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Wang H. Anti-NMDA Receptor Encephalitis, Human Papillomavirus, and microRNA. Curr Med Chem 2025; 32:771-787. [PMID: 38549528 DOI: 10.2174/0109298673264615231124072130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 08/20/2023] [Accepted: 10/26/2023] [Indexed: 02/19/2025]
Abstract
BACKGROUND Anti-N-methyl-d-aspartate (Anti-NMDA) receptor encephalitis is a rare autoimmune disease, which is caused by antibodies attacking NMDA receptors in the brain. Previous studies revealed that this disorder might be induced by vaccination. Vaccination is the most useful strategy to prevent human or animal infectious diseases. Although vaccines can produce immunity against diseases, at low risk, they may trigger serious adverse events. Anti-NMDA receptor encephalitis has been studied to be related to the H1N1 (influenza A virus subtype H1N1), tetanus/diphtheria/pertussis and polio vaccine, Japanese encephalitis, yellow fever, and coronavirus disease 2019 (COVID-19) vaccination. Several cases have been reported that anti-NMDA receptor encephalitis could also be triggered by the human papillomavirus (HPV) vaccine. However, there is a lack of studies to investigate the underlying mechanism. METHODS In this paper, the association between anti-NMDA receptor encephalitis and HPV vaccination is discussed in terms of their microRNA (miRNA) biomarkers. Phylogenetic tree and distance similarity analyses are used to explore the relationship between their miRNA biomarkers. RESULTS The results show a higher degree of similarity between miRNA biomarkers associated with HPV and anti-NMDA receptor encephalitis or related vaccines when compared to the overall miRNAs. It indicates that while the risk of HPV triggering anti-NMDA receptor encephalitis is low, a connection between anti-NMDA receptor encephalitis and HPV vaccination cannot be ruled out. CONCLUSION This finding suggests that in cases where individuals receiving HPV vaccination experience psychiatric or neurological symptoms, it should be considered to diagnose anti-NMDA receptor encephalitis, given the exclusion of other possible complications.
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Affiliation(s)
- Hsiuying Wang
- Institute of Statistics, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
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Vasilevska V, Guest PC, Szardenings M, Benros ME, Steiner J. Possible temporal relationship between SARS-CoV-2 infection and anti-NMDA receptor encephalitis: a meta-analysis. Transl Psychiatry 2024; 14:139. [PMID: 38459000 PMCID: PMC10923949 DOI: 10.1038/s41398-024-02831-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 03/10/2024] Open
Abstract
The global impact of SARS-CoV-2 infection has raised concerns about secondary diseases beyond acute illness. This review explores the significance and potential underlying mechanisms of how SARS-CoV-2 infection might elicit an immune response targeting N-methyl-D-aspartate (NMDA) receptors, and its implications for autoimmune-driven neuropsychiatric manifestations. We identified 19 published case reports of NMDA receptor encephalitis associated with SARS-CoV-2 infection or vaccination by a systematic literature search. The significance of these reports was limited since it is not clear if a coincidental or causal relationship exists between SARS-CoV-2 infection or vaccination and manifestation of NMDA receptor encephalitis. The included studies were hampered by difficulties in establishing if these patients had pre-existing NMDA receptor antibodies which entered the brain by infection- or vaccination-associated transient blood-brain barrier leakage. In addition, four cases had comorbid ovarian teratoma, which is a known trigger for development of NMDA receptor encephalitis. Considering that billions of people have contracted COVID-19 or have been vaccinated against this virus, the publication of only 19 case reports with a possible link to NMDA receptor encephalitis, indicates that it is rare. In conclusion, these findings do not support the case that SARS-CoV-2 infection or vaccination led to an increase of existing or de novo encephalitis mediated by an autoimmune response targeting NMDA receptor function. Nevertheless, this work underscores the importance of ongoing vigilance in monitoring viral outbreaks and their potential impact on the central nervous system through basic, epidemiological and translational research.
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Affiliation(s)
- Veronika Vasilevska
- Department of Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
- Laboratory of Translational Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Paul C Guest
- Department of Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
- Laboratory of Translational Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Michael Szardenings
- Ligand Development Unit, Fraunhofer Institute of Cell Therapy and Immunology, Leipzig, Germany
| | - Michael E Benros
- Copenhagen Research Centre for Mental Health, Mental Health Center Copenhagen, Copenhagen University Hospital, Hellerup, Denmark
| | - Johann Steiner
- Department of Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
- Laboratory of Translational Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
- Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany.
- Center for Health and Medical Prevention (CHaMP), Magdeburg, Germany.
- German Center for Mental Health (DZPG), Partner Site Halle-Jena-Magdeburg, Magdeburg, Germany.
- Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C-I-R-C), Halle-Jena-Magdeburg, Magdeburg, Germany.
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Ding Z, Wei X, Pan H, Shi H, Shi Y. Unveiling the intricacies of COVID-19: Autoimmunity, multi-organ manifestations and the role of autoantibodies. Scand J Immunol 2024; 99:e13344. [PMID: 39007954 DOI: 10.1111/sji.13344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 11/06/2023] [Accepted: 11/16/2023] [Indexed: 07/16/2024]
Abstract
COVID-19 is a severe infectious disease caused by a SARS-CoV-2 infection. It has caused a global pandemic and can lead to acute respiratory distress syndrome (ARDS). Beyond the respiratory system, the disease manifests in multiple organs, producing a spectrum of clinical symptoms. A pivotal factor in the disease's progression is autoimmunity, which intensifies its severity and contributes to multi-organ injuries. The intricate interaction between the virus' spike protein and human proteins may engender the generation of autoreactive antibodies through molecular mimicry. This can further convolute the immune response, with the potential to escalate into overt autoimmunity. There is also emerging evidence to suggest that COVID-19 vaccinations might elicit analogous autoimmune responses. Advanced technologies have pinpointed self-reactive antibodies that target diverse organs or immune-modulatory proteins. The interplay between autoantibody levels and multi-organ manifestations underscores the importance of regular monitoring of serum antibodies and proinflammatory markers. A combination of immunosuppressive treatments and antiviral therapy is crucial for managing COVID-19-associated autoimmune diseases. The review will focus on the generation of autoantibodies in the context of COVID-19 and their impact on organ health.
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Affiliation(s)
- Zetao Ding
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xingyi Wei
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Haoyu Pan
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Shi
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yue Shi
- School of Athletic Performance, Shanghai University of Sport, Shanghai, China
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Khannanova AN, Brylev LV, Prusova AA, Aksenova EV, Kondrasheva EA, Kovaleva IS. [Autoimmune encephalitis: psychiatric aspects]. Zh Nevrol Psikhiatr Im S S Korsakova 2024; 124:20-27. [PMID: 38465807 DOI: 10.17116/jnevro202412402120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Autoimmune encephalitis is a group of diseases researched by both neurologists and psychiatrists. Despite a large number of studies and practical recommendations, the differential diagnosis and early diagnostics still remains an important issue. The most difficult to diagnose are cases that debut as mental disorders and/or occur without neurological symptoms. The literature review presents the current state of the problem with an emphasis on the practice of a psychiatrist.
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Affiliation(s)
- A N Khannanova
- Gannushkin Psychiatric Clinical Hospital No. 4, Moscow, Russia
- Russian Biotechnological University, Moscow, Russia
| | - L V Brylev
- V.M. Bujanov Moscow Clinical Hospital, Moscow, Russia
- Institute of Higher Nervous Activity and Neurophysiology, Moscow, Russia
| | - A A Prusova
- Gannushkin Psychiatric Clinical Hospital No. 4, Moscow, Russia
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Sawalha A, Alkilani H, Abdelaziz R. The association between autoimmune encephalitis mediated by N-methyl-ᴅ-aspartate receptor autoantibodies and COVID-19: a systematic review. ENCEPHALITIS 2024; 4:3-10. [PMID: 38126079 PMCID: PMC11007402 DOI: 10.47936/encephalitis.2023.00171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/06/2023] [Accepted: 11/15/2023] [Indexed: 12/23/2023] Open
Abstract
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.
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Affiliation(s)
- Ahmad Sawalha
- Department of Neurology, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA
| | - Huda Alkilani
- Department of Medicine, University of Sharjah, College of Medicine, Sharjah, United Arab Emirates
| | - Rami Abdelaziz
- Department of Child Neurology, Mayo Clinic, Rochester, MN, USA
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Hainmueller T, Lewis L, Furer T. Case report: Anti N-methyl-D-aspartate autoimmune encephalitis following a mildly symptomatic COVID-19 infection in an adolescent male. Front Psychiatry 2023; 14:1270572. [PMID: 38111616 PMCID: PMC10725953 DOI: 10.3389/fpsyt.2023.1270572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 10/30/2023] [Indexed: 12/20/2023] Open
Abstract
Background Antibodies against N-methyl-D-aspartate receptors are the most commonly identified cause of autoimmune encephalitis. While predominantly associated with malignancies, cases of anti-N-methyl-D-aspartate receptor autoimmune encephalitis have been reported after infections with the herpes-simplex virus or, more recently, in patients with severe COVID-19 disease. Case presentation A previously healthy 17-year-old male adolescent acutely developed psychosis with auditory and visual hallucinations, fluctuating mental status, and an isolated seizure 5 weeks after a mildly symptomatic COVID-19 infection. The symptoms continued to worsen, accompanied by catatonia, and additional neurological symptoms developed during the initial antipsychotic treatment. A diagnostic workup revealed antibodies against N-methyl-D-aspartate receptors in the cerebrospinal fluid without other major abnormalities. After establishing the diagnosis, initiation of immunomodulatory therapy stopped the symptom progression and led to full recovery within 2 months. Conclusion The case is remarkable in that anti-N-methyl-D-aspartate receptor autoimmune encephalitis developed shortly after a COVID-19 infection in an adolescent, despite the individual experiencing only mild COVID symptoms. The diagnosis should be considered in cases of acute-onset psychotic symptoms during or after COVID-19 infection, particularly in individuals without a prior psychiatric history, who present with atypical psychiatric or neurological features.
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Affiliation(s)
- Thomas Hainmueller
- Department of Psychiatry, New York University Langone Medical Center, New York, NY, United States
| | - Lambert Lewis
- Department of Psychiatry, New York University Langone Medical Center, New York, NY, United States
- Department of Child and Adolescent Psychiatry, Child Study Center at Hassenfeld Children's Hospital of New York at NYU Langone, New York, NY, United States
| | - Tzvi Furer
- Department of Psychiatry, New York University Langone Medical Center, New York, NY, United States
- Department of Child and Adolescent Psychiatry, Child Study Center at Hassenfeld Children's Hospital of New York at NYU Langone, New York, NY, United States
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Nersesjan V, Amiri M, Nilsson AC, Wamberg C, Jensen VVS, Petersen CB, Hejl AM, Lebech AM, Theut AM, Jørgensen CS, Blaabjerg M, Benros ME, Kondziella D. SARS-CoV-2 and autoantibodies in the cerebrospinal fluid of COVID-19 patients: prospective multicentre cohort study. Brain Commun 2023; 5:fcad274. [PMID: 37908236 PMCID: PMC10613856 DOI: 10.1093/braincomms/fcad274] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 06/23/2023] [Accepted: 10/16/2023] [Indexed: 11/02/2023] Open
Abstract
Disease mechanisms underlying neurological and neuropsychiatric symptoms after coronavirus disease 2019 (COVID-19), termed neuro-COVID, are poorly understood. Investigations of the cerebrospinal fluid (CSF) for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antibodies, as well as autoantibodies against neuronal surface antigens, could improve our understanding in that regard. We prospectively collected CSF and blood from patients investigated by lumbar puncture for neurological or neuropsychiatric symptoms during or after COVID-19. Primary outcomes were the presence of (i) SARS-CoV-2 RNA in CSF via polymerase chain reaction (PCR), (ii) SARS-CoV-2 immunoglobulin G (IgG) anti-S receptor-binding-domain antibodies via the Euroimmun and Wantai assays and (iii) IgG autoantibodies against neuronal surface antigens using commercial cell- and tissue-based assays (Euroimmun). Secondary outcomes were (i) routine CSF investigations and (ii) correlation between SARS-CoV-2 antibody levels in CSF with serum levels, blood-brain barrier permeability and peripheral inflammation. We obtained CSF from 38 COVID-19 patients (mean age 56.5 ± 19.2 years, 53% women) who developed neurological and neuropsychiatric symptoms. CSF pleocytosis (>5 cells) was observed in 9/38 patients (23.7%), elevated CSF protein (>0.50 g/L) in 13/38 (34.2%) and elevated CSF/serum albumin ratio in 12/35 (34.3%). PCR for SARS-CoV-2 RNA in CSF was negative in all. SARS-CoV-2 CSF antibodies were detected in 15/34 (44.1%; Euroimmun assay) and 7/31 (22.6%; Wantai assay) individuals, but there were no signs of intrathecal SARS-CoV-2 IgG production. SARS-CoV-2 CSF antibodies were positively correlated with serum levels (R = 0.93, P < 0.001), blood-brain barrier permeability (R = 0.47, P = 0.006), peripheral inflammation (R = 0.51, P = 0.002) and admission to the intensive care unit [odds ratio (OR) 17.65; 95% confidence interval (CI) 1.18-264.96; P = 0.04; n = 15]. Cell-based assays detected weakly positive NMDAR, LGI1 and CASPR2 antibodies in serum of 4/34 (11.8%) patients but not in CSF. The tissue-based assay showed anti-neuronal fluorescence in CSF from one individual, staining for Purkinje cells. In summary, whereas we did not detect active SARS-CoV-2 infection in the CSF, SARS-CoV-2 antibodies were prevalent. The absence of intrathecal antibody production points towards blood-brain barrier impairment as the origin of CSF SARS-CoV-2 antibodies. In contrast, CSF autoantibodies against neuronal surface antigens were rare. There was no evidence for a clinical correlate of these antibodies. We conclude that, rather than specific autoimmune neuronal injury, non-specific effects of critical illness including an impaired blood-brain barrier are more likely to contribute to neuro-COVID.
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Affiliation(s)
- Vardan Nersesjan
- Biological and Precision Psychiatry, Copenhagen Research Center for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Hellerup 2900, Denmark
- Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen 2100, Denmark
- Faculty of Health and Medical Sciences, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen 2200, Denmark
| | - Moshgan Amiri
- Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen 2100, Denmark
| | | | - Christian Wamberg
- Department of Anesthesia and Intensive Care, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen 2400, Denmark
| | | | - Charlotte Bjerg Petersen
- Department of Neurology, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen 2400, Denmark
| | - Anne-Mette Hejl
- Department of Neurology, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen 2400, Denmark
| | - Anne-Mette Lebech
- Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen 2100, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen 2200, Denmark
| | - Anna Marie Theut
- Virus and Microbiological Special Diagnostics, Statens Serum Institut, Copenhagen S 2300, Denmark
| | | | - Morten Blaabjerg
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense 5000, Denmark
| | - Michael E Benros
- Biological and Precision Psychiatry, Copenhagen Research Center for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Hellerup 2900, Denmark
- Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen 2100, Denmark
| | - Daniel Kondziella
- Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen 2100, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen 2200, Denmark
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8
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Wilpert NM, de Almeida Marcelino AL, Knierim E, Incoronato P, Sanchez-Sendin E, Staudacher O, Drenckhahn A, Bittigau P, Kreye J, Prüss H, Schuelke M, Kühn AA, Kaindl AM, Nikolaus M. Pediatric de novo movement disorders and ataxia in the context of SARS-CoV-2. J Neurol 2023; 270:4593-4607. [PMID: 37515734 PMCID: PMC10511612 DOI: 10.1007/s00415-023-11853-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/26/2023] [Accepted: 06/27/2023] [Indexed: 07/31/2023]
Abstract
OBJECTIVE In the fourth year of the COVID-19 pandemic, mortality rates decreased, but the risk of neuropsychiatric disorders remained the same, with a prevalence of 3.8% of pediatric cases, including movement disorders (MD) and ataxia. METHODS In this study, we report on a 10-year-old girl with hemichorea after SARS-CoV-2 infection and immunostained murine brain with patient CSF to identify intrathecal antibodies. Additionally, we conducted a scoping review of children with MD and ataxia after SARS-CoV-2 infection. RESULTS We detected antibodies in the patient's CSF binding unknown antigens in murine basal ganglia. The child received immunosuppression and recovered completely. In a scoping review, we identified further 32 children with de novo MD or ataxia after COVID-19. While in a minority of cases, MD or ataxia were a symptom of known clinical entities (e.g. ADEM, Sydenham's chorea), in most children, the etiology was suspected to be of autoimmune origin without further assigned diagnosis. (i) Children either presented with ataxia (79%), but different from the well-known postinfectious acute cerebellar ataxia (older age, less favorable outcome, or (ii) had hypo-/hyperkinetic MD (21%), which were choreatic in most cases. Besides 14% of spontaneous recovery, immunosuppression was necessary in 79%. Approximately one third of children only partially recovered. CONCLUSIONS Infection with SARS-CoV-2 can trigger de novo MD in children. Most patients showed COVID-19-associated-ataxia and fewer-chorea. Our data suggest that patients benefit from immunosuppression, especially steroids. Despite treatment, one third of patients recovered only partially, which makes up an increasing cohort with neurological sequelae.
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Affiliation(s)
- Nina-Maria Wilpert
- Department of Neuropediatrics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
- Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Ana Luísa de Almeida Marcelino
- Department of Neurology with Experimental Neurology, Movement Disorders and Neuromodulation Unit, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Ellen Knierim
- Department of Neuropediatrics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
- Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Pasquale Incoronato
- Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Elisa Sanchez-Sendin
- German Center for Neurodegenerative Diseases (DZNE), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
- Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Olga Staudacher
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
- NeuroCure Clinical Research Center, Berlin, Germany
| | - Anne Drenckhahn
- Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Petra Bittigau
- Department of Neuropediatrics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
- Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Jakob Kreye
- Department of Neuropediatrics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
- Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
- German Center for Neurodegenerative Diseases (DZNE), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
- Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Harald Prüss
- German Center for Neurodegenerative Diseases (DZNE), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
- Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Markus Schuelke
- Department of Neuropediatrics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
- Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
- Department of Immunology, Labor Berlin GmbH, Berlin, Germany
| | - Andrea A. Kühn
- Department of Neurology with Experimental Neurology, Movement Disorders and Neuromodulation Unit, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Angela M. Kaindl
- Department of Neuropediatrics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
- Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Marc Nikolaus
- Department of Neuropediatrics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
- Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
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Xue H, Zeng L, He H, Xu D, Ren K. Autoimmune encephalitis in COVID-19 patients: a systematic review of case reports and case series. Front Neurol 2023; 14:1207883. [PMID: 37771454 PMCID: PMC10525333 DOI: 10.3389/fneur.2023.1207883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 08/22/2023] [Indexed: 09/30/2023] Open
Abstract
Background There is mounting evidence suggesting that autoimmune encephalitis (AE) can be observed as a neurological complication in patients with COVID-19. This review aimed to summarize the clinical manifestations, types, and outcomes of COVID-19-associated AE. Methods A systematic search was conducted in the PubMed, Embase, and Web of Science databases to identify case reports and case series related to COVID-19-associated AE from 1 January 2020 to 31 March 2023. After a thorough screening and evaluation, irrelevant articles were excluded. Relevant information concerning types, clinical manifestations, and outcomes was extracted and synthesized. Results A total of 37 studies, comprising 34 case reports and 3 case series, were included in this review. Among the 42 COVID-19-associated AE patients, 21 (50%) cases were classified as an unknown antibodies (Ab) type of COVID-19-associated AE, 10 (23.80%) cases as anti-N-methyl-D-aspartate (NMDA) encephalitis, 4 (9.5%) cases as limbic encephalitis, and 3 (7.1%) cases as anti-myelin-oligodendrocyte-glycoprotein encephalitis, along with other rare types of AE. Disturbance of consciousness, seizures, and psychiatric symptoms were identified as the main clinical manifestations of COVID-19-associated AE. While the symptoms of AE displayed variation, most patients achieved full recovery although a few experienced residual symptoms of neurological damage. Conclusion This systematic review comprehensively describes the characteristics of COVID-19-associated AE. The main type of COVID-19-associated AE identified in this study is an unknown Ab type of COVID-19-associated AE. Despite the potentially life-threatening risks of COVID-19-associated AE, the majority of patients survived, with some patients reporting residual neurological symptoms.
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Affiliation(s)
- Hua Xue
- Department of Neurology, Sichuan Taikang Hospital, Chengdu, Sichuan, China
| | - Li Zeng
- Department of Respiratory, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Hongxian He
- Department of Neurology, Sichuan Taikang Hospital, Chengdu, Sichuan, China
| | - Dongxun Xu
- Department of Neurology, Sichuan Taikang Hospital, Chengdu, Sichuan, China
| | - Kaixin Ren
- Department of Rehabilitation, Affiliated Hospital of Yunnan University, Kunming, Yunnan, China
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Deb N, Roy P, Biswakarma A, Mary T, Mahajan S, Khan J, Shah A. Neurological Manifestations of Coronavirus Disease 2019 and Mpox in Pediatric Patients and Their Management: A State-of-the-Art Systematic Review. Pediatr Neurol 2023; 146:65-78. [PMID: 37441883 PMCID: PMC10195769 DOI: 10.1016/j.pediatrneurol.2023.05.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 05/13/2023] [Accepted: 05/13/2023] [Indexed: 07/15/2023]
Abstract
BACKGROUND There is an increasing number of cases being reported of neurological manifestations of Coronavirus disease 2019 (COVID-19) infection and Monkeypox (Mpox), both during the course of the infection and as a presenting symptom. We aim to review the neurological manifestations of COVID-19 and monkeypox in pediatric patients and their management. METHODS We conducted a systematic review that included cohort studies and case series or reports involving a pediatric population of patients with a confirmed COVID-19 or Mpox infection and their neurological manifestations. We searched the following electronic databases: PubMed, EMBASE, and Scopus. RESULTS From 1136 articles identified, 127 studies were included. Headache, stroke, Guillain-Barré syndrome, seizure, nerve palsies, and multisystem inflammatory syndrome in children were the most common neurological symptoms caused by COVID-19, whereas encephalitis was commonly seen in patients with Mpox. Rare neurological manifestations of COVID-19 included cerebral venous sinus thrombosis, plexopathies, demyelinating disorders, encephalitis, etc., and rare neurological manifestations of Mpox included headache. CONCLUSIONS Our review highlights the importance of investigating possible neurological manifestations and closely monitoring these patients to develop a better understanding of the treatment strategies that can be adopted.
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Affiliation(s)
- Novonil Deb
- North Bengal Medical College and Hospital, West Bengal, India
| | - Poulami Roy
- North Bengal Medical College and Hospital, West Bengal, India.
| | | | - Therese Mary
- Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Mangaluru, Karnataka, India
| | - Sanah Mahajan
- Government Medical College, Jammu, Jammu and Kashmir, India
| | - Javeria Khan
- Veer Narmad South Gujarat University, Surat, Gujarat, India
| | - Aatam Shah
- Veer Narmad South Gujarat University, Surat, Gujarat, India
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11
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Akbari A, Hadizadeh A, Islampanah M, Salavati Nik E, Atkin SL, Sahebkar A. COVID-19, G protein-coupled receptor, and renin-angiotensin system autoantibodies: Systematic review and meta-analysis. Autoimmun Rev 2023; 22:103402. [PMID: 37490975 DOI: 10.1016/j.autrev.2023.103402] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 07/20/2023] [Indexed: 07/27/2023]
Abstract
INTRODUCTION There are an increasing number of reports of autoantibodies (AAbs) against host proteins such as G-protein coupled receptors (GPCRs) and the renin-angiotensin system (RAS) in COVID-19 disease. Here we have undertaken a systematic review and meta-analysis of all reports of AAbs against GPCRs and RAS in COVID-19 patients including those with long-COVID or post-COVID symptoms. METHODS PubMed, Embase, Web of Science, and Scopus databases were searched to find papers on the role of GPCR and RAS AAbs in the presence and severity of COVID-19 or post- COVID symptoms available through March 21, 2023. Data on the prevalence of AngII or ACE, comparing AngII or ACE between COVID-19 and non-COVID-19, or comparing AngII or ACE between COVID-19 patients with different disease stages were pooled and a meta-analysed using random- or fixed-effects models were undertaken. RESULTS The search yielded a total of 1042 articles, of which 68 studies were included in this systematic review and nine in the meta-analysis. Among 18 studies that investigated GPCRs and COVID-19 severity, 18 distinct AAbs were detected. In addition, nine AAbs were found in case reports that assessed post- COVID, and 19 AAbs were found in other studies that assessed post- COVID or long- COVID symptoms. Meta-analysis revealed a significantly higher number of seropositive ACE2 AAbs in COVID-19 patients (odds ratio = 7.766 [2.056, 29.208], p = 0.002) and particularly in severe disease (odds ratio = 11.49 [1.04, 126.86], p = 0.046), whereas AngII-AAbs seropositivity was no different between COVID-19 and control subjects (odds ratio = 2.890 [0.546-15.283], p = 0.21). CONCLUSIONS GPCR and RAS AAbs may play an important role in COVID-19 severity, the development of disease progression, long-term symptoms COVID and post- COVID symptoms.
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Affiliation(s)
- Abolfazl Akbari
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Hadizadeh
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Advanced Technologies in Cardiovascular Medicine, Cardiovascular Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Muhammad Islampanah
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ensie Salavati Nik
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Stephen L Atkin
- Royal College of Surgeons in Ireland, Bahrain, Adliya, PO Box 15503, Bahrain
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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12
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Pillai KS, Misra S, Siripurapu G, Aliyar A, Bhat P, Rajan R, Srivastava A, Goyal V, Venkitachalam A, Radhakrishnan DM. De Novo Movement Disorders Associated with COVID-19- A Systematic Review of Individual Patients. Ann Indian Acad Neurol 2023; 26:702-707. [PMID: 38022478 PMCID: PMC10666879 DOI: 10.4103/aian.aian_572_23] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/28/2023] [Accepted: 08/14/2023] [Indexed: 12/01/2023] Open
Abstract
Background COVID-19 infection is associated with neurological manifestations, including various types of movement disorders (MD). A thorough review of individual patients with COVID-19-induced MD would help in better understanding the clinical profile and outcome of these patients and in prognostication. Objective We conducted an individual patient-systematic review to study the clinical and imaging profile and outcomes of patients with COVID-19-associated MD. Methods A systematic literature search of PubMed, EMBASE, and Cochrane databases was conducted by two independent reviewers. Individual patient data COVID from case reports and case series on COVID-19-associated MD, published between December 2019 and December 2022, were extracted and analyzed. Results Data of 133 patients with COVID-19-associated MD from 82 studies were analyzed. Mean age was 55 ± 18 years and 77% were males. A mixed movement disorder was most commonly seen (41%); myoclonus-ataxia was the most frequent (44.4%). Myoclonus significantly correlated with age (odds ratio (OR) 1.02 P = 0.03, CI 1-1.04). Tremor had the longest latency to develop after SARS-CoV-2 infection [median (IQR) 21 (10-40) days, P = 0.009, CI 1.01-1.05]. At short-term follow-up, myoclonus improved (OR 14.35, P value = 0.01, CI 1.71-120.65), whereas parkinsonism (OR 0.09, P value = 0.002, CI 0.19-0.41) and tremor (OR 0.16, P value = 0.016, CI 0.04-0.71) persisted. Conclusion Myoclonus-ataxia was the most common movement disorder after COVID-19 infection. Myoclonus was seen in older individuals and usually improved. Tremor and parkinsonism developed after a long latency and did not improve in the short-term.
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Affiliation(s)
- Kanchana S. Pillai
- Department of Neurology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India
| | - Shubham Misra
- Department of Neurology, Yale University School of Medicine, New Haven, CT, USA
| | - Govinda Siripurapu
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
| | - Aminu Aliyar
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
| | - Priyanka Bhat
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
| | - Roopa Rajan
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
| | - Achal Srivastava
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
| | - Vinay Goyal
- Institute of Neurosciences, Medanta the Medicity, Gurugram, Haryana, India
| | - Anil Venkitachalam
- Department of Neurology, Lokmanya Tilak Municipal Medical College, Mumbai, Maharashtra, India
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13
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Li Y, Jia Y. Case report: Anti-IgLON5 disease and anti-LGI1 encephalitis following COVID-19. Front Immunol 2023; 14:1195341. [PMID: 37383232 PMCID: PMC10293611 DOI: 10.3389/fimmu.2023.1195341] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 05/30/2023] [Indexed: 06/30/2023] Open
Abstract
Anti-IgLON family member 5 (IgLON5) disease is a rare autoimmune encephalitis, characterized by sleep problems, cognitive decline, gait abnormalities, and bulbar dysfunction. Anti-leucine-rich glioma-inactivated 1 (LGI1) autoimmune encephalitis is characterized by cognitive dysfunction, mental disorders, faciobrachial dystonic seizures (FBDS), and hyponatremia. Various studies report that coronavirus disease 2019 (COVID-19) have an effect on the nervous system and induce a wide range of neurological symptoms. Autoimmune encephalitis is one of the neurological complications in severe acute respiratory syndrome coronavirus 2 infection. Until now, autoimmune encephalitis with both anti-IgLON5 and anti-LGI1 receptor antibodies following COVID-19 is rarely reported. The case report described a 40-year-old man who presented with sleep behavior disorder, daytime sleepiness, paramnesia, cognitive decline, FBDS, and anxiety following COVID-19. Anti-IgLON5 and anti-LGI1 receptor antibodies were positive in serum, and anti-LGI1 receptor antibodies were positive in cerebrospinal fluid. The patient presented with typical symptoms of anti-IgLON5 disease such as sleep behavior disorder, obstructive sleep apnea, and daytime sleepiness. Moreover, he presented with FBDS, which is common in anti-LGI1 encephalitis. Therefore, the patient was diagnosed with anti-IgLON5 disease and anti-LGI1 autoimmune encephalitis. The patient turned better after high-dose steroid and mycophenolate mofetil therapy. The case serves to increase the awareness of rare autoimmune encephalitis after COVID-19.
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14
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Zouari Mallouli S, Jallouli O, Bouchaala W, Ben Nsir S, Kamoun Feki F, Charfi Triki C. Challenges to associate early onset epilepsy with COVID-19 autoimmune encephalitis: A case report. World J Immunol 2023; 13:1-10. [DOI: 10.5411/wji.v13.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 01/14/2023] [Accepted: 02/02/2023] [Indexed: 05/30/2023] Open
Abstract
BACKGROUND Diagnosis of coronavirus disease 2019 (COVID-19)-related neurological events in the pediatric population is challenging. Overlapping clinical picture of children with altered neurological state and inborn errors of metabolism, in addition to the frequency of asymptomatic COVID-19 cases, pose the main challenges for diagnosis. Diagnostic approaches to the onset post-COVID 19 subacute encephalopathy are still troublesome as seronegative autoimmune encephalitis (AIE) is reported.
CASE SUMMARY A 27-mo-old boy was admitted for stormy refractory seizure of polymorphic semiology and altered mental status followed by various neuropsychiatric features that were suggestive of AIE. Brain magnetic resonance imaging and cerebrospinal fluid analysis were normal. Neither the immunological assessment, including viral serologies, antinuclear antibodies, autoimmune antibodies (NMDA, AMPA, CASPR2, LG11, GABARB, Hu, Yo, Ri, CV2, PNMA2, SOX1, Titin, amphiphysin, Recoverin), nor the metabolic assessment for lactate and pyruvate showed significant anomaly. Both positive history of COVID-19 infection and the findings of characteristic repetitive extreme delta brush played a key role in the diagnosis of COVID-19-related AIE. A remarkable improvement in the state of the child was noted after two pulse doses of intravenous Veino-globulin and high dose of intravenous Corticosteroid.
CONCLUSION Diagnostic biomarkers for AIE might aid effective treatment.
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Affiliation(s)
- Salma Zouari Mallouli
- Department of Child Neurology, Hedi Chaker Sfax University Hospital and Research Laboratory LR19ES15-University of Sfax, Tunisia, Sfax 3029, Tunisia
| | - Olfa Jallouli
- Department of Child Neurology, Hedi Chaker Sfax University Hospital and Research Laboratory LR19ES15-University of Sfax, Tunisia, Sfax 3029, Tunisia
| | - Wafa Bouchaala
- Department of Child Neurology, Hedi Chaker Sfax University Hospital and Research Laboratory LR19ES15-University of Sfax, Tunisia, Sfax 3029, Tunisia
| | - Sihem Ben Nsir
- Department of Child Neurology, Hedi Chaker Sfax University Hospital and Research Laboratory LR19ES15-University of Sfax, Tunisia, Sfax 3029, Tunisia
| | - Fatma Kamoun Feki
- Department of Child Neurology, Hedi Chaker Sfax University Hospital and Research Laboratory LR19ES15-University of Sfax, Tunisia, Sfax 3029, Tunisia
| | - Chahnez Charfi Triki
- Department of Child Neurology, Hedi Chaker Sfax University Hospital and Research Laboratory LR19ES15-University of Sfax, Tunisia, Sfax 3029, Tunisia
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15
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Vengalil A, Nizamutdinov D, Su M, Huang JH. Mechanisms of SARS-CoV-2-induced Encephalopathy and Encephalitis in COVID-19 Cases. Neurosci Insights 2023; 18:26331055231172522. [PMID: 37255742 PMCID: PMC10225804 DOI: 10.1177/26331055231172522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 04/12/2023] [Indexed: 06/01/2023] Open
Abstract
The SARS-CoV-2 virus caused an unprecedented pandemic around the globe, infecting 36.5 million people and causing the death of over 1 million in the United States of America alone. COVID-19 patients demonstrated respiratory symptoms, cardiovascular complications, and neurologic symptoms, which in most severe cases included encephalopathy and encephalitis. Hypoxia and the uncontrolled proliferation of cytokines are commonly recognized to cause encephalopathy, while the retrograde trans-synaptic spread of the virus is thought to cause encephalitis in SARS-CoV-2-induced pathogenesis. Although recent research revealed some mechanisms explaining the development of neurologic symptoms, it still remains unclear whether interactions between these mechanisms exist. This review focuses on the discussion and analysis of previously reported hypotheses of SARS-CoV-2-induced encephalopathy and encephalitis and looks into possible overlaps between the pathogenesis of both neurological outcomes of the disease. Promising therapeutic approaches to prevent and treat SARS-CoV-2-induced neurological complications are also covered. More studies are needed to further investigate the dominant mechanism of pathogenesis for developing more effective preventative measures in COVID-19 cases with the neurologic presentation.
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Affiliation(s)
- Aaron Vengalil
- Neurosurgery, Texas A&M University,
College of Medicine, Temple, TX, USA
| | - Damir Nizamutdinov
- Neurosurgery, Texas A&M University,
College of Medicine, Temple, TX, USA
- Neurosurgery, Baylor Scott and White
Health, Neuroscience Institute, Temple, TX, USA
| | - Matthew Su
- Department of BioSciences, Rice
University, Houston, TX, USA
| | - Jason H Huang
- Neurosurgery, Texas A&M University,
College of Medicine, Temple, TX, USA
- Neurosurgery, Baylor Scott and White
Health, Neuroscience Institute, Temple, TX, USA
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16
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Raynowska J, Wu V, Kazer M, LaBuzetta JN, Ferrey D, Dunn‐Pirio A. COVID-19-associated AMPA-R and CRMP-5 autoimmune encephalitis in a patient with thymoma and myasthenia gravis. Clin Case Rep 2023; 11:e7064. [PMID: 36950670 PMCID: PMC10025254 DOI: 10.1002/ccr3.7064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 01/06/2023] [Accepted: 02/22/2023] [Indexed: 03/24/2023] Open
Abstract
Thymomas are associated with autoimmune disease, most commonly myasthenia gravis, and rarely with autoimmune encephalitis. More recently, viral triggers including COVID-19 have also been implicated in autoimmunity. We present a case of antibody-positive autoimmune encephalitis that developed in the setting of COVID-19 in a patient with thymomatous myasthenia gravis.
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Affiliation(s)
- Jenelle Raynowska
- Department of NeurosciencesUniversity of California, San DiegoLa JollaCaliforniaUSA
| | - Victoria Wu
- Department of NeurosciencesUniversity of California, San DiegoLa JollaCaliforniaUSA
| | - Max Kazer
- Department of NeurosciencesUniversity of California, San DiegoLa JollaCaliforniaUSA
| | | | - Dominic Ferrey
- Department of NeurosciencesUniversity of California, San DiegoLa JollaCaliforniaUSA
| | - Anastasie Dunn‐Pirio
- Department of NeurosciencesUniversity of California, San DiegoLa JollaCaliforniaUSA
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17
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Hauptman AJ, Ferrafiat V. Neuroinflammatory syndromes in children. Curr Opin Psychiatry 2023; 36:87-95. [PMID: 36705007 DOI: 10.1097/yco.0000000000000846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
PURPOSE OF REVIEW Neuropsychiatric symptoms due to paediatric neuroinflammatory diseases are increasingly recognized and reported. Psychiatrists are crucial in front-lines identification, diagnosis and care of individuals with disorders such as autoimmune encephalitis and management of long-term neurobehavioral sequelae. This review summarizes recent literature on autoimmune and post-infectious encephalitis, discusses special considerations in children with neurodevelopmental conditions and presents a paradigm for evaluation and management. RECENT FINDINGS There is a growing body of evidence on neuropsychiatric symptom burdens of paediatric neuroinflammatory diseases. A particular development is the evolution of diagnostic and treatment guidelines for conditions such as autoimmune encephalitis, which take into account phenotypes of acute, short-term and long-term sequelae. Interest in inflammatory sequelae of viral illness, such as SARS-CoV-2, in children remains in early development. SUMMARY Neuroimmunological disease data are constantly evolving. New recommendations exist for multiple common neuroimmunological disorders with behavioural, emotional, cognitive and neurological sequelae. Anti-NMDA receptor encephalitis now has well-recognized patterns of symptom semiology, diagnostic and treatment recommendations, and outcome patterns. Recognizing psychiatric symptoms heralding autoimmune brain disease and understanding neuropsychiatric sequelae are now a crucial skill set for paediatric psychiatrists. Exploration of inflammatory features of other diseases, such as genetic syndromes, is a burgeoning research area.
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Affiliation(s)
- Aaron J Hauptman
- Kennedy Krieger Institute
- Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Vladimir Ferrafiat
- Reference Center for Inborn Errors of Metabolism
- Reference Center for Intellectual Disabilities of Rare Causes, La Timone University Hospital, Assistance Publique - Hopitaux de Marseille, Marseille, France
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18
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Casabianca M, Caula C, Titomanlio L, Lenglart L. Neurological consequences of SARS-CoV-2 infections in the pediatric population. Front Pediatr 2023; 11:1123348. [PMID: 36865695 PMCID: PMC9973732 DOI: 10.3389/fped.2023.1123348] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 01/16/2023] [Indexed: 02/16/2023] Open
Abstract
COVID-19 in the pediatric population is mostly asymptomatic. However, 1 out of 5 children presents non-specific neurologic symptoms such as headache, weakness, or myalgia. Furthermore, rarer forms of neurological diseases are increasingly being described in association to a SARS-CoV-2 infection. Encephalitis, stroke, cranial nerves impairment, Guillain-Barré syndrome or acute transverse myelitis have been reported and account for around 1% of pediatric COVID-19 cases. Some of these pathologies may occur during or after the SARS-CoV-2 infection. The pathophysiological mechanisms range from direct invasion of the central nervous system (CNS) by SARS-CoV-2 itself to postinfectious immune-mediated CNS inflammation. In most cases, patients presenting neurological pathologies related to SARS-CoV-2 infection are at greater risk of life-threatening complications and should be closely monitored. Further studies are needed to acknowledge the potential long-term neurodevelopmental consequences of the infection.
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Affiliation(s)
- Manon Casabianca
- Pediatric Emergency Department, APHP - Hopital Robert Debré, Paris Cité University, Paris, France
| | - Caroline Caula
- Pediatric Emergency Department, APHP - Hopital Robert Debré, Paris Cité University, Paris, France
| | - Luigi Titomanlio
- Pediatric Emergency Department, APHP - Hopital Robert Debré, Paris Cité University, Paris, France.,Pediatric Migraine and Neurovascular Diseases Unit, APHP - Hopital Robert Debré, Paris Cité University, Paris, France.,DHU Protect, INSERM U1141, Paris Cité University, Paris, France
| | - Léa Lenglart
- Pediatric Emergency Department, APHP - Hopital Robert Debré, Paris Cité University, Paris, France
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19
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Chi H, Chang L, Chao YC, Lin DS, Yang HW, Fang LC, Lin CH, Ho CS, Yang KD. Pathogenesis and Preventive Tactics of Immune-Mediated Non-Pulmonary COVID-19 in Children and Beyond. Int J Mol Sci 2022; 23:14157. [PMID: 36430629 PMCID: PMC9696849 DOI: 10.3390/ijms232214157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 11/05/2022] [Accepted: 11/10/2022] [Indexed: 11/19/2022] Open
Abstract
The COVID-19 pandemic has evolved to immune escape and threatened small children and the elderly with a higher severity and fatality of non-pulmonary diseases. These life-threatening non-pulmonary COVID-19 diseases such as acute necrotizing encephalopathies (ANE) and multisystem inflammatory syndrome in children (MIS-C) are more prevalent in children. However, the mortality of multisystem inflammatory syndrome in adults (MIS-A) is much higher than that of MIS-C although the incidence of MIS-A is lower. Clarification of immunopathogenesis and genetic susceptibility of inflammatory non-pulmonary COVID-19 diseases would provide an appropriate guide for the crisis management and prevention of morbidity and fatality in the ongoing pandemic. This review article described three inflammatory non-pulmonary COVID-19 diseases including (1) meningoencephalitis (ME), (2) acute necrotizing encephalopathies (ANE), and (3) post-infectious multisystem inflammatory syndrome in children (MIS-C) and in adults (MIS-A). To prevent these life-threatening non-pulmonary COVID-19 diseases, hosts carrying susceptible genetic variants should receive prophylactic vaccines, avoid febrile respiratory tract infection, and institute immunomodulators and mitochondrial cocktails as early as possible.
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Affiliation(s)
- Hsin Chi
- MacKay Children’s Hospital, Taipei 103, Taiwan
- Department of Medicine, MacKay Medical College, Sanzhi, New Taipei City 252, Taiwan
| | - Lung Chang
- Department of Medicine, MacKay Medical College, Sanzhi, New Taipei City 252, Taiwan
- Departments of Pediatrics and Medical Research, MacKay Memorial Hospital, TamSui, New Taipei City 251, Taiwan
| | - Yen-Chun Chao
- MacKay Children’s Hospital, Taipei 103, Taiwan
- Department of Medicine, MacKay Medical College, Sanzhi, New Taipei City 252, Taiwan
| | - Dar-Shong Lin
- Department of Medicine, MacKay Medical College, Sanzhi, New Taipei City 252, Taiwan
- Departments of Pediatrics and Medical Research, MacKay Memorial Hospital, TamSui, New Taipei City 251, Taiwan
| | - Horng-Woei Yang
- Departments of Pediatrics and Medical Research, MacKay Memorial Hospital, TamSui, New Taipei City 251, Taiwan
| | - Li-Chih Fang
- MacKay Children’s Hospital, Taipei 103, Taiwan
- Department of Medicine, MacKay Medical College, Sanzhi, New Taipei City 252, Taiwan
| | - Chia-Hsueh Lin
- Departments of Pediatrics and Medical Research, MacKay Memorial Hospital, TamSui, New Taipei City 251, Taiwan
| | - Che-Sheng Ho
- MacKay Children’s Hospital, Taipei 103, Taiwan
- Department of Medicine, MacKay Medical College, Sanzhi, New Taipei City 252, Taiwan
| | - Kuender D. Yang
- MacKay Children’s Hospital, Taipei 103, Taiwan
- Departments of Pediatrics and Medical Research, MacKay Memorial Hospital, TamSui, New Taipei City 251, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Department of Microbiology & Immunology, National Defense Medical Center, Taipei 114, Taiwan
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20
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Saini L, Krishna D, Tiwari S, Goyal JP, Kumar P, Khera D, Choudhary B, Didel S, Gadepalli R, Singh K. Post-COVID-19 Immune-Mediated Neurological Complications in Children: An Ambispective Study. Pediatr Neurol 2022; 136:20-27. [PMID: 36049379 PMCID: PMC9258417 DOI: 10.1016/j.pediatrneurol.2022.06.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 03/13/2022] [Accepted: 06/13/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND The neurological manifestation following a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is varied, and till now, only a few studies have reported the same. METHODS We used retrospective data from May to July 2021 and prospective study data from August to September 2021, including that from children aged between one month and 18 years who presented to a tertiary care referral center with the neurological manifestation and had a history of coronavirus disease 2019 (COVID-19) infection or exposure and positive SARS-CoV-2 serology. The neuroradiological manifestations were further categorized as in a predesigned proforma. RESULTS Case records of the 18 children who fulfilled the criteria were included in the study; among them, seven (38.8%) were male and 11 (61.1%) were female. Predominant presentation in our study group was status epilepticus (six of 18) and Guillain-Barré syndrome (five of 18). Other manifestations included stroke (two of 18), demyelinating syndromes (three of 18), and autoimmune encephalitis (two of 18). Most of the children had favorable outcomes except for one mortality in our cohort. CONCLUSIONS Delayed complications following SARS-CoV-2 infection are seen in children. A temporal correlation was noted between the COVID-19 infection and the increasing number of neurological cases after the second wave. Steroids could be beneficial while treating such patients, especially in the presence of high inflammatory markers. Testing for SARS-CoV-2 serology during the pandemic can give a clue to the underlying etiology. Further multicentric studies are required to understand the varied neurological manifestations following SARS-CoV-2 infection in children.
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Affiliation(s)
- Lokesh Saini
- Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India.
| | - Deepthi Krishna
- Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Sarbesh Tiwari
- Department of Diagnostic and Interventional Radiology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Jagdish Prasad Goyal
- Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Prawin Kumar
- Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Daisy Khera
- Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Bharat Choudhary
- Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Siyaram Didel
- Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Ravisekhar Gadepalli
- Department of Microbiology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Kuldeep Singh
- Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
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Samim MM, Dhar D, Goyal S, Dey T, Parvin N, Shah RD, Singh V, Chowdhury S, Lal BM, Varghese N, Gohel A, Chowdhury A, Chatterjee A, Siddiqui S. AI-CoV Study: Autoimmune Encephalitis Associated With COVID-19 and Its Vaccines-A Systematic Review. J Clin Neurol 2022; 18:692-710. [PMID: 36367067 PMCID: PMC9669562 DOI: 10.3988/jcn.2022.18.6.692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/19/2022] [Accepted: 04/20/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND AND PURPOSE Autoimmune encephalitis (AIE) following coronavirus disease 2019 (COVID-19) is an underexplored condition. This study aims to systematically review the clinico-investigational and pathophysiologic aspects of COVID-19 and its vaccines in association with AIE, and identify the factors predicting neurological severity and outcomes. METHODS Relevant data sources were searched using appropriate search terms on January 15, 2022. Studies meeting the criteria for AIE having a temporal association with COVID-19 or its vaccines were included. RESULTS Out of 1,894 citations, we included 61 articles comprising 88 cases: 71 of COVID-19-associated AIE, 3 of possible Bickerstaff encephalitis, and 14 of vaccine-associated AIE.There were 23 definite and 48 possible seronegative AIE cases. Anti-NMDAR (N-methyl-D-aspartate receptor; n=12, 16.9%) was the most common definite AIE. Males were more commonly affected (sex ratio=1.63) in the AIE subgroup. The neurological symptoms included alteredmental state (n=53, 74.6%), movement disorders (n=28, 39.4%), seizures (n=24, 33.8%), behavioural (n=25, 35.2%), and speech disturbances (n=17, 23.9%). The median latency to AIE diagnosis was 14 days (interquartile range=4-22 days). Female sex and ICU admission had higherrisks of sequelae, with odds ratio (OR) of 2.925 (95% confidence interval [CI]=1.005-8.516)and 3.515 (95% CI=1.160-10.650), respectively. Good immunotherapy response was seen in42/48 (87.5%) and 13/13 (100%) of COVID-19-associated and vaccine-associated AIE patients, respectively. Sequelae were reported in 22/60 (36.7%) COVID-19 associated and 10/13 (76.9%) vaccine-associated cases. CONCLUSIONS The study has revealed diagnostic, therapeutic, and pathophysiological aspects of AIE associated with COVID-19 and its vaccines, and its differences from postinfectious AIE. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration number CRD42021299215.
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Affiliation(s)
- M M Samim
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India
| | - Debjyoti Dhar
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India.
| | - Sheetal Goyal
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India
| | - Treshita Dey
- Department of Radiation Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Naznin Parvin
- Department of Pediatrics, Lady Hardinge Medical College and Hospital, New Delhi, India
| | - Rutul D Shah
- Department of Neurology, Amrita Institute of Medical Sciences, Kochi, Kerala, India
| | - Vikram Singh
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India
| | - Sampurna Chowdhury
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
| | - Bhavesh Mohan Lal
- Department of General Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Nibu Varghese
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India
| | - Abhishek Gohel
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India
| | - Abhishek Chowdhury
- Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India
| | - Aritra Chatterjee
- Centre For Biosystems Science and Engineering, Indian Institute of Science, Bangalore, Karnataka, India
| | - Shahyan Siddiqui
- Consultant Neuroradiologist, Department of Neuroimaging and Interventional Radiology, STAT Institute of Neurosciences, Hyderabad, India
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Scheuermeier M, Chaves KQ, Marín-Sanabria D, Acosta-Lazo H, Ulate-Campos A. First Pediatric Case of Autoimmune Encephalitis Associated With COVID-19 in Costa Rica. Cureus 2022; 14:e30616. [DOI: 10.7759/cureus.30616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/23/2022] [Indexed: 11/07/2022] Open
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Cascardo C, Ismail A, Fullmer J, Davila F. Anti-NMDA receptor encephalitis with initial negative markers: diagnostic and therapeutic challenges of a refractory case with 9-month-long follow-up. BMJ Case Rep 2022; 15:e249126. [PMID: 35764337 PMCID: PMC9240890 DOI: 10.1136/bcr-2022-249126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/14/2022] [Indexed: 11/06/2022] Open
Abstract
Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a progressively debilitating, frequently fatal disease caused by autoantibodies against the NMDA receptor. Risk of delayed treatment is high due to variable presentations, lack of awareness and potential false negative diagnostic studies. In this case report, a woman in her 20s presented with psychiatric manifestations and rapidly declined. Dyskinetic movements and dysautonomia were observed. Initial cerebrospinal fluid and serum anti-NMDA receptor antibodies were negative. MRI was inconclusive. Electroencephalography demonstrated extreme delta brush. Pelvic CT revealed an adnexal teratoma. She remained refractory to treatment until day 126 when, after two cycles of cyclophosphamide, she started to improve. She participated in rehabilitation with eventual discharge home on day 269. Recognising the variable presentations of anti-NMDA receptor encephalitis is important in avoiding misdiagnosis and delayed treatment. If clinical suspicion remains high despite negative results, repeat testing should be pursued. Clinical response should guide treatment decisions in refractory cases.
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Affiliation(s)
- Camilla Cascardo
- Oakland University William Beaumont School of Medicine, Rochester, Michigan, USA
| | | | - Joseph Fullmer
- Pathology, William Beaumont Hospital, Royal Oak, Michigan, USA
| | - Francisco Davila
- Internal Medicine, William Beaumont Hospital, Royal Oak, Michigan, USA
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24
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Carneiro VCDS, Alves-Leon SV, Sarmento DJDS, Coelho WLDCNP, Moreira ODC, Salvio AL, Ramos CHF, Ramos Filho CHF, Marques CAB, da Costa Gonçalves JP, Leon LAA, de Paula VS. Herpesvirus and neurological manifestations in patients with severe coronavirus disease. Virol J 2022; 19:101. [PMID: 35676707 PMCID: PMC9174631 DOI: 10.1186/s12985-022-01828-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 05/25/2022] [Indexed: 12/14/2022] Open
Abstract
Background Certain clinical manifestations of coronavirus disease (COVID-19) mimic those associated with human herpesvirus (HHV) infection. In this study, we estimated the prevalence of herpesvirus in patients with COVID-19 and determined if coinfection is associated with poorer outcomes and neurological symptoms. Methods We analyzed samples of 53 patients diagnosed with COVID-19. The samples were evaluated for the presence of alphaherpesviruses, betaherpesviruses, and gammaherpesviruses, and the viral loads were quantified using quantitative polymerase chain reaction (qPCR) method. Results Among the patients, in 79.2% had detection at least one type of herpesvirus. HHV-6 (47.2%), cytomegalovirus (43.3%), and HHV-7 (39.6%) showed the highest detection rates. Patients with a high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) load were more likely to show herpes simplex virus 1 detection (p = 0.037). Among patients coinfected with SARS-CoV-2 and HHVs, 26.4% showed central nervous system-associated neurological symptoms and herpetic manifestations. A statistically significant association was observed between neurological changes and HHV-6 detection (p = 0.034). Conclusions The findings showed a high prevalence of herpesvirus in patients with COVID-19. Furthermore, even though SARS-CoV-2 and HHV coinfection was not associated with poorer outcomes, the findings demonstrated the association between neurological symptoms and HHV-6 detection. Supplementary Information The online version contains supplementary material available at 10.1186/s12985-022-01828-9.
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25
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Ariño H, Heartshorne R, Michael BD, Nicholson TR, Vincent A, Pollak TA, Vogrig A. Neuroimmune disorders in COVID-19. J Neurol 2022; 269:2827-2839. [PMID: 35353232 PMCID: PMC9120100 DOI: 10.1007/s00415-022-11050-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/22/2022] [Accepted: 02/23/2022] [Indexed: 12/15/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the aetiologic agent of the coronavirus disease 2019 (COVID-19), is now rapidly disseminating throughout the world with 147,443,848 cases reported so far. Around 30-80% of cases (depending on COVID-19 severity) are reported to have neurological manifestations including anosmia, stroke, and encephalopathy. In addition, some patients have recognised autoimmune neurological disorders, including both central (limbic and brainstem encephalitis, acute disseminated encephalomyelitis [ADEM], and myelitis) and peripheral diseases (Guillain-Barré and Miller Fisher syndrome). We systematically describe data from 133 reported series on the Neurology and Neuropsychiatry of COVID-19 blog ( https://blogs.bmj.com/jnnp/2020/05/01/the-neurology-and-neuropsychiatry-of-covid-19/ ) providing a comprehensive overview concerning the diagnosis, and treatment of patients with neurological immune-mediated complications of SARS-CoV-2. In most cases the latency to neurological disorder was highly variable and the immunological or other mechanisms involved were unclear. Despite specific neuronal or ganglioside antibodies only being identified in 10, many had apparent responses to immunotherapies. Although the proportion of patients experiencing immune-mediated neurological disorders is small, the total number is likely to be underestimated. The early recognition and improvement seen with use of immunomodulatory treatment, even in those without identified autoantibodies, makes delayed or missed diagnoses risk the potential for long-term disability, including the emerging challenge of post-acute COVID-19 sequelae (PACS). Finally, potential issues regarding the use of immunotherapies in patients with pre-existent neuro-immunological disorders are also discussed.
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Affiliation(s)
- Helena Ariño
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Rosie Heartshorne
- Department of Neurology, The Walton Centre NHS Foundation Trust, Liverpool, UK
| | - Benedict D Michael
- Department of Neurology, The Walton Centre NHS Foundation Trust, Liverpool, UK
- The National Institute for Health Research Health Protection Research Unit for Emerging and Zoonotic Infections, University of Liverpool, Liverpool, UK
- Department of Clinical Infection Microbiology and Immunology, Institute of Infection, Veterinary, and Ecological Sciences, University of Liverpool, Liverpool, UK
| | - Timothy R Nicholson
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Angela Vincent
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Thomas A Pollak
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
| | - Alberto Vogrig
- Centre de Référence National pour les Syndromes Neurologiques Paranéoplasique, Hôpital Neurologique, Hospices Civils de Lyon, Lyon, France
- Clinical Neurology Unit, Azienda Sanitaria Universitaria Friuli Centrale, Presidio Ospedaliero Santa Maria Della Misericordia, Udine, Italy
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Autoimmune Encephalitis in COVID-19 Infection: Our Experience and Systematic Review of the Literature. Biomedicines 2022; 10:biomedicines10040774. [PMID: 35453524 PMCID: PMC9024859 DOI: 10.3390/biomedicines10040774] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 03/02/2022] [Accepted: 03/21/2022] [Indexed: 01/08/2023] Open
Abstract
The neurologic complications of COVID-19 infection are frequent in hospitalized patients; a high percentage of them present neurologic manifestations at some point during the course of their disease. Headache, muscle pain, encephalopathy and dizziness are among the most common complications. Encephalitis is an inflammatory condition with many etiologies. There are several forms of encephalitis associated with antibodies against intracellular neuronal proteins, cell surfaces or synaptic proteins, referred to as autoimmune encephalitis. Several case reports published in the literature document autoimmune encephalitis cases triggered by COVID-19 infection. Our paper first presents our experience in this issue and then systematically reviews the literature on autoimmune encephalitis that developed in the background of SARS-CoV-2 infections and also discusses the possible pathophysiological mechanisms of auto-immune-mediated damage to the nervous system. This review contributes to improve the management and prognosis of COVID-19-related autoimmune encephalitis.
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Abstract
The coronavirus disease 2019 (COVID-19) pandemic has had an enormous impact on the world, affecting people's lifestyle, economy, and livelihood. Recently, with the development of vaccines, the number of infected cases has decreased. Many case reports have revealed that COVID-19 may induce other serious comorbidities such as anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis. Anti-NMDA receptor encephalitis is an acute autoimmune disease that occurs more commonly in women than in men. To explore the association between COVID-19 and anti-NMDA receptor encephalitis, the microRNA (miRNA) biomarkers of COVID-19, anti-NMDA receptor encephalitis, and other related diseases from the literature are reviewed; then on the basis of these miRNA biomarkers, the relationship between COVID-19 and anti-NMDA receptor encephalitis is discussed. miRNAs are small non-coding RNAs that play important roles in cell differentiation, development, cell-cycle regulation, and apoptosis. miRNAs have been used as biological biomarkers for many diseases. The results in this study reveal that the relationship between anti-NMDA receptor encephalitis and COVID-19 infection or COVID-19 vaccination cannot be excluded; however, the risk that COVID-19 triggers the anti-NMDA receptor encephalitis is not high.
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Affiliation(s)
- Hsiuying Wang
- Institute of Statistics, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
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29
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Payus AO, Jeffree MS, Ohn MH, Tan HJ, Ibrahim A, Chia YK, Raymond AA. Immune-mediated neurological syndrome in SARS-CoV-2 infection: a review of literature on autoimmune encephalitis in COVID-19. Neurol Sci 2022; 43:1533-1547. [PMID: 34853897 PMCID: PMC8635316 DOI: 10.1007/s10072-021-05785-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/23/2021] [Indexed: 12/23/2022]
Abstract
INTRODUCTION The novel Coronavirus Disease 2019 (COVID-19) is an infection caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which has been spreading rapidly amongst humans and causing a global pandemic. The notorious infection has shown to cause a wide spectrum of neurological syndrome, including autoimmune encephalitis. OBJECTIVE Here, we systematically review the literature on autoimmune encephalitis that developed in the background of SARS-CoV-2 infections and also the possible pathophysiological mechanisms of auto-immune mediated damage to the nervous system. METHODOLOGY An exhaustive search was made in Medline/PubMed, Embase, Scopus and other medical databases, and 28 relevant published articles were selected according to the strict inclusion criteria. RESULTS Autoimmune encephalitis can occur via three possible proposed pathophysiological mechanism and can manifest during or after the acute infection period. It is more common in adult but can also occur in the paediatric patients. There were various spectra of autoantibody panels reported including antineuronal antibody, anti-gangliosides antibody and onconeural antibody. Majority of the patients responded well to the immunomodulating therapy and achieved good recovery. CONCLUSION In conclusion, SARSCoV-2 infection can induce various spectrum of autoimmune encephalitis. It is a major concern since there is very limited long-term study on the topic. Hence, this review aims to elucidate on the potential long-term complication of SARS-CoV-2 infection and hopefully to improve the management and prognosis of COVID-19.
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Affiliation(s)
- Alvin Oliver Payus
- Faculty of Medicine and Health Science, Universiti Malaysia Sabah (UMS), Jalan UMS, 88400 Kota Kinabalu, Sabah Malaysia
| | - Mohammad Saffree Jeffree
- Faculty of Medicine and Health Science, Universiti Malaysia Sabah (UMS), Jalan UMS, 88400 Kota Kinabalu, Sabah Malaysia
| | - May Honey Ohn
- Cardiology Department, University Lewisham Hospital, High Street, London, SE13 6LH UK
| | - Hui Jan Tan
- Department of Internal Medicine, Universiti Kebangsaan Malaysia Medical Centre (UKMMC), Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur Malaysia
| | - Azliza Ibrahim
- Department of Neurology, Hospital Pengajar Universiti Putra Malaysia, Persiaran Mardi - UPM, 43400 Serdang, Selangor Malaysia
| | - Yuen Kang Chia
- Neurology Unit, Department of Medicine, Queen Elizabeth Hospital, 13a Jalan Penampang, 88200 Kota Kinabalu, Sabah Malaysia
| | - Azman Ali Raymond
- Department of Medicine, Faculty of Medicine, Universiti Teknologi MARA, Jalan Hospital, 47000, Sungai Buloh, Selangor Malaysia
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Hampe CS, Mitoma H. A Breakdown of Immune Tolerance in the Cerebellum. Brain Sci 2022; 12:brainsci12030328. [PMID: 35326284 PMCID: PMC8946792 DOI: 10.3390/brainsci12030328] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/22/2022] [Accepted: 02/25/2022] [Indexed: 11/21/2022] Open
Abstract
Cerebellar dysfunction can be associated with ataxia, dysarthria, dysmetria, nystagmus and cognitive deficits. While cerebellar dysfunction can be caused by vascular, traumatic, metabolic, genetic, inflammatory, infectious, and neoplastic events, the cerebellum is also a frequent target of autoimmune attacks. The underlying cause for this vulnerability is unclear, but it may be a result of region-specific differences in blood–brain barrier permeability, the high concentration of neurons in the cerebellum and the presence of autoantigens on Purkinje cells. An autoimmune response targeting the cerebellum—or any structure in the CNS—is typically accompanied by an influx of peripheral immune cells to the brain. Under healthy conditions, the brain is protected from the periphery by the blood–brain barrier, blood–CSF barrier, and blood–leptomeningeal barrier. Entry of immune cells to the brain for immune surveillance occurs only at the blood-CSF barrier and is strictly controlled. A breakdown in the barrier permeability allows peripheral immune cells uncontrolled access to the CNS. Often—particularly in infectious diseases—the autoimmune response develops because of molecular mimicry between the trigger and a host protein. In this review, we discuss the immune surveillance of the CNS in health and disease and also discuss specific examples of autoimmunity affecting the cerebellum.
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Affiliation(s)
- Christiane S. Hampe
- Department of Medicine, University of Washington, Seattle, WA 98195, USA
- Correspondence: ; Tel.: +1-206-554-9181
| | - Hiroshi Mitoma
- Department of Medical Education, Tokyo Medical University, Tokyo 160-0023, Japan;
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Marques FMC, Nardi AE, Teixeira AL, Caixeta L. Immunopsychiatry: An Update on Autoimmune Encephalitis for Neuropsychiatrists. Expert Rev Neurother 2022; 22:155-167. [PMID: 35130814 DOI: 10.1080/14737175.2022.2038136] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Autoimmune encephalitis (AIE) is a group of immune-mediated inflammatory processes of the brain with marked psychiatric features. Although relatively rare, they might offer difficult differential diagnosis with psychiatric conditions, especially catatonia and psychotic syndromes. Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is the most common AIE, presenting with psychiatric syndromes in 90% of cases. The associated psychopathology is complex, pleomorphic and best characterized when there is involvement of a psychiatrist in the assessment. AREAS COVERED This text will review the main aspects of AIE to psychiatrists and/or neuropsychiatrists. EXPERT OPINION Immune system dysfunction has been implicated in the pathophysiology of psychiatric symptoms and disorders. The use of diagnostic criteria of possible AIE, especially when specific antibodies of AIE are not available, allows early diagnosis and prompt treatment which are associated with better clinical outcomes. The study of the psychiatric aspects of AIE can broaden our knowledge of the underlying mechanisms of various psychiatric manifestations.
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Affiliation(s)
- Frederico Moraes Cardoso Marques
- Cognitive and Behavioral Neurology, Department of Clinical Medicine, Federal University of Goiás, School of Medicine, Goiânia, GO, Brazil
| | - Antônio Egídio Nardi
- Institute of Psychiatry, Federal University of Rio de Janeiro, School of Medicine, Rio de Janeiro, RJ, Brazil
| | - Antonio L Teixeira
- Neurology and Psychiatry, University of Texas Health Science Center McGovern Medical School, Houston, TX, USA
| | - Leonardo Caixeta
- Neurology and Neuropsychiatry, Department of Clinical Medicine, Federal University of Goiás, School of Medicine, Goiânia, GO, Brazil
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Urso L, Distefano MG, Cambula G, Colomba AI, Nuzzo D, Picone P, Giacomazza D, Sicurella L. The case of encephalitis in a COVID-19 pediatric patient. Neurol Sci 2022; 43:105-112. [PMID: 34668122 PMCID: PMC8525855 DOI: 10.1007/s10072-021-05670-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 10/15/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND The COVID-19 pandemic, induced by the worldwide spreading of the SARS-CoV-2, is well known for its clinical picture consistent with respiratory symptoms. If pulmonary complications are the most common manifestation of the disease, neurological problems are also significantly present, with complications including acute cerebrovascular events, encephalitis, Guillain-Barré and Miller Fisher syndromes, acute necrotizing hemorrhagic encephalopathy and hemophagocytic lymphohistiocytosis. These medical signs can be considered direct effects of the virus on the nervous system, para-infectious or post-infectious immune-mediated diseases, and neurological complications of the systemic effects of the SARS-CoV-2. CASE In the present article, the encephalitis case in a 5-year-old girl positive for COVID-19 admitted to the emergency department complaining of fever and swelling in the neck is described. At this time, her neurological examination was unremarkable. Over the next few days, the fever went down and she experienced acute behavioral changes, mild confusion, and drowsiness. The brain MRI and electroencephalography (EEG) showed CNS involvement, suggestive of encephalitis. CONCLUSION The dramatic improvement of the symptoms after immunotherapy with corticosteroids reinforced the hypothesis of an immune-related mechanism.
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Affiliation(s)
- Lidia Urso
- Dipartimento di Neurologia P.O. S. Antonio Abate, Azienda Sanitaria Provinciale di Trapani, Trapani, Italy
| | - Maria Grazia Distefano
- Dipartimento di Neurologia P.O. S. Antonio Abate, Azienda Sanitaria Provinciale di Trapani, Trapani, Italy
| | - Gaetano Cambula
- Unità Operativa Complessa Radiologia P.O.S. Antonio Abate, Azienda Sanitaria Provinciale di Trapani, Trapani, Italy
| | - Angela Irene Colomba
- Dipartimento di Neurologia P.O. S. Antonio Abate, Azienda Sanitaria Provinciale di Trapani, Trapani, Italy
| | - Domenico Nuzzo
- Consiglio Nazionale delle Ricerche, Istituto per la Ricerca e l’Innovazione Biomedica (CNR-IRIB), Palermo, Italy
- Dipartimento of Scienze Biologiche, Chimiche, Farmaceutiche e Tecnologiche (STEBICEF), University of Palermo, Palermo, Italy
| | - Pasquale Picone
- Consiglio Nazionale delle Ricerche, Istituto per la Ricerca e l’Innovazione Biomedica (CNR-IRIB), Palermo, Italy
- Dipartimento of Scienze Biologiche, Chimiche, Farmaceutiche e Tecnologiche (STEBICEF), University of Palermo, Palermo, Italy
| | - Daniela Giacomazza
- Consiglio Nazionale delle Ricerche, Istituto di Biofisica (CNR-IBF), Palermo, Italy
| | - Luigi Sicurella
- Dipartimento di Neurologia P.O. S. Antonio Abate, Azienda Sanitaria Provinciale di Trapani, Trapani, Italy
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Valderas C, Méndez G, Echeverría A, Suarez N, Julio K, Sandoval F. COVID-19 and neurologic manifestations: a synthesis from the child neurologist's corner. World J Pediatr 2022; 18:373-382. [PMID: 35476245 PMCID: PMC9044375 DOI: 10.1007/s12519-022-00550-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 03/29/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Since December 2019, the SARS-CoV-2 virus has been a global health issue. The main clinical presentation of this virus is a flu-like disease; however, patients with diverse neurologic manifestations have also been reported. In this review, we attempt to summarize, discuss and update the knowledge of the neurologic manifestations in the pediatric population affected by SARS-CoV-2 infection and the pandemic's effects in children with neurologic diseases. DATA SOURCES This review analyzes studies found on the PubMed database using the following keywords: Neurologic manifestations COVID-19, Neurological COVID-19, coronavirus, SARS-CoV-2, pediatric COVID-19, COVID-19 in children, MIS-C, Pediatric Inflammatory Multisystem Syndrome, Guillain Barré Syndrome, Stroke, ADEM, and Anti-NMDA encephalitis. All studies cited were published between 2004 and 2022, and represent the most relevant articles in the field. The World Health Organization COVID-19 online dashboard was assessed to obtain updated epidemiological data. RESULTS The most common neurologic symptoms in the pediatric population are headache, seizures, encephalopathy, and muscle weakness. These can be present during COVID-19 or weeks after recovering from it. Children who presented with multi-system inflammatory syndrome had a higher incidence of neurologic manifestations, which conferred a greater risk of morbidity and mortality. Several neuro-pathophysiological mechanisms have been proposed, including direct virus invasion, hyper-inflammatory reactions, multi-systemic failure, prothrombotic states, and immune-mediated processes. On the other hand, the COVID-19 pandemic has affected patients with neurologic diseases, making it challenging to access controls, treatment, and therapies. CONCLUSIONS Various neurologic manifestations have been associated with children's SARS-CoV-2 infection. It is important to identify and give them proper and opportune treatment because they can be potentially grave and life-threatening; some can lead to long-lasting sequelae. Different neuro-pathophysiological mechanisms have been proposed, however, a causal relationship between SARS-CoV-2 infection and neurologic manifestations remains to be proven. Patients with neurologic diseases are especially affected by COVID-19, not only by the disease itself but also by its complications and pandemic management measures.
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Affiliation(s)
- Carolina Valderas
- Department of Neurology, Hospital Dr. Exequiel González Cortés, Gran Avenida José Miguel Carrera 3300, 8900085 Santiago, Región Metropolitana Chile
| | - Gastón Méndez
- Department of Neurology, Hospital Dr. Exequiel González Cortés, Gran Avenida José Miguel Carrera 3300, 8900085 Santiago, Región Metropolitana Chile
| | - Alejandra Echeverría
- Department of Neurology, Hospital Dr. Exequiel González Cortés, Gran Avenida José Miguel Carrera 3300, 8900085 Santiago, Región Metropolitana Chile
| | - Nelson Suarez
- Department of Neurology, Hospital Dr. Exequiel González Cortés, Gran Avenida José Miguel Carrera 3300, 8900085 Santiago, Región Metropolitana Chile
| | - Katherin Julio
- Department of Neurology, Hospital Dr. Exequiel González Cortés, Gran Avenida José Miguel Carrera 3300, 8900085 Santiago, Región Metropolitana Chile
| | - Francisca Sandoval
- Department of Neurology, Hospital Dr. Exequiel González Cortés, Gran Avenida José Miguel Carrera 3300, 8900085, Santiago, Región Metropolitana, Chile.
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Simon DW, Schober ME. Acute central and peripheral nervous system injury associated with coronavirus disease 2019: recognition and treatment strategies. Curr Opin Pediatr 2021; 33:591-596. [PMID: 34670263 PMCID: PMC8577290 DOI: 10.1097/mop.0000000000001070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Acute central and peripheral nervous system injury may occur in association with coronavirus disease 2019 (COVID-19) caused by infection with the severe acute respiratory syndrome coronavirus 2 virus. This review will assist readers to recognize neurologic manifestations associated with COVID-19 including common and life-threatening symptoms and diagnostic testing. We will also review current recommendations for treatment of neurologic injury associated with COVID-19 infection in children. RECENT FINDINGS Data from systematic reviews and prospectively collected cohorts of children with COVID-19 are beginning to characterize the breadth of neurologic manifestations associated with COVID-19 in the acute infectious and postinfectious periods. Among hospitalized children in particular, neurologic symptoms are common. Life threatening conditions including encephalitis, myelitis, stroke, and demyelinating syndromes have been reported. Within the pediatric population, age, and preexisting neurologic conditions appear to be important factors in determining likely phenotypes. Treatment at this time is based on careful neuromonitoring, supportive care, and neuromodulatory therapies as indicated. SUMMARY Neurologic symptoms are common in children with COVID-19 and may be life threatening. The pathophysiology, therapeutic options, and long-term outcomes from COVID-19 associated neurologic injury are currently being investigated.
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Affiliation(s)
- Dennis W. Simon
- Department of Critical Care Medicine
- Safar Center for Resuscitation Research
- UPMC Children's Hospital of Pittsburgh Neuroscience Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Michelle E. Schober
- Department of Pediatrics, Division of Critical Care, University of Utah, Salt Lake City, Utah, USA
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Wong AMC, Toh CH. Spectrum of neuroimaging mimics in children with COVID-19 infection. Biomed J 2021; 45:50-62. [PMID: 34793991 PMCID: PMC8591861 DOI: 10.1016/j.bj.2021.11.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 10/21/2021] [Accepted: 11/07/2021] [Indexed: 12/17/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has affected over 200 million people globally (including over 30 million people in the United States), with children comprising 12.9% of reported cases in the United States. In children, COVID-19 infection appears to be associated with mild respiratory symptoms; however, serious neurological complications may occur in conjunction with multisystem inflammatory syndrome. A wide spectrum of neurological diseases have been observed in children with COVID-19 infection including encephalitis, acute necrotizing encephalopathy, acute disseminated encephalomyelitis, cytotoxic lesion of the callosal splenium, posterior reversible encephalopathy syndrome, venous sinus thrombosis, vasculitis and infarction, Guillain-Barré syndrome, transverse myelitis, and myositis. This review describes the characteristic magnetic resonance neuroimaging features of these diseases and their differentiations from other imaging mimics. In addition, we review the possible pathophysiology underlying the association between these diseases and COVID-19-infection. As new SARS-CoV-2 variants emerge and COVID-19 infection continues to spread worldwide, pediatricians, radiologists, and first-line care givers should be aware of possible neurological diseases associated with COVID-19 infection when these reported neuroimaging patterns are observed in children during this pandemic.
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Affiliation(s)
- Alex Mun-Ching Wong
- Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
| | - Cheng Hong Toh
- College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
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36
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Intrathecal inflammatory responses in the absence of SARS-CoV-2 nucleic acid in the CSF of COVID-19 hospitalized patients. J Neurol Sci 2021; 430:120023. [PMID: 34678659 PMCID: PMC8489278 DOI: 10.1016/j.jns.2021.120023] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 09/06/2021] [Accepted: 09/30/2021] [Indexed: 11/21/2022]
Abstract
OBJECTIVE Little is known about CSF profiles in patients with acute COVID-19 infection and neurological symptoms. Here, CSF was tested for SARS-CoV-2 RNA and inflammatory cytokines and chemokines and compared to controls and patients with known neurotropic pathogens. METHODS CSF from twenty-seven consecutive patients with COVID-19 and neurological symptoms was assayed for SARS-CoV-2 RNA using quantitative reverse transcription PCR (RT-qPCR) and unbiased metagenomic sequencing. Assays for blood brain barrier (BBB) breakdown (CSF:serum albumin ratio (Q-Alb)), and proinflammatory cytokines and chemokines (IL-6, IL-8, IL-15, IL-16, monocyte chemoattractant protein -1 (MCP-1) and monocyte inhibitory protein - 1β (MIP-1β)) were performed in 23 patients and compared to CSF from patients with HIV-1 (16 virally suppressed, 5 unsuppressed), West Nile virus (WNV) (n = 4) and 16 healthy controls (HC). RESULTS Median CSF cell count for COVID-19 patients was 1 white blood cell/μL; two patients were infected with a second pathogen (Neisseria, Cryptococcus neoformans). No CSF samples had detectable SARS-CoV-2 RNA by either detection method. In patients with COVID-19 only, CSF IL-6, IL-8, IL-15, and MIP-1β levels were higher than HC and suppressed HIV (corrected-p < 0.05). MCP-1 and MIP-1β levels were higher, while IL-6, IL-8, IL-15 were similar in COVID-19 compared to WNV patients. Q-Alb correlated with all proinflammatory markers, with IL-6, IL-8, and MIP-1β (r ≥ 0.6, p < 0.01) demonstrating the strongest associations. CONCLUSIONS Lack of SARS-CoV-2 RNA in CSF is consistent with pre-existing literature. Evidence of intrathecal proinflammatory markers in a subset of COVID-19 patients with BBB breakdown despite minimal CSF pleocytosis is atypical for neurotropic pathogens.
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Steiner J, Vasilevska V. Inflammation und psychische Erkrankung. INFO NEUROLOGIE + PSYCHIATRIE 2021. [PMCID: PMC8601778 DOI: 10.1007/s15005-021-2121-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Affiliation(s)
- Johann Steiner
- Universitätsklinikum Magdeburg, Klinik für Psychiatrie und Psychotherapie & Labor für Translationale Psychiatrie, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Veronika Vasilevska
- Universitätsklinikum Magdeburg, Klinik für Psychiatrie und Psychotherapie & Labor für Translationale Psychiatrie, Leipziger Str. 44, 39120 Magdeburg, Germany
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38
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Vasilevska V, Guest PC, Bernstein HG, Schroeter ML, Geis C, Steiner J. Molecular mimicry of NMDA receptors may contribute to neuropsychiatric symptoms in severe COVID-19 cases. J Neuroinflammation 2021; 18:245. [PMID: 34711233 PMCID: PMC8551937 DOI: 10.1186/s12974-021-02293-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 10/08/2021] [Indexed: 02/02/2023] Open
Abstract
Approximately 30% of individuals with severe SARS-CoV-2 infections also develop neurological and psychiatric complaints. In rare cases, the occurrence of autoimmune encephalitis has been reported after SARS-CoV-2 infection. In this systematic review, we have identified eight SARS-CoV-2-associated cases of anti-NMDA receptor encephalitis. All had cerebrospinal fluid antibodies against the NMDA receptor and a recent onset of working memory deficits, altered mental status, or psychiatric symptoms, such as confusion, agitation, auditory hallucination, catatonia and speech dysfunction. All patients received high-dose steroid and immunoglobulin therapeutics and conditions improved in each case. These findings suggest that clinical attention should be paid to warning signs of autoimmune encephalitis in severe COVID-19 cases. If characteristic features of autoimmune encephalitis are present, autoantibody diagnostics should be performed and confirmed cases should be treated with immunotherapy to minimize neurological impairments.
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Affiliation(s)
- Veronika Vasilevska
- Laboratory of Translational Psychiatry, Department of Psychiatry and Psychotherapy, Otto-Von-Guericke-University Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany
| | - Paul C Guest
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Hans-Gert Bernstein
- Laboratory of Translational Psychiatry, Department of Psychiatry and Psychotherapy, Otto-Von-Guericke-University Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany
| | - Matthias L Schroeter
- Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Clinic for Cognitive Neurology, University Hospital Leipzig, Leipzig, Germany
| | - Christian Geis
- Section Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Jena, Germany.,German Center for Mental Health (DZP), Center for Intervention and Research On Adaptive and Maladaptive Brain Circuits Underlying, Mental Health (C-I-R-C), Jena-Magdeburg-Halle, Germany
| | - Johann Steiner
- Laboratory of Translational Psychiatry, Department of Psychiatry and Psychotherapy, Otto-Von-Guericke-University Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany. .,German Center for Mental Health (DZP), Center for Intervention and Research On Adaptive and Maladaptive Brain Circuits Underlying, Mental Health (C-I-R-C), Jena-Magdeburg-Halle, Germany. .,Center for Behavioral Brain Sciences, Magdeburg, Germany.
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Sanchez CV, Theel E, Binnicker M, Toledano M, McKeon A. Autoimmune Encephalitis Post-SARS-CoV-2 Infection: Case Frequency, Findings, and Outcomes. Neurology 2021; 97:e2262-e2268. [PMID: 34635560 PMCID: PMC8671045 DOI: 10.1212/wnl.0000000000012931] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 09/30/2021] [Indexed: 12/03/2022] Open
Abstract
Background and Objectives Autoimmune encephalitis (AE) cases after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported, but the frequency is unknown. We aimed to determine the frequency and diagnostic features of coronavirus disease 2019 (COVID-19)–related AE. Methods Residual sera from 556 consecutive Mayo Clinic Rochester patients (laboratory cohort) who underwent autoimmune encephalopathy neural immunoglobulin G (IgG) evaluation were tested for total antibodies against the SARS-CoV-2 spike glycoprotein using a Food and Drug Administration–authorized chemiluminescence assay (October 2019–December 2020). Clinical records from patients with a positive SARS-CoV-2 antibody result and available research consent were reviewed. This laboratory cohort was cross-referenced with the Department of Neurology's COVID-19–related consultative experience (encephalopathy cohort, n = 31). Results Eighteen of the laboratory cohort (3%) were SARS-CoV-2 antibody positive (April–December 2020). Diagnoses were as follows: AE, 2; postacute sequelae of SARS CoV-2 infection (PASC), 3; toxic-metabolic encephalopathy during COVID-19 pneumonia, 2; diverse non–COVID-19 relatable neurologic diagnoses, 9; unavailable, 2. Five of the encephalopathy cohort had AE (16%, including the 2 laboratory cohort cases that overlapped), representing 0.05% of 10,384 patients diagnosed and cared for with any COVID-19 illness at Mayo Clinic Rochester in 2020. The 5 patients met definite (n = 1), probable (n = 1), or possible (n = 3) AE diagnostic criteria; median symptom onset age was 61 years (range, 46–63); 3 were women. All 5 were neural IgG negative and 4 tested were SARS-CoV-2 PCR/IgG index negative in CSF. Phenotypes (and accompanying MRI and EEG findings) were diverse (delirium [n = 5], seizures [n = 2], rhombencephalitis [n = 1], aphasia [n = 1], and ataxia [n = 1]). No acute disseminated encephalomyelitis cases were encountered. The 3 patients with possible AE had spontaneously resolving syndromes. One with definite limbic encephalitis was immune therapy responsive but had residual mood and memory problems. One patient with probable autoimmune rhombencephalitis died despite immune therapy. The remaining 26 encephalopathy cohort patients had toxic-metabolic diagnoses. Discussion We encountered occasional cases of AE in our 2020 COVID-19 experience. Consistent with sporadic reports and small case series during the COVID-19 pandemic, and prior experience of postinfectious AE, our cases had diverse clinical presentations and were neural IgG and CSF viral particle negative. Application of diagnostic criteria assists in differentiation of AE from toxic-metabolic causes arising in the setting of systemic infection.
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Affiliation(s)
| | - Elitza Theel
- Division of Microbiology, Department of Laboratory Medicine and Pathology Mayo Clinic, Rochester, MN, USA
| | - Matthew Binnicker
- Division of Microbiology, Department of Laboratory Medicine and Pathology Mayo Clinic, Rochester, MN, USA
| | | | - Andrew McKeon
- Department of Neurology, Mayo Clinic, Rochester, MN, USA .,Neuroimmunology Laboratory, Department of Laboratory Medicine and Pathology, and Neurology, Mayo Clinic, Rochester, MN, USA
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40
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Parwani J, Ortiz JF, Alli A, Lalwani A, Ruxmohan S, Tamton H, Cuenca VD, Gonzalez D, Anwer F, Eissa-Garcés A, Alzamora IM, Paez M. Understanding Seizures and Prognosis of the Extreme Delta Brush Pattern in Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: A Systematic Review. Cureus 2021; 13:e18154. [PMID: 34589370 PMCID: PMC8460549 DOI: 10.7759/cureus.18154] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2021] [Indexed: 11/05/2022] Open
Abstract
Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis (ANMDARE) is an autoimmune disorder with neurological and psychiatric features. The disease presents with a viral prodrome, followed by psychiatric manifestations. In the next phase, movement disorders or/and seizures occur. Finally, in the last phase, there is a decrease in the level of consciousness. Central hypoventilation and autonomic dysfunction can occur. Recently a unique EEG (electroencephalogram) pattern has been associated with anti-NMDA receptor encephalitis, the extreme delta brush (EDB). Although the association of the EDB with ANMDARE is known by the medical community, its significance is mainly unknown. A systematic review on NMDARE is also scarce. We decided to conduct a systematic review on this topic to consolidate the knowledge and establish the importance of the EDB as a prognostic factor. To conduct this systematic review, we used only studies conducted in humans, written in English, and published in the last 20 years. We used PubMed as a database and searched the following search terms: ("NMDA encephalitis"[Title/Abstract] AND "Epilepsy"[Title/Abstract]) OR (NMDA encephalitis"[Title/Abstract] AND "seizures" [Title/Abstract]) OR ("NMDA encephalitis"[Title/Abstract] AND "extreme delta brush"[Title/Abstract]). The protocol used for this systematic review was the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) protocol, and to analyze the bias of the studies, we used the ROBINS-1 tool. Eight studies were collected from our search strategy. Our data pulling showed that seizures were present in 178/249 (71.48%) patients. Status Epilepticus was reported in 29/96 (30.20%), and the EBD was seen in 30.89% (55/178) patients with seizures. The range of EDB was 5.9%-33% among the studies. Because the sample size was small, the statistical power was decreased. We had a low overall risk of bias. The wide range in the results could be related to the timing of the EEG recording. EDB was associated overall with increased length of hospital stay, increased ICU admission, and incidence of status epilepticus. The etiology of the EDB remains mainly unknown. However, it has been postulated that in NMDAR encephalitis, there is a disruption of the rhythmic neuronal activity. When antibodies block/target the NMDAR, the rhythmic neuronal activity is disrupted, leading to the unique EDB pattern. Another theory suggests that delta activity is caused because of focal abnormalities in the brain, and the superimposition of the beta waves is related to the alterations of the NMDA receptors.
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Affiliation(s)
- Jashank Parwani
- Neurology, Lokmanya Tilak Municipal Medical College, Mumbai, IND
| | - Juan Fernando Ortiz
- Neurology, Universidad San Francisco de Quito, Quito, ECU.,Neurology, Larkin Community Hospital, Miami, USA
| | - Ammar Alli
- Medicine, Tishreen University Faculty of Medicine, Lattakia, SYR.,Internal Medicine, Universitat de Barcelona, Barcelona, ESP
| | - Ayushi Lalwani
- Internal Medicine, KJ Somaiya Medical College, Mumbai, IND
| | | | - Hyder Tamton
- Neurology, Larkin Community Hospital, Miami, USA
| | | | | | - Fatima Anwer
- Neurology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | | | | | - Maria Paez
- General Medicine, Pontificia Universidad Catolica del Ecuador, Quito, ECU
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41
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Reiff DD, Meyer CG, Marlin B, Mannion ML. New onset ANCA-associated vasculitis in an adolescent during an acute COVID-19 infection: a case report. BMC Pediatr 2021; 21:333. [PMID: 34353302 PMCID: PMC8338201 DOI: 10.1186/s12887-021-02812-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/15/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND SARS-CoV-2 has been found to be exquisitely adept at triggering autoimmunity and multiple new onset autoimmune diseases have been described as a post-infectious complication of COVID-19 infection in the adult population. Less has been described in the pediatric population, as infections are more likely to be asymptomatic and less severe. This case reports a previously healthy adolescent patient with new onset antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) diagnosed in the setting of acute COVID-19 infection. CASE PRESENTATION A previously healthy adolescent male was diagnosed with COVID-19 pneumonia after presenting with infectious symptoms of fever, cough, congestion, and shortness of breath. After worsening of disease, he was found to have pulmonary nodules, atypical for COVID-19. Further imaging and laboratory workup showed elevated inflammatory markers, negative infectious testing, and positive antineutrophil cytoplasmic antibodies (ANCA) diagnostic for AAV. He was treated with pulse dose steroids followed by a prolonged taper and rituximab. Symptoms resolved and laboratory abnormalities improved over time. At six-month follow-up, lesions were much improved, laboratory markers were within normal limits, and patient remained asymptomatic off medications. CONCLUSIONS This case is one of the first in the pediatric population to describe new onset AAV presenting with an acute, symptomatic COVID-19 infection. There is increasing evidence for COVID-19 induced autoimmunity in the pediatric population and pediatric care providers should be on high alert for new onset autoimmune disease in children afflicted by COVID-19.
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Affiliation(s)
- Daniel D Reiff
- Children's of Alabama, Division of Rheumatology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Ave. S., CPPN #G10, Birmingham, AL, 35233-1711, USA.
| | - Chloe G Meyer
- UAB Pediatric Residency Program, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Brittany Marlin
- Division of Pediatric Hospital Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Melissa L Mannion
- Children's of Alabama, Division of Rheumatology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Ave. S., CPPN #G10, Birmingham, AL, 35233-1711, USA
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42
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Emekli AS, Parlak A, Göcen NY, Kürtüncü M. Anti-GAD associated post-infectious cerebellitis after COVID-19 infection. Neurol Sci 2021; 42:3995-4002. [PMID: 34328578 PMCID: PMC8322110 DOI: 10.1007/s10072-021-05506-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Accepted: 07/18/2021] [Indexed: 12/20/2022]
Abstract
The coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread rapidly all over the world. Besides severe pneumonia, it causes multisystemic disease, including neurological findings. Here, we present a patient with anti–glutamic acid decarboxylase (anti-GAD) antibody-associated cerebellitis developed after COVID-19 infection. The patient responded well to the immune treatments. Our knowledge about SARS-CoV-2 infection–related neurological disorders is limited. New data are needed to recognize the clinical spectrum of autoimmune neurological disorders that emerges after SARS-CoV-2 infection.
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Affiliation(s)
- Ahmed Serkan Emekli
- Department of Neurology, Karabuk University Training and Research Hospital, Karabuk, Turkey.
| | - Asuman Parlak
- Department of Neurology, Karabuk University Training and Research Hospital, Karabuk, Turkey
| | - Nejla Yılmaz Göcen
- Department of Infectious Diseases, Karabuk University Training and Research Hospital, Karabuk, Turkey
| | - Murat Kürtüncü
- Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
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Simon OJ, Menzler K, Timmermann L. [Update 2021: COVID-19 from the perspective of neurology]. Dtsch Med Wochenschr 2021; 146:918-923. [PMID: 34256409 DOI: 10.1055/a-1449-5098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Neurological complications, direct affection of neuronal structures in the course of infections with SARS-CoV-2 and long-term effects ("long COVID") are evident. This article aims to summarize and evaluate the current literature on this topic.
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Vasilevska V, Guest PC, Schlaaff K, Incesoy EI, Prüss H, Steiner J. Potential Cross-Links of Inflammation With Schizophreniform and Affective Symptoms: A Review and Outlook on Autoimmune Encephalitis and COVID-19. Front Psychiatry 2021; 12:729868. [PMID: 34650454 PMCID: PMC8507462 DOI: 10.3389/fpsyt.2021.729868] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 08/23/2021] [Indexed: 01/08/2023] Open
Abstract
Based on current implications of the SARS-CoV-2 pandemic with regards to mental health, we show that biological links exist between inflammation and mental illness in addition to psychoreactive effects. We describe key principles of the biological interaction of the immune system and the mind, as well as the possible routes of viral entry into the brain. In addition, we provide a stepwise scheme for the diagnosis and therapy of autoimmune-encephalitis with schizophrenia-like symptomatology as a general guide for clinical practice and in the specialized scenario of infections, such as those caused by the SARS-CoV-2 virus.
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Affiliation(s)
- Veronika Vasilevska
- Department of Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.,Laboratory of Translational Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Paul C Guest
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, University of Campinas, Campinas, Brazil
| | - Konstantin Schlaaff
- Department of Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.,Laboratory of Translational Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Enise I Incesoy
- Department of Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.,Laboratory of Translational Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.,German Center for Neurodegenerative Diseases, Magdeburg, Germany.,Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke-University, Magdeburg, Germany
| | - Harald Prüss
- German Center for Neurodegenerative Diseases, Berlin, Germany.,Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Johann Steiner
- Department of Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.,Laboratory of Translational Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.,Center for Behavioral Brain Sciences, Magdeburg, Germany.,German Center for Mental Health, Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health, Magdeburg, Germany
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