Isaacs syndrome with LGI1 and CASPR2 antibodies after HPV vaccination: A case report

Isaacs syndrome with LGI1 and CASPR2 antibodies after HPV vaccination: 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 Isaacs syndrome with LGI1 and CASPR2 antibodies after HPV vaccination: A case report Bu-Fan Yang, Wei Wei, Jing-Feng Duan, Pei Xiao, Yu Jing, Yu-Feng Tang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2412829/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Isaacs syndrome is peripheral nerve hyperexcitability characterized by spontaneous muscle twitching and rigidity and is often associated with antibodies to CASPR2 (contactin-associated protein-like 2) and LGI1(leucine-rich glioma-inactivated 1). We report a patient with Isaacs syndrome, including clinical features, electrophysiological and laboratory investigations and post-treatment response. The patient presented with limb pain, muscle twitching, numbness in the extremities and around the mouth, and hand rash after the second dose of HPV vaccine. Laboratory tests indicated positive for LGI1 antibodies, CASPR2 antibodies, anti- phosphatidylserine/prothrombin antibodies and anti-sulfatide antibodies. The patient's IVIG (intravenous immunoglobulin) treatment resulted in significant relief of symptoms and a negative antibody profile. This case report suggests a possible adverse reaction to HPV (Human Papilloma Virus) vaccination, which could be treated by attempting several periods of IVIG therapy. The underlying immune mechanisms need to be studied with further extensive data. Isaacs syndrome HPV CASPR2 LGI1 Anti-sulfatide antibody Figures Figure 1 Figure 2 Figure 3 1. Introduction Isaacs syndrome, first described by Hyam Isaacs in 1961[1], is a syndrome of acquired autoimmune disease in which peripheral nerve hyperexcitability predominates, characterized by spontaneous twitching and rigidity of muscles, spasticity and autonomic disturbances, occasionally accompanied by neuropathic pain and paresthesia. Electromyography can reveal spontaneous irregular discharges of motor nerve fibers. Indeed, a significant proportion of Isaacs syndrome cases have detectable autoantibodies, and it is generally believed that the target antigens are CASPR2 and LGI1 of the presynaptic membrane of the neuromuscular junction [2]. Patients may therefore benefit from plasma exchange or IVIG therapy [3]. The exact cause of Isaacs syndrome remains unclear and may be related to genetic, autoimmune and paraneoplastic factors[2]. The quadrivalent human papillomavirus (qHPV) vaccine, first approved in 2006, is a highly effective prophylaxis against papillomavirus types 6, 11, 16 and 18. Since the vaccine was approved, several studies have investigated the possibility of autoimmune disease following application of the vaccine [4]. Here, we report the clinical features of a case of Isaacs syndrome that occurred after the second dose of qHPV vaccination and their response to symptomatic and immunomodulatory treatment, which was positive for CASPR2 antibodies and positive for LGI1 antibodies with positive antiphospholipid antibodies and positive anti-sulfatide antibodies. 2. Case Presentation A 28-year-old woman was vaccinated with the second dose of tetravalent qHPV vaccine after 3 days. Her first dose of the same vaccine given 3 months earlier was uneventful. She presented with left-sided hip and lower limb pain, which worsened with activity and got progressively worse during the pain, in the hip, arm and leg, with discontinuous involuntary muscle twitches (video-1), with limb numbness and perioral, with hand rash, poor appetite and poor sleep. There was no family history or disease in the past. On neurological examination, her vital signs, mental status, cranial nerves, muscle tone, various senses, and cerebellar signs were normal. Upper limbs muscle strength level 5, lower limbs muscle strength level 4. Scattered red rashes were seen on both hands (Fig. 1 A); Weakened tendon reflexes in the extremities. Pain score: 10.Lab examination: immunoglobulin E 170IU/ml (< 100); Thyroglobulin antibody 366.72IU/ml, anti-thyroid peroxidase antibody 164.04IU/ml, electrolytes: sodium 134mmol/L (137–147 mmol/L). Other serum examinations were in the normal ranges. Examination: chest CT (computerized tomography) scan: irregular low-density shadow in the anterior superior mediastinum, not thymoma. Other examination including video electroencephalogram, routine electrocardiogram, simple cognitive scale, abdominal CT, cranial MRI (magnetic resonance imaging), thoracolumbar MRI, left thigh MRI and PET-CT (Positron Emission Tomography-Computed Tomography) were normal. By the cell-based indirect immunofluorescence method (Sichuan kingmed center for clinical laboratory to detect serum antibody, which showed positive CASPR2 (1:100, results with a titer 1:< 10 were considered negative) antibodies (Fig. 2 A), andLGI1 (1:30, results with a titer 1:< 10 were considered negative) (Fig. 2 B), and Anti-Sulfatide IgG: positive, anti-phosphatidyl serine/prothrombin IgM antibody: 36.26U/ml. Other serum antibodies were negative. Electrophysiological examination of the nerve showed a posterior M-wave releasing potential in the F wave of the posterior tibial nerve (Fig. 3 A). After 5 days of IVIG(S10970032, HUALAN BIO, Xinxiang, Henan, China) therapy (0. 4mg.kg. d), the rash on the hand disappeared (Fig. 1 B), the pain was relieved (pain score 3), the sleep well, and the condition was improved and discharged. 2.1. Follow-up and outcomes After discharge, gabapentin (H20040527, ENHUA, Xuzhou, Jiangsu, China ) 0.3g quaque nocte was continued. After two months, the patient was hospitalized again due to worsening pain (pain score 5). The patient was treated with IVIG (S10970032, HUALAN BIO, Xinxiang, Henan, China)(0. 4mg.kg.d) for 5 days. Compared with the first electrophysiological examination, the conduction amplitude of sensory nerves in both upper limbs was significantly increased, and the discharge after F wave and M wave in both posterior tibial nerves disappeared (Figure. 3B), and the pain was relieved (pain score 2). She continued to take gabapentin (H20040527, ENHUA, Xuzhou, Jiangsu, China) 0.1g three times a day after discharge from the hospital. One month later, the patient's pain (pain score of 3) worsened again. Enhanced CT of the chest showed no definite change from before. CASPR2 antibody 1:10, the rest negative. After 5 days of treatment with IVIG(S10970032, HUALAN BIO, Xinxiang, Henan, China) (0. 4 mg.kg.d), the pain was completely relieved. At the outpatient follow-up 4 months after discharge, the antibody test was negative and his symptoms had disappeared entirely. 3. Discussion CASPR2 and LGI1 are important components of voltage-gated Kv1 potassium channel complexes, widely expressed in the central and peripheral nervous systems. Autoimmune CASPR2 and LGI1 diseases usually manifest as Morvan syndrome and/or limbic encephalitis. We report a case of Isaacs with positive CASPR2, LGI1, anti-phospholipid antibody, and anti-Sulfatide antibody after the second dose of qHPV vaccine, and described the classic clinical feature of Isaacs: muscle spasms, which was confirmed by Cerami and Maryam Hatami[4, 5]. Although one study reported a case of CASPR2 and LGI1 double antibody positivity, the clinical presentation was GBS-like syndrome that developed into typical respiratory paralysis, and the neurological symptoms in this patient resolved quickly after plasma washing [6]. The patient we reported was multiantibody positive for CASPR2 and LGI1, antiphospholipid antibodies, and anti-Sulfatide antibodies, and physical examination revealed weakened tendon reflex-a rare Guillain-Barre like symptom. Whether Guillain-Barre-syndrome (GBS) is a specific clinical phenotype is unknown. Our finding expands the phenotypic spectrum of CASPR2 and LGI1 autoimmune syndromes, suggesting that these two antigens, especially CASPR2, may be involved in the etiology of GBS as potential novel target antigens and deserve further exploration. On the other hand, it has been reported that in some cases, Isaacs syndrome in the central nervous system shows symptoms leading to hallucinations, dancing, insomnia and intracranial hippocampal lesions[7]. Our patient also had intractable insomnia and antibody positivity, but no intracranial lesions were found. Studies have found that patients with both anti-CASPR2 and anti-LGI1 antibodies are at risk of thymoma [8, 9]. In some tumor-associated syndromes, neurological deficits may occur before the tumor is detected, so patients with negative malignancy should be followed for a long time. In this case, although screening for systemic malignancy was negative, the patient should be followed up for a long time. Concerning the treatment of this disease, studies have found inconsistent efficacy of IVIG or plasma exchange in this syndrome, mainly suggesting that high-dose steroid therapy should be tried when the IVIG 2mg.kg. d is not effective [2, 10] .Recent research indicates that vaccines may be a possible trigger factor for some inflammatory autoimmune diseases affecting the nervous system, which may be attributed to the stimulatory effect of HPV virus-like particles on the immune system through "bystander activation"[11]. Immunomodulatory signals provided to dendritic cells through IL-6 and TNF-α secretion may also cause inflammatory responses in the nervous system [12]. Isaacs syndrome is a rare condition, and it is even rarer to appear after HPV vaccination. Studies have found that inflammatory central nervous system diseases are more common in young people [4]. So, there is some overlap between this group and the population that receives HPV vaccination. Nonetheless, ISAACS syndrome symptoms in young patients vaccinated with HPV may indicate inflammatory activity affecting the peripheral nervous system. 4. Conclusion In summary, this is the first case we have identified in which a combination of positive LGI1 antibodies, CASPR2 antibodies, anti-phospholipid antibodies and anti-sulphate antibodies were present after the second dose of qHPV vaccine. This patient presented with Isaacs syndrome and similar Guillain-Barré, expanding the phenotypic spectrum of CASPR2 and LGI1 autoimmune syndromes. Our finding indicates that the symptoms of Isaacs syndrome in young HPV-vaccinated patients may affect the autoimmune activity of the peripheral nervous system, suggesting a possible potential adverse event following HPV vaccination. The efficacy of intravenous immunoglobulin therapy also validated this in patients. Although the pathogenesis of the disease due to the HPV vaccine is not cleared and further research is needed. Declarations Availability of data and materials The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. Ethical approval and consent to participate This study was approved by the internal review board for ethics at Mianyang Central Hospital. All methods in our study were performed in accordance with the guidelines and regulations of Declaration of Helsinki. Informed consent forms of participants was obtained before enrollment. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgment We thank the physicians who provided clinical support and clinical examination. We also wish to thank our patient and her family. Consent for publication Written informed consent for publication was obtained from all participants. Conflict of interest Authors declare no direct or indirect financial or personal conflict of interest related to the submitted work. Author’s contributions BFY and YFT interviewed, diagnosed and treated the patient. BFY and WW interpreted the data and drafted the manuscript for content. BFY and YJ interviewed the patient and tested the antibodies in the CSF of this patient. PX did the electromyography for the patient. BFY, JFD and YJ contributed to the follow-up of the patients and literature reviewing. All authors read and approved the final manuscript. Consent to publish A statement to confirm informed consent for publication was obtained from the patient(s) and/or their legal guardian(s) —for study publication of identifying information/images in an online open-access publication. References Isaacs H: A SYNDROME OF CONTINUOUS MUSCLE-FIBRE ACTIVITY . Journal of neurology, neurosurgery, and psychiatry 1961, 24 (4):319-325. Ahmed A, Simmons Z: Isaacs syndrome: A review . Muscle & nerve 2015, 52 (1):5-12. Samogalskyi V, Alcalay Y, Gadoth A, Eilam A, Gilad R: Case report: Isolated muscle neuromyotonia, as presenting feature of Isaacs' syndrome . Journal of neuroimmunology 2021, 353 :577491. Hatami M, Förster M, Weyers V, Räuber S, Meuth SG, Kremer D: Neuromyotonia with Central Nervous System Lesions following Quadrivalent Human Papilloma Virus Vaccination . Vaccines 2022, 10 (7). Cerami C, Corbo M, Piccolo G, Iannaccone S: Autoimmune neuromyotonia following human papilloma virus vaccination . Muscle & nerve 2013, 47 (3):466-467. Tan X, Liu Y, Wu X, Guo Y: Guillain-Barré-like syndrome: an uncommon feature of CASPR2 and LGI1 autoimmunity . Journal of neurology 2022, 269 (11):5893-5900. Zhang SJ, Xue YY, Yu H, Tao QQ: Morvan syndrome associated with LGI1 antibody: a case report . BMC neurology 2021, 21 (1):185. Titulaer MJ, Soffietti R, Dalmau J, Gilhus NE, Giometto B, Graus F, Grisold W, Honnorat J, Sillevis Smitt PA, Tanasescu R et al : Screening for tumours in paraneoplastic syndromes: report of an EFNS task force . European journal of neurology 2011, 18 (1):19-e13. Li KC, Liao MF, Wu YR, Lyu RK: Isaacs' syndrome as the initial presentation of malignant thymoma and associated with double-positive voltage-gated potassium channel complex antibodies, a case report . BMC neurology 2022, 22 (1):74. van Sonderen A, Ariño H, Petit-Pedrol M, Leypoldt F, Körtvélyessy P, Wandinger KP, Lancaster E, Wirtz PW, Schreurs MW, Sillevis Smitt PA et al : The clinical spectrum of Caspr2 antibody-associated disease . Neurology 2016, 87 (5):521-528. Sutton I, Lahoria R, Tan I, Clouston P, Barnett M: CNS demyelination and quadrivalent HPV vaccination . Multiple sclerosis (Houndmills, Basingstoke, England) 2009, 15 (1):116-119. Lenz P, Day PM, Pang YY, Frye SA, Jensen PN, Lowy DR, Schiller JT: Papillomavirus-like particles induce acute activation of dendritic cells . Journal of immunology (Baltimore, Md : 1950) 2001, 166 (9):5346-5355. Additional Declarations No competing interests reported. Supplementary Files Isaacs1Clipchamp.mp4 Cite Share Download PDF Status: Posted Version 1 posted 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-2412829","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":169064241,"identity":"f39dc12c-d1f7-47d1-bc28-4311aac1817a","order_by":0,"name":"Bu-Fan Yang","email":"","orcid":"","institution":"Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Bu-Fan","middleName":"","lastName":"Yang","suffix":""},{"id":169064242,"identity":"d39bb9c3-344e-46c8-a4b3-8aa5b5c43202","order_by":1,"name":"Wei Wei","email":"","orcid":"","institution":"University Medical Center of Göttingen, Georg-August-University of Göttingen","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Wei","suffix":""},{"id":169064243,"identity":"cd2e72a3-aedd-4378-870e-b260c2d3d20b","order_by":2,"name":"Jing-Feng Duan","email":"","orcid":"","institution":"Mianyang Central Hospital, University of Electronic Science and Technology of China","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jing-Feng","middleName":"","lastName":"Duan","suffix":""},{"id":169064244,"identity":"104837f2-8ccb-4bbf-b0e4-1601ba847792","order_by":3,"name":"Pei Xiao","email":"","orcid":"","institution":"Mianyang Central Hospital, University of Electronic Science and Technology of China","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Pei","middleName":"","lastName":"Xiao","suffix":""},{"id":169064245,"identity":"56f8f98a-db24-4da9-8f9c-16a45c5fe48e","order_by":4,"name":"Yu Jing","email":"","orcid":"","institution":"Mianyang Central Hospital, University of Electronic Science and Technology of China","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Jing","suffix":""},{"id":169064246,"identity":"2e90a172-cd95-4e8d-991f-05bda2915128","order_by":5,"name":"Yu-Feng Tang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1UlEQVRIiWNgGAWjYDCCA0BcAcT8QMxMvJYzQCzZANXCQ7QWgwPEauG7fcZM4kDFHbvNN5IPfi5guCNnT0iL5LkcoJYzz5K33UhLlp7B8MyYoC0GZ3jMpD+2HU42u5FjIM3DcDixhxgtEgf/HU42npH/+TdQSz2RWhoO2xlI5LCBbEkg6DDJM2zFFgeOHU6QOPPMzJrH4LBhzwECWvjOMG+8caDmsD1/e/Lj2zwVh+XZGwhZw8BhACITGwQSQO4kqBwE2B+ASHsGfkIOGgWjYBSMghELAMKJRJcSpdd7AAAAAElFTkSuQmCC","orcid":"","institution":"Mianyang Central Hospital, University of Electronic Science and Technology of China","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yu-Feng","middleName":"","lastName":"Tang","suffix":""}],"badges":[],"createdAt":"2022-12-25 06:59:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2412829/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2412829/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":31968653,"identity":"4734f1b4-858d-4007-a6d8-e0a9e2c73ea2","added_by":"auto","created_at":"2023-01-23 23:09:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":652980,"visible":true,"origin":"","legend":"\u003cp\u003ehands scattered in rash(A), rash disappeared(B),\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2412829/v1/d91ba81089a1f1b045412161.png"},{"id":31968655,"identity":"3fa5a6d4-0d3f-433b-9cb2-51c332ca746a","added_by":"auto","created_at":"2023-01-23 23:09:11","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2288767,"visible":true,"origin":"","legend":"\u003cp\u003ePatients’ antibodies reacted with Mammalian cells transfected with CASPR2(A) and LGI1(B). Diluted serum samples (1:10) were collected on August 5, 2021. Reacted with mammalian cells with CASPR2 and LGI1 on August 7, 2021.Scale bars, 10 μm (A) and (B). Abbreviation: CASPR2, contactin-associated protein-like 2, LGI1, leucine-rich glioma-inactivated 1.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-2412829/v1/e772f16dbd8406e1f30a20fc.png"},{"id":31968654,"identity":"58989024-0636-42c9-bee6-35a40ad8869b","added_by":"auto","created_at":"2023-01-23 23:09:10","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":412081,"visible":true,"origin":"","legend":"\u003cp\u003ea posterior M-wave releasing potential in the F wave of the posterior tibial nerve(A),the discharge after F wave and M wave in posterior tibial nerves disappeared (B).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviation:\u003c/strong\u003e CASPR2 contactin-associated protein-like 2, LGI1 leucine-rich glioma-inactivated 1, HPV Human Papilloma Virus, IVIG intravenous immunoglobulin, qHPV quadrivalent human papillomavirus, CT computerized tomography, MRI magnetic resonance imaging, PET-CT Positron Emission Tomography-Computed Tomography.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-2412829/v1/915e451e87a01c7d3833973a.png"},{"id":39903645,"identity":"f21d9f44-b9fa-457b-9b48-484a70ba823b","added_by":"auto","created_at":"2023-07-12 10:14:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2561970,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2412829/v1/0729156b-1f62-41af-b15d-fabc4664469c.pdf"},{"id":31968656,"identity":"0273548f-f247-4820-b1b3-12e95231cb71","added_by":"auto","created_at":"2023-01-23 23:09:11","extension":"mp4","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13774586,"visible":true,"origin":"","legend":"","description":"","filename":"Isaacs1Clipchamp.mp4","url":"https://assets-eu.researchsquare.com/files/rs-2412829/v1/956c32f899e0b49fccb6f01b.mp4"}],"financialInterests":"No competing interests reported.","formattedTitle":"Isaacs syndrome with LGI1 and CASPR2 antibodies after HPV vaccination: A case report","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eIsaacs syndrome, first described by Hyam Isaacs in 1961[1], is a syndrome of acquired autoimmune disease in which peripheral nerve hyperexcitability predominates, characterized by spontaneous twitching and rigidity of muscles, spasticity and autonomic disturbances, occasionally accompanied by neuropathic pain and paresthesia. Electromyography can reveal spontaneous irregular discharges of motor nerve fibers. Indeed, a significant proportion of Isaacs syndrome cases have detectable autoantibodies, and it is generally believed that the target antigens are CASPR2 and LGI1 of the presynaptic membrane of the neuromuscular junction [2]. Patients may therefore benefit from plasma exchange or IVIG therapy [3]. The exact cause of Isaacs syndrome remains unclear and may be related to genetic, autoimmune and paraneoplastic factors[2]. The quadrivalent human papillomavirus (qHPV) vaccine, first approved in 2006, is a highly effective prophylaxis against papillomavirus types 6, 11, 16 and 18. Since the vaccine was approved, several studies have investigated the possibility of autoimmune disease following application of the vaccine [4]. Here, we report the clinical features of a case of Isaacs syndrome that occurred after the second dose of qHPV vaccination and their response to symptomatic and immunomodulatory treatment, which was positive for CASPR2 antibodies and positive for LGI1 antibodies with positive antiphospholipid antibodies and positive anti-sulfatide antibodies.\u003c/p\u003e"},{"header":"2. Case Presentation","content":"\u003cp\u003eA 28-year-old woman was vaccinated with the second dose of tetravalent qHPV vaccine after 3 days. Her first dose of the same vaccine given 3 months earlier was uneventful. She presented with left-sided hip and lower limb pain, which worsened with activity and got progressively worse during the pain, in the hip, arm and leg, with discontinuous involuntary muscle twitches (video-1), with limb numbness and perioral, with hand rash, poor appetite and poor sleep. There was no family history or disease in the past. On neurological examination, her vital signs, mental status, cranial nerves, muscle tone, various senses, and cerebellar signs were normal. Upper limbs muscle strength level 5, lower limbs muscle strength level 4. Scattered red rashes were seen on both hands (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA); Weakened tendon reflexes in the extremities. Pain score: 10.Lab examination: immunoglobulin E 170IU/ml (\u0026lt;\u0026thinsp;100); Thyroglobulin antibody 366.72IU/ml, anti-thyroid peroxidase antibody 164.04IU/ml, electrolytes: sodium 134mmol/L (137\u0026ndash;147 mmol/L). Other serum examinations were in the normal ranges. Examination: chest CT (computerized tomography) scan: irregular low-density shadow in the anterior superior mediastinum, not thymoma. Other examination including video electroencephalogram, routine electrocardiogram, simple cognitive scale, abdominal CT, cranial MRI (magnetic resonance imaging), thoracolumbar MRI, left thigh MRI and PET-CT (Positron Emission Tomography-Computed Tomography) were normal. By the cell-based indirect immunofluorescence method (Sichuan kingmed center for clinical laboratory to detect serum antibody, which showed positive CASPR2 (1:100, results with a titer 1:\u0026lt; 10 were considered negative) antibodies (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA), andLGI1 (1:30, results with a titer 1:\u0026lt; 10 were considered negative) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB), and Anti-Sulfatide IgG: positive, anti-phosphatidyl serine/prothrombin IgM antibody: 36.26U/ml. Other serum antibodies were negative. Electrophysiological examination of the nerve showed a posterior M-wave releasing potential in the F wave of the posterior tibial nerve (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). After 5 days of IVIG(S10970032, HUALAN BIO, Xinxiang, Henan, China) therapy (0. 4mg.kg. d), the rash on the hand disappeared (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB), the pain was relieved (pain score 3), the sleep well, and the condition was improved and discharged.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Follow-up and outcomes\u003c/h2\u003e \u003cp\u003eAfter discharge, gabapentin (H20040527, ENHUA, Xuzhou, Jiangsu, China ) 0.3g quaque nocte was continued. After two months, the patient was hospitalized again due to worsening pain (pain score 5). The patient was treated with IVIG (S10970032, HUALAN BIO, Xinxiang, Henan, China)(0. 4mg.kg.d) for 5 days. Compared with the first electrophysiological examination, the conduction amplitude of sensory nerves in both upper limbs was significantly increased, and the discharge after F wave and M wave in both posterior tibial nerves disappeared (Figure. 3B), and the pain was relieved (pain score 2). She continued to take gabapentin (H20040527, ENHUA, Xuzhou, Jiangsu, China) 0.1g three times a day after discharge from the hospital. One month later, the patient's pain (pain score of 3) worsened again. Enhanced CT of the chest showed no definite change from before. CASPR2 antibody 1:10, the rest negative. After 5 days of treatment with IVIG(S10970032, HUALAN BIO, Xinxiang, Henan, China) (0. 4 mg.kg.d), the pain was completely relieved. At the outpatient follow-up 4 months after discharge, the antibody test was negative and his symptoms had disappeared entirely.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eCASPR2 and LGI1 are important components of voltage-gated Kv1 potassium channel complexes, widely expressed in the central and peripheral nervous systems. Autoimmune CASPR2 and LGI1 diseases usually manifest as Morvan syndrome and/or limbic encephalitis. We report a case of Isaacs with positive CASPR2, LGI1, anti-phospholipid antibody, and anti-Sulfatide antibody after the second dose of qHPV vaccine, and described the classic clinical feature of Isaacs: muscle spasms, which was confirmed by Cerami and Maryam Hatami[4, 5]. Although one study reported a case of CASPR2 and LGI1 double antibody positivity, the clinical presentation was GBS-like syndrome that developed into typical respiratory paralysis, and the neurological symptoms in this patient resolved quickly after plasma washing [6]. The patient we reported was multiantibody positive for CASPR2 and LGI1, antiphospholipid antibodies, and anti-Sulfatide antibodies, and physical examination revealed weakened tendon reflex-a rare Guillain-Barre like symptom. Whether Guillain-Barre-syndrome (GBS) is a specific clinical phenotype is unknown. Our finding expands the phenotypic spectrum of CASPR2 and LGI1 autoimmune syndromes, suggesting that these two antigens, especially CASPR2, may be involved in the etiology of GBS as potential novel target antigens and deserve further exploration. On the other hand, it has been reported that in some cases, Isaacs syndrome in the central nervous system shows symptoms leading to hallucinations, dancing, insomnia and intracranial hippocampal lesions[7]. Our patient also had intractable insomnia and antibody positivity, but no intracranial lesions were found. Studies have found that patients with both anti-CASPR2 and anti-LGI1 antibodies are at risk of thymoma [8, 9]. In some tumor-associated syndromes, neurological deficits may occur before the tumor is detected, so patients with negative malignancy should be followed for a long time. In this case, although screening for systemic malignancy was negative, the patient should be followed up for a long time. Concerning the treatment of this disease, studies have found inconsistent efficacy of IVIG or plasma exchange in this syndrome, mainly suggesting that high-dose steroid therapy should be tried when the IVIG 2mg.kg. d is not effective [2, 10] .Recent research indicates that vaccines may be a possible trigger factor for some inflammatory autoimmune diseases affecting the nervous system, which may be attributed to the stimulatory effect of HPV virus-like particles on the immune system through \"bystander activation\"[11]. Immunomodulatory signals provided to dendritic cells through IL-6 and TNF-α secretion may also cause inflammatory responses in the nervous system [12]. Isaacs syndrome is a rare condition, and it is even rarer to appear after HPV vaccination. Studies have found that inflammatory central nervous system diseases are more common in young people [4]. So, there is some overlap between this group and the population that receives HPV vaccination. Nonetheless, ISAACS syndrome symptoms in young patients vaccinated with HPV may indicate inflammatory activity affecting the peripheral nervous system.\u003c/p\u003e"},{"header":"4. Conclusion","content":"\u003cp\u003eIn summary, this is the first case we have identified in which a combination of positive LGI1 antibodies, CASPR2 antibodies, anti-phospholipid antibodies and anti-sulphate antibodies were present after the second dose of qHPV vaccine. This patient presented with Isaacs syndrome and similar Guillain-Barr\u0026eacute;, expanding the phenotypic spectrum of CASPR2 and LGI1 autoimmune syndromes. Our finding indicates that the symptoms of Isaacs syndrome in young HPV-vaccinated patients may affect the autoimmune activity of the peripheral nervous system, suggesting a possible potential adverse event following HPV vaccination. The efficacy of intravenous immunoglobulin therapy also validated this in patients. Although the pathogenesis of the disease due to the HPV vaccine is not cleared and further research is needed.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the internal review board for ethics at Mianyang Central Hospital. All methods in our study were performed in accordance with the guidelines and regulations of Declaration of Helsinki. Informed consent forms of participants was obtained before enrollment.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the physicians who provided clinical support and clinical examination. We also wish to thank our patient and her family.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication was obtained from all participants.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors declare no direct or indirect financial or personal conflict of interest related to the submitted work.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBFY and YFT interviewed, diagnosed and treated the patient. BFY and WW interpreted the data and drafted the manuscript for content. BFY and YJ interviewed the patient and tested the antibodies in the CSF of this patient. PX did the electromyography for the patient. BFY, JFD and YJ contributed to the follow-up of the patients and literature reviewing. All authors read and approved the final manuscript. \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA statement to confirm informed consent for publication was obtained from the patient(s) and/or their legal guardian(s) \u0026mdash;for study publication of identifying information/images in an online open-access publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eIsaacs H: \u003cstrong\u003eA SYNDROME OF CONTINUOUS MUSCLE-FIBRE ACTIVITY\u003c/strong\u003e. \u003cem\u003eJournal of neurology, neurosurgery, and psychiatry \u003c/em\u003e1961, \u003cstrong\u003e24\u003c/strong\u003e(4):319-325.\u003c/li\u003e\n\u003cli\u003eAhmed A, Simmons Z: \u003cstrong\u003eIsaacs syndrome: A review\u003c/strong\u003e. \u003cem\u003eMuscle \u0026amp; nerve \u003c/em\u003e2015, \u003cstrong\u003e52\u003c/strong\u003e(1):5-12.\u003c/li\u003e\n\u003cli\u003eSamogalskyi V, Alcalay Y, Gadoth A, Eilam A, Gilad R: \u003cstrong\u003eCase report: Isolated muscle neuromyotonia, as presenting feature of Isaacs\u0026apos; 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syndrome as the initial presentation of malignant thymoma and associated with double-positive voltage-gated potassium channel complex antibodies, a case report\u003c/strong\u003e. \u003cem\u003eBMC neurology \u003c/em\u003e2022, \u003cstrong\u003e22\u003c/strong\u003e(1):74.\u003c/li\u003e\n\u003cli\u003evan Sonderen A, Ari\u0026ntilde;o H, Petit-Pedrol M, Leypoldt F, K\u0026ouml;rtv\u0026eacute;lyessy P, Wandinger KP, Lancaster E, Wirtz PW, Schreurs MW, Sillevis Smitt PA\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eThe clinical spectrum of Caspr2 antibody-associated disease\u003c/strong\u003e. \u003cem\u003eNeurology \u003c/em\u003e2016, \u003cstrong\u003e87\u003c/strong\u003e(5):521-528.\u003c/li\u003e\n\u003cli\u003eSutton I, Lahoria R, Tan I, Clouston P, Barnett M: \u003cstrong\u003eCNS demyelination and quadrivalent HPV vaccination\u003c/strong\u003e. \u003cem\u003eMultiple sclerosis (Houndmills, Basingstoke, England) \u003c/em\u003e2009, \u003cstrong\u003e15\u003c/strong\u003e(1):116-119.\u003c/li\u003e\n\u003cli\u003eLenz P, Day PM, Pang YY, Frye SA, Jensen PN, Lowy DR, Schiller JT: \u003cstrong\u003ePapillomavirus-like particles induce acute activation of dendritic cells\u003c/strong\u003e. \u003cem\u003eJournal of immunology (Baltimore, Md : 1950) \u003c/em\u003e2001, \u003cstrong\u003e166\u003c/strong\u003e(9):5346-5355.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Isaacs syndrome, HPV, CASPR2, LGI1, Anti-sulfatide antibody","lastPublishedDoi":"10.21203/rs.3.rs-2412829/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2412829/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIsaacs syndrome is peripheral nerve hyperexcitability characterized by spontaneous muscle twitching and rigidity and is often associated with antibodies to CASPR2 (contactin-associated protein-like 2) and LGI1(leucine-rich glioma-inactivated 1). We report a patient with Isaacs syndrome, including clinical features, electrophysiological and laboratory investigations and post-treatment response. The patient presented with limb pain, muscle twitching, numbness in the extremities and around the mouth, and hand rash after the second dose of HPV vaccine. Laboratory tests indicated positive for LGI1 antibodies, CASPR2 antibodies, anti- phosphatidylserine/prothrombin antibodies and anti-sulfatide antibodies. The patient's IVIG (intravenous immunoglobulin) treatment resulted in significant relief of symptoms and a negative antibody profile. This case report suggests a possible adverse reaction to HPV (Human Papilloma Virus) vaccination, which could be treated by attempting several periods of IVIG therapy. The underlying immune mechanisms need to be studied with further extensive data.\u003c/p\u003e","manuscriptTitle":"Isaacs syndrome with LGI1 and CASPR2 antibodies after HPV vaccination: A case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-01-23 23:09:05","doi":"10.21203/rs.3.rs-2412829/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9833f200-fa75-4ada-bec5-ce00944b195e","owner":[],"postedDate":"January 23rd, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-07-12T10:14:14+00:00","versionOfRecord":[],"versionCreatedAt":"2023-01-23 23:09:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2412829","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2412829","identity":"rs-2412829","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}