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Zeballos L, García-Peral C, Ledesma MM, Auzmendi J, Lazarowski A, López DE. Changes in the Proteomic Profile After Audiogenic Kindling in the Inferior Colliculus of the GASH/Sal Model of Epilepsy. Int J Mol Sci 2025; 26:2331. [PMID: 40076950 PMCID: PMC11900993 DOI: 10.3390/ijms26052331] [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: 01/22/2025] [Revised: 02/27/2025] [Accepted: 03/02/2025] [Indexed: 03/14/2025] Open
Abstract
Epilepsy is a multifaceted neurological disorder characterized by recurrent seizures and associated with molecular and immune alterations in key brain regions. The GASH/Sal (Genetic Audiogenic Seizure Hamster, Salamanca), a genetic model for audiogenic epilepsy, provides a powerful tool to study seizure mechanisms and resistance in predisposed individuals. This study investigates the proteomic and immune responses triggered by audiogenic kindling in the inferior colliculus, comparing non-responder animals exhibiting reduced seizure severity following repeated stimulation versus GASH/Sal naïve hamsters. To assess auditory pathway functionality, Auditory Brainstem Responses (ABRs) were recorded, revealing reduced neuronal activity in the auditory nerve of non-responders, while central auditory processing remained unaffected. Cytokine profiling demonstrated increased levels of proinflammatory markers, including IL-1 alpha (Interleukin-1 alpha), IL-10 (Interleukin-10), and TGF-beta (Transforming Growth Factor beta), alongside decreased IGF-1 (Insulin-like Growth Factor 1) levels, highlighting systemic inflammation and its interplay with neuroprotection. Building on these findings, a proteomic analysis identified 159 differentially expressed proteins (DEPs). Additionally, bioinformatic approaches, including Gene Set Enrichment Analysis (GSEA) and Weighted Gene Co-expression Network Analysis (WGCNA), revealed disrupted pathways related to metabolic and inflammatory epileptic processes and a module potentially linked to a rise in the threshold of seizures, respectively. Differentially expressed genes, identified through bioinformatic and statistical analyses, were validated by RT-qPCR. This confirmed the upregulation of six genes (Gpc1-Glypican-1; Sdc3-Syndecan-3; Vgf-Nerve Growth Factor Inducible; Cpne5-Copine 5; Agap2-Arf-GAP with GTPase domain, ANK repeat, and PH domain-containing protein 2; and Dpp8-Dipeptidyl Peptidase 8) and the downregulation of two (Ralb-RAS-like proto-oncogene B-and S100b-S100 calcium-binding protein B), aligning with reduced seizure severity. This study may uncover key proteomic and immune mechanisms underlying seizure susceptibility, providing possible novel therapeutic targets for refractory epilepsy.
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Affiliation(s)
- Laura Zeballos
- Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, 37007 Salamanca, Spain; (L.Z.); (C.G.-P.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
- Departamento de Biología Celular y Patología, Facultad de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Carlos García-Peral
- Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, 37007 Salamanca, Spain; (L.Z.); (C.G.-P.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
- Departamento de Biología Celular y Patología, Facultad de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Martín M. Ledesma
- Unidad de Conocimiento Traslacional, Hospital de Alta Complejidad del Bicentenario Esteban Echeverría, Monte Grande B1842, Argentina;
- Hospital de Alta Complejidad en Red El Cruce Dr. N. C. Kirchner SAMIC, Florencio Varela B1888, Argentina
| | - Jerónimo Auzmendi
- Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires C1417, Argentina; (J.A.); (A.L.)
- Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Godoy Cruz M2290, Argentina
| | - Alberto Lazarowski
- Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires C1417, Argentina; (J.A.); (A.L.)
| | - Dolores E. López
- Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, 37007 Salamanca, Spain; (L.Z.); (C.G.-P.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
- Departamento de Biología Celular y Patología, Facultad de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
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Banach W, Banach P, Szweda H, Wiśniewski A, Andrusiewicz M, Gurynowicz I, Szepieniec WK, Szymanowski P. Ovarian teratoma-associated Anti-NMDAR encephalitis in women with first-time neuropsychiatric symptoms: A meta-analysis and systematic review of reported cases. Heliyon 2024; 10:e36042. [PMID: 39435085 PMCID: PMC11492448 DOI: 10.1016/j.heliyon.2024.e36042] [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: 11/03/2023] [Revised: 08/07/2024] [Accepted: 08/08/2024] [Indexed: 10/23/2024] Open
Abstract
Objective Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is frequently associated with ovarian teratomas. The diverse clinical presentations and several stages of disease development pose a significant diagnostic challenge for clinicians. The main objective of this research was to show the prevalence of neuropsychiatric symptoms of ovarian-teratoma-associated anti-NMDAR encephalitis and to highlight the importance of multidisciplinary collaboration in the diagnosis, treatment, and prevention of disease progression. Methods Literature searches were carried out using PubMed, Scopus, and Web of Science Core Collection. The following data were retrieved: authors' names, year of publication, type of study, number and age of patients included, diagnostic methods of disease evaluation, prevalence of anti-NMDAR antibodies, psychiatric manifestations, other symptoms, initial diagnosis, treatment strategies, and histopathology results. Data analyses were performed and considered statistically significant when p < 0.05. Results Our study included 98 female patients with encephalitis associated with a teratoma. The study group reported specific symptoms more often than expected in the general population (p < 0.05). The incidence of seizures deviated most from rates in the general population. The major significant differences were observed in cases of psychosis, seizures, hypoventilation, aphasia, and coma. Conclusions Teratoma-associated anti-NMDAR encephalitis diagnosis should be systematically investigated in patients presenting with first-time psychotic episodes. Prompt diagnosis and treatment are imperative for prevention of disease progression and better outcomes. Screening and identification of anti-NMDAR antibodies and considering the association of ovarian teratoma and neuropsychiatric symptoms suggesting encephalitis are critical for establishing the proper diagnosis.
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Affiliation(s)
- Weronika Banach
- Department of Gynecology and Urogynecology, Andrzej Frycz Modrzewski Krakow University, Kraków, Poland
- Chair and Department of Cell Biology, Poznan University of Medical Sciences, Poznań, Poland
| | - Paulina Banach
- Department of Gynecology and Urogynecology, Andrzej Frycz Modrzewski Krakow University, Kraków, Poland
- Department of Gynecology and Obstetrics. University of Zielona Góra, Zielona Góra, Poland
| | - Hanna Szweda
- Department of Gynecology and Urogynecology, Andrzej Frycz Modrzewski Krakow University, Kraków, Poland
| | - Andrzej Wiśniewski
- Department of Gynecology and Urogynecology, Andrzej Frycz Modrzewski Krakow University, Kraków, Poland
| | - Mirosław Andrusiewicz
- Chair and Department of Cell Biology, Poznan University of Medical Sciences, Poznań, Poland
| | - Igor Gurynowicz
- Department of Gynecology and Urogynecology, Andrzej Frycz Modrzewski Krakow University, Kraków, Poland
| | - Wioletta K. Szepieniec
- Department of Gynecology and Urogynecology, Andrzej Frycz Modrzewski Krakow University, Kraków, Poland
| | - Paweł Szymanowski
- Department of Gynecology and Urogynecology, Andrzej Frycz Modrzewski Krakow University, Kraków, Poland
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Sun Y, Li G, Liu X, Zhao X, Ren J, Ren G, Liu Y, Ai L, Wang Q. Cerebral glucose hypometabolism and hypoperfusion of cingulate gyrus: an imaging biomarker of autoimmune encephalitis with psychiatric symptoms. J Neurol 2024; 271:1247-1255. [PMID: 37945763 PMCID: PMC10896782 DOI: 10.1007/s00415-023-12051-z] [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: 08/08/2023] [Revised: 10/04/2023] [Accepted: 10/07/2023] [Indexed: 11/12/2023]
Abstract
BACKGROUND About 60% of autoimmune encephalitis (AE) patients present psychiatric symptoms, but the underlying mechanism remains unknown. This study examined the role of the cingulate cortex in such patients to identify predictive poor psychiatric factors. METHODS In this study, 49 AE patients and 39 healthy controls were enrolled. AE patients were further divided into two groups based on the presence/absence of psychiatric symptoms. The ratio of the standardized uptake value (SUVR) and relative cerebral blood flow (rCBF) in different regions of the cingulate cortex were calculated through positron emission tomography-computed tomography (PET/CT) and arterial spin labeling (ASL) MRI, and the results were compared among the three groups. In addition, we followed-up on the psychiatric outcomes and identified the risk factors for poor psychiatric prognosis, focusing on the cingulate cortex. RESULTS More than half of the AE patients (27/49) exhibited psychiatric symptoms. Agitation and thought blocking were typical psychiatric phenotypes, except for anti-glutamic acid decarboxylase 65 (GAD65) encephalitis, which mainly presented with catatonia and a depressed mood. AE patients with psychiatric symptoms experienced reduced metabolism and perfusion of the anterior cingulate cortex (ACC), midcingulate cortex (MCC), and posterior cingulate cortex (PCC). The SUVR of ACC can be used as an independent risk factor of poor psychiatric outcomes, which had an area under the ROC curve (AUC) of 0.865. CONCLUSION Impaired cingulate cortex function in AE may be the potential mechanism of psychiatric symptoms. Hypometabolism of ACC is an independent prognostic factor predicting an unfavorable psychiatric prognosis in AE.
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Affiliation(s)
- Yueqian Sun
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing, 100070, China
| | - Gongfei Li
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing, 100070, China
- Department of Neurology & Stroke, University of Tübingen, Tübingen, Germany
| | - Xiao Liu
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing, 100070, China
| | - Xiaobin Zhao
- Department of Nuclear Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Jiechuan Ren
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing, 100070, China
| | - Guoping Ren
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing, 100070, China
| | - Yaou Liu
- Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Lin Ai
- Department of Nuclear Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Qun Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing, 100070, China.
- National Center for Clinical Medicine of Neurological Diseases, Beijing, China.
- Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China.
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Espinola-Nadurille M, Restrepo-Martínez M, Bayliss L, Flores-Montes E, Rivas-Alonso V, Vargas-Cañas S, Hernández L, Martínez-Juarez I, Gonzalez-Aguilar A, Solis-Vivanco R, Fricchione GL, Flores-Rivera J, Ramirez-Bermudez J. Neuropsychiatric phenotypes of anti-NMDAR encephalitis: a prospective study. Psychol Med 2023; 53:4266-4274. [PMID: 35534479 DOI: 10.1017/s0033291722001027] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Patients with anti-N-methyl-d-aspartate (NMDA) receptor encephalitis (ANMDARE) show a wide range of behavioral abnormalities and are often mistaken for primary psychiatric presentations. We aimed to determine the behavioral hallmarks of ANMDARE with the use of systematic neuropsychiatric and cognitive assessments. METHODS A prospective study was conducted, with 160 patients admitted to the National Institute of Neurology and Neurosurgery of Mexico, who fulfilled criteria for possible autoimmune encephalitis and/or red flags along a time window of seven years. Cerebrospinal fluid (CSF) antibodies against the NR1 subunit of the NMDAR were processed with rat brain immunohistochemistry and cell-based assays with NMDA expressing cells. Systematic cognitive, neuropsychiatric, and functional assessments were conducted before knowing NMDAR antibodies results. A multivariate analysis was used to compare patients with and without definite ANMDARE according to antibodies in CSF. RESULTS After obtaining the CSF antibodies results in 160 consecutive cases, 100 patients were positive and classified as having definite ANMDARE. The most frequent neuropsychiatric patterns were psychosis (81%), delirium (75%), catatonia (69%), anxiety-depression (65%), and mania (27%). Cognition was significantly impaired. A total of 34% of the patients had a predominantly neuropsychiatric presentation without seizures. After multivariate analysis, the clinical hallmarks of ANMDARE consisted of a catatonia-delirium comorbidity, tonic-clonic seizures, and orolingual dyskinesia. CONCLUSIONS Our study supports the notion of a neurobehavioral phenotype of ANMDARE characterized by a fluctuating course with psychotic and affective symptoms, catatonic signs, and global cognitive dysfunction, often accompanied by seizures and dyskinesia. The catatonia-delirium comorbidity could be a distinctive neurobehavioral phenotype of ANMDARE.
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Affiliation(s)
- M Espinola-Nadurille
- Department of Neuropsychiatry, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico
| | - M Restrepo-Martínez
- Department of Neuropsychiatry, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico
| | - L Bayliss
- Department of Neurology, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico
| | - E Flores-Montes
- Department of Neuropsychiatry, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico
| | - V Rivas-Alonso
- Department of Neurology, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico
| | - S Vargas-Cañas
- Department of Neurology, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico
| | - L Hernández
- Department of Neurology, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico
| | - I Martínez-Juarez
- Department of Neurology, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico
| | - A Gonzalez-Aguilar
- Department of Neurology, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico
| | - R Solis-Vivanco
- Laboratory of Cognitive and Clinical Neurophysiology, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico
| | - G L Fricchione
- Psychiatry Department, Massachusetts General Hospital, Boston, MA, USA
| | - J Flores-Rivera
- Department of Neurology, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico
| | - J Ramirez-Bermudez
- Department of Neuropsychiatry, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico
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Shorter JR, Meijsen J, Nudel R, Krebs M, Gådin J, Mikkelsen DH, Nogueira Avelar E Silva R, Benros ME, Thompson WK, Ingason A, Werge T. Infection Polygenic Factors Account for a Small Proportion of the Relationship Between Infections and Mental Disorders. Biol Psychiatry 2022; 92:283-290. [PMID: 35305821 DOI: 10.1016/j.biopsych.2022.01.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 01/07/2022] [Accepted: 01/07/2022] [Indexed: 12/27/2022]
Abstract
BACKGROUND Several recent studies have suggested a role for infections in the development of mental disorders; however, the genetic contribution to this association is understudied. METHODS We use the iPSYCH case-cohort genotyped sample (n = 65,534) and Danish health care registry data to study the genetic association between infections and mental disorders. To test the hypothesis that these associations are due to genetic pleiotropy, we estimated the genetic correlation between infection and mental disorders. Polygenic risk scores (PRSs) were used to assess whether genetic pleiotropy of infections and mental disorders was mediated by actual infection diagnoses. RESULTS We observed that schizophrenia, attention-deficit/hyperactivity disorder, major depressive disorder, bipolar disorder, and posttraumatic stress disorder (rg ranging between 0.18 and 0.83), but not autism spectrum disorder and anorexia nervosa, were significantly genetically correlated with infection diagnoses. PRSs for infections were associated with modest increase in risk of attention-deficit/hyperactivity disorder, major depressive disorder, and schizophrenia in the iPSYCH case-cohort (hazard ratios = 1.04 to 1.10) but was not associated with risk of anorexia, autism, or bipolar disorder. Using mediation analysis, we show that infection diagnoses account for only a small proportion (6%-14%) of the risk for mental disorders conferred by infection PRSs. CONCLUSIONS Infections and mental disorders share a modest genetic architecture. Infection PRSs can predict risk of certain mental disorders; however, this effect is moderate. Finally, recorded infections partially explain the relationship between infection PRSs and mental disorders.
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Affiliation(s)
- John R Shorter
- Institute of Biological Psychiatry, Mental Health Centre Sct Hans, Mental Health Services, Copenhagen, Denmark; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
| | - Joeri Meijsen
- Institute of Biological Psychiatry, Mental Health Centre Sct Hans, Mental Health Services, Copenhagen, Denmark; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
| | - Ron Nudel
- Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
| | - Morten Krebs
- Institute of Biological Psychiatry, Mental Health Centre Sct Hans, Mental Health Services, Copenhagen, Denmark; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
| | - Jesper Gådin
- Institute of Biological Psychiatry, Mental Health Centre Sct Hans, Mental Health Services, Copenhagen, Denmark; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
| | - Dorte H Mikkelsen
- Institute of Biological Psychiatry, Mental Health Centre Sct Hans, Mental Health Services, Copenhagen, Denmark; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
| | - Raquel Nogueira Avelar E Silva
- Institute of Biological Psychiatry, Mental Health Centre Sct Hans, Mental Health Services, Copenhagen, Denmark; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
| | - Michael E Benros
- Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark; Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
| | - Wesley K Thompson
- Institute of Biological Psychiatry, Mental Health Centre Sct Hans, Mental Health Services, Copenhagen, Denmark; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark; Population Neuroscience and Genetics Lab, University of California San Diego, San Diego, California; Division of Biostatistics and Department of Radiology, University of California San Diego, San Diego, California
| | - Andrés Ingason
- Institute of Biological Psychiatry, Mental Health Centre Sct Hans, Mental Health Services, Copenhagen, Denmark; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
| | - Thomas Werge
- Institute of Biological Psychiatry, Mental Health Centre Sct Hans, Mental Health Services, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
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Taib NIA, Wahab S, Khoo CS, Tan HJ, Kamaruzaman L, Woon LSC, Gan LLY. Case Report: Cotard's Syndrome in Anti-N-methyl D-aspartate (NMDA) Receptor (Anti-NMDAR) Encephalitis. Front Psychiatry 2022; 13:779520. [PMID: 35599755 PMCID: PMC9114484 DOI: 10.3389/fpsyt.2022.779520] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 03/25/2022] [Indexed: 12/23/2022] Open
Abstract
Cotard's syndrome is uncommon psychopathology among patients with psychotic illnesses. Limited cases had been reported regarding the occurrence of this syndrome in anti-NMDAR encephalitis which itself is a relatively new disease that often presents with florid psychotic symptoms. This poses difficulties in differentiating it from a primary psychiatric illness. Late recognition of anti-NMDAR encephalitis can lead to death as it can progress to autonomic instability in its natural course of illness. We report a patient who first presented with psychotic symptoms with initial negative findings from baseline investigations. Further investigation revealed anti NMDAR antibodies in the cerebrospinal fluid. Prompt treatment was initiated and despite early poor response to the first-line treatment with the development of allergic reaction, our patient recovered completely after 1 month of hospitalization. This case report aims to highlight the importance of early detection of anti-NMDAR encephalitis and the possibility of uncommon psychopathology such as Cotard's syndrome occurring in this disease.
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Affiliation(s)
- Nur Iwana Abdul Taib
- Department of Psychological Medicine, Faculty of Medicine and Health Sciences, University Malaysia Sarawak, Kota Samarahan, Malaysia
| | - Suzaily Wahab
- Department of Psychiatry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Ching Soong Khoo
- Neurology Unit, Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Hui Jan Tan
- Neurology Unit, Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Lydia Kamaruzaman
- Department of Medicine, Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Luke Sy-Cherng Woon
- Department of Psychiatry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Lydia Lay Yen Gan
- Department of Pharmacy, Hospital Canselor Tuanku Muhriz, Kuala Lumpur, Malaysia
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Dorney K, Murphy M. Recommendations for the medical work-up of first episode psychosis, including specific relevance to Indigenous Australians: A narrative review. Early Interv Psychiatry 2021; 15:423-438. [PMID: 32543124 DOI: 10.1111/eip.12980] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 03/24/2020] [Accepted: 04/28/2020] [Indexed: 12/15/2022]
Abstract
AIMS To collate existing literature for busy practicing psychiatrists about the medical work-up for first-episode psychosis (FEP). Therefore, (a) to review current guidelines for the medical work-up of first episode psychosis. (b) To examine whether any specific recommendations for Indigenous Australians exist. (c) To produce an easy reference table of evidence based investigations. METHOD A multi-part narrative review process was undertaken. Step 1 "Source identification and summary": identified key existing national and international guidelines and expert opinions related to the medical work-up of FEP and summarised these suggestions. Step 2 "Exploration of each investigation": examined each of the identified investigations for its importance. Step 3 "Relevance to Indigenous Australians": reviewed any particular relevance to the Indigenous Australian population. Step 4 "Clinician guide": involved presenting recommended investigations in a simple table. RESULTS Multiple guidelines were identified. There was clear consensus for many aspects. However, there were also differences in the approach for some investigations. Clinical reasoning for the proposed investigations was commonly absent. There were limited specific recommendations for Indigenous Australians. Evidence and importance was explored for each investigation and auseful table for the practicing psychiatrist was constructed. Investigations were stratified into those considered to be "universal," "low yield," or "unecessary." CONCLUSION A narrative review of multiple guidelines relating to the medical work-up of FEP identified many similarities and some differences to their approach. Little additional information exists for the Indigenous Australian context. A clinician friendly worksheet for everyday use may be helpful to busy clinicians.
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Affiliation(s)
- Kiernan Dorney
- Department of Psychiatry, Northern Sydney Local Health District, Sydney, New South Wales, Australia
| | - Michael Murphy
- Department of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia
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Kokkosis AG, Tsirka SE. Neuroimmune Mechanisms and Sex/Gender-Dependent Effects in the Pathophysiology of Mental Disorders. J Pharmacol Exp Ther 2020; 375:175-192. [PMID: 32661057 PMCID: PMC7569311 DOI: 10.1124/jpet.120.266163] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 07/09/2020] [Indexed: 12/12/2022] Open
Abstract
Innate and adaptive immune mechanisms have emerged as critical regulators of CNS homeostasis and mental health. A plethora of immunologic factors have been reported to interact with emotion- and behavior-related neuronal circuits, modulating susceptibility and resilience to mental disorders. However, it remains unclear whether immune dysregulation is a cardinal causal factor or an outcome of the pathologies associated with mental disorders. Emerging variations in immune regulatory pathways based on sex differences provide an additional framework for discussion in these psychiatric disorders. In this review, we present the current literature pertaining to the effects that disrupted immune pathways have in mental disorder pathophysiology, including immune dysregulation in CNS and periphery, microglial activation, and disturbances of the blood-brain barrier. In addition, we present the suggested origins of such immune dysregulation and discuss the gender and sex influence of the neuroimmune substrates that contribute to mental disorders. The findings challenge the conventional view of these disorders and open the window to a diverse spectrum of innovative therapeutic targets that focus on the immune-specific pathophenotypes in neuronal circuits and behavior. SIGNIFICANCE STATEMENT: The involvement of gender-dependent inflammatory mechanisms on the development of mental pathologies is gaining momentum. This review addresses these novel factors and presents the accumulating evidence introducing microglia and proinflammatory elements as critical components and potential targets for the treatment of mental disorders.
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Affiliation(s)
- Alexandros G Kokkosis
- Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York
| | - Stella E Tsirka
- Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York
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Keever MR, Zhang P, Bolt CR, Antonson AM, Rymut HE, Caputo MP, Houser AK, Hernandez AG, Southey BR, Rund LA, Johnson RW, Rodriguez-Zas SL. Lasting and Sex-Dependent Impact of Maternal Immune Activation on Molecular Pathways of the Amygdala. Front Neurosci 2020; 14:774. [PMID: 32848554 PMCID: PMC7431923 DOI: 10.3389/fnins.2020.00774] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 07/01/2020] [Indexed: 12/23/2022] Open
Abstract
The prolonged and sex-dependent impact of maternal immune activation (MIA) during gestation on the molecular pathways of the amygdala, a brain region that influences social, emotional, and other behaviors, is only partially understood. To address this gap, we investigated the effects of viral-elicited MIA during gestation on the amygdala transcriptome of pigs, a species of high molecular and developmental homology to humans. Gene expression levels were measured using RNA-Seq on the amygdala for 3-week-old female and male offspring from MIA and control groups. Among the 403 genes that exhibited significant MIA effect, a prevalence of differentially expressed genes annotated to the neuroactive ligand-receptor pathway, glutamatergic functions, neuropeptide systems, and cilium morphogenesis were uncovered. Genes in these categories included corticotropin-releasing hormone receptor 2, glutamate metabotropic receptor 4, glycoprotein hormones, alpha polypeptide, parathyroid hormone 1 receptor, vasointestinal peptide receptor 2, neurotensin, proenkephalin, and gastrin-releasing peptide. These categories and genes have been associated with the MIA-related human neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Gene network reconstruction highlighted differential vulnerability to MIA effects between sexes. Our results advance the understanding necessary for the development of multifactorial therapies targeting immune modulation and neurochemical dysfunction that can ameliorate the effects of MIA on offspring behavior later in life.
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Affiliation(s)
- Marissa R. Keever
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Pan Zhang
- Illinois Informatics Institute, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Courtni R. Bolt
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Adrienne M. Antonson
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Haley E. Rymut
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Megan P. Caputo
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Alexandra K. Houser
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Alvaro G. Hernandez
- High-throughput Sequencing and Genotyping Unit, Roy J. Carver Biotechnology Center, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Bruce R. Southey
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Laurie A. Rund
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Rodney W. Johnson
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States
- Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Sandra L. Rodriguez-Zas
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States
- Illinois Informatics Institute, University of Illinois at Urbana-Champaign, Urbana, IL, United States
- Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, United States
- Department of Statistics, University of Illinois at Urbana-Champaign, Urbana, IL, United States
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, United States
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10
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Characterisation and outcome of neuropsychiatric symptoms in patients with anti-NMDAR encephalitis. Acta Neuropsychiatr 2020; 32:92-98. [PMID: 31753060 DOI: 10.1017/neu.2019.46] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Encephalitis due to anti-N-methyl-D-aspartate receptor antibodies (ANMDARE) is the most frequent immune-mediated encephalitis. It is distinguished by the subacute onset of neuropsychiatric symptoms. OBJECTIVE To evaluate the characteristic neuropsychiatric symptoms and their outcome in patients diagnosed with ANMDARE. METHODS This was a prospective, longitudinal study in patients with a diagnostic suspicion of ANMDARE that presented to the National Institute of Neurology from March 2018 to February 2019. A comparative analysis of two groups (positive N-methyl-D-aspartate receptor [NMDAR] vs. negative NMDAR antibodies in cerebrospinal fluid [CSF]) was done on admission and at discharge. Neuropsychiatric systematic assessments included the Neuropsychiatric Inventory Questionnaire, the Bush Francis Catatonia Rating Scale, the Confusion Assessment Method Severity, the Montreal Cognitive Assessment, and the Overt Agitation Severity Scale. RESULTS 24 individuals were analysed: 14 had positive NMDAR antibodies, and 10 had negative NMDAR antibodies in CSF. On admission, agitation/aggression, euphoria/exaltation, and disinhibition were more common in patients with positive antibodies. Excited catatonia and delirium were diagnosed more frequently in patients with positive antibodies. At discharge, there was an important decrease in neuropsychiatric symptoms, but substantial cognitive impairment remained. The mean hospitalisation length was 41.71 (SD 39.33) days for patients with definitive ANMDARE (p 0.259). CONCLUSIONS Neuropsychiatric symptoms profile in ANMDARE was associated with the early onset of euphoria/exaltation and disinhibition, accompanied by marked psychomotor agitation. When ANMDARE was suspected, the presence of excited-type catatonia and delirium showed a tendency to predict definitive ANMDARE. At discharged, most patients recovered from catatonia, delirium, and psychosis, but marked cognitive symptoms, anxiety, and depression persisted at discharge.
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11
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Wang W, Zhang L, Chi XS, He L, Zhou D, Li JM. Psychiatric Symptoms of Patients With Anti-NMDA Receptor Encephalitis. Front Neurol 2020; 10:1330. [PMID: 32038450 PMCID: PMC6993807 DOI: 10.3389/fneur.2019.01330] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 12/02/2019] [Indexed: 02/05/2023] Open
Abstract
Objective: We conducted this study to analyze the clinical characteristics of the psychiatric symptoms of patients with anti-NMDAR encephalitis. Methods: A retrospective study of anti-NMDAR encephalitis in China was performed. The clinical characteristics of the psychiatric symptoms, the relationship between the antibodies titers and clinical characteristics of patients with anti-NMDAR encephalitis were determined. Results: A total of 108 patients with a definitive diagnosis of anti-NMDAR encephalitis were included in this study. 103 patients (95%) developed one or several psychiatric symptoms. The comparison of the high titer group and the low titer group showed that more patients presented psychiatric symptoms as the initial symptom in the high titer group (P = 0.020), the prevalence of the symptoms such as depressive, catatonic, and central hypoventilation were also higher in the high titer group than the low titer group (P = 0.033, 0.031 and 0.006, respectively). Meanwhile, more patients received a combination treatment of IVIg and corticosteroids in the high titer group than the low titer group and patients in high titer group were prescript with anti-psychiatric drugs more often than the patients in low titer group (P = 0.026 and 0.003, respectively). Conclusions: Psychiatric symptoms are the most common clinical characteristics of patients with anti-NMDAR encephalitis. Patients with higher antibodies titers more often presented with psychiatric symptoms as the initial symptom, and showed a more severe clinical feature. Screening for the anti-NMDAR antibodies is essentially important in patients who present psychiatric symptoms with or without other neurological symptoms.
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Affiliation(s)
- Wei Wang
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.,Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Le Zhang
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiao-Sa Chi
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
| | - Li He
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
| | - Dong Zhou
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
| | - Jin-Mei Li
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
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12
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Konstantinou GN, Konstantinou GN. Psychiatric comorbidity in chronic urticaria patients: a systematic review and meta-analysis. Clin Transl Allergy 2019; 9:42. [PMID: 31462988 PMCID: PMC6706894 DOI: 10.1186/s13601-019-0278-3] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 07/29/2019] [Indexed: 01/06/2023] Open
Abstract
Background Dermatological illness can affect the quality of life and may coexist with psychiatric disorders. Objective The aim of this review was to systematically evaluate the published evidence of any psychiatric disorders that may coexist with chronic urticaria (CU) and any effect psychiatric interventions may have on CU. Methods Following the Cochrane guidance, we conducted a systematic literature search using web-based search engines provided by PubMed (for Medline database), Google Scholar and Scopus for studies that have investigated the existence of psychiatric comorbidity in patients with CU. To be included, a study had to possess features, such as: (1) distinction between chronic urticaria and allergic conditions, (2) direct collection of diagnostic psychiatric data by using clinical interview and standardized questionnaires, (3) International Classification of Disorders criteria or the Diagnostic and Statistical Manual of Mental Disorders criteria for the diagnosis of mental disorders, and (4) manuscripts written or published in the English language. Unpublished research and research in progress were not included. All the eligible studies were scrutinized for any reported psychiatric interventions that had any effect on CU. The systematic review has been registered on PROSPERO (registration number CRD42019122811) and was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Results Twenty-five studies were identified. Almost one out of three CU patients have at least one underlying psychiatric disorder. None of the studies clarified whether the psychiatric disorders pre-existed the CU onset, and no association was found between CU severity and duration, and psychological functioning. Only one case report and two case series mentioned that treatment of psychiatric disorders with either anti-depressants, anti-anxiety drugs or psychological interventions might result in improvement of urticaria. Conclusions Patients with CU frequently experience psychiatric disorders. This highlights the need for a multidisciplinary therapeutic approach involving prompt recognition and management of any potential psychiatric disorder in addition to urticaria treatment. Further studies are needed to assess whether psychiatric disorders coexist with CU independently or follow urticaria onset and whether any psychological or psychiatric intervention may help in CU control.
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Affiliation(s)
| | - George N Konstantinou
- Department of Allergy and Clinical Immunology, 424 General Military Training Hospital, 11 Eleftheriou Benizelou Street, Kalamaria, 55 133 Thessaloniki, Greece
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13
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Goutte J, Killian M, Antoine JC, Massoubre C, Fakra E, Cathébras P. [First-episode psychosis as primary manifestation of medical disease: An update]. Rev Med Interne 2019; 40:742-749. [PMID: 31421899 DOI: 10.1016/j.revmed.2019.07.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 06/09/2019] [Accepted: 07/17/2019] [Indexed: 11/15/2022]
Abstract
A huge variety of medical diseases may potentially present with isolated psychotic symptoms, and disease-specific treatment or management is available for a significant part of them. The initial medical work-up of a first-episode psychosis (FEP) is of crucial importance. This literature review aimed to identify medical conditions potentially revealed by FEP, to list the warning signs of secondary psychosis, and to discuss a screening strategy. Underlying organic conditions may be drugs and medications, neurologic diseases, infections, inflammatory and/or autoimmune pathologies, and metabolic disorders whether of hereditary origin. Each patient presenting with a first-episode psychosis should be evaluated with a precise anamnesis, a careful clinical examination, and routine laboratory tests. Brain imaging and tests (depending on the context) should be performed in the presence of atypical clinical features or "red flags", leading to suspect an organic disease.
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Affiliation(s)
- J Goutte
- Service de médecine interne, CHU de Saint-Étienne, 42055 Saint-Étienne Cedex 2, France.
| | - M Killian
- Service de médecine interne, CHU de Saint-Étienne, 42055 Saint-Étienne Cedex 2, France.
| | - J C Antoine
- Service de neurologie, CHU de Saint-Étienne, 42055 Saint-Étienne Cedex 2, France.
| | - C Massoubre
- Service de psychiatrie, CHU de Saint-Étienne, 42055 Saint-Étienne Cedex 2, France.
| | - E Fakra
- Service de psychiatrie, CHU de Saint-Étienne, 42055 Saint-Étienne Cedex 2, France.
| | - P Cathébras
- Service de médecine interne, CHU de Saint-Étienne, 42055 Saint-Étienne Cedex 2, France.
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14
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Krajcovic B, Fajnerova I, Horacek J, Kelemen E, Kubik S, Svoboda J, Stuchlik A. Neural and neuronal discoordination in schizophrenia: From ensembles through networks to symptoms. Acta Physiol (Oxf) 2019; 226:e13282. [PMID: 31002202 DOI: 10.1111/apha.13282] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 03/27/2019] [Accepted: 04/12/2019] [Indexed: 12/22/2022]
Abstract
Despite the substantial knowledge accumulated by past research, the exact mechanisms of the pathogenesis of schizophrenia and causal treatments still remain unclear. Deficits of cognition and information processing in schizophrenia are today often viewed as the primary and core symptoms of this devastating disorder. These deficits likely result from disruptions in the coordination of neuronal and neural activity. The aim of this review is to bring together convergent evidence of discoordinated brain circuits in schizophrenia at multiple levels of resolution, ranging from principal cells and interneurons, neuronal ensembles and local circuits, to large-scale brain networks. We show how these aberrations could underlie deficits in cognitive control and other higher order cognitive-behavioural functions. Converging evidence from both animal models and patients with schizophrenia is presented in an effort to gain insight into common features of deficits in the brain information processing in this disorder, marked by disruption of several neurotransmitter and signalling systems and severe behavioural outcomes.
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Affiliation(s)
- Branislav Krajcovic
- Department of Neurophysiology of Memory Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic
- Third Faculty of Medicine Charles University Prague Czech Republic
| | - Iveta Fajnerova
- Department of Neurophysiology of Memory Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic
- Research Programme 3 - Applied Neurosciences and Brain Imaging National Institute of Mental Health Klecany Czech Republic
| | - Jiri Horacek
- Third Faculty of Medicine Charles University Prague Czech Republic
- Research Programme 3 - Applied Neurosciences and Brain Imaging National Institute of Mental Health Klecany Czech Republic
| | - Eduard Kelemen
- Research Programme 1 - Experimental Neurobiology National Institute of Mental Health Klecany Czech Republic
| | - Stepan Kubik
- Department of Neurophysiology of Memory Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic
| | - Jan Svoboda
- Department of Neurophysiology of Memory Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic
| | - Ales Stuchlik
- Department of Neurophysiology of Memory Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic
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15
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Bharadwaj B, Sathyanarayanan G, Kaliaperumal V, Dhodapkar R. Anti-NMDA receptor antibody positivity in acute psychotic states: An exploratory study. Asian J Psychiatr 2019; 43:95-98. [PMID: 31121536 DOI: 10.1016/j.ajp.2019.05.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 05/13/2019] [Accepted: 05/13/2019] [Indexed: 10/26/2022]
Abstract
The glutamatergic theory of schizophrenia postulates N-methyl-D-aspartate receptor (NMDA-R) dysfunction. Anti-NMDA receptor antibodies may be present in some patients with psychosis. Fifteen patients presenting with acute psychotic states having one additional clinical feature suggestive of autoimmune etiology were recruited. Serum antibodies against NMDA-receptor were tested at baseline and at follow-up using Indirect Immunofluorescence Technique. None of the 15 patients had positive anti-NMDA antibody at baseline or at follow-up. The study failed to detect anti-NMDA antibodies in patients with acute psychotic states with clinical suspicion of autoimmunity. This does not rule out other mechanisms of NMDA receptor dysfunction in these patients. The glutamatergic theory of schizophrenia postulates N-methyl-D-aspartate receptor (NMDA-R) dysfunction. Anti-NMDA receptor antibodies may be present in some patients with psychosis. Fifteen patients presenting with acute psychotic states having one additional clinical feature suggestive of autoimmune etiology were recruited. Serum antibodies against NMDA-receptor were tested at baseline and at follow-up using Indirect Immunofluorescence Technique. None of the 15 patients had positive anti-NMDA antibody at baseline or at follow-up. The study failed to detect anti-NMDA antibodies in patients with acute psychotic states with clinical suspicion of autoimmunity. This does not rule out other mechanisms of NMDA receptor dysfunction in these patients.
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Affiliation(s)
- Balaji Bharadwaj
- Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantri Nagar, Puducherry - 605006, India.
| | - Gopinath Sathyanarayanan
- Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantri Nagar, Puducherry - 605006, India
| | - Venkatesh Kaliaperumal
- Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantri Nagar, Puducherry - 605006, India
| | - Rahul Dhodapkar
- Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantri Nagar, Puducherry - 605006, India
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16
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Kelleher E, Barry H, Cotter DR, Corvin A, Murphy KC. Autoantibodies and Psychosis. Curr Top Behav Neurosci 2019; 44:85-123. [PMID: 31292938 DOI: 10.1007/7854_2019_90] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Research into antibody-mediated disease, in response to immune dysfunction or to tumour development, has rapidly expanded in recent years. Antibodies binding to neuroreceptors can cause psychiatric features, including psychosis, in a minority of patients as well as neurological features. The responsiveness of some of these cases to immunotherapy supports the hypothesis that antibody-associated mechanisms play a role in the pathogenesis of psychotic diseases. The purpose of this chapter is to review autoantibodies that are most likely to be relevant for patients with psychotic symptoms. Herein, we describe receptor structure and mechanism of action, clinical and psychiatric features for the growing number of neuronal surface antibodies, including those to the N-methyl-D-aspartate (NMDA) receptor. The identification of a subgroup of patients with psychiatric features having antibody-mediated disease highlights the importance of considering the diagnosis, particularly in those patients presenting with a first episode of psychosis.
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Affiliation(s)
- Eric Kelleher
- Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland.
| | - Helen Barry
- Department of Psychiatry, Royal College of Surgeons of Ireland, Dublin, Ireland
| | - David R Cotter
- Department of Psychiatry, Royal College of Surgeons of Ireland, Dublin, Ireland
| | - Aiden Corvin
- Department of Psychiatry, Trinity College Dublin, Dublin, Ireland
| | - Kieran C Murphy
- Department of Psychiatry, Royal College of Surgeons of Ireland, Dublin, Ireland
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17
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Abstract
There is wide variability in how psychiatry guidelines and textbooks address the question of cerebrospinal fluid (CSF) diagnostics in the screening of psychiatric disorders. A United States-based textbook confirms that there is no consensus about which laboratory investigation should be routinely performed in psychiatric patients, but with respect to CSF diagnostics, the differences are even more striking. A survey among European experts showed a wide variety of opinions regarding clinical use and criteria in various countries of Europe and worldwide: some psychiatrists, mostly university hospital-based, recommended performing CSF diagnostics in every patient first experiencing severe mental illness (SMI), but especially in patients from the schizophrenia spectrum, whereas others almost never perform CSF examinations themselves and usually refer patients to neurology departments if necessary. Minor neurologic signs are generally frequent in SMI, mainly in affective and schizophrenic disorders. Even with neurologic signs present, there are no clear guidelines regarding CSF evaluation, leaving doctors with experience-based decision making. However, the field is evolving. A recent review provides helpful yellow and red flags for differential diagnosis of SMI from autoimmune encephalitis; interestingly, minor CSF abnormalities are considered a red flag, suggesting that CSF should be routinely performed in acute psychiatric patients. There are reports of single cases identified as an established neurologic disorder: patients within affective and schizophrenic spectrum disorders systematically underwent CSF examination, and were rediagnosed based on CSF results. This was often to the surprise of the psychiatric doctors. Overall, an increasing number of psychiatrists believe that CSF is too rarely examined in psychiatric patients. This chapter provides an overview of differential diagnostic issues in SMI, particularly for new-onset cases. The general recommendations regarding CSF examination procedures can be found in other chapters of this book. Here we focus on specific aspects of differential diagnosis in SMI. Also, there will be an overview of admittedly limited CSF research efforts in psychiatric disorders, focusing on more recent CSF studies. CSF studies in SMI performed with state-of-the-art methods, for example proteomics or assessments of cytokines, were intriguing but difficult to interpret and required critical considerations regarding respective methodology, an undertaking which is outside the scope of this chapter.
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18
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Rudzki L, Szulc A. "Immune Gate" of Psychopathology-The Role of Gut Derived Immune Activation in Major Psychiatric Disorders. Front Psychiatry 2018; 9:205. [PMID: 29896124 PMCID: PMC5987016 DOI: 10.3389/fpsyt.2018.00205] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 05/03/2018] [Indexed: 12/12/2022] Open
Abstract
Interaction between the gastrointestinal tract (GI) and brain functions has recently become a topic of growing interest in psychiatric research. These multidirectional interactions take place in the so-called gut-brain axis or more precisely, the microbiota-gut-brain axis. The GI tract is the largest immune organ in the human body and is also the largest surface of contact with the external environment. Its functions and permeability are highly influenced by psychological stress, which are often a precipitating factor in the first episode, reoccurrence and/or deterioration of symptoms of psychiatric disorders. In recent literature there is growing evidence that increased intestinal permeability with subsequent immune activation has a major role in the pathophysiology of various psychiatric disorders. Numerous parameters measured in this context seem to be aftermaths of those mechanisms, yet at the same time they may be contributing factors for immune mediated psychopathology. For example, immune activation related to gut-derived bacterial lipopolysaccharides (LPS) or various food antigens and exorphins were reported in major depression, schizophrenia, bipolar disorder, alcoholism and autism. In this review the authors will summarize the evidence and roles of such parameters and their assessment in major psychiatric disorders.
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Affiliation(s)
- Leszek Rudzki
- Department of Psychiatry, Medical University of BialystokBialystok, Poland
- Three Towns Resource Centre, Saltcoats, United Kingdom
| | - Agata Szulc
- Department of Psychiatry, Medical University of WarsawWarsaw, Poland
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19
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Jézéquel J, Johansson EM, Leboyer M, Groc L. Pathogenicity of Antibodies against NMDA Receptor: Molecular Insights into Autoimmune Psychosis. Trends Neurosci 2018; 41:502-511. [PMID: 29807730 DOI: 10.1016/j.tins.2018.05.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 04/05/2018] [Accepted: 05/01/2018] [Indexed: 11/16/2022]
Abstract
Recent years have seen a flourishing literature on detection of circulating autoantibodies against neurotransmitter receptors in patients with neuropsychiatric disorders. These studies have generated hope for a better understanding of the underlying molecular dysfunctions and for appropriate therapeutic strategies. However, the detection of these autoantibodies in healthy subjects, and the lack of mechanistic insights have fostered debate about the pathogenic role of such autoantibodies. Here, we specifically discuss the biological evidence linking autoantibodies directed against the glutamatergic N-methyl-d-aspartate (NMDA) receptor (NMDAR-Abs) and psychosis, emphasising recent single-molecule imaging investigations that unveiled the impaired surface trafficking of NMDAR in the presence of NMDAR-Abs from psychotic patients. Although still in its infancy, the hypothesis that NMDAR-Abs from patients with psychosis play a pathogenic role is thus gaining support, opening avenues of fundamental and translational investigations.
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Affiliation(s)
- J Jézéquel
- Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, Bordeaux, France; CNRS, IINS UMR 5297, Bordeaux, France
| | - E M Johansson
- Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, Bordeaux, France; CNRS, IINS UMR 5297, Bordeaux, France
| | - M Leboyer
- University Paris Est Créteil, Psychiatry Department, Hopitaux Universitaires Henri Mondor, AP-HP, DHU PePSY, INSERM, U955, Créteil, France
| | - L Groc
- Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, Bordeaux, France; CNRS, IINS UMR 5297, Bordeaux, France.
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20
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Nicolle DCM, Moses JL. A Systematic Review of the Neuropsychological Sequelae of People Diagnosed with Anti N-Methyl-D-Aspartate Receptor Encephalitis in the Acute and Chronic Phases. Arch Clin Neuropsychol 2018; 33:964-983. [DOI: 10.1093/arclin/acy005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 01/16/2018] [Indexed: 11/13/2022] Open
Affiliation(s)
- Della C M Nicolle
- Cardiff University, Tower Building, 70 Park Place, Cardiff CF10 3AT, UK
| | - Jennifer L Moses
- Cardiff University, Tower Building, 70 Park Place, Cardiff CF10 3AT, UK
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21
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Abstract
SummaryIt has long been recognised that the pathology of schizophrenia may involve the immune system, yet this has been a relatively neglected area of research. Recent advances in our understanding of the complexities and functioning of the immune system have allowed new investigation into this area from many angles, including cellular and genetic avenues. A number of prominent theories have been developed. This article gives an overview of our understanding of the immune system and highlights recent advances pertaining to schizophrenia.LEARNING OBJECTIVES•To refresh and update understanding of the innate and adaptive immune system, presented clearly to the non-expert audience.•To understand key advances in immunological theories of schizophrenia.•To engender clinicians' enthusiasm for further reading and interest in this topic.
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22
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Bechter K. Encephalitis, Mild Encephalitis, Neuroprogression, or Encephalopathy-Not Merely a Question of Terminology. Front Psychiatry 2018; 9:782. [PMID: 30787887 PMCID: PMC6372546 DOI: 10.3389/fpsyt.2018.00782] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 12/28/2018] [Indexed: 12/17/2022] Open
Abstract
Background: Psychoneuroimmunology research has presented emerging evidence of the involvement of inflammatory and immune mechanisms in the pathogenesis of severe mental disorders. In this context, new terms with increasing clinical relevance have been proposed, challenging the existing terms, and requiring consensus definitions of the new ones. Method: From a perspective of longstanding personal involvement in clinical settings and research in psychoneuroimmunology, the new and the existing terms are critically reconsidered. Results: Meningoencephalitis and encephalitis are comparably well defined clinical terms in neuropsychiatry, although in the individual case approach diagnosis can be difficult, for example in some cases of encephalitis that are described with normal cerebrospinal fluid findings, or often in chronic encephalitis. Encephalopathy is also a widely accepted term, however, with a surprisingly broad meaning with regard to the assigned underlying pathophysiology, ranging from one-hit traumatic encephalopathy to inflammatory encephalopathy, the latter term addressing a type of brain dysfunction secondary to acute systemic inflammation without proven brain autochthonus inflammation (neuroinflammation). However, this latter assumption and term may be wrong as neuroinflammation is difficult to prove in vivo. With emerging insights into prevailing inflammatory and neuroinflammatory mechanisms that are involved in the pathogenesis of severe mental disorders, the interdependent aspects of sensitive assessment and potential clinical relevance of mild neuroinflammation are becoming more apparent and of increasing clinical interest. The new terms "mild encephalitis," "parainflammation," and "neuroprogression" show considerable overlap in addition to gaps and hardly defined borders. However, details are hard to discuss as available studies use many biomarkers, but most of these are done without an established categorical attribution to exclusive terms. Most important, the three new concepts (neruoprogression, parainflammation, and mild encephalitis) are not mutually exclusive, even at the individual case level, and therefore will require state-related individual assessment approaches beyond large confirmatory studies. Conclusion: The newly proposed terms of mild encephalitis, parainflammation, and neuroprogression have an emerging clinical relevance, but respective borders, gaps and overlap in between them remain unclear, and these concepts may even be seen as complementary. Categorical delineation of the new and reconsideration of the existing terms with respect to individualized psychiatric treatment is required for better clinical use, eventually requiring a consensus approach. Here, a critique based on available data and a focus on clinical perspective was outlined, which may help to enhance fruitful discussion. The idea followed here is in line with pillar number six as proposed for the Research Diagnostic Domains, i.e., to provide and follow new concepts in psychiatric research.
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Affiliation(s)
- Karl Bechter
- Department Psychiatry and Psychotherapy II, Bezirkskrankenhaus Günzburg, Ulm University, Ulm, Germany
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23
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Restrepo Martínez M, Paola Bautista G, Espínola-Nadurille M, Bayliss L. Red flags for suspecting anti-NMDAr encephalitis in a first psychotic episode: report of two cases. ACTA ACUST UNITED AC 2017; 48:127-130. [PMID: 30981326 DOI: 10.1016/j.rcp.2017.10.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 10/22/2017] [Indexed: 11/16/2022]
Abstract
Anti-N-methyl-D-Aspartate receptor (NMDAr) encephalitis is a recently described clinical entity with an increasing number of reported cases. Psychiatric symptoms in the early stages of the disease constitute a diagnostic challenge for the treating physician. We present two clinical cases: clinical case 1, a 26-year-old man, and clinical case 2, an 18-year-old man; both presented with a first episode of psychosis and were hospitalized as psychiatric disorders. Subsequently, both cases were diagnosed as anti-NMDAr encephalitis. The high prevalence of psychiatric symptoms in anti-NMDAr encephalitis forces psychiatrists and neurologists to have a high degree of suspicion in the presence of atypical symptoms in patients evaluated for the first episode of psychosis.
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Affiliation(s)
| | - G Paola Bautista
- Instituto Nacional de Neurología y Neurocirugía, Ciudad de México, México
| | | | - Leo Bayliss
- Unidad de Neurología, Instituto Nacional de Neurología y Neurocirugía, Ciudad de México, México
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Tzang RF, Hsu K, Chang YC, Liu TP. Immunotherapy for anti-NMDAR encephalitis: A review of paraneoplastic, autoimmune encephalopathy. JOURNAL OF CANCER RESEARCH AND PRACTICE 2017. [DOI: 10.1016/j.jcrpr.2016.08.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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Herken J, Prüss H. Red Flags: Clinical Signs for Identifying Autoimmune Encephalitis in Psychiatric Patients. Front Psychiatry 2017; 8:25. [PMID: 28261116 PMCID: PMC5311041 DOI: 10.3389/fpsyt.2017.00025] [Citation(s) in RCA: 137] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 02/01/2017] [Indexed: 01/17/2023] Open
Abstract
Autoimmune mechanisms causing diverse psychiatric symptoms are increasingly recognized and brought about a paradigm shift in neuropsychiatry. Identification of underlying antibodies against neuronal ion channels or receptors led to the speculation that a number of patients go misdiagnosed with a primary psychiatric disease. However, there is no clear consensus which clinical signs in psychiatric patients should prompt further investigations including measurement of anti-neuronal autoantibodies. We therefore aimed to analyze the presenting symptoms in patients with autoimmune encephalitis and the time between symptom onset and initiation of antibody diagnostics. For this, we recruited 100 patients from the Charité Center for Autoimmune Encephalitis between May and October 2016, including all types of autoimmune encephalitides. Psychiatric abnormalities were the most common clinical symptoms and were the presenting sign in 60%. One-third of patients were initially hospitalized in a psychiatric ward. All patients positive for antibodies against the N-methyl-d-aspartate receptor showed behavioral changes, hallucinations, memory deficits, catatonia, or delusions. Patients positive for antibodies against other cell surface or intracellular antigens were often hospitalized with a psychosomatic diagnosis. The time between occurrence of first symptoms and antibody testing was often alarmingly prolonged. In patients with symptom onset between 2013 and 2016, the mean delay was 74 days, in cases diagnosed between 2007 and 2012 even 483 days, suggesting though that increased awareness of this novel disease group helped to expedite proper diagnosis and treatment. By analyzing the medical records in detail, we identified clinical signs that may help to assist in earlier diagnosis, including seizures, catatonia, autonomic instability, or hyperkinesia. Indeed, reanalyzing the whole cohort using these "red flags" led to a 58% reduction of time between symptom onset and diagnosis. We conclude that the timely diagnosis of an autoimmune psychiatric disease can be facilitated by use of the described clinical warning signs, likely enabling earlier immunotherapy and better prognosis. Also, the threshold for cerebrospinal fluid analysis and autoantibody testing should be low.
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Affiliation(s)
- Julia Herken
- Autoimmune Encephalopathies Group, German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany
- Department of Neurology and Experimental Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Harald Prüss
- Autoimmune Encephalopathies Group, German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany
- Department of Neurology and Experimental Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany
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26
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Tsutsui K, Kanbayashi T, Takaki M, Omori Y, Imai Y, Nishino S, Tanaka K, Shimizu T. N-Methyl-D-aspartate receptor antibody could be a cause of catatonic symptoms in psychiatric patients: case reports and methods for detection. Neuropsychiatr Dis Treat 2017; 13:339-345. [PMID: 28223808 PMCID: PMC5308574 DOI: 10.2147/ndt.s125800] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The symptoms of catatonia have been reported to be similar to the initial symptoms of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Subsequently, this autoimmune limbic encephalitis has been noticed by many psychiatrists. For a differential diagnosis of catatonic state, it is important to detect anti-NMDAR encephalitis. This encephalitis is expected to be in remission by early detection and treatment. We should be more cautious about catatonic symptoms of schizophrenia. When a patient is suspected of having encephalitis, we should screen for anti-NMDAR antibodies in cerebrospinal fluid samples using a cell-based assay. We describe the methods of NMDAR antibody detection and the etiology of this encephalitis with case reports. Two representative cases with catatonia and non-catatonia (brief psychotic disorder) were reported. Schizophrenia is a general, heterogeneous, and complicated disorder, and its pathophysiology is unknown. There is an established evidence of NMDAR hypofunction, which is the functional disconnection of the central component; this is one of the most recognized models for schizophrenia. Furthermore, it is said that autoimmune mechanisms have been involved, at least in subgroups of schizophrenia patients. Further study of anti-NMDAR antibody and its related encephalitis would give essential clues for the research of schizophrenia, catatonia, and atypical psychosis.
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Affiliation(s)
- Ko Tsutsui
- Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita
| | - Takashi Kanbayashi
- Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba
| | - Manabu Takaki
- Department of Neuropsychiatry, Okayama University, Okayama
| | - Yuki Omori
- Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita
| | - Yumiko Imai
- Biological Informatics and Experimental Therapeutics, Akita University Graduate School of Medicine, Akita, Japan
| | - Seiji Nishino
- Sleep and Circadian Neurobiology Laboratory, Stanford University School of Medicine, Palo Alto, California, USA
| | - Keiko Tanaka
- Brain Research Institute, Niigata University, Niigata, Japan
| | - Tetsuo Shimizu
- Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba
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Neuropathology of mood disorders: do we see the stigmata of inflammation? Transl Psychiatry 2016; 6:e946. [PMID: 27824355 PMCID: PMC5314124 DOI: 10.1038/tp.2016.212] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 07/08/2016] [Accepted: 08/30/2016] [Indexed: 12/15/2022] Open
Abstract
A proportion of cases with mood disorders have elevated inflammatory markers in the blood that conceivably may result from stress, infection and/or autoimmunity. However, it is not yet clear whether depression is a neuroinflammatory disease. Multiple histopathological and molecular abnormalities have been found postmortem but the etiology of these abnormalities is unknown. Here, we take an immunological perspective of this literature. Increases in activated microglia or perivascular macrophages in suicide victims have been reported in the parenchyma. In contrast, astrocytic markers generally are downregulated in mood disorders. Impairment of astrocytic function likely compromises the reuptake of glutamate potentially leading to excitotoxicity. Inflammatory cytokines and microglia/macrophage-derived quinolinic acid (QA) downregulate the excitatory amino acid transporters responsible for this reuptake, while QA has the additional effect of inhibiting astroglial glutamine synthetase, which converts glutamate to glutamine. Given that oligodendroglia are particularly vulnerable to inflammation, it is noteworthy that reductions in numbers or density of oligodendrocyte cells are one of the most prominent findings in depression. Structural and/or functional changes to GABAergic interneurons also are salient in postmortem brain samples, and may conceivably be related to early inflammatory insults. Although the postmortem data are consistent with a neuroimmune etiology in a subgroup of depressed individuals, we do not argue that all depression-associated abnormalities are reflective of a neuroinflammatory process or even that all immunological activity in the brain is deleterious. Rather, we highlight the pervasive role of immune signaling pathways in brain function and provide an alternative perspective on the current postmortem literature.
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Bost C, Pascual O, Honnorat J. Autoimmune encephalitis in psychiatric institutions: current perspectives. Neuropsychiatr Dis Treat 2016; 12:2775-2787. [PMID: 27822050 PMCID: PMC5089825 DOI: 10.2147/ndt.s82380] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Autoimmune encephalitis is a rare and newly described group of diseases involving autoantibodies directed against synaptic and neuronal cell surface antigens. It comprises a wide range of neuropsychiatric symptoms. Sensitive and specific diagnostic tests such as cell-based assay are primordial for the detection of neuronal cell surface antibodies in patients' cerebrospinal fluid or serum and determine the treatment and follow-up of the patients. As neurological symptoms are fairly well described in the literature, this review focuses on the nature of psychiatric symptoms occurring at the onset or during the course of the diseases. In order to help the diagnosis, the main neurological symptoms of the most representative synaptic and neuronal cell surface autoantibodies were detailed. Finally, the exploration of these autoantibodies for almost a decade allowed us to present an overview of autoimmune encephalitis incidence in psychiatric disease and the general guidelines for the management of psychiatric manifestations. For the majority of autoimmune encephalitis, the prognosis depends on the rapidity of the detection, identification, and the management of the disease. Because the presence of pronounced psychiatric symptoms drives patients to psychiatric institutions and can hinder the diagnosis, the aim of this work is to provide clues to help earlier detection by physicians and thus provide better medical care to patients.
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Affiliation(s)
- Chloe Bost
- French Reference Center of Paraneoplastic Neurological Syndrome, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France
- Synatac Team, NeuroMyoGene Institut, INSERM U1217/CNRS UMR5310, Lyon, France
- University Claude Bernard Lyon 1, Lyon, France
| | - Olivier Pascual
- Synatac Team, NeuroMyoGene Institut, INSERM U1217/CNRS UMR5310, Lyon, France
- University Claude Bernard Lyon 1, Lyon, France
| | - Jérôme Honnorat
- French Reference Center of Paraneoplastic Neurological Syndrome, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France
- Synatac Team, NeuroMyoGene Institut, INSERM U1217/CNRS UMR5310, Lyon, France
- University Claude Bernard Lyon 1, Lyon, France
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Benros ME, Trabjerg BB, Meier S, Mattheisen M, Mortensen PB, Mors O, Børglum AD, Hougaard DM, Nørgaard-Pedersen B, Nordentoft M, Agerbo E. Influence of Polygenic Risk Scores on the Association Between Infections and Schizophrenia. Biol Psychiatry 2016; 80:609-16. [PMID: 27364036 DOI: 10.1016/j.biopsych.2016.04.008] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 03/18/2016] [Accepted: 04/12/2016] [Indexed: 12/30/2022]
Abstract
BACKGROUND Several studies have suggested an important role of infections in the etiology of schizophrenia; however, shared genetic liability toward infections and schizophrenia could influence the association. We therefore investigated the possible effect of polygenic risk scores (PRSs) for schizophrenia on the association between infections and the risk of schizophrenia. METHODS We conducted a nested case-control study on a Danish population-based sample born after 1981 comprising of 1692 cases diagnosed with schizophrenia between 1994 and 2008 and 1724 matched controls. All individuals were linked utilizing nationwide population-based registers with virtually complete registration of all hospital contacts for infections. PRSs were calculated using discovery effect size estimates weights from an independent meta-analysis (34,600 cases and 45,968 control individuals). RESULTS A prior hospital contact with infection had occurred in 41% of the individuals with schizophrenia and increased the incidence rate ratio (IRR) of schizophrenia by 1.43 (95% confidence interval [CI] = 1.22-1.67). Adding PRS, which was robustly associated with schizophrenia (by an IRR of 1.46 [95% CI = 1.34-1.60] per standard deviation of the score), did not alter the association with infections and the increased risk of schizophrenia remained (IRR = 1.41; 95% CI = 1.20-1.66). Furthermore, there were no interactions between PRS and infections on the risk of developing schizophrenia (p = .554). Neither did PRS affect the risk of acquiring infections among patients with schizophrenia (odds ratio = 1.00; 95% CI = 0.89-1.12) nor among controls (odds ratio = 1.09; 95% CI: 0.96-1.24). CONCLUSIONS PRS and a history of infections have independent effects on the risk for schizophrenia, and the common genetic risk measured by PRS did not account for the association with infection in this sample.
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Affiliation(s)
- Michael E Benros
- Mental Health Centre Copenhagen, University of Copenhagen, Faculty of Health Sciences, Copenhagen; National Centre for Register-Based Research, Aarhus University, Aarhus; The Lundbeck Foundation Initiative for Integrative Psychiatric Research iPSYCH, Copenhagen.
| | - Betina B Trabjerg
- National Centre for Register-Based Research, Aarhus University, Aarhus; The Lundbeck Foundation Initiative for Integrative Psychiatric Research iPSYCH, Copenhagen
| | - Sandra Meier
- National Centre for Register-Based Research, Aarhus University, Aarhus; The Lundbeck Foundation Initiative for Integrative Psychiatric Research iPSYCH, Copenhagen
| | - Manuel Mattheisen
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research iPSYCH, Copenhagen; Department of Biomedicine and Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus
| | - Preben B Mortensen
- National Centre for Register-Based Research, Aarhus University, Aarhus; The Lundbeck Foundation Initiative for Integrative Psychiatric Research iPSYCH, Copenhagen
| | - Ole Mors
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research iPSYCH, Copenhagen; Research Department P, Aarhus University Hospital, Risskov
| | - Anders D Børglum
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research iPSYCH, Copenhagen; Department of Biomedicine and Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus
| | - David M Hougaard
- Danish Centre for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
| | - Bent Nørgaard-Pedersen
- Danish Centre for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
| | - Merete Nordentoft
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research iPSYCH, Copenhagen
| | - Esben Agerbo
- National Centre for Register-Based Research, Aarhus University, Aarhus; The Lundbeck Foundation Initiative for Integrative Psychiatric Research iPSYCH, Copenhagen; CIRRAU-Centre for Integrated Register-Based Research, Aarhus University, Aarhus
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Gough JL, Coebergh J, Chandra B, Nilforooshan R. Electroconvulsive therapy and/or plasmapheresis in autoimmune encephalitis? World J Clin Cases 2016; 4:223-228. [PMID: 27574610 PMCID: PMC4983693 DOI: 10.12998/wjcc.v4.i8.223] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 04/01/2016] [Accepted: 06/16/2016] [Indexed: 02/05/2023] Open
Abstract
Autoimmune encephalitis is a poorly understood condition that can present with a combination of neurological and psychiatric symptoms, either of which may predominate. There are many autoantibodies associated with a variety of clinical syndromes - anti-N-Methyl-D-Aspartate receptor (NMDAR) is the commonest. Currently, the most widely used therapy is prompt plasmapheresis and steroid treatment (and tumour resection if indicated), followed by second line immunosuppression if this fails. Given the growing awareness of autoimmune encephalitis as an entity, it is increasingly important that we consider it as a potential diagnosis in order to provide timely, effective treatment. We discuss several previously published case reports and one new case. These reports examined the effects of electroconvulsive therapy (ECT) on patients with autoimmune encephalitis, particularly those in whom psychiatric symptoms are especially debilitating and refractory to standard treatment. We also discuss factors predicting good outcome and possible mechanisms by which ECT may be effective. Numerous cases, such as those presented by Wingfield, Tsutsui, Florance, Sansing, Braakman and Matsumoto, demonstrate effective use of ECT in anti-NMDAR encephalitis patients with severe psychiatric symptoms such as catatonia, psychosis, narcolepsy and stupor who had failed to respond to standard treatments alone. We also present a new case of a 71-year-old female who presented to a psychiatric unit initially with depression, which escalated to catatonia, delusions, nihilism and auditory hallucinations. After anti-NMDAR antibodies were isolated, she was treated by the neurology team with plasmapheresis and steroids, with a partial response. She received multiple sessions of ECT and her psychiatric symptoms completely resolved and she returned to her premorbid state. For this reason, we suggest that ECT should be considered, particularly in those patients who are non-responders to standard therapies.
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Timucin D, Ozdemir O, Parlak M. The role of NMDAR antibody in the etiopathogenesis of schizophrenia. Neuropsychiatr Dis Treat 2016; 12:2327-2332. [PMID: 27695333 PMCID: PMC5028168 DOI: 10.2147/ndt.s113872] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Many authors have reported the presence of serum NMDAR antibodies in varying proportions of patients with schizophrenia; however, many others have not been able to confirm this. Because of the contradictory findings reported in various studies, more definitive research on this issue is required. Hence, we have investigated the NR1 subunit of NMDAR antibodies in patients with schizophrenia (n=49) and healthy controls (n=48). None of the investigated patients with schizophrenia and none of the healthy controls showed positive antibody against the NR1 subunit of the NMDAR. On the basis of this result, we conclude that the NR1 subunit of the NMDAR antibodies does not seem to have a role in schizophrenia.
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Affiliation(s)
- Damla Timucin
- Department of Psychiatry, University of Health Sciences, Van Training and Research Hospital, Van
| | | | - Mehmet Parlak
- Department of Microbiology, Faculty of Medicine, Yuzuncu Yil University, Van, Turkey
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33
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Burhan AM, Marlatt NM, Palaniyappan L, Anazodo UC, Prato FS. Role of Hybrid Brain Imaging in Neuropsychiatric Disorders. Diagnostics (Basel) 2015; 5:577-614. [PMID: 26854172 PMCID: PMC4728476 DOI: 10.3390/diagnostics5040577] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 11/21/2015] [Accepted: 11/26/2015] [Indexed: 01/09/2023] Open
Abstract
This is a focused review of imaging literature to scope the utility of hybrid brain imaging in neuropsychiatric disorders. The review focuses on brain imaging modalities that utilize hybrid (fusion) techniques to characterize abnormal brain molecular signals in combination with structural and functional changes that have been observed in neuropsychiatric disorders. An overview of clinical hybrid brain imaging technologies for human use is followed by a selective review of the literature that conceptualizes the use of these technologies in understanding basic mechanisms of major neuropsychiatric disorders and their therapeutics. Neuronal network abnormalities are highlighted throughout this review to scope the utility of hybrid imaging as a potential biomarker for each disorder.
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Affiliation(s)
- Amer M Burhan
- St. Joseph's Health Care London, Parkwood Institute, 550 Wellington Road, London, ON N6C 0A7, Canada.
- Department of Psychiatry, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON N6C 2R6, Canada.
| | - Nicole M Marlatt
- St. Joseph's Health Care London, Parkwood Institute, 550 Wellington Road, London, ON N6C 0A7, Canada.
| | - Lena Palaniyappan
- Department of Psychiatry, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON N6C 2R6, Canada.
| | | | - Frank S Prato
- Lawson Health Research Institute, London, ON N6C 2R5, Canada.
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Quaranta G, Maremmani AGI, Perugi G. Anti-AMPA-Receptor Encephalitis Presenting as a Rapid-Cycling Bipolar Disorder in a Young Woman with Turner Syndrome. Case Rep Psychiatry 2015; 2015:273192. [PMID: 26495149 PMCID: PMC4606164 DOI: 10.1155/2015/273192] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 09/08/2015] [Accepted: 09/10/2015] [Indexed: 12/19/2022] Open
Abstract
Background. Autoimmune encephalitis is a disorder characterised by the subacute onset of seizures, short-term memory loss, and psychiatric and behavioural symptoms. Initially, it was recognised as a paraneoplastic disorder, but recently a subgroup of patients without systemic cancer was identified. Case Description. We describe a 20-year-old woman with Turner syndrome presenting with a treatment-resistant rapid cycling bipolar disorder with cognitive impairment. She was diagnosed with anti-AMPA-receptor encephalitis. She showed marked improvement after starting memantine and valproic acid. Conclusion. This case description emphasises the importance of timely recognition of autoimmune limbic encephalitis in patients with psychiatric manifestations and a possible predisposition to autoimmune conditions, in order to rule out malignancy and to quickly initiate treatment.
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Affiliation(s)
- Giuseppe Quaranta
- Department of Experimental and Clinic Medicine, Section of Psychiatry, University of Pisa, Via Roma 67, 56100 Pisa, Italy
| | - Angelo Giovanni Icro Maremmani
- Department of Experimental and Clinic Medicine, Section of Psychiatry, University of Pisa, Via Roma 67, 56100 Pisa, Italy
| | - Giulio Perugi
- Department of Experimental and Clinic Medicine, Section of Psychiatry, University of Pisa, Via Roma 67, 56100 Pisa, Italy
- The Institute of Behavioural Science “G. De Lisio”, Via di Pratale 3, 56127 Pisa, Italy
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Kirkpatrick B, Miller B, García-Rizo C, Fernandez-Egea E. Schizophrenia: a systemic disorder. ACTA ACUST UNITED AC 2015; 8:73-9. [PMID: 23518782 DOI: 10.3371/csrp.kimi.031513] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The concept of schizophrenia that is most widely taught is that it is a disorder in which psychotic symptoms are the main problem, and a dysregulation of dopamine signaling is the main feature of pathophysiology. However, this concept limits clinical assessment, the treatments offered to patients, research, and the development of therapeutics. A more appropriate conceptual model is that: 1) schizophrenia is not a psychotic disorder, but a disorder of essentially every brain function in which psychosis is present; 2) it is not a brain disease, but a disorder with impairments throughout the body; 3) for many patients, neuropsychiatric problems other than psychosis contribute more to impairment in function and quality of life than does psychosis; and, 4) some conditions that are considered to be comorbid are integral parts of the illness. In conclusion, students, patients, and family members should be taught this model, along with its implications for assessment, research, and therapeutics.
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Affiliation(s)
- Brian Kirkpatrick
- Department of Psychiatry and Behavioral Sciences, University of Nevada, Reno, NV
| | - Brian Miller
- Department of Psychiatry and Health Behavior, Georgia Health Sciences University, Augusta, GA
| | - Clemente García-Rizo
- Schizophrenia Program, Department of Psychiatry, Neuroscience Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Emilio Fernandez-Egea
- Department of Psychiatry, Behavioural and Clinical Neuroscience Institute (BCNI), University of Cambridge, Good Outcome Schizophrenia Clinic, Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK, Huntingdon, UK
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Khandaker GM, Cousins L, Deakin J, Lennox BR, Yolken R, Jones PB. Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry 2015; 2:258-270. [PMID: 26359903 PMCID: PMC4595998 DOI: 10.1016/s2215-0366(14)00122-9] [Citation(s) in RCA: 625] [Impact Index Per Article: 62.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Accepted: 10/03/2014] [Indexed: 12/16/2022]
Abstract
Complex interactions between the immune system and the brain might have important aetiological and therapeutic implications for neuropsychiatric brain disorders. A possible association between schizophrenia and the immune system was postulated over a century ago, and is supported by epidemiological and genetic studies pointing to links with infection and inflammation. Contrary to the traditional view that the brain is an immunologically privileged site shielded behind the blood-brain barrier, studies in the past 20 years have noted complex interactions between the immune system, systemic inflammation, and the brain, which can lead to changes in mood, cognition, and behaviour. In this Review, we describe some of the important areas of research regarding innate and adaptive immune response in schizophrenia and related psychotic disorders that, we think, will be of interest to psychiatric clinicians and researchers. We discuss potential mechanisms and therapeutic implications of these findings, including studies of anti-inflammatory drugs in schizophrenia, describe areas for development, and offer testable hypotheses for future investigations.
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Affiliation(s)
- Golam M Khandaker
- Department of Psychiatry, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK
| | - Lesley Cousins
- Department of Psychiatry, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK
| | - Julia Deakin
- Department of Psychiatry, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK
| | | | - Robert Yolken
- Stanley Division of Developmental Neurovirology, Johns Hopkins University, Baltimore, MD, USA
| | - Peter B Jones
- Department of Psychiatry, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK
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37
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Abnormal immune system development and function in schizophrenia helps reconcile diverse findings and suggests new treatment and prevention strategies. Brain Res 2015; 1617:93-112. [PMID: 25736181 DOI: 10.1016/j.brainres.2015.02.043] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 02/20/2015] [Accepted: 02/21/2015] [Indexed: 12/20/2022]
Abstract
Extensive research implicates disturbed immune function and development in the etiology and pathology of schizophrenia. In addition to reviewing evidence for immunological factors in schizophrenia, this paper discusses how an emerging model of atypical immune function and development helps explain a wide variety of well-established - but puzzling - findings about schizophrenia. A number of theorists have presented hypotheses that early immune system programming, disrupted by pre- and perinatal adversity, often combines with abnormal brain development to produce schizophrenia. The present paper focuses on the hypothesis that disruption of early immune system development produces a latent immune vulnerability that manifests more fully after puberty, when changes in immune function and the thymus leave individuals more susceptible to infections and immune dysfunctions that contribute to schizophrenia. Complementing neurodevelopmental models, this hypothesis integrates findings on many contributing factors to schizophrenia, including prenatal adversity, genes, climate, migration, infections, and stress, among others. It helps explain, for example, why (a) schizophrenia onset is typically delayed until years after prenatal adversity, (b) individual risk factors alone often do not lead to schizophrenia, and (c) schizophrenia prevalence rates actually tend to be higher in economically advantaged countries. Here we discuss how the hypothesis explains 10 key findings, and suggests new, potentially highly cost-effective, strategies for treatment and prevention of schizophrenia. Moreover, while most human research linking immune factors to schizophrenia has been correlational, these strategies provide ethical ways to experimentally test in humans theories about immune function and schizophrenia. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.
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Kiani R, Lawden M, Eames P, Critchley P, Bhaumik S, Odedra S, Gumber R. Anti-NMDA-receptor encephalitis presenting with catatonia and neuroleptic malignant syndrome in patients with intellectual disability and autism. BJPsych Bull 2015; 39:32-5. [PMID: 26191422 PMCID: PMC4495827 DOI: 10.1192/pb.bp.112.041954] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2012] [Accepted: 12/13/2012] [Indexed: 11/23/2022] Open
Abstract
We report anti-N-methyl-d-aspartate (NMDA) receptor encephalitis in two patients with autism and intellectual disability presenting with neuropsychiatric symptoms of catatonia and neuroleptic malignant syndrome. Case reports such as these help raise awareness of this clinical issue. By paving the way for earlier diagnoses they ultimately maximise the potential for curative treatments and prevention of long-term complications.
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Affiliation(s)
- Reza Kiani
- Adult Learning Disability Service, Leicestershire Partnership NHS Trust ; Department of Medical Education, School of Medicine, University of Leicester
| | - Mark Lawden
- Department of Neurology, University Hospitals of Leicester
| | - Penelope Eames
- Department of Neurology, University Hospitals of Leicester
| | | | - Sabyasachi Bhaumik
- Adult Learning Disability Service, Leicestershire Partnership NHS Trust ; University of Leicester
| | | | - Rohit Gumber
- Adult Learning Disability Service, Leicestershire Partnership NHS Trust
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Lazar-Molnar E, Tebo AE. Autoimmune NMDA receptor encephalitis. Clin Chim Acta 2015; 438:90-7. [DOI: 10.1016/j.cca.2014.08.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 08/06/2014] [Accepted: 08/10/2014] [Indexed: 12/15/2022]
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Perugi G, Quaranta G, Belletti S, Casalini F, Mosti N, Toni C, Dell'Osso L. General medical conditions in 347 bipolar disorder patients: clinical correlates of metabolic and autoimmune-allergic diseases. J Affect Disord 2015; 170:95-103. [PMID: 25237732 DOI: 10.1016/j.jad.2014.08.052] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Accepted: 08/29/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND Patients with bipolar disorder (BD) suffer from greater physical morbidity and mortality than the general population. The aim of the present study is to explore the prevalence and clinical correlates of General Medical Conditions (GMC) in a large consecutive sample of patients with BD. METHOD The study sample comprised of 347 patients who met DSM-IV-TR criteria for BD I (n=207, 59.7%), BD II or Cyclothymic Disorder (n=140, 40.3). Diagnostic information was collected by means of the Structured Clinical Interview for DSM-IV Axis I Disorders- Clinical Version (SCID-I), and information about personal and family history were collected by the Semi-Structured Interview for Mood Disorder-Revised (SIMD-R). Standardized procedure was used to assess the diagnosis of GMC, which was considered present only if a specific therapy to treat the condition was prescribed by a specialist or a general practitioner. In order to explore possible relationships between physical comorbidity and clinical features of BD, we compared patients with (MD) and without (No-MD) Metabolic Diseases (MD) and patients with (AAD) and without (No-AAD) Autoimmune-Allergic Diseases (AAD). RESULTS The most commonly reported GMCs were: Headache, Hypercholesterolemia (>200mg/dl), Chronic Constipation, Obesity, Arterial Hypertension (BP >140/90 mmHg), Hypothyroidism, Allergic Rhino-Conjunctivitis, Irritable Bowel Syndrome, Hypertriglyceridemia (>150 mg/dl), Metabolic Syndrome, Hiatus Hernia, Dysmenorrhea, Urticaria, Atopic Dermatitis, Psoriasis, Seborrheic Dermatitis, Diabetes Mellitus, Bronchial Asthma, Cardiac Arrhythmias, Biliary Lithiasis, and COPD. In our sample, MD (n=148, 42.7%) and AAD (n=167, 48.1%) were the most common categories of GMCs. Interestingly, the lifetime prevalence of cancer and neoplastic diseases was very low: 1 patient (.3%) reported Lung Adenocarcinoma and 2 (.6%) patients Bowel Cancer. In the group comparisons, length of pharmacological treatment (OR=1.054; 95% CI=1.030-1.078), age at onset of first major episode (OR=1.043; 95% CI=1.019-1.067), length of the current episode (OR=1.025; 95% CI=1.020-1.533) and absence of lifetime comorbid substance abuse (OR=.373; 95% CI=.141-.989) were statistically associated with the presence of comorbid MD; while only AD-induced hypomania (OR=1.62; 95% CI=1.011-2.597), and cyclothymic temperament (OR=1.051; 95% CI=1.016-1.087) were statistically associated with the presence of comorbid AAD. LIMITATIONS Possible referral and selection bias; retrospective, non-blind, cross-sectional evaluation. CONCLUSION MD and AAD were highly represented in our sample, while cancer and neoplastic diseases were uncommon. The clinical correlates of different sub-groups of GMC suggest different interpretations. The presence of MD seems to be correlated with the progression of BD and the chronic medication exposure, while comorbid AAD seems to correlate with a specific clinical subtype of BD, characterized by mood reactivity and temperamental mood instability. If the link with autoimmune-allergic diathesis will be confirmed, it could provide an interesting new paradigm for the study of the "systemic" nature of mood disorders and a promising target for future treatment options.
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Affiliation(s)
- Giulio Perugi
- Department of Clinical and Experimental Medicine, Clinica Psichiatrica Università di Pisa, Via Roma, 67, Pisa 56126, Italy; Institute of Behavioural Sciences "G. De Lisio", Pisa, Italy.
| | - Giuseppe Quaranta
- Department of Clinical and Experimental Medicine, Clinica Psichiatrica Università di Pisa, Via Roma, 67, Pisa 56126, Italy
| | - Serena Belletti
- Department of Clinical and Experimental Medicine, Clinica Psichiatrica Università di Pisa, Via Roma, 67, Pisa 56126, Italy
| | - Francesca Casalini
- Department of Clinical and Experimental Medicine, Clinica Psichiatrica Università di Pisa, Via Roma, 67, Pisa 56126, Italy
| | - Nicola Mosti
- Department of Clinical and Experimental Medicine, Clinica Psichiatrica Università di Pisa, Via Roma, 67, Pisa 56126, Italy
| | - Cristina Toni
- Institute of Behavioural Sciences "G. De Lisio", Pisa, Italy
| | - Liliana Dell'Osso
- Department of Clinical and Experimental Medicine, Clinica Psichiatrica Università di Pisa, Via Roma, 67, Pisa 56126, Italy
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Masopust J, Andrýs C, Bažant J, Vyšata O, Kuca K, Vališ M. Anti-NMDA receptor antibodies in patients with a first episode of schizophrenia. Neuropsychiatr Dis Treat 2015; 11:619-23. [PMID: 25834440 PMCID: PMC4358648 DOI: 10.2147/ndt.s80746] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDA-R) is classified as an autoimmune disorder with psychotic symptoms, which are frequently dominant. However, it remains unclear how frequently NMDA-R antibodies lead to a condition that mimics psychosis and first-episode schizophrenia. In our work, we investigated the presence of antibodies against NMDA-R in patients with first-episode psychosis (FEP) in comparison with healthy volunteers. METHODS This study included 50 antipsychotic-naïve patients with FEP (including 21 women) and 50 healthy volunteers (including 21 women). The mean age of the patients was 27.4 (±7.4) years and that of the healthy controls was 27.0 (±7.3) years. Antibodies against NMDA-R in the serum were detected by immunofluorescence. RESULTS None of the investigated patients with an FEP and none of the healthy controls showed positive antibodies against NMDA-Rs. CONCLUSION According to results of studies, a small proportion of patients with an FEP possess antibodies against NMDA-R. However, the extent to which this finding contributes to the etiopathogenesis of the response to antipsychotic medication and whether immunomodulatory therapy is indicated in these cases remains uncertain.
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Affiliation(s)
- Jiří Masopust
- Department of Psychiatry, Faculty of Medicine in Hradec Kralové, Charles University in Prague, University Hospital Hradec Králové, Hradec Králové, Czech Republic ; National Institute of Mental Health, Klecany, Czech Republic
| | - Ctirad Andrýs
- Institute of Clinical Immunology and Allergology, Charles University in Prague, Faculty of Medicine in Hradec Králové, and University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Jan Bažant
- Department of Psychiatry, Faculty of Medicine in Hradec Kralové, Charles University in Prague, University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Oldřich Vyšata
- Department of Neurology, Charles University in Prague, Faculty of Medicine in Hradec Králové, and University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Kamil Kuca
- Biomedical Research Centrum, University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Martin Vališ
- Department of Neurology, Charles University in Prague, Faculty of Medicine in Hradec Králové, and University Hospital Hradec Králové, Hradec Králové, Czech Republic
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Debnath M, Berk M. Th17 pathway-mediated immunopathogenesis of schizophrenia: mechanisms and implications. Schizophr Bull 2014; 40:1412-21. [PMID: 24711545 PMCID: PMC4193719 DOI: 10.1093/schbul/sbu049] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Schizophrenia is a highly complex and severe neuropsychiatric disorder with an unknown etiopathology. Evidence for a dysregulated immune system in both the risk for and progression of schizophrenia has recently been overwhelming. Importantly, chronic low-grade inflammation both in the periphery and central nervous system has been shown to contribute predominantly to the pathogenesis of schizophrenia in a subset of individuals. Inflammation in the central nervous system is mediated by a range of proinflammatory cytokines, resident immune cells such as microglia, and brain infiltrating peripheral immunocompetent cells, such as T lymphocytes. Recently, Th17 cells, a subset of T helper cells have emerged as crucial players in mucosal defense against infections. It is linked to atopic, inflammatory, and autoimmune disorders. The risk factors/mechanisms leading to low-grade inflammation in schizophrenia are diverse and include infectious agents, stress, trauma, environmental toxins, genetic vulnerability, physical inactivity, obesity, poor diet, and sleep disruption. Herein, we propose that fetal programming of cellular immune components driven by intrauterine adversity can lead to the generation of long-lasting effector/memory Th17 cells. Th17 cells can disrupt the blood-brain barrier, infiltrate the central nervous system, and, along with other cytokines and microglia, lead to neuroprogression through neuroinflammation in schizophrenia.
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Affiliation(s)
- Monojit Debnath
- Department of Human Genetics, National Institute of Mental Health & Neurosciences, Bangalore, Karnataka, India;
| | - Michael Berk
- IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, Victoria, Australia;,Department of Psychiatry, Florey Institute of Neuroscience and Mental Health, Orygen Youth Health Research Centre, University of Melbourne, Parkville, Australia
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Pollak TA, McCormack R, Peakman M, Nicholson TR, David AS. Prevalence of anti-N-methyl-D-aspartate (NMDA) receptor [corrected] antibodies in patients with schizophrenia and related psychoses: a systematic review and meta-analysis. Psychol Med 2014; 44:2475-2487. [PMID: 24330811 DOI: 10.1017/s003329171300295x] [Citation(s) in RCA: 115] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune condition caused by immunoglobulin (Ig)G antibodies directed against the NR1 subunit of the NMDA glutamate receptor. Approximately 65% of cases present with psychiatric symptoms, particularly psychosis. It remains to be established whether anti-NMDA receptor antibodies can cause a 'purely' psychotic illness without overt neurological symptoms. METHOD We conducted a systematic literature search to establish what proportion of patients with schizophrenia and related psychoses have antibodies directed against the NMDA receptor. Studies were included if (a) subjects had a diagnosis of schizophrenia, schizophrenia spectrum disorder or first-episode psychosis (FEP) using standard criteria, (b) serum was analysed for the presence of anti-NMDA receptor antibodies; and (c) the purpose of the study was to look for the presence of anti-NMDA receptor antibodies in patients with a primary psychiatric diagnosis without clinical signs of encephalitis. RESULTS Seven studies were included, comprising 1441 patients, of whom 115 [7.98%, 95% confidence interval (CI) 6.69-9.50] were anti-NMDA receptor antibody positive. Of these, 21 (1.46%, 95% CI 0.94-2.23) patients were positive for antibodies of the IgG subclass. Prevalence rates were greater in cases than controls only for IgG antibodies; other subclasses are of less certain aetiological relevance. There was significant heterogeneity in terms of patient characteristics and the antibody assay used. CONCLUSIONS A minority of patients with psychosis are anti-NMDA receptor antibody positive. It remains to be established whether this subset of patients differs from antibody-negative patients in terms of underlying pathology and response to antipsychotic treatment, and whether immunomodulatory treatments are effective in alleviating psychotic symptoms in this group.
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Affiliation(s)
- T A Pollak
- National Institute for Health Research (NIHR) Biomedical Research Centre, South London and Maudsley NHS FoundationTrust and Institute of Psychiatry, King's College London,UK
| | - R McCormack
- National Institute for Health Research (NIHR) Biomedical Research Centre, South London and Maudsley NHS FoundationTrust and Institute of Psychiatry, King's College London,UK
| | - M Peakman
- Department of Immunobiology,King's College London,UK
| | - T R Nicholson
- Section of Cognitive Neuropsychiatry, Department of Psychosis Studies,Institute of Psychiatry, King's College London,UK
| | - A S David
- Section of Cognitive Neuropsychiatry, Department of Psychosis Studies,Institute of Psychiatry, King's College London,UK
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Müller UJ, Teegen B, Probst C, Bernstein HG, Busse S, Bogerts B, Schiltz K, Stoecker W, Steiner J. Absence of dopamine receptor serum autoantibodies in schizophrenia patients with an acute disease episode. Schizophr Res 2014; 158:272-4. [PMID: 25000914 DOI: 10.1016/j.schres.2014.06.025] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 06/19/2014] [Accepted: 06/20/2014] [Indexed: 01/24/2023]
Affiliation(s)
- Ulf J Müller
- Department of Psychiatry, University of Magdeburg, Magdeburg, Germany
| | - Bianca Teegen
- Institute for Experimental Immunology, Affiliated to Euroimmun, Lübeck, Germany
| | - Christian Probst
- Institute for Experimental Immunology, Affiliated to Euroimmun, Lübeck, Germany
| | | | - Stefan Busse
- Department of Psychiatry, University of Magdeburg, Magdeburg, Germany
| | - Bernhard Bogerts
- Department of Psychiatry, University of Magdeburg, Magdeburg, Germany; Center for Behavioral Brain Sciences, Magdeburg, Germany
| | - Kolja Schiltz
- Department of Psychiatry, University of Magdeburg, Magdeburg, Germany; Center for Behavioral Brain Sciences, Magdeburg, Germany
| | - Winfried Stoecker
- Institute for Experimental Immunology, Affiliated to Euroimmun, Lübeck, Germany
| | - Johann Steiner
- Department of Psychiatry, University of Magdeburg, Magdeburg, Germany; Center for Behavioral Brain Sciences, Magdeburg, Germany.
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Late cortical plasticity in motor and auditory cortex: role of met-allele in BDNF Val66Met polymorphism. Int J Neuropsychopharmacol 2014; 17:705-13. [PMID: 24405657 DOI: 10.1017/s1461145713001636] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The brain-derived neurotropic factor (BDNF) Val66Met polymorphism has been associated with abnormalities of synaptic plasticity in animal models, and abnormalities in motor cortical plasticity have also been described in humans using transcranial direct current stimulation. No study has yet been done on plasticity in non-motor regions, and the effect of two Met alleles (i.e. 'Met dose') is not well understood. We studied the effect of the BDNF Val66Met polymorphism on the after-effects of transcranial direct current stimulation and tetanic auditory stimulation in 65 subjects (23; Val66Val, 22; Val66Met and 20; Met66Met genotypes). In the first session, motor evoked potentials (MEP) were recorded under stereotaxic guidance for 90 min after 9 min of anodal transcranial direct current stimulation (TDCS). In the second session, auditory-evoked potentials (AEP) were recorded before and after 2 min of auditory 13 Hz tetanic stimulation. There was a difference in MEP facilitation post-TDCS comparing Met carriers with non-Met carriers, with Met carriers having a modest late facilitation at 30-90 min. There was no difference in responses between Val66Met genotype and Met66Met genotype subjects. Tetanic auditory stimulation also produced late facilitation of N1-P2 AEP at 25 min, but there was no apparent effect of genetic status. This study indicates that Met66Met carriers behave like Val66Met carriers for TDCS-induced plasticity, and produce a late facilitation of MEPs. Auditory cortical plasticity was not affected by the BDNF Val66Met polymorphism. This study sheds light on the differences between auditory and motor cortical plasticity and the role of the BDNF Val66Met polymorphism.
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Jones AL, Mowry BJ, McLean DE, Mantzioris BX, Pender MP, Greer JM. Elevated levels of autoantibodies targeting the M1 muscarinic acetylcholine receptor and neurofilament medium in sera from subgroups of patients with schizophrenia. J Neuroimmunol 2014; 269:68-75. [PMID: 24636402 DOI: 10.1016/j.jneuroim.2014.02.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 02/17/2014] [Accepted: 02/19/2014] [Indexed: 01/22/2023]
Abstract
Schizophrenia is a severe debilitating brain disorder with a poorly understood aetiology. Among the diverse aetiological clues lies evidence for immune abnormalities in some individuals. The aim of this study was to investigate the frequency and specificity of autoantibodies directed against the brain in people with schizophrenia. Sera were screened for reactivity against human brain tissue (hippocampus and prefrontal cortex). Neuronal cell body and filamentous patterns of brain tissue staining were observed significantly more frequently in sera from schizophrenia patients (n=30) compared to controls (n=24). Sera that showed a neuronal cell body pattern of staining on hippocampus reacted strongly to an extracellular epitope of the M1 muscarinic acetylcholine receptor (m1AChR) in ELISA. Both cell body staining and elevated m1AChR reactivity correlated with higher symptom scores for poverty of speech. Sera showing a filamentous staining pattern predominantly targeted microfilaments, intermediate filaments or neurofilaments, particularly neurofilament medium (NFM), which is a dopamine receptor interacting protein. By ELISA, there was strongly elevated reactivity against NFM in a subset (15%) of schizophrenia patients (n=101) compared to healthy controls (n=55) or patients with multiple sclerosis (n=32). These results support the hypothesis that neurotransmitter receptors or molecules involved in regulation of neurotransmission are targets of autoantibodies in some people with schizophrenia.
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Affiliation(s)
- Amanda L Jones
- The University of Queensland, UQ Centre for Clinical Research, Brisbane, Australia
| | - Bryan J Mowry
- The University of Queensland, Queensland Brain Institute, Brisbane, Australia; The University of Queensland, Queensland Centre for Mental Health Research Brisbane, Australia
| | - Duncan E McLean
- The University of Queensland, Queensland Centre for Mental Health Research Brisbane, Australia
| | - Basil X Mantzioris
- The University of Queensland, Queensland Brain Institute, Brisbane, Australia
| | - Michael P Pender
- The University of Queensland, School of Medicine, Brisbane, Australia; Department of Neurology, Royal Brisbane & Women's Hospital, Brisbane, Australia
| | - Judith M Greer
- The University of Queensland, UQ Centre for Clinical Research, Brisbane, Australia.
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Ekizoglu E, Tuzun E, Woodhall M, Lang B, Jacobson L, Icoz S, Bebek N, Gurses C, Gokyigit A, Waters P, Vincent A, Baykan B. Investigation of neuronal autoantibodies in two different focal epilepsy syndromes. Epilepsia 2014; 55:414-22. [PMID: 24502404 DOI: 10.1111/epi.12528] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/26/2013] [Indexed: 01/17/2023]
Abstract
OBJECTIVE Neuronal antibodies have been identified in patients with seizures as the main or sole symptom. Our aim was to investigate the prevalence of these autoantibodies in patients with focal epilepsy of unknown cause (FEoUC) and in the group having mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). METHODS We studied anti-neuronal antibodies of consecutive adult patients diagnosed with FEoUC and MTLE-HS in our epilepsy center. The clinical and laboratory features of antibody-positive patients were compared with those of seronegative patients. The responses to therapy have also been investigated. RESULTS Sera from 81 patients with epilepsy were tested. We found antibodies against glycine receptor (GLY-R) in 5 (6.2%), contactin-associated protein 2 (CASPR-2) in 4 (4.9%), N-methyl-d-aspartate receptor (NMDA-R) in 2 (2.5%), and voltage-gated potassium channel (VGKC)-complex in 2 (2.5%) of our patients with epilepsy. Psychotic attacks and nonspecific magnetic resonance imaging (MRI) white matter changes (WMCs) showed significant associations in seropositive patients (p = 0.003 and p = 0.03, respectively). Poor drug-response rates and total seizure counts were also higher in the seropositive patients but without reaching statistical significance. Three seropositive patients with previous epilepsy surgery showed typical histopathologic results for MTLE-HS, but not inflammatory changes. Moreover, some patients harboring these antibodies partly benefited from immunotherapy. SIGNIFICANCE We detected neuronal antibodies in one sixth of patients with focal epilepsy, GLY-R antibodies being the leading one. Psychosis or nonspecific MRI WMCs were frequent in the seropositive group. Our results suggested that relevant antibodies should be screened for a treatment possibility in these groups.
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Affiliation(s)
- Esme Ekizoglu
- Department of Neurology, Epilepsy Center (EPIMER) and Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
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Thachil A, Baptista A, Agrawal N. Antibodies attacking the brain: Is it time for a paradigm shift in psychiatric practice and service models? Aust N Z J Psychiatry 2013; 47:1108-12. [PMID: 24168813 DOI: 10.1177/0004867413510053] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Ajoy Thachil
- 1Department of Liaison Psychiatry, St George's Hospital, London, UK
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Fuxe K, Borroto-Escuela DO, Tarakanov A, Fernandez WR, Manger P, Rivera A, van Craenenbroeck K, Skieterska K, Diaz-Cabiale Z, Filip M, Ferraro L, Tanganelli S, Guidolin D, Cullheim S, de la Mora MP, Agnati LF. Understanding the balance and integration of volume and synaptic transmission. Relevance for psychiatry. ACTA ACUST UNITED AC 2013. [DOI: 10.1016/j.npbr.2013.10.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Autoimmune-induced glutamatergic receptor dysfunctions: conceptual and psychiatric practice implications. Eur Neuropsychopharmacol 2013; 23:1659-71. [PMID: 23791073 DOI: 10.1016/j.euroneuro.2013.05.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 05/27/2013] [Accepted: 05/28/2013] [Indexed: 01/03/2023]
Abstract
Glutamatergic neurotransmission is mediated via complex receptorial systems including N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA) and metabotropic receptor subtypes and plays a critical role in the modulation of synaptic plasticity, mood, cognitive processes and motor behavior. Glutamatergic function deficits are hypothesized to contribute to the pathogenesis of neuropsychiatric disorders, including schizophrenia, mood and movement disorders. Accumulating data are rapidly leading to the characterization of specific types of autoimmune encephalitis in which the receptors and proteins critically involved in glutamatergic neurotransmission, e.g., NMDA, AMPA receptors, are antigen targets. Characteristic of these syndromes, antibodies alter the structure and/or function of the corresponding neuronal antigen resulting in clinical pictures that resemble pharmacological disease models. Presently the best characterized autoimmune glutamatergic disorder is anti-NMDA receptor encephalitis. This disorder manifests with intertwined psychiatric and neurological features, defines a new syndrome, reclassifies poorly defined clinical states and extends previous hypotheses, such as hypo-NMDA receptor function in schizophrenia. The characterization of autoimmune-induced glutamatergic receptor dysfunctions (AGRD) is likely to have a substantial conceptual impact upon our understanding of neuropsychiatric disorders including schizophrenia, affective and movement dysfunctions. Further definition of AGRD will provide additional guidelines for psychiatric diagnoses, identification of homogeneous patient subtypes within broad phenomenological classifications and will contribute to the development of personalized treatments. The body of knowledge already accumulated on anti-NMDA receptor encephalitis highlights the need for wide dissemination of these concepts among psychiatrists, and in suspected cases, for early recognition, prompt clinical and laboratory investigation and efficient interface between mental health and medical teams.
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