Kikuchi disease-associated Mollaret meningitis with MEFV gene mutation successfully treated with colchicine

Kikuchi disease-associated Mollaret meningitis with MEFV gene mutation successfully treated with colchicine | 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 Kikuchi disease-associated Mollaret meningitis with MEFV gene mutation successfully treated with colchicine Hideo Handa, Atsuhiko Sugiyama, Hitoshi Kubosawa, Yuki Nakagawa, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4648915/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Nov, 2024 Read the published version in BMC Neurology → Version 1 posted 12 You are reading this latest preprint version Abstract Background: This case report aims to present a case of Mollaret meningitis caused by Kikuchi disease, an uncommon benign inflammatory disorder, thereby highlighting a novel etiology for Mollaret meningitis. Additionally, it discusses colchicine as a new potential treatment option for Kikuchi disease. Case presentation: A 41-year-old Japanese woman presented with fever and headache. She had nuchal rigidity and bilateral cervical lymphadenopathies. Her past medical history included multiple episodes of aseptic meningitis and cervical lymphadenopathy for more than twenty years. Lumbar puncture showed increased lymphocytes and IL-6 level and pathognomonic Mollaret cells. Excisional lymph node biopsy revealed histiocytic necrotizing lymphadenitis, confirming the diagnosis of Kikuchi disease. Subsequently, her recurrent Kikuchi disease was successfully treated with colchicine. Furthermore, genetic analysis of the MEFV gene revealed heterozygous P369S/R408Q mutation in exon 3. Conclusion: Mollaret meningitis can be caused by Kikuchi disease, and recurrence of both may be suppressed by colchicine. Kikuchi disease MEFV Familial Mediterranean fever (FMF) Colchicine Figures Figure 1 Figure 2 Background Mollaret meningitis is a rare neurological disorder that is characterized by recurrent episodes of aseptic meningitis and the presence of pathognomonic Mollaret cells, which are thought to be abnormal monocytes and are marked by large basophilic and cleaved nuclei, resembling a clover leaf 1 . Mollaret meningitis is caused by herpes simplex virus type 2 (HSV-2), systemic lupus erythematous and, familial Mediterranean fever (FMF) 2 . Kikuchi disease is a systemic inflammatory disorder, which mainly affects Asian populations 3 . Its main manifestations are fever and cervical lymphadenopathy. Although Kikuchi disease has been reported to be accompanied by recurrent aseptic meningitis 4 , no Mollaret cells have ever been identified in the cerebrospinal fluid (CSF). The diagnosis of Kikuchi disease is based on the pathologic findings of histiocytic necrotizing lymphadenitis on excisional lymph node biopsy. It can resolve spontaneously but often recur, which can be suppressed by corticosteroid treatment 5 . However, given that prolonged corticosteroid treatment causes a variety of side effects, including osteoporosis and diabetes, a corticosteroid-sparing agent has been sought 6 . Here, we report the first case of Mollaret meningitis that was caused by Kikuchi disease and associated with MEFV gene mutation. Moreover, this case demonstrated the efficacy of colchicine in suppressing the recurrence of Kikuchi disease. Case presentation A 41-year-old Japanese woman came to our hospital because of fever and headache. Her past medical history was significant for 21 years of recurrent aseptic meningitis, which was often accompanied by cervical lymphadenopathy and with each episode lasting for 3–7 days. Although the aseptic meningitis and cervical lymphadenopathy were always responsive to prednisolone 15–20 mg per day, these recurred whenever the prednisolone dose was tapered. She had these recurrent episodes approximately every 6 months. Her vital signs were remarkable only for high fever. Physical examination revealed nuchal rigidity and bilateral multiple tender cervical lymphadenopathies. Laboratory tests showed decreased white blood cell count of 2520/µL and a normal C-reactive protein level of 0.10 mg/dL. Antinuclear antibody test was negative. CSF analysis revealed mildly increased lymphocyte count (14 cells/µL), normal protein (40 mg/dL), increased IL-6 level (280 pg/mL), positive oligoclonal bands, and characteristic Mollaret cells (Fig. 1 ). Histologic evaluation of the anterior cervical lymph node biopsy specimen revealed histiocytic necrotizing lymphadenitis (Fig. 2 ). Her clinical course and pathologic findings confirmed the diagnosis of Mollaret meningitis caused by Kikuchi disease. In addition, there were no serum IgM and IgG antibodies for HSV. Genetic analysis of the MEFV gene detected heterozygous P369S/R408Q mutations in exon 3. Her fever, headache, and cervical lymphadenopathy improved with NSAIDs. Based on the failure of prolonged corticosteroid therapy to manage her recurrent aseptic meningitis, we initiated colchicine and gradually increased the colchicine dose from 0.5 mg/day to 1.5 mg/day. Although she had another episode of aseptic meningitis on a colchicine dose of 1.0 mg/day, there was no recurrence of both meningitis and lymphadenopathies under a colchicine dose of 1.5 mg/day over a follow-up period of one and a half years. Discussion and Conclusions The current report described a case of Kikuchi disease-associated Mollaret meningitis with MEFV gene mutation, which was successfully treated with colchicine. This case of recurrent aseptic meningitis fulfilled the diagnostic criteria reported by Bruyn et al 1 and demonstrated the presence of Mollaret cells in the CSF. The lymphadenopathies, which often accompanied the meningitis, was confirmed by biopsy as Kikuchi disease, which was presumed to be the cause of Mollaret meningitis. We found out two new important clinical issues. First, Mollaret meningitis can be caused by Kikuchi disease. Although Kikuchi disease had been reported to cause recurrent episodes of aseptic meningitis 4 , there had been no previous reports on Kikuchi disease-associated recurrent meningitis, in which Mollaret cells were identified in the CSF. Clinicians should consider Kikuchi disease as one of the possible causative diseases of Mollaret meningitis and the necessity of excisional lymph node biopsy in a patient with recurrent meningitis and lymphadenopathy. Second, colchicine may inhibit the recurrence of Kikuchi disease, as well as Mollaret meningitis. In this case, the recurrence of both lymphadenopathy and meningitis was suppressed after starting colchicine. In general, an acute episode of Kikuchi disease is managed with NSAIDs or corticosteroids; to prevent recurrence, corticosteroid is used for a long period 5 . Some case reports showed that hydroxychloroquine and anakinra were effective for Kikuchi disease 6 , 7 , despite their risk of retinopathy and expensiveness. To our best knowledge, there had been no research that demonstrated the benefits of colchicine for the management of Kikuchi disease. Our case indicated that colchicine can be a safe and inexpensive corticosteroid-sparing agent for the prevention of recurrent Kikuchi disease. The effectiveness of colchicine for the treatment of Kikuchi disease should be further examined in a large-scale study. The clinical effectiveness of colchicine on Kikuchi disease can be explained by its activity to suppress the inflammasome signaling. Previous reports demonstrated that colchicine inhibits the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which senses pathogen-associated molecular patterns and triggers the secretion of IL1 and IL18 8 . Therefore, colchicine decreases the levels of IL1, IL6, and IL18, which were reported to contribute to the pathogenesis of Kikuchi disease 3 , 7 . These reports suggested that colchicine can prevent the recurrence of Kikuchi disease through inactivation of NLRP3 and cytokines. The presence of MEFV gene mutation may underlie the chronic recurrent inflammation that is observed not only in FMF but also in Kikuchi disease and Mollaret meningitis. This case of recurrent Kikuchi disease and Mollaret meningitis was found to have the P369S/R408Q mutation in the MEFV gene; both of these conditions were successfully treated with colchicine. Previous studies have shown that P369S/R408Q mutation was associated with atypical presentations of FMF and was detected in a patient with Kikuchi disease 9 , 10 . However, the pathological significance of P369S/R408Q mutation in the MEFV gene remains unclear 10 . Further research is needed to elucidate the association between MEFV gene mutations and Kikuchi disease, as well as the pathological role of P369S/R408Q mutation. In conclusion, Mollaret meningitis can be caused by Kikuchi disease, and recurrence of both might be suppressed by colchicine. Abbreviations Abbreviation Definition HSV-2 Herpes simplex virus type 2 FMF Familial Mediterranean fever (FMF) CSF Cerebrospinal fluid NSAIDs Non-Steroidal Anti-Inflammatory Drugs NLRP3 Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 Declarations Ethics approval and consent to participate: Not applicable. Consent for publication: Written informed consent for publication of the clinical details was obtained from the patient. Availability of data and materials: Not applicable. Competing interests: The authors declare that all authors have no competing interests. Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Authors’ contributions: All authors had roles in writing this manuscript. HH and AS wrote the main manuscript text. HH, AS, and HK prepared Figures 1 and 2. HK, YN, DK, AU, AA, and SK supervised the main manuscript. HH, AS, NY, AU, AA, and SK participated in the care of this patient. HK performed the pathologic diagnosis. DK conducted the MEFV gene analysis. All authors read and approved the final manuscript. Acknowledgements: None. References Bruyn GW, Straathof LJ, Raymakers GM. Mollaret’s meningitis. Differential diagnosis and diagnostic pitfalls. Neurology. 1962;12:745–53. 10.1212/wnl.12.11.745 . Edi VM, Rao P, Igo JO, et al. Mollaret’s syndrome: A case report. Cureus. 2023;15(5):e38559. 10.7759/cureus.38559 . Mahajan VK, Sharma V, Sharma N, Rani R. Kikuchi-Fujimoto disease: A comprehensive review. World J Clin Cases. 2023;11(16):3664–79. 10.12998/wjcc.v11.i16.3664 . Sekiguchi S, Yamamoto Y, Hatakeyama S, Matsumura M. Recurrent aseptic meningitis associated with Kikuchi’s disease (histiocytic necrotizing lymphadenitis): A case report and literature review. Intern Med. 2021;60(11):1779–84. 10.2169/internalmedicine.6494-20 . Jang YJ, Park KH, Seok HJ. Management of Kikuchi’s disease using glucocorticoid. J Laryngol Otol. 2000;114(9):709–11. 10.1258/0022215001906561 . Hyun M, So IT, Kim HA, Jung H, Ryu SY. Recurrent Kikuchi’s disease treated by hydroxychloroquine. Infect Chemother. 2016;48(2):127–31. 10.3947/ic.2016.48.2.127 . Faheem B, Kumar V, Ashkar H, Komal F, Sultana Y. Recurrent Kikuchi-Fujimoto disease masquerading as lymphoma successfully treated by anakinra. Cureus. 2020;12(11):e11655. 10.7759/cureus.11655 . Paik S, Kim JK, Silwal P, Sasakawa C, Jo EK. An update on the regulatory mechanisms of NLRP3 inflammasome activation. Cell Mol Immunol. 2021;18(5):1141–60. 10.1038/s41423-021-00670-3 . Epub 2021 Apr 13. Yamamura Y, Furuichi K, Toyama T, et al. Repeated necrotizing lymphadenitis with MEFV gene mutations. Intern Med. 2022;61(7):1105–10. 10.2169/internalmedicine.7882-21 . Ryan JG, Masters SL, Booty MG, et al. Clinical features and functional significance of the P369S/R408Q variant in pyrin, the familial Mediterranean fever protein. Ann Rheum Dis. 2010;69(7):1383–8. 10.1136/ard.2009.113415 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 14 Nov, 2024 Read the published version in BMC Neurology → Version 1 posted Editorial decision: Revision requested 16 Oct, 2024 Reviews received at journal 09 Oct, 2024 Reviews received at journal 07 Oct, 2024 Reviewers agreed at journal 02 Oct, 2024 Reviews received at journal 01 Oct, 2024 Reviewers agreed at journal 28 Sep, 2024 Reviewers agreed at journal 26 Sep, 2024 Reviewers invited by journal 05 Jul, 2024 Editor invited by journal 02 Jul, 2024 Editor assigned by journal 01 Jul, 2024 Submission checks completed at journal 01 Jul, 2024 First submitted to journal 27 Jun, 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. 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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-4648915","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":325169967,"identity":"120f056a-e2d2-48e7-9ad0-9524feec9a85","order_by":0,"name":"Hideo Handa","email":"","orcid":"","institution":"Chiba University","correspondingAuthor":false,"prefix":"","firstName":"Hideo","middleName":"","lastName":"Handa","suffix":""},{"id":325169968,"identity":"0bf10518-db38-472b-8865-29b9778133f0","order_by":1,"name":"Atsuhiko Sugiyama","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA60lEQVRIiWNgGAWjYLCCBBDB3sDGkNiA4BOhhecAKVrAQCKBjYGxgQiF/P1njF88bLOL5p/5+NmDhzvsGAwOMDx7gNfsGzlmFoltybkzbqeZGySeSQZpSTfAa80NHjODxDbm3IbbOWwSQEb9hgMMaRL4dMifPwPSUp87/+YZkJZ6kC34tRgcyDF+kNh2OHfDDR6QlsOEtRjeSCtjSDh3PHfjmTQzicQzxxkkDxPwi9z5w5s//iirzp13/PAzyZ87qhn4jvekPcCnBQjYJBjZkPnMPGkEdDAwf2D4gyLAfoyQllEwCkbBKBhZAACyaVALopPnCAAAAABJRU5ErkJggg==","orcid":"","institution":"Chiba University","correspondingAuthor":true,"prefix":"","firstName":"Atsuhiko","middleName":"","lastName":"Sugiyama","suffix":""},{"id":325169969,"identity":"9b2147ae-ac14-40ee-aeaa-26526b856058","order_by":2,"name":"Hitoshi Kubosawa","email":"","orcid":"","institution":"Chiba Aoba Municipal Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hitoshi","middleName":"","lastName":"Kubosawa","suffix":""},{"id":325169973,"identity":"eca761e6-7e7a-47f7-9bc6-e18a27fca5f7","order_by":3,"name":"Yuki Nakagawa","email":"","orcid":"","institution":"Chiba University","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Nakagawa","suffix":""},{"id":325169975,"identity":"fe83300c-e4d9-413a-b684-036b0dcf1d89","order_by":4,"name":"Dai Kishida","email":"","orcid":"","institution":"Shinshu University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Dai","middleName":"","lastName":"Kishida","suffix":""},{"id":325169977,"identity":"85c00b1a-70bd-4c96-93b1-2c6755fc5ca5","order_by":5,"name":"Akiyuki Uzawa","email":"","orcid":"","institution":"Chiba University","correspondingAuthor":false,"prefix":"","firstName":"Akiyuki","middleName":"","lastName":"Uzawa","suffix":""},{"id":325169979,"identity":"d0b10970-031b-40e0-a462-98e274a7d398","order_by":6,"name":"Akiyo Aotsuka","email":"","orcid":"","institution":"Chiba Aoba Municipal Hospital","correspondingAuthor":false,"prefix":"","firstName":"Akiyo","middleName":"","lastName":"Aotsuka","suffix":""},{"id":325169981,"identity":"0a3eb746-c250-4fec-92a4-d2d09c9e755a","order_by":7,"name":"Satoshi Kuwabara","email":"","orcid":"","institution":"Chiba University","correspondingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Kuwabara","suffix":""}],"badges":[],"createdAt":"2024-06-27 13:36:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4648915/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4648915/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12883-024-03950-3","type":"published","date":"2024-11-14T15:58:16+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":61181169,"identity":"adac09c1-4abf-4947-853d-d72e4ce1c058","added_by":"auto","created_at":"2024-07-26 16:45:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":824711,"visible":true,"origin":"","legend":"\u003cp\u003eCytomorphological image of Mollaret cells on cerebrospinal fluid smear\u003c/p\u003e\n\u003cp\u003e(A, B) During the acute phase of aseptic meningitis, there are abundant Mollaret cells, which are characterized by clover leaf-shaped basophilic nuclei (yellow arrows). Hematoxylin–eosin stain, original magnification × 400. Scale bars: 20 μm.\u003c/p\u003e","description":"","filename":"Figure1KikuchiMollaretwitharrow.png","url":"https://assets-eu.researchsquare.com/files/rs-4648915/v1/8a11d7108f20e001d09b7704.png"},{"id":61181168,"identity":"7f702c7e-85e4-46a7-b2fc-cc5c7b1b82d0","added_by":"auto","created_at":"2024-07-26 16:45:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1633423,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathology of the cervical lymph node\u003c/p\u003e\n\u003cp\u003eThere is prominent infiltration of lymphocytes and histiocytes, with a conspicuous absence of neutrophils. Apoptotic bodies (yellow arrow) are also seen. Hematoxylin–eosin stain, original magnification × 100.\u003c/p\u003e","description":"","filename":"Figure2KikuchiMollaretwitharrow.png","url":"https://assets-eu.researchsquare.com/files/rs-4648915/v1/e266da88530c21c9c4d284af.png"},{"id":69285134,"identity":"ef495fe4-2905-4b55-9b94-3f1e719f4f8f","added_by":"auto","created_at":"2024-11-18 19:24:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2939989,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4648915/v1/e926db79-a080-449d-a18e-711daceea193.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Kikuchi disease-associated Mollaret meningitis with MEFV gene mutation successfully treated with colchicine","fulltext":[{"header":"Background","content":"\u003cp\u003eMollaret meningitis is a rare neurological disorder that is characterized by recurrent episodes of aseptic meningitis and the presence of pathognomonic Mollaret cells, which are thought to be abnormal monocytes and are marked by large basophilic and cleaved nuclei, resembling a clover leaf\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Mollaret meningitis is caused by herpes simplex virus type 2 (HSV-2), systemic lupus erythematous and, familial Mediterranean fever (FMF)\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eKikuchi disease is a systemic inflammatory disorder, which mainly affects Asian populations\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Its main manifestations are fever and cervical lymphadenopathy. Although Kikuchi disease has been reported to be accompanied by recurrent aseptic meningitis\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e, no Mollaret cells have ever been identified in the cerebrospinal fluid (CSF). The diagnosis of Kikuchi disease is based on the pathologic findings of histiocytic necrotizing lymphadenitis on excisional lymph node biopsy. It can resolve spontaneously but often recur, which can be suppressed by corticosteroid treatment\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. However, given that prolonged corticosteroid treatment causes a variety of side effects, including osteoporosis and diabetes, a corticosteroid-sparing agent has been sought\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHere, we report the first case of Mollaret meningitis that was caused by Kikuchi disease and associated with \u003cem\u003eMEFV\u003c/em\u003e gene mutation. Moreover, this case demonstrated the efficacy of colchicine in suppressing the recurrence of Kikuchi disease.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 41-year-old Japanese woman came to our hospital because of fever and headache. Her past medical history was significant for 21 years of recurrent aseptic meningitis, which was often accompanied by cervical lymphadenopathy and with each episode lasting for 3\u0026ndash;7 days. Although the aseptic meningitis and cervical lymphadenopathy were always responsive to prednisolone 15\u0026ndash;20 mg per day, these recurred whenever the prednisolone dose was tapered. She had these recurrent episodes approximately every 6 months. Her vital signs were remarkable only for high fever. Physical examination revealed nuchal rigidity and bilateral multiple tender cervical lymphadenopathies.\u003c/p\u003e \u003cp\u003eLaboratory tests showed decreased white blood cell count of 2520/\u0026micro;L and a normal C-reactive protein level of 0.10 mg/dL. Antinuclear antibody test was negative. CSF analysis revealed mildly increased lymphocyte count (14 cells/\u0026micro;L), normal protein (40 mg/dL), increased IL-6 level (280 pg/mL), positive oligoclonal bands, and characteristic Mollaret cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Histologic evaluation of the anterior cervical lymph node biopsy specimen revealed histiocytic necrotizing lymphadenitis (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Her clinical course and pathologic findings confirmed the diagnosis of Mollaret meningitis caused by Kikuchi disease. In addition, there were no serum IgM and IgG antibodies for HSV. Genetic analysis of the \u003cem\u003eMEFV\u003c/em\u003e gene detected heterozygous P369S/R408Q mutations in exon 3.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eHer fever, headache, and cervical lymphadenopathy improved with NSAIDs. Based on the failure of prolonged corticosteroid therapy to manage her recurrent aseptic meningitis, we initiated colchicine and gradually increased the colchicine dose from 0.5 mg/day to 1.5 mg/day. Although she had another episode of aseptic meningitis on a colchicine dose of 1.0 mg/day, there was no recurrence of both meningitis and lymphadenopathies under a colchicine dose of 1.5 mg/day over a follow-up period of one and a half years.\u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003cp\u003eThe current report described a case of Kikuchi disease-associated Mollaret meningitis with \u003cem\u003eMEFV\u003c/em\u003e gene mutation, which was successfully treated with colchicine. This case of recurrent aseptic meningitis fulfilled the diagnostic criteria reported by Bruyn et al\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and demonstrated the presence of Mollaret cells in the CSF. The lymphadenopathies, which often accompanied the meningitis, was confirmed by biopsy as Kikuchi disease, which was presumed to be the cause of Mollaret meningitis.\u003c/p\u003e \u003cp\u003eWe found out two new important clinical issues. First, Mollaret meningitis can be caused by Kikuchi disease. Although Kikuchi disease had been reported to cause recurrent episodes of aseptic meningitis\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e, there had been no previous reports on Kikuchi disease-associated recurrent meningitis, in which Mollaret cells were identified in the CSF. Clinicians should consider Kikuchi disease as one of the possible causative diseases of Mollaret meningitis and the necessity of excisional lymph node biopsy in a patient with recurrent meningitis and lymphadenopathy.\u003c/p\u003e \u003cp\u003eSecond, colchicine may inhibit the recurrence of Kikuchi disease, as well as Mollaret meningitis. In this case, the recurrence of both lymphadenopathy and meningitis was suppressed after starting colchicine. In general, an acute episode of Kikuchi disease is managed with NSAIDs or corticosteroids; to prevent recurrence, corticosteroid is used for a long period\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Some case reports showed that hydroxychloroquine and anakinra were effective for Kikuchi disease\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, despite their risk of retinopathy and expensiveness. To our best knowledge, there had been no research that demonstrated the benefits of colchicine for the management of Kikuchi disease. Our case indicated that colchicine can be a safe and inexpensive corticosteroid-sparing agent for the prevention of recurrent Kikuchi disease. The effectiveness of colchicine for the treatment of Kikuchi disease should be further examined in a large-scale study.\u003c/p\u003e \u003cp\u003eThe clinical effectiveness of colchicine on Kikuchi disease can be explained by its activity to suppress the inflammasome signaling. Previous reports demonstrated that colchicine inhibits the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which senses pathogen-associated molecular patterns and triggers the secretion of IL1 and IL18\u003csup\u003e8\u003c/sup\u003e. Therefore, colchicine decreases the levels of IL1, IL6, and IL18, which were reported to contribute to the pathogenesis of Kikuchi disease\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. These reports suggested that colchicine can prevent the recurrence of Kikuchi disease through inactivation of NLRP3 and cytokines.\u003c/p\u003e \u003cp\u003eThe presence of \u003cem\u003eMEFV\u003c/em\u003e gene mutation may underlie the chronic recurrent inflammation that is observed not only in FMF but also in Kikuchi disease and Mollaret meningitis. This case of recurrent Kikuchi disease and Mollaret meningitis was found to have the P369S/R408Q mutation in the \u003cem\u003eMEFV\u003c/em\u003e gene; both of these conditions were successfully treated with colchicine. Previous studies have shown that P369S/R408Q mutation was associated with atypical presentations of FMF and was detected in a patient with Kikuchi disease\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. However, the pathological significance of P369S/R408Q mutation in the \u003cem\u003eMEFV\u003c/em\u003e gene remains unclear\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Further research is needed to elucidate the association between \u003cem\u003eMEFV\u003c/em\u003e gene mutations and Kikuchi disease, as well as the pathological role of P369S/R408Q mutation.\u003c/p\u003e \u003cp\u003eIn conclusion, Mollaret meningitis can be caused by Kikuchi disease, and recurrence of both might be suppressed by colchicine.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"566\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbbreviation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.03533568904594%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDefinition\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003eHSV-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.03533568904594%\" valign=\"top\"\u003e\n \u003cp\u003eHerpes simplex virus type 2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003eFMF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.03533568904594%\" valign=\"top\"\u003e\n \u003cp\u003eFamilial Mediterranean fever (FMF)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003eCSF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.03533568904594%\" valign=\"top\"\u003e\n \u003cp\u003eCerebrospinal fluid\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003eNSAIDs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.03533568904594%\" valign=\"top\"\u003e\n \u003cp\u003eNon-Steroidal Anti-Inflammatory Drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003eNLRP3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.03533568904594%\" valign=\"top\"\u003e\n \u003cp\u003eNucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e Not applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Written informed consent for publication of the clinical details was obtained from the patient.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e Not applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare that all authors have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u003c/strong\u003e All authors had roles in writing this manuscript. HH and AS wrote the main manuscript text. HH, AS, and HK prepared Figures 1 and 2. HK, YN, DK, AU, AA, and SK supervised the main manuscript. HH, AS, NY, AU, AA, and SK participated in the care of this patient. HK performed the pathologic diagnosis. DK conducted the MEFV gene analysis. All authors read and approved the final manuscript.\u003cbr\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eNone.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBruyn GW, Straathof LJ, Raymakers GM. Mollaret\u0026rsquo;s meningitis. Differential diagnosis and diagnostic pitfalls. 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Repeated necrotizing lymphadenitis with MEFV gene mutations. Intern Med. 2022;61(7):1105\u0026ndash;10. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2169/internalmedicine.7882-21\u003c/span\u003e\u003cspan address=\"10.2169/internalmedicine.7882-21\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRyan JG, Masters SL, Booty MG, et al. Clinical features and functional significance of the P369S/R408Q variant in pyrin, the familial Mediterranean fever protein. Ann Rheum Dis. 2010;69(7):1383\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/ard.2009.113415\u003c/span\u003e\u003cspan address=\"10.1136/ard.2009.113415\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\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":"Kikuchi disease, MEFV, Familial Mediterranean fever (FMF), Colchicine","lastPublishedDoi":"10.21203/rs.3.rs-4648915/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4648915/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: This case report aims to present a case of Mollaret meningitis caused by Kikuchi disease, an uncommon benign inflammatory disorder, thereby highlighting a novel etiology for Mollaret meningitis. Additionally, it discusses colchicine as a new potential treatment option for Kikuchi disease.\u003cbr\u003e\nCase presentation: A 41-year-old Japanese woman presented with fever and headache. She had nuchal rigidity and bilateral cervical lymphadenopathies. Her past medical history included multiple episodes of aseptic meningitis and cervical lymphadenopathy for more than twenty years. Lumbar puncture showed increased lymphocytes and IL-6 level and pathognomonic Mollaret cells. Excisional lymph node biopsy revealed histiocytic necrotizing lymphadenitis, confirming the diagnosis of Kikuchi disease. Subsequently, her recurrent Kikuchi disease was successfully treated with colchicine. Furthermore, genetic analysis of the \u003cem\u003eMEFV\u003c/em\u003e gene revealed heterozygous P369S/R408Q mutation in exon 3.\u003c/p\u003e\n\u003cp\u003eConclusion: Mollaret meningitis can be caused by Kikuchi disease, and recurrence of both may be suppressed by colchicine.\u003c/p\u003e","manuscriptTitle":"Kikuchi disease-associated Mollaret meningitis with MEFV gene mutation successfully treated with colchicine","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-26 16:45:52","doi":"10.21203/rs.3.rs-4648915/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-16T12:33:14+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-09T09:57:01+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-07T10:11:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"335729986026190569410581941741716943231","date":"2024-10-02T10:11:20+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-01T08:32:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"83868957675497479716988503733152808010","date":"2024-09-29T01:29:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"204067491648670610292268413443431337039","date":"2024-09-26T07:49:43+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-05T11:32:20+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-07-02T16:20:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-01T12:29:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-01T12:28:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2024-06-27T13:35:14+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":"3d847808-d0d2-4b84-a3fb-e4ff678df506","owner":[],"postedDate":"July 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-11-18T19:18:08+00:00","versionOfRecord":{"articleIdentity":"rs-4648915","link":"https://doi.org/10.1186/s12883-024-03950-3","journal":{"identity":"bmc-neurology","isVorOnly":false,"title":"BMC Neurology"},"publishedOn":"2024-11-14 15:58:16","publishedOnDateReadable":"November 14th, 2024"},"versionCreatedAt":"2024-07-26 16:45:52","video":"","vorDoi":"10.1186/s12883-024-03950-3","vorDoiUrl":"https://doi.org/10.1186/s12883-024-03950-3","workflowStages":[]},"version":"v1","identity":"rs-4648915","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4648915","identity":"rs-4648915","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}