Autoimmune Encephalitis in COVID-19 patients : a systematic review of case reports and case series

doi:10.21203/rs.3.rs-2876367/v1

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Autoimmune Encephalitis in COVID-19 patients : a systematic review of case reports and case series

https://doi.org/10.21203/rs.3.rs-2876367/v1

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Introduction: Growing evidence demonstrated the occurrence of neurological complications such as ischemic stroke, epilepsy, and autoimmune encephalitis ( AE ) associated with COVID − 19 infection. The purpose of this review was to summarize the clinical symptoms, treatment, and outcome of COVID-19-associated AE.

Methods: We searched case reports and case series of AE associated with COVID-19 between January 1, 2020, and March 31, 2023, using Pubmed, Embase, and Web of Science databases. After screening and further evaluation, irrelevant articles were excluded. Information related to treatment, clinical manifestations, comorbidities, and outcomes was extracted and summarized.

Results: 36 studies were included in this review, 34 of which were case reports and 2 were case series. A total of 39 patients with AE were included, including 18 (46%) cases of unknown type of AE, 10 (26%) cases of anti-N-methyl-D-aspartate (NMDA) encephalitis, 4 (10%) cases of limbic encephalitis, 3 (8%) cases of anti-myelin-oligodendrocyte-glycoprotein (MOG) encephalitis, and other type of AE. In addition, the clinical manifestations of AE are mainly disturbance of consciousness, seizure and psychiatric symptoms. Although the symptoms of AE are varied, most patients could recover completely, with a few having residual symptoms of neurological damage.

Conclusions: In this systematic review, the characteristics of COVID-19-associated AE are summarized, including neurological manifestations, treatment, types, and outcomes. Although COVID−19-associated AE can sometimes be life-threatening, most AE is reversible if treated promptly.

COVID-19

autoimmune encephalitis

SARS-CoV-2

systematic review

The coronavirus pneumonia (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection.¹ It has placed an unprecedented burden on economies and healthcare systems worldwide since the beginning of the COVID-19 pandemic.² It is well known that COVID-19 primarily affects the respiratory system. The respiratory system manifests as cough, shortness of breath, pneumonia, and hypoxemia.^3-4 However, a growing body of researches have shown that COVID-19 can also affect the nervous system, such as headaches, limb weakness, Guillain-Barré syndrome, seizures, strokes and even encephalitis.^4-6

The meta-analysis by Siow et al. included 129008 patients with COVID-19 and showed an encephalitis prevalence of 0.215%.⁷ How SARS-Cov-2 enters the brain and causes encephalopathy remains a controversial issue.⁸ The main theories are as follows: SARS-Cov-2 can travel retrograde through axons in the olfactory, respiratory, and enteric nervous system networks.⁹ SARS-Cov-2 enters brain tissue by breaching the blood-brain barrier through disruption of the endothelial lining.¹⁰ SARS-Cov-2 can then interact with neuronal and non-neuronal cells that express angiotensin-converting enzyme 2 ( ACE-2 ) receptors.^11-12

Despite increasing reports of COVID-19-associated autoimmune encephalitis (AE), few systematic reviews have summarized AE findings as neurologic complications of COVID-19. To gain a better understanding of AE, we performed a comprehensive assessment of the clinical manifestations, types, and outcomes of AE as complications in COVID-19 patients.

This review was conducted in accordance with the guidelines for preferred reporting elements for systematic reviews and meta-analyses (PRISMA).¹³

2.1 Search Strategy

We conducted extensive and exhaustive search of a case reports and series between January 1st 2020 to March 31th 2023 from PubMed, Embase, and Web of Science. The search terms included “Autoimmune Encephalitis”, “Antibody-Mediated Encephalitis”, “Antibody Mediated Encephalitis”, “limbic encephalitis”, “Anti NMDA”, “Anti MOG”, “Anti LGI1”, “Anti GABA”, “coronavirus disease-19”, “SARS-CoV- 2”, “COVID 19”, and “COVID-19”. All English publications describing case reports and case series of confirmed COVID-19 infection with autoimmune encephalitis were included. Two independent reviewers comprehensively searched and filtrated the eligible studies. We excluded all review articles, other types of encephalitis and unconfirmed cases of autoimmune encephalitis.

2.2 Inclusion criteria

This case reports and case series met the following inclusion criteria: ( 1 ) patients had perfect reverse transcription-polymerase chain reaction (RT - PCR) or imaging examination such as chest CT, and X-ray to confirm the diagnosis of COVID-19; ( 2) raw data on clinical symptoms, diagnosis, treatment and outcome of COVID-19 -associated AE were provided.

2.3 Study Selection and Data Extraction

Two reviewers selected studies by reading full articles and then independently extracted data from the eligible articles. The following data were extracted from the included studies: the first author’s last name, year of publication, number of patients, participant’s age, participant gender, SARS-CoV-2 diagnosis method, neurological manifestations, imaging analysis, cerebrospinal fluid (CSF), type of AE, AE diagnosis method, treatment details, outcome. When available data were not available directly from the article, we contacted the corresponding author to clarify ambiguities and provide missing information by phone or email.

3.1 Searching published literature

A total of 442 articles were yielded after comprehensive search in our literature. After removing 223 duplicate articles, 153 irrelevant title and abstract articles, and 66 full-text articles were further evaluated. Finally, 36 studies included our system review, after excluded 6 review articles, 4 modelling studies, 4 commentary, 3 editorial and 13 other encephalitis (Fig. 1). ^14–49

3.2 Study characteristics

This subject paper includes 36 studies, consisting of 34 case report studies and two case series. Table 1 provides a summary of the study characteristics. The review includes a total of 39 participants, with 26 male and 10 female. The case reports and case series were conducted in various countries, including the USA (n = 16), Italy (n = 4), Iran (n = 2), UK (n = 2), Spain (n = 2), Korea (n = 2), India (n = 2), Singapore (n = 1), France (n = 1), Egypt (n = 1), Mexico (n = 1), Germany (n = 1), Japan (n = 2), Turkey (n = 1), and China (n = 1).

Table 1

Characteristics of included studies for autoimmune encephalitis as a neurological complication in COVID-19 patients
No	Study (Location, year)	Number of patients	Sex	Age (years)	SARS-CoV−2 diagnosis method	Neurological manifestations	Imaging analysis	CSF analysis	Type of AE	AE diagnosis method	Past medical history	Treatment	Outcome
1	Sarigecili E, et al. (Turkey,2021 )¹⁴	1	M	7	RT- PCR	Ataxia, wide based gait, somnolence, seizures, choreiform movements in the hands and feet.	MRI: unremarkable	Protein, glucose, lactate, pyruvate, IgG, EBV, HSV−1, HCV−2: normal. Anti-NMDA : positive.	Anti-NMDA encephalitis	CSF analysis	No	Methylprednisolone, IVIG, Lobazam and topiramate	Complete recovery
2	Kaur P, et al. (India, 2022 )¹⁵	1	M	1	RT- PCR	Seizures, peri-oral dyskinesias, bilateral striatal toe, extrapyramidal movements	MRI:unremarkable	CSF showed 20 cells, sugar 65 mg/ dL, protein 27 mg/ dL. Anti-NMDA : positive	Anti-NMDA encephalitis	CSF analysis	No	Methylprednisolone, IVIG, Rituximab, Azathioprine, Clonidine, baclofen, and clonazepam	Complete recovery
3	Burr T, et al. (USA, 2021 )¹⁶	1	F	23	RT- PCR	Seizures.	MRI:unremarkable	Protein, glucose, lactate: normal. Anti-NMDA : positive	Anti-NMDA encephalitis	CSF analysis	No	Methylprednisolone IVIG Lorazepam and levetiracetam	Complete recovery
4	Scheuermeier M, et al. (Italy, 2022 )¹⁷	1	F	4	RT- PCR	Generalized tonic-clonic seizures, cognitive deterioration.	MRI: hyperintense lesions in the bilateral insular cortex and medial temporal region	Protein, glucose, cells lactate: normal. anti-NMDA was negetive in CSF but positive in serum.	Anti-NMDA encephalitis	CSF analysis, brain MRI	No	Benzodiazepines, plasmapheresis, rituximab, carbamazepine	Incomplete recovery with decreased language comprehension and production Focal-onset motor seizures
5	Chakraborty AP, et al. (USA, 2022 )¹⁸	1	M	61	RT- PCR	Abnormal behavior, drowsiness, aphasia.	MRI: hyperintense lesions in left temporo-parietal regions	protein :66 mg/dl. anti-NMDA: negetive SARS-Cov−2 IgG and spike protein antibodies: positive	Unknown type of AE	CSF analysis, brain MRI	Hypertension, diabetes	Methylprednisolone	Complete recovery
6	Jeanneret V, et al. (USA, 2021 )¹⁹	1	M	21	RT- PCR	gait instability, dysarthria, generalized tonic-clonic seizures.	MRI:hyperintense lesions in brainstem and cerebellum	Zero white blood cells, protein count 122 mg/dL, normal glucose, zero oligoclonal bands, and normal IgG index.	Unknown type of AE	CSF analysis, brain MRI	Diabetes	IVIG Plasmapheresis Levetiracetam	Incomplete recovery with dysarthria and ataxia
7	Hosseini AA, et al. (USA, 2020 )²⁰	2	1 M 2 F	1 46 2 79	RT- PCR	1 Delirium, disinhibition, confusion, status epilepticus 2 Generalized seizures	① MRI: three hyperintense foci on DWI ② MRI: limbic system with partial diffusion restriction	1 Mildly raised protein and oligoclonal bands 2 Protein, glucose, cells lactate: normal.	1 Unknown type of AE 2 Limbic encephalitis	Brain MRI	1 No 2 No	1 Ceftriaxone, Aciclovir and Sodium Valproate 2 Levetiracetam	Complete recovery
8	Hilado M, et al. (USA, 2022 )²¹	3	1 M 2 M 3 M	1 6 2 12 3 12	1 positive SARS-CoV−2 serum antibody 2 positive SARS-CoV−2 serum antibody 3 RT- PCR	1 headache, urinary retention, lower extremity weakness, and ataxic gait. 2 Generalized seizures 3 seizures	1 MRI: hyperintense lesions in bilateral parietal 2 MRI: unremarkable 3 MRI: bilateral frontoparietal lobes with diffuse leptomeningeal enhancement concerning.	1 anti-SARS-CoV−2, anti-NMDA: negative 2 anti-SARS-CoV−2, anti-NMDA:negative; positive anti-SARS-CoV−2 in the serum. 3 anti-SARS-CoV−2, anti-NMDA:negative	Unknown type of AE	1 Brain MRI 2 CSF analysis 3 Brain MRI	1 No 2 Autism spectrum disorders 3 Migraine	1 Methylprednisolone, acetazolamide 2 Levetiracetam 3 Methylprednisolone, levetiracetam.	1 Complete recovery 2 Complete recovery 3 Complete recovery
9	Álvarez BG, et al. ( USA, 2020)²²	1	F	30	RT- PCR	focal seizures and some generalised seizures.	MRI: hyperintense lesions in left hippocampus.	High protein levels (54.5 mg/dL) and a predominantly lymphocytic (90%) leukocyte count of 44 cells/L. Anti-NMDA : positive	Anti-NMDA encephalitis	Brain MRI, CSF analysis	No	Methylprednisolone, valproate	Incomplete recovery with hypoprosexia, emotional lability, and memory disorder
10	Farhadian S, et al. ( USA, 2020)²³	1	F	78	RT- PCR	Seizure, confusion and disorientation	MRI: atrophy and patchy periventricular and subcortical white matter hyperintensities	350 red cells/uL, 1 white blood cell/uL, 75% lymphocytes, 25% monocytes, glucose 67 mg/dL and protein 43 mg/dL.	Unknown type of AE	Brain MRI, CSF analysis	Kidney transplant	Hydroxychloroquine, tocilizumab	Complete recovery
11	Mekheal E, et al. (USA, 2022)²⁴	1	F	88	positive SARS-CoV−2 serum antibody	Leg weakness and dysarthria.	MRI: evidence of an old infarct CT brain: intraparenchymal hemorrhage	Protein: 145 mg/dL WBCs: 15	Unknown type of AE	CSF analysis	Hypertension	Methylprednisolone, IVIG, anticoagulants	Death
12	Kato S, et al. (Japan, 2022)²⁵	1	F	55	RT- PCR	Consciousness disturbance, myoclonic-like movements and gait disturbance	Not reported	Glucose:65 mg/dL protein: 59 mg/dL	Unknown type of AE	CSF analysis	No	Methylprednisolone,	Complete recovery
13	Panariello A, et al. (Italy, 2020)²⁶	1	M	23	Chest CT RT- PCR	Psychomotor agitation, anxiety, persecutory delusions and auditory hallucinations, insomnia.	CT brain: unremarkable	Protein, glucose, cells lactate: normal. Anti-NMDA : positive	Anti-NMDA encephalitis	CSF analysis	No	Valproate, hydroxychloroquine, dexamethasone, IVIG	Complete recovery
14	Monti G, et al. (Italy, 2020)²⁷	1	M	50	RT- PCR	refractory status epilepticus	MRI: unremarkable	Eurotropic fungi, bacteria and viruses: negative Anti-NMDA : positive	Anti-NMDA encephalitis	CSF analysis	Hypertension	Metilprednisolone, IGIV, plasma-exchange,antiseizure drugs	Complete recovery
15	Dono F, et al. (Italy, 2020)²⁸	1	M	81	Chest CT RT- PCR	Mild confusion with fluctuation of the mental status.	MRI: hyperintense lesions in the bilateral parietal cortex, left temporal cortex, and right cingulate cortex.	Lymphocytosis (26 cell/mm3), normal glucose level (78 mg/ dl), slight protein increase (47 mg/dl), and positive oligoclonal bands (OCB)	Unknown type of AE	Brain MRI, CSF analysis	Hypertension	Methylprednisolone, IVIG, antiseizure drugs	Death due to sepsis
16	Moriguchi T, et al. (Japan, 2020)²⁹	1	M	24	Chest CT	headache, consciousness disturbance, seizures.	MRI: hyperintense lesions in the right mesial temporal lobe and hippocampus.	Glucose,HSV−1, HSV−2, HHV−6, HHV−7: normal. anti-SARS-CoV−2 :positive	Limbic encephalitis	Brain MRI,CSF analysis	No	Ceftriaxone, vancomycin, aciclovir, steroids,Levetiraceta.	Not reported.
17	Jacobs J, et al. (USA, 2022)³⁰	1	M	65	RT- PCR	Vertigo, nonspecific blurry vision, assaultive behavior, agitated, combative, and hallucinatory.	MRI: four ring-shaped postcontrast enhanced lesions	Protein: 52 mg/dL. Detailed, extensive infectiou: negative. Anti-MOG IgG: positive.	Anti-MOG encephalitis	Brain MRI, CSF analysis	No	Methylprednisolone, IVIG.	Complete recovery
18	Raynowska J, et al. (USA, 2022)³¹	1	M	31	RT- PCR	Progressively worsening confusion, forgetfulness, visual hallucinations, dysphagia and dysarthria.	MRI: unremarkable	Protein, glucose, cell:normal Anti-AMPA and Anti-CRMP positive	Anti-AMPA and anti-CRMP−5 encephalitis	CSF analysis	Myasthenia gravis	IVIG, plasmapheresis, eculizumab, remdesivir, and dexamethasone	Not reported.
19	Durovic E, et al. (Germany, 2021)³²	1	M	22	RT- PCR	severe headache, mild impairment in executive functions.	MRI: multiple disseminated hyperintensities, predominantly cortically	Protein, glucose, cells lactate, HSV−1, HSV−2: normal. MOG IgG: positive.	Anti-MOG encephalitis	Brain MRI, CSF analysis	No	Methylprednisolone, aciclovir.	Complete recovery
20	Koh S, et al. (Korea, 2022)³³	1	F	20	Chest CT RT- PCR	Focal tonic-clonic seizure	MRI: diffuse cortical high signal intensities.	Protein, glucose, cells lactate, HSV−1: normal.	Unknown type of AE	Brain MRI	No	Acyclovir, remdesivir, methylprednisolone and IVIG	Complete recovery
21	Valadez-Calderon J, et al. (Mexico, 2022)³⁴	1	M	28	RT- PCR	altered mental state characterized by incoherent speech, somnolence, auditory hallucinations, suicidal ideation, and generalized tonic-clonic seizures.	MRI: hyperintensities in the bilateral anterior cingulate cortex and temporal lobes	anti-SARS-CoV−2: negative. anti-NMDAR and anti-GAD65: positive.	anti-NMDA and anti-GAD65 encephalitis	Brain MRI, CSF analysis	No	Methylprednisolone.	Not reported.
22	Dahshan A, et al. (Egypt, 2022)³⁵	1	M	67	RT- PCR	Confusion, behavioral changes, agitation, and one attack of loss of consciousness.	MRI: unremarkable	Normal cell count, normal proteins, glucose, LDH, and chloride anti-SARS-CoV−2 :positive	Unknown type of AE	CSF analysis	Hypertension	Methylprednisolone	Complete recovery
23	Peters J, et al. (USA, 2021)³⁶	1	M	23	RT- PCR	cognitive slowing, personality changes, generalized seizures.	MRI: hyperintensities in diffuse lefthemispheric cortical	RBC:589/µL. Protein, glucose,fungal culture, HSV, VZV, EBV,CMV: negative. MOG IgG: positive.	Anti-MOG encephalitis	Brain MRI, CSF analysis	NO	Methylprednisolone	Incomplete recovery with cognitive impairment
24	Mestre FA, et al. (Spain, 2022)³⁷	1	F	30	RT- PCR	Agitation, dysarthria and hallucinations.	MRI: hyperintensities in diffuse lefthemispheric.	Protein, glucose, cells, HSV−1: normal. Anti-NMDA : positive	Anti-NMDA encephalitis	Brain MRI, CSF analysis	NO	Methylprednisolone, antiepileptic drugs and immunotherapy.	Incomplete recovery with cognitive impairment
25	Bhagat R, et al. (USA, 2021)³⁸	1	M	54	RT- PCR	Unconsciousness, generalized seizures.	MRI: hyperintensities in the posterior aspect of right medial temporal lobe and para-hippocampal	Protein, glucose, cells lactate, HSV−1, HSV−2: normal.	Limbic encephalitis	Brain MRI	AF, hypertension, glucose−6-phosphate dehydrogenase deficiency, and hepatosteatosis.	Lorazepam, levetiracetam, methylprednisolone.	Complete recovery
26	Ayatollahi P, et al. (Iran, 2021)³⁹	1	F	18	RT- PCR	Generalized tonic–clonic seizure.	MRI: Claustrum FLAIR/T2 hyperintensities.	White blood cells: 20 cells/uL, no red blood cells, normal protein (30 mg/dL), glucose (41 mg/dL), and LDH (28 IU/L) levels.	Unknown type of AE	Brain MRI	No	Methylprednisolone, antiepileptic drugs.	Recent memory deficits
27	Grimaldi S, et al. (France, 2020)⁴⁰	1	M	72	RT- PCR	Bilateral upper-limb action tremor, a cerebellar syndrome, spontaneous diffuse myoclonus.	Brain PET with 18F-FDG : putaminal and cerebellum hypermetabolism associated with diffuse cortical hypometabolism.	Normal cell counts, a mildly elevated protein level (49 mg/dL)	Unknown type of AE	Brain PET	No	Methylprednisolone, IVGI.	Complete recovery
28	Lee H, et al. (Korea,2022)⁴¹	1	F	21	RT- PCR	Abnormal behavior.	MRI: unremarkable	Protein, glucose, cell: normal. Anti-NMDA : positive.	Anti-NMDA encephalitis	CSF analysis	No	Methylprednisolone, IVGI, acyclovir.	Memory impairment
29	Mulder J, et al. (USA, 2021)⁴²	1	M	40	RT- PCR	Catatonia, autonomic instability.	MRI: unremarkable	High red blood cell count, Protein:838 mg/L.	Unknown type of AE	CSF analysis	No	Plasmapheresis, antibiotics, acyclovir, clonidine and labetalol.	Dramatic improvement
30	Subramanyam M, et al. (India, 2022)⁴³	1	M	47	RT- PCR	postural imbalance, difficulty walking, dysarthria, hallucination	MRI: unremarkable	Protein, glucose, cell: normal. NMDAR, LGI1, AMPA12, and GABAb1−2:negative. Caspr2 and VGKC antibodies positive in serum.	Anti-Caspr2 encephalitis	CSF analysis	No	Methylprednisolone, IVGI,	Complete recovery
31	Zambreanu L, et al. (UK, 2020)⁴⁴	1	F	66	RT- PCR	Mental and behavioral disorders.	MRI: hyperintensities in mesial temporal lobes and medial thalami	Protein, glucose,fungal culture, HSV, VZV, EBV,CMV: negative.	limbic encephalitis	Brain MRI	No	Methylprednisolone, IVGI, ceftriaxone, aciclovir and levetiracetam.	Memory and verbal fluency incompletely recovered.
32	Serrano-Serrano B, et al. (Spain, 2020)⁴⁵	1	M	70	RT- PCR	Limb tremor with disturbance of consciousness.	MRI: multiple disseminated hyperintensities.	Protein:76 mg/dL. glucose, cell: normal. HSV, HIV: negative.	Unknown type of AE	Brain MRI	Hypertension, AF, COPD, HF	Methylprednisolone	Complete recovery
33	Poorshiri B, et al. (Iran, 2022)⁴⁶	1	M	1	RT- PCR	Generalized tonic-clonic seizures.	MRI: hyperintensities in the entire corpus callosum, ventral aspect of medulla oblongata, and cerebellar vermis.	No white blood cells or red blood cells were seen. Protein and glucose levels were 108 mg/dL and 72 mg/dL.	Unknown type of AE	Brain MRI	No	Methylprednisolone	Multiorgan damage
34	Shen JY, et al. (Singapore, 2022)⁴⁷	1	M	70	RT- PCR	dysphasia and mild rightsided weakness. refractory status epilepticus.	MRI: left mesial temporal lobe swelling with hyperintensity	Protein:60 mg/dL. Anti-GABA: positive	Anti-GABA encephalitis	Brain MRI, CSF analysis	Diabetes, Hypertension.	Methylprednisolone, antiepileptic drugs.	Complete recovery
35	McHattie AW, et al. (UK, 2021)⁴⁸	1	F	53	RT- PCR	Palilalia, confusion, myalgia.	MRI: hyperintensities in the left amygdala and anterior putamen.	Protein:54 mg/dL. glucose, cells: normal. Anti-NMDA : positive	Anti-NMDA encephalitis	Brain MRI, CSF analysis	Breast carcinoma, depression, and psoriasis.	IVIG, hydroxychloroquine,, tocilizumab, antibiotics, amphotericin, levetiracetam.	Dramatic improvement
36	Wang M, et al. (China, 2020)⁴⁹	1	M	68	RT- PCR	Unable to walk and with uroclepsia, coprolalia, and persecution delusion.	Brain CT scan: lacunar lesions in the left basal ganglia region	COVID−19 IgM and IgG: positive	Unknown type of AE	Brain MRI, CSF analysis	Diabetes, hypertension	IVIG, ibavirin, antipsychotic drug	Mild irritability, slight shaking of the hand.
M, male; F, female; EBV, epstein-barr virus; TR-PCR, reverse transcription-polymerase chain reaction; HSV, herpes simplex virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; NMDA, N-Methyl-D aspartate; MOG, myelin oligodendrocyte glycoprotein; GABA, gamma aminobutyric acid; SARS-CoV−2, severe acute respiratory syndrome coronavirus 2; COVID, corona virus disease; AMPA, ɑ- amino−3-hydroxy−5methyl−4- isoxazolepropionic acid; CRMP, collapsin response mediator protein; GAD, glutamic acid decarboxylase; MRI, magnetic resonance imaging; CT, computed tomography; CSF, cerebrospinal fluid; IVIG, intravenous immunoglobulin; AF, atrial fibrillation; HF, heart failure; COPD, chronic obstructive pulmonary disease; AE, Autoimmune encephalitis.

3.3 Neurological manifestations

Neurological manifestations in this study were reported in seven categories including: (A) disturbance of consciousness; (B) seizure ; (C) psychiatric symptoms; (D) neuromuscular symptoms such as myalgia, weekness and myoclonus; (E) extrapyramidal movements ; (F) cerebellar syndrome and (G) other clinical symptoms. The frequency of various neurological manifestations is shown in Fig. 2.

In this study, 13 patients experienced disturbances of consciousness, primarily characterized by symptoms such as somnolence, drowsiness, delirium, confusion, unconsciousness, and delirium. Additionally, 19 patients exhibited seizures, with five experiencing generalized tonic-clonic seizures and two experiencing refractory status epilepticus. Fifteen patients in the study exhibited psychiatric symptoms which mainly manifested as abnormal behavior, persecutory delusions, auditory hallucinations, and combative behavior. In addition, neuromuscular symptoms were observed, including myalgia, weakness, catatonia, and myoclonus. Notably, many patients displayed extravertebral movements, such as choreiform movements in the hands and feet, peri-oral dyskinesias, bilateral upper-limb action tremor and limb tremors. Eight patients had cerebellar syndrome such as ataxia, dysarthria and gait disturbance. Other clinical symptoms main including ouroclepsia, palilalia, autonomic instability, headache,vertigo and nonspecific blurry vision.

3.4 Type of Autoimmune Encephalitis

Among the included studies, 39 patients were diagnosed as AE, including 10 (26%) cases of anti-N-Methyl-D aspartate (NMDA) encephalitis, 18 (46%) cases of unknown type of AE, 4 (10%) cases of limbic encephalitis, 3 (8%) cases of anti-myelin oligodendrocyte glycoprotein (MOG) encephalitis, 1 with anti-gamma aminobutyric acid (GABA) encephalitis, 1 case of anti-Caspr2 encephalitis, 1 case with anti-NMDA and anti-glutamic acid decarboxylase−65 (GAD65) encephalitis, and 1 case with anti-ɑ- amino−3-hydroxy−5methyl−4- isoxazolepropionic acid (AMPA) and anti-collapsin response mediator protein−5 (CRMP−5) encephalitis. The frequencies of various types of AE are shown in Fig. 3.

In this study, we found the main type of COVID−19-associated AE was an unknown type of AE which despite no autoimmune encephalitis-related antibodies being detected in the CSF, a diagnosis of possible autoimmune encephalitis was made according to Graus criteria.^{17–20, 22–24, 27, 32,34,38−39, 41, 44–45,48} 18 patients diagnosed as unknown type of AE and the patients were more likely to develop consciousness disturbance, generalized tonic-clonic seizures, persecution delusion, autonomic instability, and dysarthria ( Table 1 ).

Ten studies reported cases of anti-NMDA receptor encephalitis and the ages ranged from 1 to 53 years, with a mean age of 24.2 years.^{13–16, 21, 25–26, 36,40,47} The neurological manifestations of anti-NMDA receptor encephalitis are mainly seizures, persecutory delusions, hallucinations and abnormal behavioral.

There were four cases of limbic encephalitis with mainly symptoms performed as generalized seizures and consciousness disturbance.^{19, 28, 37, 43} Three cases reported anti-MOG encephalitis and prominent clinical manifestations were vertigo, nonspecific blurry vision and assaultive behavior. It is noteworthy that the magnetic resonance imaging of anti-MOG encephalitis are usually performed diffuse and multifocal.^29,31,35

In addition, four rare cases of AE were reported here, including anti-Caspr2 encephalitis, anti-NMDA and anti-GAD65 encephalitis, anti-AMPA and anti-CRMP−5 encephalitis and anti-GABA encephalitis.^30,33,42,46 These patients mainly manifested as hallucinations, postural imbalance, generalized seizures and dysarthria.

3.5 Past medical history and Treatment

The most common past medical history were hypertension, diabetes and atrial fibrillation. The less common past medical history were autism spectrum disorders, migraine, kidney transplant, myasthenia gravis, glucose−6-phosphate dehydrogenase deficiency, and hepatosteatosis. A wide range of treatment strategies was used to treat COVID−19 associated AE. For treatment strategy, the most common of which were methylprednisolone, intravenous immunoglobulin, plasmapheresis and oral prednisone. Afterwards, symptomatic treatments such as antiepileptic medication, sedatives, and anti-infection measures are implemented.

3.6 Outcome

Although the symptoms of autoimmune encephalitis are varied, most patients recover completely if treated aggressively, with a few having residual symptoms of neurological damage. Among the 39 cases included in this study, 2 patients died due to sepsis and intracranial hemorrhage, respectively.

AE is one of the specific neurological manifestations of COVID-19 that can cause severe damage to the patient. This study reviewed case series and case reports to evaluate the neurological manifestations, type of AE, treatment, and outcome of COVID-19 associated AE. Previous studies have shown that patients with COVID-19 associated AE can develop symptoms of AE several weeks after the onset of COVID-19 symptoms, or COVID-19, and AE symptoms occur simultaneously.⁴⁹In our review, the neurological manifestations of patients can be divided into seven categories including disturbance of consciousness, seizure, psychiatric symptoms, neuromuscular symptoms, extrapyramidal movements, cerebellar syndrome and other clinical symptoms. The most common symptoms were seizure (19 cases) , disturbance of consciousness (13 cases), and psychiatric symptoms (15 cases). Patients exhibited seizures predominantly performed generalized tonic-clonic seizures, and refractory status epilepticus in severely ill. Patients suffered disturbances of consciousness, primarily characterized by symptoms of confusion, unconsciousness, and delirium. Psychiatric symptoms of COVID-19 associated AE mainly including cognitive deterioration, abnormal behavior, persecutory delusions and hallucinations. In addition, neuromuscular symptoms (8 cases) and extrapyramidal movements (5 cases) can be the initial symptoms that appeared in COVID-19-associated AE patients, the clinical symptoms of these patients include myalgia, weakness, catatonia, myoclonus, choreiform movements in the hands and feet, peri-oral dyskinesias, myoclonic-like movements, and limb tremor. Eight case reports studies showed that patients presented with cerebellar syndrome performed ataxia, dysarthria, and gait disturbance. COVID-19-associated AE patients also can occur other clinical symptoms mainly including uroclepsia, palilalia, autonomic instability, headache, vertigo, and nonspecific blurry vision.

In this review, we found that the type of COVID-19-associated AE include anti-NMDA encephalitis, unknown type of AE, limbic encephalitis, anti-MOG encephalitis, anti-GABA encephalitis, anti-Caspr2 encephalitis, anti-NMDA and anti-GAD65 encephalitis, anti-AMPA and anti-CRMP-5 encephalitis. We found that unknown type of AE (46%) was the most common COVID-19-associated AE, followed by anti-NMDA encephalitis (26%), limbic encephalitis (10%), and anti-MOG encephalitis (8%). At the same time, we also found some rare AE cases, such as anti-Caspr2 encephalitis, anti-NMDA and anti-GAD65 encephalitis, anti-AMPA and anti-CRMP-5 encephalitis.

The mechanism of COVID-19-associated AE is extremely complex and not yet fully understood. The possible mechanism is as follows: (1) Angiotensin-converting enzyme-2 (ACE-2) receptors mediated viral invasion. ACE-2 receptors is widely distributed in all tissues and organs of the body, especially in vascular endothelial cells, neuronal cells, glial cells, brainstem, etc; ⁸(2) Invasion of the central nervous system through peripheral nerves. Hyposmia or loss of sense of smell is considered to be a manifestation of COVID-19 peripheral nervous system damage. SARS-CoV- 2 can enter the olfactory bulb along the olfactory nerve through the cribriform plate, and then spread to the brainstem and affect the vital center ;^50-51 (3) Virus-triggered inflammatory storm involving the central nervous system. Similar to other pathogens, SARS-CoV-2 infection triggers an immune response in the human body. Neutrophils, monocytes, macrophages, dendritic cells, and nature killer (NK) cells flow in and activate, thereby releasing a large number of inflammatory factors. The disruption of the blood-brain barrier is exacerbated by the large number of inflammatory factors that damage vascular endothelial cells. Vascular damage, increased permeability, and disruption of the blood-brain barrier cause brain tissue edema and necrosis on the one hand, and can facilitate direct invasion of the central nervous system by SARS-CoV-2 on the other.^52-54

The diagnosis of autoimmune encephalitis is usually based on a combination of clinical presentation, imaging analysis, CSF analysis, and electroencephalogram. In patients with AE, MRI scans can detect abnormalities in approximately 60% of cases, while 40% of scans show no significant changes. Among patients with positive MRI findings, most exhibit T2 and Flair high signal shadows on one or both sides of the medial temporal lobe (including the hippocampus and sulcus gyrus), insular lobe, and amygdala. These abnormalities may appear progressively but often disappear after immunotherapy. CSF analysis typically lacks specificity, with approximately 30% of results being normal.⁵⁵It is worth noting that when diagnosing COVID-19-associated AE, it needs to be differentiated from false positives of AE. A retrospective multicenter study suggested that 72% of patients did not fulfill AE diagnostic criteria resulting in a high proportion of mistaken for AE. The reasons for misdiagnosis may be related to overinterpretation of positive serum antibodies and misinterpretation of functional/psychiatric or nonspecific cognitive dysfunction such as encephalopathy.⁵⁶

For treatment strategies and outcomes, almost all patients received methylprednisolone, intravenous immunoglobulin, plasmapheresis, and oral prednisone therapy. In our study, we found that despite the severity of autoimmune encephalitis, most patients recovered completely if treated promptly, with a small number of patients remaining with cognitive impairment.

This study has some limitations. First, this systematic review included only case reports and case series. Therefore, the existence of publication bias should be considered. Second, since the search was limited to articles published in English, some relevant articles in other languages were omitted. Third, some studies did not have sufficient data.

Various aspects of COVID-19-associated AE including neurological manifestations, treatment, types, and outcomes were described in this systematic review. COVID-19-associated AE is one of the neurological complications of SARS-CoV-2. Although COVID-19-associated AE can sometimes be life-threatening, most AE is reversible if treated promptly. We hoped that clinicians will need to carefully identify and screen patients with neurological presentations (e.g., SARS-CoV-2 asymptomatic patients or patients with mild disease) or a combination of atypical presentations.

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Availability of data and material

All data generated or analyzed during this study are included in this published article.

Competing interests

The authors declare that they have no competing interests.

Funding

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Authors' contributions

Hua Xue and Li Zeng carried out the conception and design of the research, and Hua Xue and Dongxun Xu participated in the acquisition of data. Hua Xue carried out the analysis and interpretation of data. Hua Xue and Hongxian He drafted the manuscript and Dongxun Xu participated in the revision of the manuscript for important intellectual content. All authors read and approved the final manuscript.

Acknowledgments

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Hu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol. 2021;19:141–54.
Muralidar S, Ambi SV, Sekaran S, Krishnan UM. The emergence of COVID-19 as a global pandemic: Understanding the epidemiology, immune response and potential therapeutic targets of SARS-CoV-2. Biochimie. 2020;179:85–100.
Forchette L, Sebastian W, Liu T. A Comprehensive Review of COVID-19 Virology, Vaccines, Variants, and Therapeutics. Curr Med Sci. 2021;41:1037–51.
Liu Y, Budylowski P, Dong S, et al. SARS-CoV-2-Reactive Mucosal B Cells in the Upper Respiratory Tract of Uninfected Individuals. J Immunol. 2021;207:2581–8.
Siow I, Lee KS, Zhang JJY, et al. Encephalitis as a neurological complication of COVID-19: A systematic review and meta-analysis of incidence, outcomes, and predictors. Eur J Neurol. 2021;28:3491–502.
Ellul MA, Benjamin L, Singh B, et al. Neurological associations of COVID-19. Lancet Neurol. 2020;19:767–83.
Siow I, Lee KS, Zhang JJY, Saffari SE, Ng A. Encephalitis as a Neurological Complication of Covid-19: A Systematic Review and Meta-Analysis of Incidence, Outcomes, and Predictors." [In eng]. Eur J Neurol. Oct 2021;28:10. 3491 – 502. https://doi.org/10.1111/ene.14913.
Tang KT, Hsu BC, Chen DY. Autoimmune and Rheumatic Manifestations Associated With COVID-19 in Adults: An Updated Systematic Review. Front Immunol. 2021;12:645013.
Taquet M, Sillett R, Zhu L, et al. Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1†ˆ284†ˆ437 patients. Lancet Psychiatry. 2022;9:815–27.
Angeli F, Reboldi G, Trapasso M, et al. COVID-19, vaccines and deficiency of ACE(2) and other angiotensinases. Closing the loop on the "Spike effect. Eur J Intern Med. 2022;103:23–8.
McMillan P, Dexhiemer T, Neubig RR, Uhal BD. COVID-19-A Theory of Autoimmunity Against ACE-2 Explained. Front Immunol. 2021;12:582166.
Miners S, Kehoe PG, Love S. Cognitive impact of COVID-19: looking beyond the short term. Alzheimers Res Ther. 2020;12:170.
Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700.
Sarigecili E, Arslan I, Ucar HK, Celik U. Pediatric anti-NMDA receptor encephalitis associated with COVID-19. Childs Nerv Syst. 2021;37:3919–22.
Kaur P, Vinay MV, Madarkar BS. Infantile Anti-N-Methyl-D-Aspartate Receptor Encephalitis Post-SARS-CoV-2 Infection. Indian Pediatr. 2022;59:343–4.
Burr T, Barton C, Doll E, et al. N-Methyl-d-Aspartate Receptor Encephalitis Associated With COVID-19 Infection in a Toddler. Pediatr Neurol. 2021;114:75–6.
Scheuermeier M, Chaves KQ, Marín-Sanabria D, et al. First Pediatric Case of Autoimmune Encephalitis Associated With COVID-19 in Costa Rica. Cureus. 2022;14:e30616.
Chakraborty AP, Pandit A, Dutta A, et al. Transcortical sensory aphasia heralding SARS-Cov-2-induced autoimmune encephalitis with gyral restricted diffusion hyperintensities: a novel case report. Egypt J Neurol Psychiatr Neurosurg. 2022;58:167.
Jeanneret V, Winkel D, Risman A, et al. Post-infectious rhombencephalitis after coronavirus-19 infection: A case report and literature review. J Neuroimmunol. 2021;357:577623.
Hosseini AA, Shetty AK, Sprigg N, et al. Delirium as a presenting feature in COVID-19: Neuroinvasive infection or autoimmune encephalopathy? Brain Behav Immun. 2020;88:68–70.
Hilado M, Banh M, Homans J, Partikian A. Pediatric Autoimmune Encephalitis Following COVID-19 Infection. J Child Neurol. 2022;37:268–72.
Álvarez Bravo G, Ramió ITL. Anti-NMDA receptor encephalitis secondary to SARS-CoV-2 infection. Neurologia (Engl Ed). 2020;35:699–700.
Farhadian S, Glick LR, Vogels CBF, et al. Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19. BMC Neurol. 2020;20:248.
Mekheal E, Mekheal M, Roman S, et al. A Case Report of Autoimmune Encephalitis: Could Post-COVID-19 Autoimmunity Become a Lethal. Health Issue? Cureus. 2022;14:e25910.
Kato S, Yoshikura N, Kimura A, Shimohata T. Possible Autoimmune Encephalitis Associated with the Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant Successfully Treated with Steroids. Intern Med. 2022;61:3739–41.
Panariello A, Bassetti R, Radice A, et al. Anti-NMDA receptor encephalitis in a psychiatric Covid-19 patient: A case report. Brain Behav Immun. 2020;87:179–81.
Monti G, Giovannini G, Marudi A, et al. Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19. Seizure. 2020;81:18–20.
Dono F, Carrarini C, Russo M, et al. New-onset refractory status epilepticus (NORSE) in post SARS-CoV-2 autoimmune encephalitis: a case report. Neurol Sci. 2021;42:35–8.
Moriguchi T, Harii N, Goto J, et al. A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis. 2020;94:55–8.
Jacobs J, Vu P, Liu AK. A Patient With Myelin Oligodendrocyte Glycoprotein Positive Encephalitis With Ring Enhancing Lesions on Magnetic Resonance Imaging (MRI) After COVID-19 Exposure. Cureus. 2022;14:e31844.
Raynowska J, Wu V, Kazer M, et al. COVID-19-associated AMPA-R and CRMP-5 autoimmune encephalitis in a patient with thymoma and myasthenia gravis. Clin Case Rep. 2023;11:e7064.
Durovic E, Bien C, Bien CG, Isenmann S. MOG antibody-associated encephalitis secondary to Covid-19: case report. BMC Neurol. 2021;21:414.
Koh S, Kim YS, Kim MH, et al. Encephalitis with status epilepticus and stroke as complications of non-severe COVID-19 in a young female patient: a case report. BMC Neurol. 2022;22:253.
Valadez-Calderon J, Ordinola Navarro A, Rodriguez-Chavez E, Vera-Lastra O. Co-expression of anti-NMDAR and anti-GAD65 antibodies. A case of autoimmune encephalitis in a post-COVID-19 patient. Neurologia (Engl Ed). 2022;37:503–4.
Dahshan A, Abdellatef AA. Autoimmune encephalitis as a complication of COVID-19 infection: a case report. Egypt J Intern Med. 2022;34:32.
Peters J, Alhasan S, Vogels CBF, et al. MOG-associated encephalitis following SARS-COV-2 infection. Mult Scler Relat Disord. 2021;50:102857.
Mestre Fusco A, Beltrán Mármol B, Álvarez Bravo G, et al. PET co-registered with MRI imaging of anti-NMDAR encephalitis patient with SARS-CoV-2 infection. Rev Esp Med Nucl Imagen Mol (Engl Ed). 2022;41(Suppl 1):46–s47.
Bhagat R, Kwiecinska B, Smith N, et al. New-Onset Seizure With Possible Limbic Encephalitis in a Patient With COVID-19 Infection: A Case Report and Review. J Investig Med High Impact Case Rep. 2021;9:2324709620986302.
Ayatollahi P, Tarazi A, Wennberg R. Possible Autoimmune Encephalitis with Claustrum Sign in case of Acute SARS-CoV-2 Infection. Can J Neurol Sci. 2021;48:430–2.
Grimaldi S, Lagarde S, Harlé JR, et al. Autoimmune Encephalitis Concomitant with SARS-CoV-2 Infection: Insight from (18)F-FDG PET Imaging and Neuronal Autoantibodies. J Nucl Med. 2020;61:1726–9.
Lee H, Jeon JH, Choi H, et al. Anti-N-methyl-D-aspartate receptor encephalitis after coronavirus disease 2019: A case report and literature review. Med (Baltim). 2022;101:e30464.
Mulder J, Feresiadou A, Fällmar D, et al. Autoimmune Encephalitis Presenting With Malignant Catatonia in a 40-Year-Old Male Patient With COVID-19. Am J Psychiatry. 2021;178:485–9.
Subramanyam M, Gupta SB, Chamraj S. Caspr2 autoimmune Encephalitis with COVID-19 Infection. J Assoc Physicians India. 2022;70:11–2.
Zambreanu L, Lightbody S, Bhandari M, et al. A case of limbic encephalitis associated with asymptomatic COVID-19 infection. J Neurol Neurosurg Psychiatry. 2020;91:1229–30.
Serrano-Serrano B, López-Hernández N, Dahl-Cruz F, et al. [Multifocal encephalitis as a neurological manifestation of COVID-19 infection]. Rev Neurol. 2020;71:351–2.
Poorshiri B, Raeisi S, Barzegar M. A Toddler With Acute Encephalitis Associated With COVID-19: A Case Report. Clin Pediatr (Phila). 2022;61:232–5.
Shen JY, Ng GJ, Yeo T. Anti-GABAB receptor encephalitis after COVID-19 infection. QJM. 2022;115:686–8.
McHattie AW, Coebergh J, Khan F, Morgante F. Palilalia as a prominent feature of anti-NMDA receptor encephalitis in a woman with COVID-19. J Neurol. 2021;268:3995–7.
Wang M, Li T, Qiao F, et al. Coronavirus disease 2019 associated with aggressive neurological and mental abnormalities confirmed based on cerebrospinal fluid antibodies: A case report. Med (Baltim). 2020;99:e21428.
Zamani R, Pouremamali R, Rezaei N. Central neuroinflammation in Covid-19: a systematic review of 182 cases with encephalitis, acute disseminated encephalomyelitis, and necrotizing encephalopathies. Rev Neurosci. 2022;33:397–412.
Qi F, Qian S, Zhang S, Zhang Z. Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem Biophys Res Commun. 2020;526:135–40.
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181:271–280e278.
Pennisi M, Lanza G, Falzone L et al. SARS-CoV-2 and the Nervous System: From Clinical Features to Molecular Mechanisms. Int J Mol Sci 2020; 21.
Kempuraj D, Selvakumar GP, Ahmed ME, et al. COVID-19, Mast Cells, Cytokine Storm, Psychological Stress, and Neuroinflammation. Neuroscientist. 2020;26:402–14.
Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, et al. A Clinical Approach to Diagnosis of Autoimmune Encephalitis." [In eng]. Lancet Neurol. Apr 2016;15:391–404. https://doi.org/10.1016/s1474-4422(15)00401-9.
Flanagan EP, Geschwind MD, Lopez-Chiriboga AS, Blackburn KM, Turaga S, Binks S, Zitser J et al. ,. "Autoimmune Encephalitis Misdiagnosis in Adults." [In eng]. JAMA Neurol 80, no. 1 (Jan 1 2023): 30–39. https://doi.org/10.1001/jamaneurol.2022.4251.

No competing interests reported.

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Autoimmune Encephalitis in COVID-19 patients : a systematic review of case reports and case series

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1. Introduction

2. Methods

3. Results

3.1 Searching published literature

3.2 Study characteristics

3.3 Neurological manifestations

3.4 Type of Autoimmune Encephalitis

3.5 Past medical history and Treatment

3.6 Outcome

4. Discussion

5. Conclusion

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