Efficacy of early rituximab treatment in anti-mGluR1 encephalitis: A case report

Efficacy of early rituximab treatment in anti-mGluR1 encephalitis: 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 Efficacy of early rituximab treatment in anti-mGluR1 encephalitis: A case report Kazuki Yamada, Hiroaki Yaguchi, Shuntaro Nakamura, Kazuhiro Horiuchi, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5635966/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Aug, 2025 Read the published version in BMC Neurology → Version 1 posted 10 You are reading this latest preprint version Abstract Background Anti-mGluR1 encephalitis is a form of autoimmune encephalitis, with limited reports globally and only two cases reported from Japan. There are uncertainties regarding the optimal immunosuppressive agents and individual drug responses. Herein, we report a case of anti-mGluR1 encephalitis from Japan, notable for a favorable outcome after an early rituximab initiation and an observed increase in cerebellar blood flow during the early disease stages. Case presentation The patient was a 65-year-old woman who experienced dizziness for 3 months, followed by worsening gait instability. She was referred to our department due to progressive difficulty standing and walking. Neurological examination revealed dysarthria, severe cerebellar ataxia, and impaired performance on the finger-to-nose and knee-to-heel tests. Blood tests were negative for autoantibodies, and cerebrospinal fluid (CSF) analysis showed a cell count of 4/µL and a protein level of 40.0 mg/dL. However, the IgG index was elevated at 1.35, and oligoclonal bands were positive. Brain magnetic resonance imaging showed no abnormalities, but ¹²³I-iodoamphetamine single-photon emission computed tomography revealed mild hyperperfusion in the bilateral cerebellar hemispheres. Based on the clinical presentation, immune-mediated cerebellar ataxia was suspected. The patient was treated with intravenous methylprednisolone, oral prednisolone, and intravenous immunoglobulin. Further diagnostic testing using tissue- and cell-based assays detected mGluR1 antibodies in pretreatment serum and CSF, confirming the diagnosis of anti-mGluR1 encephalitis. As the initial treatment was insufficient, rituximab was administered, leading to significant improvement, including the ability to walk unaided. At the most recent follow-up, > 6 months postonset, she showed no symptom progression or cerebellar atrophy. Conclusions We experienced a case of anti-mGluR1 encephalitis with increased cerebellar blood flow, where early RTX administration led to a favorable outcome. Its early use, as an acute treatment and for maintenance, may help prevent recurrence and contribute to a positive prognosis. anti-mGluR1 encephalitis cerebellar blood flow mGluR1 antibody rituximab Figures Figure 1 Figure 2 Background The metabotropic glutamate receptor 1 (mGluR1) plays a key role in excitatory neurotransmission and synaptic plasticity. It is predominantly expressed on the postsynaptic surface of cerebellar Purkinje cells, as well as in the olfactory bulb, thalamus, ventral tegmental area, and hippocampal glutamatergic synapses ( 1 ). Passive immunization against mGluR1 has been shown to induce ataxic symptoms in mice, and a significant reduction in mGluR1 clusters has been observed in neurons cultured with mGluR1 antibodies. These findings suggest that mGluR1 antibodies act as pathogenic cell surface antigen antibodies ( 2 , 3 ). Smitt et al. first described two cases of cerebellar ataxia associated with Hodgkin lymphoma, identifying them as anti-mGluR1 encephalitis ( 4 ). Since then, additional cases have been reported, contributing to a better understanding of the clinical features of this condition. The median age of onset is 55 years, and while cerebellar ataxia is the primary symptom, patients may also present with psychiatric symptoms, seizures, and dysgeusia. Most patients respond favorably to immunotherapy and achieve a good prognosis, although cases of symptom recurrence or progression despite treatment have been documented ( 3 ). Reports from Japan are exceedingly rare, with only two cases identified in the literature to date ( 5 , 6 ). Globally, the number of reported cases remains limited, leaving many uncertainties regarding the selection of optimal immunosuppressive agents and the therapeutic response to individual drugs. In this study, we report a case of anti-mGluR1 encephalitis with a favorable outcome following the early initiation of rituximab (RTX). This case represents a rare report from Japan and is notable for the observed increase in cerebellar blood flow during the early stages of the disease, contrasting with previous findings. Case presentation The patient was a 65-year-old woman with no medical or family history. She experienced dizziness for 3 months, followed by gradual worsening of gait instability and dysgeusia. Initially diagnosed with benign paroxysmal positional vertigo by a local otolaryngologist, she was referred to our department due to progressive difficulty in standing and walking. Neurological examination revealed dysarthria, severe cerebellar ataxia, and impaired performance on finger-to-nose and knee-to-heel tests, which were predominantly right-sided. However, no nystagmus was observed. She could not stand unassisted or walk even with support, scoring 24 on the Scale for the Assessment and Rating of Ataxia (SARA) and 4 on the modified Rankin Scale (mRS). Although formal taste testing was unavailable, she reported dysgeusia. Blood tests were negative for antinuclear antibody, thyroglobulin antibody, thyroid peroxidase antibody, Sjögren syndrome-A/B antibodies, and myeloperoxidase/proteinase 3-antineutrophil cytoplasmic antibodies. However, glutamic acid decarboxylase (GAD) antibody levels were elevated at 53.5 U/mL, and HbA1c was 7.4%. Cerebrospinal fluid (CSF) analysis revealed a cell count of 4/µL and a protein level of 40.0 mg/dL, both normal, but the IgG index was elevated at 1.35, and oligoclonal bands (OCB) were positive. GAD antibody levels in the CSF were < 5.0 U/mL, below the assay’s sensitivity threshold. She was diagnosed with autoimmune diabetes in adults (LADA); however, the detection of GAD antibodies was unrelated to cerebellar ataxia. Brain MRI showed no abnormalities, but ¹²³I-iodoamphetamine single-photon emission computed tomography (123I-IMP-SPECT) revealed mild hyperperfusion in the bilateral cerebellar hemispheres, more prominent on the right (Fig. 1 ). Comprehensive evaluations, including contrast-enhanced whole-body CT, esophagogastroduodenoscopy, colonoscopy, and breast ultrasonography, showed no malignancy. Based on her presentation, immune-mediated cerebellar ataxia was suspected. Tests for voltage-gated calcium channel antibodies, seizure-related 6 homolog-like 2 antibodies, and onconeuronal antibodies (AMPH, CV2, PNMA2, Ri, Yo, Hu, recoverin, SOX1, titin, zic4, and Tr antibodies) were negative. Although a definitive diagnosis was initially elusive, autoimmune cerebellar ataxia was diagnosed based on her clinical history and test results. She received intravenous methylprednisolone (IVMP) (1000 mg/day) for 3 days, followed by oral prednisolone (PSL) at 40 mg/day with a tapering schedule. The 123I-IMP-SPECT performed immediately after the intravenous administration of methylprednisolone revealed a slight improvement in cerebellar hyperperfusion (Fig. 1 ). Plasma exchange (PEX) was initiated but discontinued after two sessions due to a catheter-related bloodstream infection. Intravenous immunoglobulin (IVIg) (20 g/day) was administered for 5 days. Post-treatment, her SARA score improved to 14.5. Further diagnostic testing, including a tissue-based assay (TBA) using pretreatment CSF, revealed strong immunoreactivity in the cerebellar molecular layer (Fig. 2 ). We investigated mGluR1 antibodies in this patient by a cell-based assay (CBA) using COS7 cells expressing mGluR1. COS7 cells were transfected with the mGluR1 plasmid. Twenty-four hours after the transfection, the cells were incubated with the patient’s serum (diluted 1:50) or CSF (diluted 1:2) for 1 h at 37°C. After washing, the cells were fixed with 2% paraformaldehyde/phosphate buffered saline (PBS) at room temperature for 20 min. After another washing step, the cells were blocked with PBS containing 1% bovine serum albumin (BSA)/PBS at 4°C for 20 min. The fixed cells were incubated with Alexa Fluor 546-conjugated antihuman IgG antibody (diluted 1:1500) at room temperature for 1 h. Images of fluorescence were acquired with a confocal laser scanning microscopy system. Consequently, a CBA detected mGluR1 antibodies in pretreatment serum and CSF (serum 1:200, CSF 1:10), confirming anti-mGluR1 encephalitis. As initial treatments proved insufficient, rituximab (RTX) (560 mg; 375 mg/m 2 ) was administered as second-line therapy weekly for 4 weeks. The use of RTX was approved by the institutional review board of the hospital. Following RTX, she regained the ability to walk unaided, with improvements in her mRS score ( 1 ) and SARA score ( 9 ). An additional movie file shows this in detail (Additional file 1). Dysgeusia also resolved. A follow-up CSF examination showed normalization of the IgG index (0.60), though OCB remained positive. mGluR1 antibody titers were 1:400 in serum and 1:5 in CSF post-treatment. She remains on 5 mg/day of PSL and receives RTX every 6 months. As of the most recent follow-up, > 6 months postonset, she has shown no symptom progression or cerebellar atrophy. We plan to perform annual antibody retests and MRI follow-ups to assess the risk of chronic neurodegeneration. Discussion and conclusions In this study, we report a case of anti-mGluR1 encephalitis treated with rituximab (RTX) as a second-line therapy during the acute phase, resulting in a favorable outcome. Notably, this case is distinctive due to the observed increase in cerebellar blood flow before treatment, contrasting with findings from previous studies. Smitt et al. first reported two cases of anti-mGluR1 encephalitis presenting with cerebellar ataxia associated with Hodgkin lymphoma ( 4 ). To date, fewer than 40 cases have been reported worldwide ( 7 ), with only two cases documented in Japan ( 5 , 6 ). The median age of onset is 55 years, and 47% of patients are female. The primary clinical feature is cerebellar ataxia, reported in 97% of cases, often accompanied by symptoms such as abnormal behavior, cognitive dysfunction, autonomic disturbances, and seizures ( 3 ). Dysgeusia, a distinguishing characteristic compared to other forms of autoimmune encephalitis, was also reported ( 8 ). In this case, the patient experienced dysgeusia alongside cerebellar ataxia, and this symptom resolved following treatment. The patient also had LADA. As reported, 16.7% of patients with anti-mGluR1 encephalitis also have other autoimmune diseases, such as Hashimoto’s disease and Sjögren’s syndrome ( 9 ). Herein, the complication of LADA was an autoimmune disease overlapping with anti-mGluR1 encephalitis and is not accidental. RTX was administered early, in addition to intravenous methylprednisolone (IVMP) and intravenous immunoglobulin (IVIg), leading to a favorable outcome. IVMP, IVIg, and plasma exchange (PEX) are commonly recommended for first-line treatment of autoimmune encephalitis. If there is no response to these treatments, early initiation of second-line therapies, such as RTX or intravenous cyclophosphamide, is recommended ( 10 ). The recommended RTX dosing regimens are either 375 mg/m² per week for 4 weeks or two doses of 1000 mg administered 2 weeks apart ( 10 ). In this case, the former regimen was adopted. Though anti-mGluR1 encephalitis remains rare, there are reports of second-line therapies, including RTX, mycophenolate mofetil, azathioprine, and tacrolimus ( 3 , 9 ). However, the optimal choice of agent remains unclear. Including the present case, we identified 11 reported cases of anti-mGluR1 encephalitis treated with RTX ( 3 , 5 , 8 , 9 , 11 – 13 ). Among these, 9 cases showed clinical improvement, supporting the high efficacy of RTX (Table 1 ). In one case with no improvement, the patient had been initially diagnosed with primary progressive multiple sclerosis and treated with a combination of RTX and bendamustine for concurrent mantle cell lymphoma ( 8 ), which introduced multiple confounding factors in assessing RTX efficacy in anti-mGluR1 encephalitis. Relapses occurred in 4 of the 11 cases. In one, the relapse was successfully suppressed after RTX treatment, and in another, the relapse occurred after RTX discontinuation ( 8 , 11 ). In the case reported by Yoshikura et al., RTX was administered only once, and the relapse occurred > 1 year later, suggesting that insufficient B-cell depletion may have contributed to the relapse ( 5 ). Therefore, the only relapse case where RTX was deemed adequately used was reported by Khojah et al. ( 9 ). A review of 30 cases of anti-mGluR1 encephalitis found 6 relapses ( 3 ), and compared to these figures, RTX appears to have a high potential for reducing relapse risk. Herein, mGluR1 antibodies were persistently positive; however, recurrence was suppressed, potentially due to a mechanism in which rituximab suppresses neuroinflammation by indirectly inhibiting T-cell activity through B-cell-driven T-cell activation ( 10 ). However, cerebellar atrophy progression was observed in nearly half of the cases (5 of 11) during follow-up. Chronic autoantibody production in anti-mGluR1 encephalitis has been linked to irreversible cerebellar atrophy, likely due to Purkinje cell degeneration ( 5 ). Among the three cases where antibody titers were retested after RTX treatment, one showed no reduction in antibody levels, while two showed a decrease, though none achieved seronegativity. In the present case, the antibody remained persistently positive after RTX administration, suggesting the need for ongoing monitoring for potential cerebellar atrophy. Long-term use of RTX may further reduce antibody titers, highlighting the importance of monitoring antibody levels and cerebellar atrophy over time. Only a few studies have reported on cerebellar blood flow before treatment in anti-mGluR1 encephalitis. As mentioned earlier, cerebellar atrophy in anti-mGluR1 encephalitis results from chronic, persistent autoantibody production, and cerebellar blood flow decreases with atrophy progression ( 5 ). Studies have also reported on cerebellar hypometabolism on 18 F-fluoro-2-deoxy-d-glucose positron emission tomography during the acute phase ( 12 ). However, to our knowledge, this is the first report on increasing cerebral blood flow in anti-mGluR1 antibody encephalitis. In contrast, in other autoimmune encephalitides, such as anti-NMDAR encephalitis, increased cerebral blood flow has been observed in the affected area during the acute stage as a temporal change ( 14 ). Similarly, in the present case of anti-mGluR1 encephalitis, an increase in cerebellar blood flow during the acute phase was noted. This increase likely reflects active disease before cell death progresses. Cerebellar ataxia and increased cerebellar blood flow were predominantly right-sided. A slight improvement in cerebellar blood flow was observed immediately after the intravenous administration of methylprednisolone, proposing a mild correlation between increased cerebellar blood flow and clinical symptoms. Thus, with contributed treatment, further improvement in cerebellar blood flow is anticipated. In this case, the early and aggressive treatment, including RTX, during the phase of increased cerebellar blood flow may have contributed to the favorable outcome. In addition, autoimmune encephalitis in the early stages often do not show abnormalities on MRI, and only 37% of patients with anti-mGluR1 encephalitis demonstrate abnormalities on MRI ( 3 ). Yoshikura et al. reported that although MRI findings appeared normal in the early stages, cerebellar atrophy was detected in follow-up MRI after 57 months ( 5 ). Therefore, even if MRI does not reveal abnormalities in the early stage, cerebral blood flow SPECT may detect potential irregularities, as demonstrated in this case, and should be performed proactively. In this study, we present a case of anti-mGluR1 encephalitis with increased cerebellar blood flow, where early administration of RTX led to a favorable outcome. Early use of RTX, as an acute treatment and for maintenance, may help prevent recurrence and contribute to a positive prognosis. Furthermore, accumulating future data on the long-term relationship between antibody production and cerebellar atrophy is crucial. List of abbreviations mGluR1 metabotropic glutamate receptor 1 RTX rituximab SARA Scale for the Assessment and Rating of Ataxia mRS modified Rankin Scale GAD glutamic acid decarboxylase CSF cerebrospinal fluid OCB oligoclonal band MRI magnetic resonance imaging 123 I-IMP-SPECT ¹²³I-iodoamphetamine single-photon emission computed tomography CT computed tomography IVMP intravenous methylprednisolone PSL prednisolone PEX plasma exchange IVIg intravenous immunoglobulin TBA tissue-based assay CBA cell-based assay NMDAR N-methyl-D-aspartate receptor Declarations This case is reported according to CARE guidelines. Ethical Approval and consent to participate Not applicable. Consent for publication Written informed consent was obtained from the patient for publication of this case report. Availability of data and materials Data is provided within the manuscript or supplementary information files. Data supporting additional file 1 is not publicly available in order to protect patient privacy. Competing interests The authors declare that they have no competing interests. Funding Not applicable. Authors’ contributions KY, SN and KH contributed to the evaluation and management of the patient and wrote the manuscript. HY, SF, TN, AK, AT, NY, AK, TS and IY contributed to the measurement of antibodies. All authors reviewed the manuscript. Acknowledgments We would like to thank the patient for her participation in this study. Clinical trial number: not applicable References Pin JP, Duvoisin R. The metabotropic glutamate receptors: structure and functions. Neuropharmacology. 1995;34:1-26. Coesmans M, Sillevis Smitt PA, Linden DJ, Shigemoto R, Hirano T, Yamakawa Y, et al. Mechanisms underlying cerebellar motor deficits due to mGluR1-autoantibodies. Ann Neurol. 2003;53:325-36. Spatola M, Petit Pedrol M, Maudes E, Simabukuro M, Muñiz-Castrillo S, Pinto AL, et al. Clinical features, prognostic factors, and antibody effects in anti-mGluR1 encephalitis. Neurology. 2020;95:E3012-25. Smitt PS, Kinoshita A, De Leeuw B, Moll W, Coesmans M, Jaarsma D, et al. Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med. 2000;342:21-7. Yoshikura N, Kimura A, Fukata M, Fukata Y, Yokoi N, Harada N, et al. Long-term clinical follow-up of a patient with non-paraneoplastic cerebellar ataxia associated with anti-mGluR1 autoantibodies. J Neuroimmunol. 2018;319:63-7. Sakashita K, Nishida K, Takenaka Y, Yokota I, Yamasaki H, Nishimoto K, et al. Favorable outcome with intravenous immunoglobulin therapy in late-onset anti-mGluR1 encephalitis: a case report and literature review. Case Rep Neurol. 2023;14:494-500. Chen X, Chen Y, Di L, Liu N, Liu T, Cai Y, et al. Cerebellar encephalitis associated with anti-mGluR1 antibodies: a case report and comprehensive literature review. Front Neurol. 2024;15:1333658. Lopez-Chiriboga AS, Komorowski L, Kümpfel T, Probst C, Hinson SR, Pittock SJ, et al. Metabotropic glutamate receptor type 1 autoimmunity: clinical features and treatment outcomes. Neurology. 2016;86:1009-13. Khojah O, Makkawi S, Alghamdi S. Anti-mGluR1 encephalitis: case illustration and systematic review. Front Neurol. 2023;14:1142160. Abboud H, Probasco JC, Irani S, Ances B, Benavides DR, Bradshaw M, et al. Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. J Neurol Neurosurg Psychiatry. 2021;92:757-68. Christ M, Müller T, Bien C, Hagen T, Naumann M, Bayas A. Autoimmune encephalitis associated with antibodies against the metabotropic glutamate receptor type 1: case report and review of the literature. Ther Adv Neurol Disord. 2019;12:1756286419847418. Chaumont H, Petit A, Mameri T, Schollhammer R, Honnorat J, Lannuzel A. Successful management of anti-mGluR1 encephalitis with immunosuppressive treatment: dengue virus as a trigger? Mov Disord Clin Pract. 2019;6:727-8. Pedroso JL, Dutra LA, Espay AJ, Höftberger R, Barsottini OGP. Video NeuroImages: head titubation in anti-mGluR1 autoantibody-associated cerebellitis. Neurology. 2018;90:746-7. Kasahara H, Sato M, Nagamine S, Makioka K, Tanaka K, Ikeda Y. Temporal changes on 123I-iomazenil and cerebral blood flow single-photon emission computed tomography in a patient with anti-N-methyl-D-aspartate receptor encephalitis. Intern Med. 2019;58:1501-5. Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx table2.xlsx Additionalfile120MB.mp4 Cite Share Download PDF Status: Published Journal Publication published 04 Aug, 2025 Read the published version in BMC Neurology → Version 1 posted Editorial decision: Revision requested 10 Jun, 2025 Reviews received at journal 09 Jun, 2025 Reviewers agreed at journal 29 May, 2025 Reviewers agreed at journal 19 May, 2025 Reviewers agreed at journal 17 Apr, 2025 Reviews received at journal 28 Mar, 2025 Reviewers agreed at journal 26 Mar, 2025 Reviewers invited by journal 25 Mar, 2025 Submission checks completed at journal 25 Mar, 2025 First submitted to journal 18 Mar, 2025 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. 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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-5635966","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":434239606,"identity":"a98fe172-5365-43f4-ad30-2b54b5f2117d","order_by":0,"name":"Kazuki 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1","display":"","copyAsset":false,"role":"figure","size":1088124,"visible":true,"origin":"","legend":"\u003cp\u003eBrain magnetic resonance imaging and ¹²³I-iodoamphetamine single-photon emission computed tomography (\u003csup\u003e123\u003c/sup\u003eI-IMP-SPECT)\u003c/p\u003e\n\u003cp\u003eBrain MRI revealed no significant abnormalities (A), (B), (C), and (D). Conversely, \u003csup\u003e123\u003c/sup\u003eI-IMP-SPECT demonstrated mild hyperperfusion on bilateral cerebellar hemispheres, more prominent on the right side (E). A slight improvement in cerebellar blood flow was observed immediately after the intravenous administration of methylprednisolone (F).\u003c/p\u003e","description":"","filename":"Figure1revise.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5635966/v1/095fc56253081e297adbc7ee.jpg"},{"id":79330613,"identity":"8ac6b676-221d-487d-a841-0f2f9c2b4a0f","added_by":"auto","created_at":"2025-03-27 06:34:55","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1696680,"visible":true,"origin":"","legend":"\u003cp\u003eTissue-based assay (TBA) of a rat brain frozen section using pretreatment cerebrospinal fluid (CSF)\u003c/p\u003e\n\u003cp\u003e(A) represents immunohistochemical staining using CSF from a healthy control, (B) represents immunohistochemical staining using CSF from the patient, and (C) and (D) show the respective merged images (blue: nuclei). (C) and (D) demonstrated strong immunoreactivity in the cerebellar molecular layer. (E) shows no signs of immunoreactivity to cytoplasmic antigens in Purkinje cells. (F) demonstrated a neuropil pattern in the molecular layer of the hippocampal dentate gyrus; however, the immunoreactivity level was weaker than that in the cerebellar molecular layer.\u003c/p\u003e\n\u003cp\u003eGL, granular cell layer; ML, molecular layer; PL, Purkinje cell layer.\u003c/p\u003e","description":"","filename":"Figure2revise.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5635966/v1/232583e0e20754741cfa7da5.jpg"},{"id":88814130,"identity":"70e9caf6-c3c7-4aa9-a435-01a67e30cc00","added_by":"auto","created_at":"2025-08-11 16:07:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3250486,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5635966/v1/eda812b8-c7a9-43bc-8423-fe8009d81fbe.pdf"},{"id":79330612,"identity":"cbdc2176-6985-4fe8-a98a-07eb720df89c","added_by":"auto","created_at":"2025-03-27 06:34:55","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":22668,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5635966/v1/0387bee15387c5ee2838a9d1.docx"},{"id":79330614,"identity":"03db1e71-e95e-44b1-9ed1-cf6fb7b938a5","added_by":"auto","created_at":"2025-03-27 06:34:55","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":10692,"visible":true,"origin":"","legend":"","description":"","filename":"table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5635966/v1/84a6b6489617e217ae6c3fc9.xlsx"},{"id":79330637,"identity":"0226d20e-2874-48da-9987-586b5e01aa85","added_by":"auto","created_at":"2025-03-27 06:34:56","extension":"mp4","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":16732852,"visible":true,"origin":"","legend":"","description":"","filename":"Additionalfile120MB.mp4","url":"https://assets-eu.researchsquare.com/files/rs-5635966/v1/548bf5fa5bf3857984f72182.mp4"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy of early rituximab treatment in anti-mGluR1 encephalitis: A case report","fulltext":[{"header":"Background","content":"\u003cp\u003eThe metabotropic glutamate receptor 1 (mGluR1) plays a key role in excitatory neurotransmission and synaptic plasticity. It is predominantly expressed on the postsynaptic surface of cerebellar Purkinje cells, as well as in the olfactory bulb, thalamus, ventral tegmental area, and hippocampal glutamatergic synapses (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Passive immunization against mGluR1 has been shown to induce ataxic symptoms in mice, and a significant reduction in mGluR1 clusters has been observed in neurons cultured with mGluR1 antibodies. These findings suggest that mGluR1 antibodies act as pathogenic cell surface antigen antibodies (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Smitt et al. first described two cases of cerebellar ataxia associated with Hodgkin lymphoma, identifying them as anti-mGluR1 encephalitis (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Since then, additional cases have been reported, contributing to a better understanding of the clinical features of this condition. The median age of onset is 55 years, and while cerebellar ataxia is the primary symptom, patients may also present with psychiatric symptoms, seizures, and dysgeusia. Most patients respond favorably to immunotherapy and achieve a good prognosis, although cases of symptom recurrence or progression despite treatment have been documented (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Reports from Japan are exceedingly rare, with only two cases identified in the literature to date (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Globally, the number of reported cases remains limited, leaving many uncertainties regarding the selection of optimal immunosuppressive agents and the therapeutic response to individual drugs. In this study, we report a case of anti-mGluR1 encephalitis with a favorable outcome following the early initiation of rituximab (RTX). This case represents a rare report from Japan and is notable for the observed increase in cerebellar blood flow during the early stages of the disease, contrasting with previous findings.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eThe patient was a 65-year-old woman with no medical or family history. She experienced dizziness for 3 months, followed by gradual worsening of gait instability and dysgeusia. Initially diagnosed with benign paroxysmal positional vertigo by a local otolaryngologist, she was referred to our department due to progressive difficulty in standing and walking. Neurological examination revealed dysarthria, severe cerebellar ataxia, and impaired performance on finger-to-nose and knee-to-heel tests, which were predominantly right-sided. However, no nystagmus was observed. She could not stand unassisted or walk even with support, scoring 24 on the Scale for the Assessment and Rating of Ataxia (SARA) and 4 on the modified Rankin Scale (mRS). Although formal taste testing was unavailable, she reported dysgeusia.\u003c/p\u003e \u003cp\u003eBlood tests were negative for antinuclear antibody, thyroglobulin antibody, thyroid peroxidase antibody, Sjögren syndrome-A/B antibodies, and myeloperoxidase/proteinase 3-antineutrophil cytoplasmic antibodies. However, glutamic acid decarboxylase (GAD) antibody levels were elevated at 53.5 U/mL, and HbA1c was 7.4%. Cerebrospinal fluid (CSF) analysis revealed a cell count of 4/µL and a protein level of 40.0 mg/dL, both normal, but the IgG index was elevated at 1.35, and oligoclonal bands (OCB) were positive. GAD antibody levels in the CSF were \u0026lt; 5.0 U/mL, below the assay’s sensitivity threshold. She was diagnosed with autoimmune diabetes in adults (LADA); however, the detection of GAD antibodies was unrelated to cerebellar ataxia. Brain MRI showed no abnormalities, but ¹²³I-iodoamphetamine single-photon emission computed tomography (123I-IMP-SPECT) revealed mild hyperperfusion in the bilateral cerebellar hemispheres, more prominent on the right (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Comprehensive evaluations, including contrast-enhanced whole-body CT, esophagogastroduodenoscopy, colonoscopy, and breast ultrasonography, showed no malignancy.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBased on her presentation, immune-mediated cerebellar ataxia was suspected. Tests for voltage-gated calcium channel antibodies, seizure-related 6 homolog-like 2 antibodies, and onconeuronal antibodies (AMPH, CV2, PNMA2, Ri, Yo, Hu, recoverin, SOX1, titin, zic4, and Tr antibodies) were negative. Although a definitive diagnosis was initially elusive, autoimmune cerebellar ataxia was diagnosed based on her clinical history and test results. She received intravenous methylprednisolone (IVMP) (1000 mg/day) for 3 days, followed by oral prednisolone (PSL) at 40 mg/day with a tapering schedule. The 123I-IMP-SPECT performed immediately after the intravenous administration of methylprednisolone revealed a slight improvement in cerebellar hyperperfusion (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Plasma exchange (PEX) was initiated but discontinued after two sessions due to a catheter-related bloodstream infection. Intravenous immunoglobulin (IVIg) (20 g/day) was administered for 5 days. Post-treatment, her SARA score improved to 14.5.\u003c/p\u003e \u003cp\u003eFurther diagnostic testing, including a tissue-based assay (TBA) using pretreatment CSF, revealed strong immunoreactivity in the cerebellar molecular layer (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). We investigated mGluR1 antibodies in this patient by a cell-based assay (CBA) using COS7 cells expressing mGluR1. COS7 cells were transfected with the mGluR1 plasmid. Twenty-four hours after the transfection, the cells were incubated with the patient’s serum (diluted 1:50) or CSF (diluted 1:2) for 1 h at 37°C. After washing, the cells were fixed with 2% paraformaldehyde/phosphate buffered saline (PBS) at room temperature for 20 min. After another washing step, the cells were blocked with PBS containing 1% bovine serum albumin (BSA)/PBS at 4°C for 20 min. The fixed cells were incubated with Alexa Fluor 546-conjugated antihuman IgG antibody (diluted 1:1500) at room temperature for 1 h. Images of fluorescence were acquired with a confocal laser scanning microscopy system. Consequently, a CBA detected mGluR1 antibodies in pretreatment serum and CSF (serum 1:200, CSF 1:10), confirming anti-mGluR1 encephalitis. As initial treatments proved insufficient, rituximab (RTX) (560 mg; 375 mg/m\u003csup\u003e2\u003c/sup\u003e) was administered as second-line therapy weekly for 4 weeks. The use of RTX was approved by the institutional review board of the hospital. Following RTX, she regained the ability to walk unaided, with improvements in her mRS score (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) and SARA score (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). An additional movie file shows this in detail (Additional file 1). Dysgeusia also resolved. A follow-up CSF examination showed normalization of the IgG index (0.60), though OCB remained positive. mGluR1 antibody titers were 1:400 in serum and 1:5 in CSF post-treatment.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eShe remains on 5 mg/day of PSL and receives RTX every 6 months. As of the most recent follow-up, \u0026gt; 6 months postonset, she has shown no symptom progression or cerebellar atrophy. We plan to perform annual antibody retests and MRI follow-ups to assess the risk of chronic neurodegeneration.\u003c/p\u003e "},{"header":"Discussion and conclusions","content":"\u003cp\u003eIn this study, we report a case of anti-mGluR1 encephalitis treated with rituximab (RTX) as a second-line therapy during the acute phase, resulting in a favorable outcome. Notably, this case is distinctive due to the observed increase in cerebellar blood flow before treatment, contrasting with findings from previous studies.\u003c/p\u003e\u003cp\u003eSmitt et al. first reported two cases of anti-mGluR1 encephalitis presenting with cerebellar ataxia associated with Hodgkin lymphoma (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). To date, fewer than 40 cases have been reported worldwide (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), with only two cases documented in Japan (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The median age of onset is 55 years, and 47% of patients are female. The primary clinical feature is cerebellar ataxia, reported in 97% of cases, often accompanied by symptoms such as abnormal behavior, cognitive dysfunction, autonomic disturbances, and seizures (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Dysgeusia, a distinguishing characteristic compared to other forms of autoimmune encephalitis, was also reported (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). In this case, the patient experienced dysgeusia alongside cerebellar ataxia, and this symptom resolved following treatment. The patient also had LADA. As reported, 16.7% of patients with anti-mGluR1 encephalitis also have other autoimmune diseases, such as Hashimoto’s disease and Sjögren’s syndrome (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Herein, the complication of LADA was an autoimmune disease overlapping with anti-mGluR1 encephalitis and is not accidental.\u003c/p\u003e\u003cp\u003eRTX was administered early, in addition to intravenous methylprednisolone (IVMP) and intravenous immunoglobulin (IVIg), leading to a favorable outcome. IVMP, IVIg, and plasma exchange (PEX) are commonly recommended for first-line treatment of autoimmune encephalitis. If there is no response to these treatments, early initiation of second-line therapies, such as RTX or intravenous cyclophosphamide, is recommended (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The recommended RTX dosing regimens are either 375 mg/m² per week for 4 weeks or two doses of 1000 mg administered 2 weeks apart (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). In this case, the former regimen was adopted. Though anti-mGluR1 encephalitis remains rare, there are reports of second-line therapies, including RTX, mycophenolate mofetil, azathioprine, and tacrolimus (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). However, the optimal choice of agent remains unclear. Including the present case, we identified 11 reported cases of anti-mGluR1 encephalitis treated with RTX (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e–\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Among these, 9 cases showed clinical improvement, supporting the high efficacy of RTX (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In one case with no improvement, the patient had been initially diagnosed with primary progressive multiple sclerosis and treated with a combination of RTX and bendamustine for concurrent mantle cell lymphoma (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), which introduced multiple confounding factors in assessing RTX efficacy in anti-mGluR1 encephalitis.\u003c/p\u003e\u003cp\u003eRelapses occurred in 4 of the 11 cases. In one, the relapse was successfully suppressed after RTX treatment, and in another, the relapse occurred after RTX discontinuation (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). In the case reported by Yoshikura et al., RTX was administered only once, and the relapse occurred \u0026gt; 1 year later, suggesting that insufficient B-cell depletion may have contributed to the relapse (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Therefore, the only relapse case where RTX was deemed adequately used was reported by Khojah et al. (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). A review of 30 cases of anti-mGluR1 encephalitis found 6 relapses (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), and compared to these figures, RTX appears to have a high potential for reducing relapse risk. Herein, mGluR1 antibodies were persistently positive; however, recurrence was suppressed, potentially due to a mechanism in which rituximab suppresses neuroinflammation by indirectly inhibiting T-cell activity through B-cell-driven T-cell activation (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). However, cerebellar atrophy progression was observed in nearly half of the cases (5 of 11) during follow-up. Chronic autoantibody production in anti-mGluR1 encephalitis has been linked to irreversible cerebellar atrophy, likely due to Purkinje cell degeneration (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Among the three cases where antibody titers were retested after RTX treatment, one showed no reduction in antibody levels, while two showed a decrease, though none achieved seronegativity. In the present case, the antibody remained persistently positive after RTX administration, suggesting the need for ongoing monitoring for potential cerebellar atrophy. Long-term use of RTX may further reduce antibody titers, highlighting the importance of monitoring antibody levels and cerebellar atrophy over time.\u003c/p\u003e\u003cp\u003eOnly a few studies have reported on cerebellar blood flow before treatment in anti-mGluR1 encephalitis. As mentioned earlier, cerebellar atrophy in anti-mGluR1 encephalitis results from chronic, persistent autoantibody production, and cerebellar blood flow decreases with atrophy progression (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Studies have also reported on cerebellar hypometabolism on \u003csup\u003e18\u003c/sup\u003eF-fluoro-2-deoxy-d-glucose positron emission tomography during the acute phase (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). However, to our knowledge, this is the first report on increasing cerebral blood flow in anti-mGluR1 antibody encephalitis. In contrast, in other autoimmune encephalitides, such as anti-NMDAR encephalitis, increased cerebral blood flow has been observed in the affected area during the acute stage as a temporal change (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Similarly, in the present case of anti-mGluR1 encephalitis, an increase in cerebellar blood flow during the acute phase was noted. This increase likely reflects active disease before cell death progresses. Cerebellar ataxia and increased cerebellar blood flow were predominantly right-sided. A slight improvement in cerebellar blood flow was observed immediately after the intravenous administration of methylprednisolone, proposing a mild correlation between increased cerebellar blood flow and clinical symptoms. Thus, with contributed treatment, further improvement in cerebellar blood flow is anticipated. In this case, the early and aggressive treatment, including RTX, during the phase of increased cerebellar blood flow may have contributed to the favorable outcome.\u003c/p\u003e\u003cp\u003eIn addition, autoimmune encephalitis in the early stages often do not show abnormalities on MRI, and only 37% of patients with anti-mGluR1 encephalitis demonstrate abnormalities on MRI (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Yoshikura et al. reported that although MRI findings appeared normal in the early stages, cerebellar atrophy was detected in follow-up MRI after 57 months (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Therefore, even if MRI does not reveal abnormalities in the early stage, cerebral blood flow SPECT may detect potential irregularities, as demonstrated in this case, and should be performed proactively.\u003c/p\u003e\u003cp\u003eIn this study, we present a case of anti-mGluR1 encephalitis with increased cerebellar blood flow, where early administration of RTX led to a favorable outcome. Early use of RTX, as an acute treatment and for maintenance, may help prevent recurrence and contribute to a positive prognosis. Furthermore, accumulating future data on the long-term relationship between antibody production and cerebellar atrophy is crucial.\u003c/p\u003e"},{"header":"List of abbreviations","content":"\u003cp\u003emGluR1 metabotropic glutamate receptor 1\u003c/p\u003e \u003cp\u003eRTX rituximab\u003c/p\u003e \u003cp\u003eSARA Scale for the Assessment and Rating of Ataxia\u003c/p\u003e \u003cp\u003emRS modified Rankin Scale\u003c/p\u003e \u003cp\u003eGAD glutamic acid decarboxylase\u003c/p\u003e \u003cp\u003eCSF cerebrospinal fluid\u003c/p\u003e \u003cp\u003eOCB oligoclonal band\u003c/p\u003e \u003cp\u003eMRI magnetic resonance imaging\u003c/p\u003e \u003cp\u003e \u003csup\u003e123\u003c/sup\u003eI-IMP-SPECT \u0026sup1;\u0026sup2;\u0026sup3;I-iodoamphetamine single-photon emission computed tomography\u003c/p\u003e \u003cp\u003eCT computed tomography\u003c/p\u003e \u003cp\u003eIVMP intravenous methylprednisolone\u003c/p\u003e \u003cp\u003ePSL prednisolone\u003c/p\u003e \u003cp\u003ePEX plasma exchange\u003c/p\u003e \u003cp\u003eIVIg intravenous immunoglobulin\u003c/p\u003e \u003cp\u003eTBA tissue-based assay\u003c/p\u003e \u003cp\u003eCBA cell-based assay\u003c/p\u003e \u003cp\u003eNMDAR N-methyl-D-aspartate receptor\u003c/p\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThis case is reported according to CARE guidelines.\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eEthical Approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData is provided within the manuscript or supplementary information files. Data supporting additional file 1 is not publicly available in order to protect patient privacy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKY, SN and KH contributed to the evaluation and management of the patient and wrote the manuscript. HY, SF, TN, AK, AT, NY, AK, TS and IY contributed to the measurement of antibodies. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank the patient for her participation in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u0026nbsp;\u003c/strong\u003enot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePin JP, Duvoisin R. The metabotropic glutamate receptors: structure and functions. Neuropharmacology. 1995;34:1-26.\u003c/li\u003e\n\u003cli\u003eCoesmans M, Sillevis Smitt PA, Linden DJ, Shigemoto R, Hirano T, Yamakawa Y, et al. Mechanisms underlying cerebellar motor deficits due to mGluR1-autoantibodies. Ann Neurol. 2003;53:325-36.\u003c/li\u003e\n\u003cli\u003eSpatola M, Petit Pedrol M, Maudes E, Simabukuro M, Mu\u0026ntilde;iz-Castrillo S, Pinto AL, et al. Clinical features, prognostic factors, and antibody effects in anti-mGluR1 encephalitis. 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Front Neurol. 2024;15:1333658.\u003c/li\u003e\n\u003cli\u003eLopez-Chiriboga AS, Komorowski L, K\u0026uuml;mpfel T, Probst C, Hinson SR, Pittock SJ, et al. Metabotropic glutamate receptor type 1 autoimmunity: clinical features and treatment outcomes. Neurology. 2016;86:1009-13.\u003c/li\u003e\n\u003cli\u003eKhojah O, Makkawi S, Alghamdi S. Anti-mGluR1 encephalitis: case illustration and systematic review. Front Neurol. 2023;14:1142160.\u003c/li\u003e\n\u003cli\u003eAbboud H, Probasco JC, Irani S, Ances B, Benavides DR, Bradshaw M, et al. Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. J Neurol Neurosurg Psychiatry. 2021;92:757-68.\u003c/li\u003e\n\u003cli\u003eChrist M, M\u0026uuml;ller T, Bien C, Hagen T, Naumann M, Bayas A. Autoimmune encephalitis associated with antibodies against the metabotropic glutamate receptor type 1: case report and review of the literature. Ther Adv Neurol Disord. 2019;12:1756286419847418.\u003c/li\u003e\n\u003cli\u003eChaumont H, Petit A, Mameri T, Schollhammer R, Honnorat J, Lannuzel A. Successful management of anti-mGluR1 encephalitis with immunosuppressive treatment: dengue virus as a trigger? Mov Disord Clin Pract. 2019;6:727-8.\u003c/li\u003e\n\u003cli\u003ePedroso JL, Dutra LA, Espay AJ, H\u0026ouml;ftberger R, Barsottini OGP. Video NeuroImages: head titubation in anti-mGluR1 autoantibody-associated cerebellitis. Neurology. 2018;90:746-7.\u003c/li\u003e\n\u003cli\u003eKasahara H, Sato M, Nagamine S, Makioka K, Tanaka K, Ikeda Y. Temporal changes on 123I-iomazenil and cerebral blood flow single-photon emission computed tomography in a patient with anti-N-methyl-D-aspartate receptor encephalitis. Intern Med. 2019;58:1501-5.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\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":"anti-mGluR1 encephalitis, cerebellar blood flow, mGluR1 antibody, rituximab","lastPublishedDoi":"10.21203/rs.3.rs-5635966/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5635966/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e \u003cb\u003eBackground\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAnti-mGluR1 encephalitis is a form of autoimmune encephalitis, with limited reports globally and only two cases reported from Japan. There are uncertainties regarding the optimal immunosuppressive agents and individual drug responses. Herein, we report a case of anti-mGluR1 encephalitis from Japan, notable for a favorable outcome after an early rituximab initiation and an observed increase in cerebellar blood flow during the early disease stages.\u003c/p\u003e \u003cp\u003e \u003cb\u003eCase presentation\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe patient was a 65-year-old woman who experienced dizziness for 3 months, followed by worsening gait instability. She was referred to our department due to progressive difficulty standing and walking. Neurological examination revealed dysarthria, severe cerebellar ataxia, and impaired performance on the finger-to-nose and knee-to-heel tests. Blood tests were negative for autoantibodies, and cerebrospinal fluid (CSF) analysis showed a cell count of 4/\u0026micro;L and a protein level of 40.0 mg/dL. However, the IgG index was elevated at 1.35, and oligoclonal bands were positive. Brain magnetic resonance imaging showed no abnormalities, but \u0026sup1;\u0026sup2;\u0026sup3;I-iodoamphetamine single-photon emission computed tomography revealed mild hyperperfusion in the bilateral cerebellar hemispheres.\u003c/p\u003e \u003cp\u003eBased on the clinical presentation, immune-mediated cerebellar ataxia was suspected. The patient was treated with intravenous methylprednisolone, oral prednisolone, and intravenous immunoglobulin. Further diagnostic testing using tissue- and cell-based assays detected mGluR1 antibodies in pretreatment serum and CSF, confirming the diagnosis of anti-mGluR1 encephalitis. As the initial treatment was insufficient, rituximab was administered, leading to significant improvement, including the ability to walk unaided. At the most recent follow-up, \u0026gt;\u0026thinsp;6 months postonset, she showed no symptom progression or cerebellar atrophy.\u003c/p\u003e \u003cp\u003e \u003cb\u003eConclusions\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWe experienced a case of anti-mGluR1 encephalitis with increased cerebellar blood flow, where early RTX administration led to a favorable outcome. Its early use, as an acute treatment and for maintenance, may help prevent recurrence and contribute to a positive prognosis.\u003c/p\u003e","manuscriptTitle":"Efficacy of early rituximab treatment in anti-mGluR1 encephalitis: A case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-27 06:34:50","doi":"10.21203/rs.3.rs-5635966/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-10T17:08:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-09T18:08:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"152650553848039790325713369485129442431","date":"2025-05-29T08:32:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"292909407259211657367866740413611347959","date":"2025-05-19T15:32:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"83012243819543730483578105720162745273","date":"2025-04-17T23:58:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-28T14:10:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"36458785580803110895151066230084401548","date":"2025-03-26T10:26:59+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-26T03:03:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-26T02:48:19+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2025-03-18T07:59:11+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":"2227cabc-f569-4d97-bc39-050ee05acb23","owner":[],"postedDate":"March 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-11T16:00:53+00:00","versionOfRecord":{"articleIdentity":"rs-5635966","link":"https://doi.org/10.1186/s12883-025-04345-8","journal":{"identity":"bmc-neurology","isVorOnly":false,"title":"BMC Neurology"},"publishedOn":"2025-08-04 15:57:25","publishedOnDateReadable":"August 4th, 2025"},"versionCreatedAt":"2025-03-27 06:34:50","video":"","vorDoi":"10.1186/s12883-025-04345-8","vorDoiUrl":"https://doi.org/10.1186/s12883-025-04345-8","workflowStages":[]},"version":"v1","identity":"rs-5635966","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5635966","identity":"rs-5635966","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}