered mental status IVMP Good
Derakhshani et al. [11] 2023 11 F Normal None Present NA 0 51 9 Altered mental status IVIG Good
Psychosis Rituximab
Cognitive dysfunction
Khan et al. [12] 2022 18 M Normal None Absent NA 21 Normal Altered mental status IVMP Good
Seizures Plasmapheresis
Dystonic posturing
Hara et al. [13] 2021 65 M Normal Respiratory Present After 7 days 18 115 Altered mental status IVMP Good
Cognitive dysfunction IVIG
Kaur et al. [14] 2022 1 M Normal Respiratory Present Simultaneous Normal Normal Altered mental status IVMP Poor
Seizures IVIG
Perioral dyskinesias Rituximab
Lee et al. [15] 2022 21 F Hippocampal None Absent After 10 days 500 57 402 Altered mental status IVMP Recovering
Bilateral Psychosis IVIG
Cognitive dysfunction
McHattie et al. [16] 2021 53 F Hippocampal Respiratory Present Simultaneous 141 54 Altered mental status IVIG Good
Unilateral Psychosis
Cognitive dysfunction
Monti et al. [17] 2020 50 M Normal None Present Simultaneous 25 68 48 Altered mental status IVMP Good
Seizures (refractory status epilepticus) IVIG
Orofacial dyskinesia/automatisms Plasmapheresis
Naidu et al. [18] 2023 50 F Diffuse subcortical edema Respiratory Present Simultaneous 0 54 770 Altered mental status IVMP Recovering
Seizures IVIG
Panariello et al. [19] 2020 23 M Normal Respiratory Present 0 70 65 Psychosis IVIG Good
Sanchez-Larsen et al. [20] 2023 22 F Normal Respiratory Present Simultaneous 7 Normal Altered mental status IVMP Good
Seizures IVIG
Psychosis Rituximab
Sarigecili et al. [21] 2021 7 M Normal None Absent NA Normal Normal Altered mental status IVMP Good
Seizures IVIG
Choreiform movements in the hands and feet, tongue protrusion, bruxism, and lip smacking Plasmapheresis
Psychosis, catatonia
Simonavičiutė et al. [22] 2023 11 M Hippocampal None Absent NA Normal Altered mental status IVMP Good
Bilateral Seizures IVIG
Tiraboschi et al. [23] 2021 40 F Normal Respiratory Present After 14 days Normal Normal Altered mental status IVIG Good
Dyskinesias and parkinsonism
Valadez-Calderon et al. [24] 2022 28 M Hippocampal Respiratory Absent After 14 days Normal Normal Altered mental status IVMP Poor
Bilateral Seizures IVIG
Incoherent speech, somnolence, auditory hallucinations, suicidal ideation

MRI, magnetic resonance imaging; COVID-19, coronavirus disease 2019; CSF, cerebrospinal fluid; M, male; F, female; IVIG, intravenous immunoglobulin; IVMP, intravenous methylprednisolone; NA, not available or not applicable.

a)Other than fever.


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