Anti-GluK2 Antibody-Positive Autoimmune Encephalitis Concurrent with Multiple Myeloma: A Case Report

Anti-GluK2 Antibody-Positive Autoimmune Encephalitis Concurrent with Multiple Myeloma: A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Anti-GluK2 Antibody-Positive Autoimmune Encephalitis Concurrent with Multiple Myeloma: A Case Report Zheng ping Cheng, Yang Song, Shuqi Zhao, Xiaowen Sui, Lili Xie, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5372393/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Jan, 2025 Read the published version in BMC Neurology → Version 1 posted 9 You are reading this latest preprint version Abstract Background It is the first reported instance of GluK2 antibody-associated autoimmune encephalitis with involuntary movement. Case presentation A 60-year-old woman who experienced involuntary movements of her lower limbs and facial muscle for two years，sometimes accompanied with hysterical shouting. Ater the treatment for multiple myeloma, bone marrow examinations showed that the proportion of myeloma cells have a sustained decline which indicated the treatment worked, meanwhile, all the symptoms disappeared and the concentrations of anti-GluK2 antibody IgG decreased sharply. Conclusions This case revealed that the involuntary movements and the emotion is a new phenotype of Anti-GluK2 Antibody-Positive Autoimmune Encephalitis. Extrapyramidal symptoms multiple myeloma Anti-GluK2 antibody Figures Figure 1 Figure 2 Background Autoimmune encephalitis encompasses a group of inflammatory brain diseases mediated by autoimmune mechanisms. These include classical encephalitis, characterized by antibodies targeting intracellular antigens, cell membrane surface antigens, or synaptic proteins, as well as encephalitis associated with other autoimmune abnormalities [1] . Since the first recognition of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in 2007 [2] , numerous novel autoantibodies have been identified, expanding our understanding of autoimmune encephalitis. Multiple myeloma (MM) is the second most common hematologic malignancy, accounting for 1–2% of all tumors and 17% of hematological malignancies [3] . The clinical misdiagnosis rate for MM is high due to its diverse manifestations. As our understanding of MM has advanced, extramedullary manifestations have become increasingly recognized. Recently discovered in 2021, anti-GluK2 (glutamate kainate receptor subunit 2) encephalitis primarily manifests as acute cerebellar inflammation. In this case, the patient presented with involuntary motor symptoms, typical of anti-GluK2 antibody-positive autoimmune encephalitis, concurrent with MM. This case highlights the complex interplay between autoimmune encephalitis and MM, and the importance of considering both conditions in the differential diagnosis. Case presntation A 60-year-old woman was admitted to the hospital for the first time due to a month-long exacerbation of episodic involuntary movements she had been experiencing for two years. These movements primarily affected her lower limbs but could also involve her upper limbs and, in severe cases, her entire body, accompanied by eye squeezing, lip smacking, chewing, and other facial muscle movements. The symptoms worsened, with episodes typically occurring 1–2 times per month. The patient had a history of chronic glomerulonephritis. Both the Babinski sign and the Chaddock sign were observed bilaterally during clinical investigations. Routine blood tests, liver and kidney function tests were within normal ranges, except for albumin levels (26 g/L), urine protein levels (10.0 g/L), and D-dimers (3.64 µg/ml). Tumor markers, including carbohydrate antigens CA125, CA153, and CA724, as well as neuron-specific enolase, were abnormally elevated. A computed tomography (CT) scan of the lungs and abdomen did not reveal any tumors. Cerebrospinal fluid and blood tests for antibodies to demyelinating diseases of the central nervous system, autoimmune encephalitis, and paraneoplastic syndromes were all negative, were performed by Jiangsu Simcere Diagnostics Co. Ltd. (Nanjing 210002, China). Cranial magnetic resonance imaging (MRI) suggested microischemic demyelinating changes, and nerve conduction velocity in the extremities was normal. Serum protein electrophoresis identified M protein (Fig. 1 A), and immunoelectrophoresis showed IgG λ paraproteinemia (Fig. 1 B). The discharge diagnosis was involuntary movements pending further investigation and possible plasma cell disease. The patient was admitted to the hospital for the second time by hematology department-due to fatigue and swelling after two months. Laboratory tests revealed low hemoglobin levels (113 g/L), low albumin levels (19 g/L), and normal levels of blood calcium and serum creatinine. An X-ray of flat bones, such as the skull, showed no bone destruction. Urine protein quantification was elevated (18,640 mg/24 h), and myeloma cells (14.5%) were found in the bone marrow. Flow cytometry indicated monoclonal plasma cells expressing CD27, CD38, CD138, CD200, CD229, CD269, and cκ, but not CD19. The fluorescence in situ hybridization test detected IGH/FGFR3 (14q32/4p16) fusion gene (40%+) in myeloma cells. The patient was diagnosed with IgG-κ group B MM, ISS stage II (high risk). She was treated with bortezomib 1.35 mg/m² on days 1, 4, 8, and 11; cyclophosphamide 0.3 g/m² on days 1, 4, 8, and 11; and dexamethasone 20 mg on days 1–4 and 8–11. After two treatment sessions, there was a significant decrease in 24-hour urine protein levels, improvement in anemia, and reduction of involuntary movements. The patient was assessed as having a partial response (PR). Subsequent serum autoimmune encephalitis autoantibody profiling by cell-based assay (CBA) before immunotherapy showed positive GluK2 antibody IgG (1:100+), and tissue-based assay (TBA) revealed weak positivity in the cerebellum, hippocampus, and cerebral cortex, suggesting autoimmune encephalitis, TBA and CBA were performed by Jiangsu Simcere Diagnostics Co. Ltd. (Nanjing 210002, China). After completing four cycles of this treatment regimen, serum GluK2 antibody IgG concentrations decreased to 1:10+, indicating reduced antibody levels and disease activity. The patient underwent regular follow-up examinations, including blood tests, bone marrow examinations, and relevant imaging studies, to monitor disease progression and treatment response. Regular hematological evaluations and bone marrow examinations showed a sustained decline in the proportion of myeloma cells, confirming effective treatment and disease control. The ethics committee of the Dalian Municipal Central Hospital approved the retrospective study. Serum, cerebrospinal fluid, and clinical data from previously treated patients were stored and used for research with the consent of the patients or their proxies. Discussion Over the past decade, the spectrum of autoimmune encephalitis and paraneoplastic syndromes has developed rapidly, characterized by the presence of specific autoantibodies in cerebrospinal fluid and/or serum. Autoimmune encephalitis typically involves antibodies against neuronal synapses and cell surface antigens, while paraneoplastic syndromes are primarily associated with antibodies to intracellular antigens. These antibodies are often used as diagnostic biomarkers [4] . Different types of autoantibodies often present with unique clinical features, differences in sex ratio, age of onset, and disease prognosis. Some of these antibodies are highly associated with dyskinesia and may act on the basal ganglia through autoimmunity, leading to an imbalance of direct and indirect pathways in neurotransmitters, which in turn triggers involuntary movements. Various neuronal surface antibodies associated with immune-mediated movement disorders have been summarized, such as NMDAR, LGI-1, Caspr-2, GABA receptors, mGluR1 and R5, IgLON5, Dopamine 2 receptor, DPPX, Neurexin 3α, P/Q and N-type VGCC, PCA-Tr, and antibodies against neuronal intracellular antigens, such as Hu, Ri, GAD-65, Amphiphysin, CRMP-5, Ma1/Ma2, and PCA1/PCA2 [5] . In this case, the patient's clinical manifestations were involuntary movements and psychiatric symptoms, and serum autoimmune encephalitis antibody test (CBA) showed a GluK2 antibody titer of 1:100+. TBA was weakly positive for cerebellum, hippocampus, and cerebral cortex. After immunotherapy, the titer of GluK2 antibody decreased, and the patient's clinical symptoms significantly improved. This process suggests that there may be a correlation between the level of anti-GluK2 antibodies and the severity of patients' clinical symptoms. GluK2 antibody, or alginate-type glutamate receptor subunit 2 (GluK2) encephalitis, is a novel autoimmune encephalitis discovered in 2021. It belongs to the large family of glutamate receptors, along with NMDA and AMPA receptors. GluK2 is a presynaptic regulator of neurotransmitter release, existing in both excitatory and inhibitory synapses. Scholars have found that the clinical manifestations of GluK2 antibody-associated encephalitis are mainly acute cerebellar inflammation, which may be accompanied by extensive MRI T2-FLAIR signal abnormalities, encephalopathy (memory deficits, behavioral changes, and epilepsy), signs of corticospinal tract involvement (hyperreflexia, positive Babinski sign, and ataxic spastic gait), or opsoclonus-myoclonus [6] . The patient in this case showed clinical symptoms of involuntary movements and emotional disorder, which was different from the main clinical symptoms of autoimmune encephalitis associated with anti-GluK2 antibodies (cerebellar ataxia), suggesting that anti-GluK2 antibodies may play a role in multiple brain regions, leading to diverse clinical symptoms. It is believed that the basal ganglia and cerebellum are not independent subcortical systems, but form a closely connected network through the cerebral cortex, in which the motor, cognitive and emotional areas of each node are interconnected [7] . Research has found that the cerebellum not only plays an important role in motor coordination and balance, but also plays a key role in cognitive and emotional processing [8] , Therefore, anti-GluK2 antibodies may cause involuntary movements and emotional disorder by affecting the neural networks in these brain regions. In other words, although the patient in this case did not have typical cerebellar ataxia, it may have affected the neural networks of the cortex-basal ganglia and cortex-cerebellar circuits by affecting the interconnection between the cerebellum and multiple areas of the brain (such as the cerebral cortex and striatum), affecting motor control and emotional regulation, resulting in involuntary movements and mental symptoms. Although there are no reports of anti-Gluk2 antibody-related encephalitis causing involuntary movements and psychiatric symptoms, by reviewing the latest literature, we found some key experimental evidence related to GluK2 and striatal function. Animal studies have found that alginate-type glutamate receptors are abundantly expressed in the basal ganglia. In mice, GluK2 subunits are the main components of the principal projection neurons (SPNs) in the striatum, especially in D1 and D2 type neurons. The axons of these neurons project to the substantia nigra and globus pallidus, and Gluk2 mRNA expression can be detected in these neurons. Chergui et al found that kainate receptors have the potential to have multiple distinct roles in regulating striatal activity and striatal circuit development, and that GluK2 is required for the expression of ionotropic kainate receptor-mediated currents in adult/juvenile mouse SPNs [9] . However, a Japanese study found that mice with all GluK1-5 knockouts showed compulsive behavior and hindlimb movement defects, indicating that the function of the striatal circuit had changed, while mice with only Gluk2 knockouts did not show similar changes [10] . There is no research on the correlation between the human genome and clinical phenotype of GluK2. Therefore, it is still unclear how GluK2 functions in the human striatal circuit. The patient's serum TBA cerebral cortex immunofluorescence staining was positive, suggesting that anti-Gluk2 antibodies acted on Gluk2 in the cerebral cortex, leading to the psychiatric symptoms shown by this patient. The mechanism is similar to that of NMDAR antibody-mediated autoimmune encephalitis, which may be the internalization and reduction of GluK2 receptors, through initial overactivation [11] , receptor isomers and cross-reactions [12] . neurotransmitter imbalance [13] , immune-mediated neuroinflammation [14] . And the compensatory mechanism of the central nervous system [12] and other mechanisms act on the cortex to cause cortical excitation symptoms. Shaltiel [15] found that in mice, GluK2 plays a unique role in controlling abnormalities associated with behavioral symptoms of mania, such as hyperactivity or psychomotor agitation, aggression, drive or increased goal-directed pursuit, risk-taking, and hypersensitivity to psychostimulants. Knight et al. [16] found that alginate receptor gene mutations are closely related to bipolar disorder and schizophrenia in their study of human genes. In addition, although current basic research and clinical reports have not yet fully revealed the specific mechanism of anti-GluK2 antibodies in neurobehavioral regulation, our case suggests its heterogeneity in clinical manifestations. This also emphasizes that future studies need to further explore the specific mechanism of action of anti-GluK2 antibodies in different brain regions to fully understand its role in neurobehavioral regulation. This will provide new directions for the diagnosis and treatment of GluK2-related autoimmune encephalitis. In addition, the patient was eventually found to have multiple myeloma, and through targeted treatment of the primary tumor, the patient's GluK2 antibody titers and clinical symptoms significantly improved. Typical signs of multiple myeloma (MM) include bone resorption, elevated blood calcium, renal impairment, anemia, and other organ function impairments. In some cases, neurological symptoms may accompany a diagnosis of MM. The most common type of peripheral neuropathy (7.5%) is caused by metabolic conditions such as myelopathy, hyperviscosity, hypercalcemia, or uremia, which compress the spinal cord and nerve roots (5%) caused by MM pathological fractures [17、18] . Yoshiki et al. reported a case of a 37-year-old Japanese woman with orthostatic hypotension who was diagnosed with MM (IgG κ type). Serological tests revealed anti-ganglionic acetylcholine receptor (anti-GAChR) antibodies. This case is extremely rare since MM with neurological symptoms through the septal effect is not typical. The patient was diagnosed with secondary MM-related autoimmune autonomic-gangliopathy. After treatment with anti-MM regimens, her autonomic dysfunction improved, and her anti-GAChR antibody titer decreased to undetectable levels [19] . Sisir also reported a case of MM with a shaky gait, which was finally diagnosed as Shy-Drager syndrome [20] . MM is theoretically prone to secondary paraneoplastic syndrome since it is a plasma cell tumor that produces pathogenic antibodies. Nevertheless, the early, rare symptoms it causes might be overlooked in clinical practice. MM is typically diagnosed when it progresses, causing fractures, anemia, kidney damage, or peripheral neuropathy that affects daily living. This case report highlights the importance of considering clonal plasma cell disease in the differential diagnosis whenever a patient experiences neurological symptoms that other causes cannot explain. Simple serum protein electrophoresis and immunofixation electrophoresis can quickly and easily identify these patients, preventing missed or incorrect diagnoses, and enabling patients to receive early diagnosis and treatment. Conclusions This case is the first reported instance of GluK2 antibody-associated autoimmune encephalitis with involuntary movement as the first symptom, and it is also the first reported case of multiple myeloma (MM) with this presentation. Although the correlation between MM and the onset of anti-GluK2 antibody-positive autoimmune encephalitis in this case cannot be clearly determined at present, their simultaneous occurrence is indeed rare. Since the VCD treatment regimen used in this case included bortezomib, cyclophosphamide, and dexamethasone, which overlaps with the treatment regimen for autoimmune encephalitis, the clinical outcome of improved treatment of multiple myeloma and decreased GluK2 antibody titers cannot determine the causal relationship between the two. Therefore, in future studies, more in-depth scientific verification such as animal experiments may be needed to explore the potential connection between the two diseases. Declarations Acknowledgements None . Author contributions CZP, ZSQ and HXR contributed to drafting the manuscript. SXW, XLL and CL contributed to collecting data. ZHL and PX contributed to analyzing the radiological and pathological findings. SY and MSB contributed to critically assessing and revising the manuscript. All the authors read and approved the final manuscript. Funding None. Data availability No datasets were generated or analysed during the current study. Ethics approval and consent to participate The case report complies with all ethics regulations. This case report was reviewed and approved by the Central Hospital of Dalian University of Technology with the approval number: YN2024-120-01. Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Competing interests The authors declare no competing interests. References Chinese Society of Neuroinfectious Diseases and Cerebrospinal Fluid Cytology.Chinese expert consensus on the diagnosis and management of autoimmune encephalitis (2022 edition)[J].Chinese Journal of Neurology,2022,55(09)：931-949.DOI:10.3760/cma.j.cn113694-20220219-00118 Dalmau J, Tüzün E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61(1):25-36. doi:10.1002/ana.21050 van de Donk NWCJ, Pawlyn C, Yong KL. Multiple myeloma. Lancet. 2021;397(10272):410-427. doi:10.1016/S0140-6736(21)00135-5 Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404. doi:10.1016/S1474-4422(15)00401-9 Ali F, Wijdicks EF. Treatment of Movement Disorder Emergencies in Autoimmune Encephalitis in the Neurosciences ICU. Neurocrit Care. 2020;32(1):286-294. doi:10.1007/s12028-019-00875-5 Landa J, Guasp M, Míguez-Cabello F, et al. Encephalitis with Autoantibodies against the Glutamate Kainate Receptors GluK2. Ann Neurol. 2021;90(1):101-117. doi:10.1002/ana.26098 Bostan AC. The basal ganglia and the cerebellum: nodes in an integrated network. 2018. Carta I, Chen CH, Schott AL, et al. Cerebellar modulation of the reward circuitry and social behavior. 2019. Chergui K, Bouron A, Normand E, Mulle C. Functional GluR6 kainate receptors in the striatum: indirect downregulation of synaptic transmission. J Neurosci. 2000;20(6):2175-2182. doi:10.1523/JNEUROSCI.20-06-02175.2000 Xu J, Marshall JJ, Fernandes HB, et al. Complete Disruption of the Kainate Receptor Gene Family Results in Corticostriatal Dysfunction in Mice. Cell Rep. 2017;18:1848–57. doi: 10.1016/j.celrep.2017.01.073 Levite, 2014: Levite M. Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor's expression, impair glutamate-induced signaling and function, activate blood brain barrier endothelial cells, kill neurons, damage the brain, induce behavioral/psychiatric/cognitive abnormalities and ataxia in animal models, and can be removed or silenced in some patients by immunotherapy. J Neural Transm (Vienna). 2014;121(8):1029-1075. doi:10.1007/s00702-014-1193-3 Haselmann H, Mannara F, Werner C, et al. Human Autoantibodies against the AMPA Receptor Subunit GluA2 Induce Receptor Reorganization and Memory Dysfunction. Neuron. 2018;100(1):91-105.e9. doi:10.1016/j.neuron.2018.07.048 Tachibana N, Shirakawa T, Ishii K, et al. Expression of various glutamate receptors including N-methyl-D-aspartate receptor (NMDAR) in an ovarian teratoma removed from a young woman with anti-NMDAR encephalitis. Intern Med. 2010;49(19):2167-2173. doi:10.2169/internalmedicine.49.4069 Yoshio T, Okamoto H, Hirohata S, Minota S. IgG anti-NR2 glutamate receptor autoantibodies from patients with systemic lupus erythematosus activate endothelial cells. Arthritis Rheum . 2013;65(2):457-463. doi:10.1002/art.37745 Shaltiel G, Maeng S, Malkesman O, et al. Evidence for the involvement of the kainate receptor subunit GluR6 (GRIK2) in mediating behavioral displays related to behavioral symptoms of mania. Mol Psychiatry . 2008;13(9):858-872. doi:10.1038/mp.2008.20 Knight HM, Walker R, James R, et al. GRIK4/KA1 protein expression in human brain and correlation with bipolar disorder risk variant status. Am J Med Genet B Neuropsychiatr Genet . 2012;159B(1):21-29. doi:10.1002/ajmg.b.31248 Dispenzieri A, Kyle RA. Neurological aspects of multiple myeloma and related disorders. Best Pract Res Clin Haematol. 2005;18(4):673-688. doi:10.1016/j.beha.2005.01.024 Tathineni P, Cancarevic I, Malik BH. Uncommon Presentations of Multiple Myeloma. Cureus. 2020;12(6):e8400. Published 2020 Jun 1. doi:10.7759/cureus.8400 Nakae Y, Hyuga M, Terada Y, et al. Multiple Myeloma Presenting with Autoimmune Autonomic Ganglionopathy. Intern Med. 2017;56(24):3347-3351. doi:10.2169/internalmedicine.9096-17 Goldstein DS, McRae A, Holmes C, Dalakas MC. Autoimmune autonomic failure in a patient with myeloma-associated Shy-Drager syndrome. Clin Auton Res. 1996;6(1):17-21. doi:10.1007/BF02291401 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 20 Jan, 2025 Read the published version in BMC Neurology → Version 1 posted Editorial decision: Revision requested 27 Nov, 2024 Reviews received at journal 26 Nov, 2024 Reviews received at journal 23 Nov, 2024 Reviewers agreed at journal 23 Nov, 2024 Reviewers agreed at journal 21 Nov, 2024 Reviewers invited by journal 21 Nov, 2024 Editor assigned by journal 13 Nov, 2024 Submission checks completed at journal 12 Nov, 2024 First submitted to journal 01 Nov, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5372393","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":383280661,"identity":"c73e1f90-0835-450a-825f-87d6df45522b","order_by":0,"name":"Zheng ping Cheng","email":"","orcid":"","institution":"Neurology Department, Central Hospital of Dalian University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Zheng","middleName":"ping","lastName":"Cheng","suffix":""},{"id":383280662,"identity":"c179d9ff-3184-4115-846f-155af45526de","order_by":1,"name":"Yang Song","email":"","orcid":"","institution":"Hematology Department ,Central Hospital of Dalian University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Song","suffix":""},{"id":383280664,"identity":"607e8ced-dca6-474a-93ea-7892503bd926","order_by":2,"name":"Shuqi Zhao","email":"","orcid":"","institution":"Neurology Department, Central Hospital of Dalian University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Shuqi","middleName":"","lastName":"Zhao","suffix":""},{"id":383280665,"identity":"c2ebde7d-7f25-4bfd-9cdd-d0a8c303f418","order_by":3,"name":"Xiaowen Sui","email":"","orcid":"","institution":"Neurology Department, Central Hospital of Dalian University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Xiaowen","middleName":"","lastName":"Sui","suffix":""},{"id":383280666,"identity":"ebaf2cb5-990a-4980-827d-7822b158f39c","order_by":4,"name":"Lili Xie","email":"","orcid":"","institution":"Neurology Department, Central Hospital of Dalian University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Lili","middleName":"","lastName":"Xie","suffix":""},{"id":383280667,"identity":"f8d4ac9a-8261-4551-a70d-baea1d37be8b","order_by":5,"name":"Hongling Zhao","email":"","orcid":"","institution":"Neurology Department, Central Hospital of Dalian University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Hongling","middleName":"","lastName":"Zhao","suffix":""},{"id":383280672,"identity":"1572036c-09d9-4ccf-9252-33c00322ba3a","order_by":6,"name":"Xin Pan","email":"","orcid":"","institution":"Neurology Department, Central Hospital of Dalian University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Xin","middleName":"","lastName":"Pan","suffix":""},{"id":383280676,"identity":"c61e8438-32b9-4d19-bafe-88eea0a1faca","order_by":7,"name":"Li Cui","email":"","orcid":"","institution":"Neurology Department, Central Hospital of Dalian University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Cui","suffix":""},{"id":383280677,"identity":"7bd61e32-1e4c-4bfc-b9cf-1f90134de1b6","order_by":8,"name":"Xinran Huang","email":"","orcid":"","institution":"Hematology Department ,Central Hospital of Dalian University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Xinran","middleName":"","lastName":"Huang","suffix":""},{"id":383280678,"identity":"7b771f34-2124-4249-8ec9-4b09ddcb3f22","order_by":9,"name":"Shubei Ma","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIiWNgGAWjYFACHjaGhAobHn4GxgYGBgMbO+K0PDiTJifZANJSkJZMlBbGh22HjQ0OgDgfDoE04ge6/WePPUhsS0vcfCO57QGDwQFmBvbDRzfg02J2Iy/dIOGcTeK2G4ntBgwGd/gYeNLSbuDXwmMmkVCWlrjtzME2CQaDZ8wMEjxm+LWcPwPUwnY4cXMPWMthxgaCWg7kALWAvM/eSKyWGznmBgnAQJY43thukGCQlsxG0C9Ahz38AYrKZvZnDz78sbHjZz98DK8WZABMBmCSBECS4lEwCkbBKBhBAABsdk7xhsMD5AAAAABJRU5ErkJggg==","orcid":"","institution":"Neurology Department, Central Hospital of Dalian University of Technology","correspondingAuthor":true,"prefix":"","firstName":"Shubei","middleName":"","lastName":"Ma","suffix":""}],"badges":[],"createdAt":"2024-11-01 09:53:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5372393/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5372393/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12883-025-04037-3","type":"published","date":"2025-01-20T15:58:20+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":71610211,"identity":"4bf5e4df-fbcc-4440-8e6e-8ae5065133f9","added_by":"auto","created_at":"2024-12-17 06:42:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":151830,"visible":true,"origin":"","legend":"\u003cp\u003eA: M protein was seen in serum protein electrophoresis. B: Immunofixation electrophoresis showed that M protein was IgG-k type.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5372393/v1/9504104784e777ad38b6ded7.png"},{"id":71608452,"identity":"bb52e0a0-9879-414e-b8c3-5114cc9b5420","added_by":"auto","created_at":"2024-12-17 06:34:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":499479,"visible":true,"origin":"","legend":"\u003cp\u003eA: Bone marrow smear showing dysplasia, with partial binuclear abnormal plasma cells accounting for 14.5% of nuclear cells (1,000x). B: Flow cytometry showing abnormal plasma cells expressing CD38, CD56, and CD138, with restricted Kappa expression, and no expression of CD19, CD20, MPC1, and CD45, indicating clonal plasma cells. C: FISH showing that the myeloma cell fusion gene IGH/FGFR3 was positive (40%+).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5372393/v1/16b73cedcfa46bf574d1670f.png"},{"id":74858539,"identity":"3c3c7f0a-58b7-48bf-8e97-6c7a8c1c4f78","added_by":"auto","created_at":"2025-01-27 16:11:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1311942,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5372393/v1/738f0f30-6c9b-4fe9-bae3-04f70b5d77e0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Anti-GluK2 Antibody-Positive Autoimmune Encephalitis Concurrent with Multiple Myeloma: A Case Report","fulltext":[{"header":"Background","content":"\u003cp\u003eAutoimmune encephalitis encompasses a group of inflammatory brain diseases mediated by autoimmune mechanisms. These include classical encephalitis, characterized by antibodies targeting intracellular antigens, cell membrane surface antigens, or synaptic proteins, as well as encephalitis associated with other autoimmune abnormalities \u003csup\u003e[1]\u003c/sup\u003e. Since the first recognition of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in 2007\u003csup\u003e[2]\u003c/sup\u003e, numerous novel autoantibodies have been identified, expanding our understanding of autoimmune encephalitis. Multiple myeloma (MM) is the second most common hematologic malignancy, accounting for 1\u0026ndash;2% of all tumors and 17% of hematological malignancies\u003csup\u003e[3]\u003c/sup\u003e. The clinical misdiagnosis rate for MM is high due to its diverse manifestations. As our understanding of MM has advanced, extramedullary manifestations have become increasingly recognized. Recently discovered in 2021, anti-GluK2 (glutamate kainate receptor subunit 2) encephalitis primarily manifests as acute cerebellar inflammation. In this case, the patient presented with involuntary motor symptoms, typical of anti-GluK2 antibody-positive autoimmune encephalitis, concurrent with MM. This case highlights the complex interplay between autoimmune encephalitis and MM, and the importance of considering both conditions in the differential diagnosis.\u003c/p\u003e"},{"header":"Case presntation","content":"\u003cp\u003eA 60-year-old woman was admitted to the hospital for the first time due to a month-long exacerbation of episodic involuntary movements she had been experiencing for two years. These movements primarily affected her lower limbs but could also involve her upper limbs and, in severe cases, her entire body, accompanied by eye squeezing, lip smacking, chewing, and other facial muscle movements. The symptoms worsened, with episodes typically occurring 1\u0026ndash;2 times per month. The patient had a history of chronic glomerulonephritis. Both the Babinski sign and the Chaddock sign were observed bilaterally during clinical investigations. Routine blood tests, liver and kidney function tests were within normal ranges, except for albumin levels (26 g/L), urine protein levels (10.0 g/L), and D-dimers (3.64 \u0026micro;g/ml). Tumor markers, including carbohydrate antigens CA125, CA153, and CA724, as well as neuron-specific enolase, were abnormally elevated. A computed tomography (CT) scan of the lungs and abdomen did not reveal any tumors. Cerebrospinal fluid and blood tests for antibodies to demyelinating diseases of the central nervous system, autoimmune encephalitis, and paraneoplastic syndromes were all negative, were performed by Jiangsu Simcere Diagnostics Co. Ltd. (Nanjing 210002, China). Cranial magnetic resonance imaging (MRI) suggested microischemic demyelinating changes, and nerve conduction velocity in the extremities was normal. Serum protein electrophoresis identified M protein (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA), and immunoelectrophoresis showed IgG λ paraproteinemia (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). The discharge diagnosis was involuntary movements pending further investigation and possible plasma cell disease.\u003c/p\u003e \u003cp\u003eThe patient was admitted to the hospital for the second time by hematology department-due to fatigue and swelling after two months. Laboratory tests revealed low hemoglobin levels (113 g/L), low albumin levels (19 g/L), and normal levels of blood calcium and serum creatinine. An X-ray of flat bones, such as the skull, showed no bone destruction. Urine protein quantification was elevated (18,640 mg/24 h), and myeloma cells (14.5%) were found in the bone marrow. Flow cytometry indicated monoclonal plasma cells expressing CD27, CD38, CD138, CD200, CD229, CD269, and cκ, but not CD19. The fluorescence in situ hybridization test detected IGH/FGFR3 (14q32/4p16) fusion gene (40%+) in myeloma cells. The patient was diagnosed with IgG-κ group B MM, ISS stage II (high risk). She was treated with bortezomib 1.35 mg/m\u0026sup2; on days 1, 4, 8, and 11; cyclophosphamide 0.3 g/m\u0026sup2; on days 1, 4, 8, and 11; and dexamethasone 20 mg on days 1\u0026ndash;4 and 8\u0026ndash;11. After two treatment sessions, there was a significant decrease in 24-hour urine protein levels, improvement in anemia, and reduction of involuntary movements. The patient was assessed as having a partial response (PR). Subsequent serum autoimmune encephalitis autoantibody profiling by cell-based assay (CBA) before immunotherapy showed positive GluK2 antibody IgG (1:100+), and tissue-based assay (TBA) revealed weak positivity in the cerebellum, hippocampus, and cerebral cortex, suggesting autoimmune encephalitis, TBA and CBA were performed by Jiangsu Simcere Diagnostics Co. Ltd. (Nanjing 210002, China).\u003c/p\u003e \u003cp\u003eAfter completing four cycles of this treatment regimen, serum GluK2 antibody IgG concentrations decreased to 1:10+, indicating reduced antibody levels and disease activity. The patient underwent regular follow-up examinations, including blood tests, bone marrow examinations, and relevant imaging studies, to monitor disease progression and treatment response. Regular hematological evaluations and bone marrow examinations showed a sustained decline in the proportion of myeloma cells, confirming effective treatment and disease control.\u003c/p\u003e \u003cp\u003eThe ethics committee of the Dalian Municipal Central Hospital approved the retrospective study. Serum, cerebrospinal fluid, and clinical data from previously treated patients were stored and used for research with the consent of the patients or their proxies.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOver the past decade, the spectrum of autoimmune encephalitis and paraneoplastic syndromes has developed rapidly, characterized by the presence of specific autoantibodies in cerebrospinal fluid and/or serum. Autoimmune encephalitis typically involves antibodies against neuronal synapses and cell surface antigens, while paraneoplastic syndromes are primarily associated with antibodies to intracellular antigens. These antibodies are often used as diagnostic biomarkers \u003csup\u003e[4]\u003c/sup\u003e. Different types of autoantibodies often present with unique clinical features, differences in sex ratio, age of onset, and disease prognosis. Some of these antibodies are highly associated with dyskinesia and may act on the basal ganglia through autoimmunity, leading to an imbalance of direct and indirect pathways in neurotransmitters, which in turn triggers involuntary movements. Various neuronal surface antibodies associated with immune-mediated movement disorders have been summarized, such as NMDAR, LGI-1, Caspr-2, GABA receptors, mGluR1 and R5, IgLON5, Dopamine 2 receptor, DPPX, Neurexin 3α, P/Q and N-type VGCC, PCA-Tr, and antibodies against neuronal intracellular antigens, such as Hu, Ri, GAD-65, Amphiphysin, CRMP-5, Ma1/Ma2, and PCA1/PCA2\u003csup\u003e[5]\u003c/sup\u003e. In this case, the patient's clinical manifestations were involuntary movements and psychiatric symptoms, and serum autoimmune encephalitis antibody test (CBA) showed a GluK2 antibody titer of 1:100+. TBA was weakly positive for cerebellum, hippocampus, and cerebral cortex. After immunotherapy, the titer of GluK2 antibody decreased, and the patient's clinical symptoms significantly improved. This process suggests that there may be a correlation between the level of anti-GluK2 antibodies and the severity of patients' clinical symptoms.\u003c/p\u003e \u003cp\u003eGluK2 antibody, or alginate-type glutamate receptor subunit 2 (GluK2) encephalitis, is a novel autoimmune encephalitis discovered in 2021. It belongs to the large family of glutamate receptors, along with NMDA and AMPA receptors. GluK2 is a presynaptic regulator of neurotransmitter release, existing in both excitatory and inhibitory synapses. Scholars have found that the clinical manifestations of GluK2 antibody-associated encephalitis are mainly acute cerebellar inflammation, which may be accompanied by extensive MRI T2-FLAIR signal abnormalities, encephalopathy (memory deficits, behavioral changes, and epilepsy), signs of corticospinal tract involvement (hyperreflexia, positive Babinski sign, and ataxic spastic gait), or opsoclonus-myoclonus\u003csup\u003e[6]\u003c/sup\u003e. The patient in this case showed clinical symptoms of involuntary movements and emotional disorder, which was different from the main clinical symptoms of autoimmune encephalitis associated with anti-GluK2 antibodies (cerebellar ataxia), suggesting that anti-GluK2 antibodies may play a role in multiple brain regions, leading to diverse clinical symptoms. It is believed that the basal ganglia and cerebellum are not independent subcortical systems, but form a closely connected network through the cerebral cortex, in which the motor, cognitive and emotional areas of each node are interconnected\u003csup\u003e[7]\u003c/sup\u003e. Research has found that the cerebellum not only plays an important role in motor coordination and balance, but also plays a key role in cognitive and emotional processing \u003csup\u003e[8]\u003c/sup\u003e, Therefore, anti-GluK2 antibodies may cause involuntary movements and emotional disorder by affecting the neural networks in these brain regions. In other words, although the patient in this case did not have typical cerebellar ataxia, it may have affected the neural networks of the cortex-basal ganglia and cortex-cerebellar circuits by affecting the interconnection between the cerebellum and multiple areas of the brain (such as the cerebral cortex and striatum), affecting motor control and emotional regulation, resulting in involuntary movements and mental symptoms.\u003c/p\u003e \u003cp\u003eAlthough there are no reports of anti-Gluk2 antibody-related encephalitis causing involuntary movements and psychiatric symptoms, by reviewing the latest literature, we found some key experimental evidence related to GluK2 and striatal function. Animal studies have found that alginate-type glutamate receptors are abundantly expressed in the basal ganglia. In mice, GluK2 subunits are the main components of the principal projection neurons (SPNs) in the striatum, especially in D1 and D2 type neurons. The axons of these neurons project to the substantia nigra and globus pallidus, and Gluk2 mRNA expression can be detected in these neurons. Chergui et al found that kainate receptors have the potential to have multiple distinct roles in regulating striatal activity and striatal circuit development, and that GluK2 is required for the expression of ionotropic kainate receptor-mediated currents in adult/juvenile mouse SPNs \u003csup\u003e[9]\u003c/sup\u003e. However, a Japanese study found that mice with all GluK1-5 knockouts showed compulsive behavior and hindlimb movement defects, indicating that the function of the striatal circuit had changed, while mice with only Gluk2 knockouts did not show similar changes \u003csup\u003e[10]\u003c/sup\u003e. There is no research on the correlation between the human genome and clinical phenotype of GluK2. Therefore, it is still unclear how GluK2 functions in the human striatal circuit. The patient's serum TBA cerebral cortex immunofluorescence staining was positive, suggesting that anti-Gluk2 antibodies acted on Gluk2 in the cerebral cortex, leading to the psychiatric symptoms shown by this patient. The mechanism is similar to that of NMDAR antibody-mediated autoimmune encephalitis, which may be the internalization and reduction of GluK2 receptors, through initial overactivation \u003csup\u003e[11]\u003c/sup\u003e, receptor isomers and cross-reactions \u003csup\u003e[12]\u003c/sup\u003e. neurotransmitter imbalance \u003csup\u003e[13]\u003c/sup\u003e, immune-mediated neuroinflammation \u003csup\u003e[14]\u003c/sup\u003e. And the compensatory mechanism of the central nervous system \u003csup\u003e[12]\u003c/sup\u003e and other mechanisms act on the cortex to cause cortical excitation symptoms. Shaltiel \u003csup\u003e[15]\u003c/sup\u003e found that in mice, GluK2 plays a unique role in controlling abnormalities associated with behavioral symptoms of mania, such as hyperactivity or psychomotor agitation, aggression, drive or increased goal-directed pursuit, risk-taking, and hypersensitivity to psychostimulants. Knight et al. \u003csup\u003e[16]\u003c/sup\u003e found that alginate receptor gene mutations are closely related to bipolar disorder and schizophrenia in their study of human genes. In addition, although current basic research and clinical reports have not yet fully revealed the specific mechanism of anti-GluK2 antibodies in neurobehavioral regulation, our case suggests its heterogeneity in clinical manifestations. This also emphasizes that future studies need to further explore the specific mechanism of action of anti-GluK2 antibodies in different brain regions to fully understand its role in neurobehavioral regulation. This will provide new directions for the diagnosis and treatment of GluK2-related autoimmune encephalitis.\u003c/p\u003e \u003cp\u003eIn addition, the patient was eventually found to have multiple myeloma, and through targeted treatment of the primary tumor, the patient's GluK2 antibody titers and clinical symptoms significantly improved. Typical signs of multiple myeloma (MM) include bone resorption, elevated blood calcium, renal impairment, anemia, and other organ function impairments. In some cases, neurological symptoms may accompany a diagnosis of MM. The most common type of peripheral neuropathy (7.5%) is caused by metabolic conditions such as myelopathy, hyperviscosity, hypercalcemia, or uremia, which compress the spinal cord and nerve roots (5%) caused by MM pathological fractures\u003csup\u003e[17、18]\u003c/sup\u003e. Yoshiki et al. reported a case of a 37-year-old Japanese woman with orthostatic hypotension who was diagnosed with MM (IgG κ type). Serological tests revealed anti-ganglionic acetylcholine receptor (anti-GAChR) antibodies. This case is extremely rare since MM with neurological symptoms through the septal effect is not typical. The patient was diagnosed with secondary MM-related autoimmune autonomic-gangliopathy. After treatment with anti-MM regimens, her autonomic dysfunction improved, and her anti-GAChR antibody titer decreased to undetectable levels \u003csup\u003e[19]\u003c/sup\u003e. Sisir also reported a case of MM with a shaky gait, which was finally diagnosed as Shy-Drager syndrome \u003csup\u003e[20]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMM is theoretically prone to secondary paraneoplastic syndrome since it is a plasma cell tumor that produces pathogenic antibodies. Nevertheless, the early, rare symptoms it causes might be overlooked in clinical practice. MM is typically diagnosed when it progresses, causing fractures, anemia, kidney damage, or peripheral neuropathy that affects daily living. This case report highlights the importance of considering clonal plasma cell disease in the differential diagnosis whenever a patient experiences neurological symptoms that other causes cannot explain. Simple serum protein electrophoresis and immunofixation electrophoresis can quickly and easily identify these patients, preventing missed or incorrect diagnoses, and enabling patients to receive early diagnosis and treatment.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis case is the first reported instance of GluK2 antibody-associated autoimmune encephalitis with involuntary movement as the first symptom, and it is also the first reported case of multiple myeloma (MM) with this presentation. Although the correlation between MM and the onset of anti-GluK2 antibody-positive autoimmune encephalitis in this case cannot be clearly determined at present, their simultaneous occurrence is indeed rare. Since the VCD treatment regimen used in this case included bortezomib, cyclophosphamide, and dexamethasone, which overlaps with the treatment regimen for autoimmune encephalitis, the clinical outcome of improved treatment of multiple myeloma and decreased GluK2 antibody titers cannot determine the causal relationship between the two. Therefore, in future studies, more in-depth scientific verification such as animal experiments may be needed to explore the potential connection between the two diseases.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCZP, ZSQ and HXR contributed to drafting the manuscript. SXW, XLL and CL contributed to collecting data. ZHL and PX contributed to analyzing the radiological and pathological findings. SY and MSB contributed to critically assessing and revising the manuscript. All the authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe case report complies with all ethics regulations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis case report was reviewed and approved by the Central Hospital of Dalian University of Technology with the approval number: YN2024-120-01.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eChinese Society of Neuroinfectious Diseases and Cerebrospinal Fluid Cytology.Chinese expert consensus on the diagnosis and management of autoimmune encephalitis (2022 edition)[J].Chinese Journal of Neurology,2022,55(09)：931-949.DOI:10.3760/cma.j.cn113694-20220219-00118\u003c/li\u003e\n\u003cli\u003eDalmau J, T\u0026uuml;z\u0026uuml;n E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61(1):25-36. doi:10.1002/ana.21050\u003c/li\u003e\n\u003cli\u003evan de Donk NWCJ, Pawlyn C, Yong KL. Multiple myeloma. Lancet. 2021;397(10272):410-427. doi:10.1016/S0140-6736(21)00135-5\u003c/li\u003e\n\u003cli\u003eGraus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404. doi:10.1016/S1474-4422(15)00401-9\u003c/li\u003e\n\u003cli\u003eAli F, Wijdicks EF. Treatment of Movement Disorder Emergencies in Autoimmune Encephalitis in the Neurosciences ICU. Neurocrit Care. 2020;32(1):286-294. doi:10.1007/s12028-019-00875-5\u003c/li\u003e\n\u003cli\u003eLanda J, Guasp M, M\u0026iacute;guez-Cabello F, et al. Encephalitis with Autoantibodies against the Glutamate Kainate Receptors GluK2. Ann Neurol. 2021;90(1):101-117. doi:10.1002/ana.26098\u003c/li\u003e\n\u003cli\u003eBostan AC. The basal ganglia and the cerebellum: nodes in an integrated network. 2018.\u003c/li\u003e\n\u003cli\u003eCarta I, Chen CH, Schott AL, et al. Cerebellar modulation of the reward circuitry and social behavior. 2019.\u003c/li\u003e\n\u003cli\u003eChergui K, Bouron A, Normand E, Mulle C. Functional GluR6 kainate receptors in the striatum: indirect downregulation of synaptic transmission. J Neurosci. 2000;20(6):2175-2182. doi:10.1523/JNEUROSCI.20-06-02175.2000\u003c/li\u003e\n\u003cli\u003eXu J, Marshall JJ, Fernandes HB, et al. Complete Disruption of the Kainate Receptor Gene Family Results in Corticostriatal Dysfunction in Mice. Cell Rep. 2017;18:1848\u0026ndash;57. doi: 10.1016/j.celrep.2017.01.073\u003c/li\u003e\n\u003cli\u003eLevite, 2014: Levite M. Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren\u0026apos;s syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor\u0026apos;s expression, impair glutamate-induced signaling and function, activate blood brain barrier endothelial cells, kill neurons, damage the brain, induce behavioral/psychiatric/cognitive abnormalities and ataxia in animal models, and can be removed or silenced in some patients by immunotherapy. J Neural Transm (Vienna). 2014;121(8):1029-1075. doi:10.1007/s00702-014-1193-3\u003c/li\u003e\n\u003cli\u003eHaselmann H, Mannara F, Werner C, et al. Human Autoantibodies against the AMPA Receptor Subunit GluA2 Induce Receptor Reorganization and Memory Dysfunction. Neuron. 2018;100(1):91-105.e9. doi:10.1016/j.neuron.2018.07.048\u003c/li\u003e\n\u003cli\u003eTachibana N, Shirakawa T, Ishii K, et al. Expression of various glutamate receptors including N-methyl-D-aspartate receptor (NMDAR) in an ovarian teratoma removed from a young woman with anti-NMDAR encephalitis. Intern Med. 2010;49(19):2167-2173. doi:10.2169/internalmedicine.49.4069\u003c/li\u003e\n\u003cli\u003eYoshio T, Okamoto H, Hirohata S, Minota S. IgG anti-NR2 glutamate receptor autoantibodies from patients with systemic lupus erythematosus activate endothelial cells. \u003cem\u003eArthritis Rheum\u003c/em\u003e. 2013;65(2):457-463. doi:10.1002/art.37745\u003c/li\u003e\n\u003cli\u003eShaltiel G, Maeng S, Malkesman O, et al. Evidence for the involvement of the kainate receptor subunit GluR6 (GRIK2) in mediating behavioral displays related to behavioral symptoms of mania. \u003cem\u003eMol Psychiatry\u003c/em\u003e. 2008;13(9):858-872. doi:10.1038/mp.2008.20\u003c/li\u003e\n\u003cli\u003eKnight HM, Walker R, James R, et al. GRIK4/KA1 protein expression in human brain and correlation with bipolar disorder risk variant status. \u003cem\u003eAm J Med Genet B Neuropsychiatr Genet\u003c/em\u003e. 2012;159B(1):21-29. doi:10.1002/ajmg.b.31248\u003c/li\u003e\n\u003cli\u003eDispenzieri A, Kyle RA. Neurological aspects of multiple myeloma and related disorders. Best Pract Res Clin Haematol. 2005;18(4):673-688. doi:10.1016/j.beha.2005.01.024\u003c/li\u003e\n\u003cli\u003eTathineni P, Cancarevic I, Malik BH. Uncommon Presentations of Multiple Myeloma. Cureus. 2020;12(6):e8400. Published 2020 Jun 1. doi:10.7759/cureus.8400\u003c/li\u003e\n\u003cli\u003eNakae Y, Hyuga M, Terada Y, et al. Multiple Myeloma Presenting with Autoimmune Autonomic Ganglionopathy. Intern Med. 2017;56(24):3347-3351. doi:10.2169/internalmedicine.9096-17\u003c/li\u003e\n\u003cli\u003eGoldstein DS, McRae A, Holmes C, Dalakas MC. Autoimmune autonomic failure in a patient with myeloma-associated Shy-Drager syndrome. Clin Auton Res. 1996;6(1):17-21. doi:10.1007/BF02291401\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Extrapyramidal symptoms multiple myeloma Anti-GluK2 antibody","lastPublishedDoi":"10.21203/rs.3.rs-5372393/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5372393/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eIt is the first reported instance of GluK2 antibody-associated autoimmune encephalitis with involuntary movement.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation \u003c/strong\u003eA 60-year-old woman who experienced involuntary movements of her lower limbs and facial muscle for two years，sometimes accompanied with hysterical shouting. Ater the treatment for multiple myeloma, bone marrow examinations showed that the proportion of myeloma cells have a sustained decline which indicated the treatment worked, meanwhile, all the symptoms disappeared and the concentrations of anti-GluK2 antibody IgG decreased sharply.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions \u003c/strong\u003eThis case revealed that the involuntary movements and the emotion is a new phenotype of Anti-GluK2 Antibody-Positive Autoimmune Encephalitis.\u003c/p\u003e","manuscriptTitle":"Anti-GluK2 Antibody-Positive Autoimmune Encephalitis Concurrent with Multiple Myeloma: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-17 06:34:43","doi":"10.21203/rs.3.rs-5372393/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-27T09:10:15+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-26T23:56:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-23T11:30:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"154613534480980746522757354400273855953","date":"2024-11-23T11:00:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"234787855774508392562013961528321551094","date":"2024-11-21T18:00:17+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-21T16:18:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-13T15:58:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-12T15:34:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2024-11-01T09:38:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a83c787b-6cd8-4cdc-8628-c5f5b36dd9d7","owner":[],"postedDate":"December 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-27T16:04:55+00:00","versionOfRecord":{"articleIdentity":"rs-5372393","link":"https://doi.org/10.1186/s12883-025-04037-3","journal":{"identity":"bmc-neurology","isVorOnly":false,"title":"BMC Neurology"},"publishedOn":"2025-01-20 15:58:20","publishedOnDateReadable":"January 20th, 2025"},"versionCreatedAt":"2024-12-17 06:34:43","video":"","vorDoi":"10.1186/s12883-025-04037-3","vorDoiUrl":"https://doi.org/10.1186/s12883-025-04037-3","workflowStages":[]},"version":"v1","identity":"rs-5372393","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5372393","identity":"rs-5372393","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}