Two Cases of Paraneoplastic Cochleovestibulopathy with Detection of Breast Cancer and Literature Review

Two Cases of Paraneoplastic Cochleovestibulopathy with Detection of Breast Cancer and Literature Review | 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 Two Cases of Paraneoplastic Cochleovestibulopathy with Detection of Breast Cancer and Literature Review Liqin Yang, Xueqing Liu, Wenxia Li, Songming Tang, Yanan Hu, Ting Zhang, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4751102/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Dec, 2025 Read the published version in BMC Neurology → Version 1 posted 10 You are reading this latest preprint version Abstract Background Paraneoplastic cochleovestibulopathy (PCVP) is an atypical neurological paraneoplastic syndrome characterized by rapidly progressive hearing loss with or without vestibular dysfunction, usually detectable malignancy, and paraneoplastic antibodies. PCVP is rare and easy to be misdiagnosed and mistreated. Previous studies have suggested that KLHL11-IgG and seminomas are associated with male patients. However, the tumors associated with female patients are not known. Case presentation: We report two cases of middle-aged women with binaural sensorineural hearing loss (SNHL) as the first symptom. Pure tone audiograms showed binaural hearing impairment, brainstem auditory evoked potentials (BAEP) and cochlear electrograms were normal, and otoacoustic emissions showed binaural cochlear dysfunction. Intracranial organic lesions and vascular lesions were excluded by cranial imaging. After steroid treatment is invalid, the positron emission tomography/computedtomography (PET/CT) and pathologic examination, and breast cancer was screened. After treatment with endocrine therapy (patient # 1) and surgical excision (patient #2) for breast cancer, no significant improvement in pure tone average (PTA) was seen at the 1 year of follow-up. Conclusion PCVP should be considered in middle-aged patients presenting with progressive hearing loss in both ears without organic pathology, mostly with vestibular dysfunction and signs of cerebellar and brainstem pathology. Regular review of PET/CT is warranted. Female patients need to be concerned about breast cancer. Paraneoplastic cochleovestibulopathy Sensorineural hearing loss Breast cancer KLHL11-IgG Neurological paraneoplastic syndrome Case report Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction McCabe first linked hearing-vestibular disorders to autoimmunity in 1979, when he identified and named "autoimmune inner ear disease" (AIED), which is rare, accounting for <1% of all cases of hearing loss and dizziness (1). AIED is most common in female middle-aged patients, and most cases present with SNHL in both ears that advance rapidly or fluctuate over a period of months. Systemic autoimmune disease is present in 30% of cases (2). Autoimmune diseases and symptoms are sometimes included in paraneoplastic syndromes. Paraneoplastic syndromes combined with cochlear vestibular lesions should be considered in patients with tumors that present with auditory and vestibular dysfunction. PCVP first proposed by Greene in 2014, is an atypical neurologic paraneoplastic syndrome presenting with progressive SNHL with or without vestibular dysfunction that is not responsive to high-dose oral or intratympanic Steroid therapy is ineffective, and antibodies to malignant tumors and paraneoplastic tumors are usually detected (3). Moreover, paraneoplastic neurological syndromes (PNS) are clinical syndromes of neurological and/or muscular damage secondary to a malignant tumor, caused by an autoimmune response in the absence of tumor metastasis, usually detected within 5 years of diagnosis of the tumor or associated antibodies (3, 4). Atypical PNS, however, is prone to misdiagnosis and mistreatment due to its atypical clinical symptoms. SNHL occurs in lesions proximal to the oval window of the cochlea, locally including the cochlea, cochlear nerve, cerebellopontine Angle, or brainstem auditory nucleus. Patients with tumors associated with cochlear vestibular lesions are rarely reported due to the lack of audiologic testing, and mild hearing loss is often overlooked, especially in patients with bilateral hearing loss. In some cases, hearing loss demonstrated by PTA alone is insufficient to determine whether it is central or peripheral. PCVP is rare in clinical practice, and we have not found reports of breast cancer detection in China. Here, we report two cases of PCVP in China with SNHL and vertigo as the initial symptoms and concomitant breast cancer, and review the relevant literature with the aim of analyzing its clinical features and pathogenesis. Case presentation Patient #1 A 40-year-old female was hospitalized in Tianjin Huanhu Hospital 2 days before admission with a sudden onset of vertigo, accompanied by unsteady walking. Ten months prior to admission, the patient with a history of hearing loss in the left ear without any obvious cause, and then the right ear was involved. Oral prednisone was given and progressive hearing loss occurred in both ears one month later, with the right side being the most prominent (Fig. 1 ). Pure-tone audiograms showed that the hearing was impaired in both ears, and Brainstem Auditory Evoked Potentials (BAEP) and cochlea electrography were normal. Computed tomography (CT) of the temporal bone, magnetic resonance imaging (MRI) of the head, and magnetic resonance angiography (MRA) showed no abnormalities. She was diagnosed as "SNHL" and was treated with steroids and neurotrophic therapy, but the result was unsatisfactory. Therefore, she underwent cochlear implantation one month before he was admitted to the hospital. Physical examination revealed impulsive, monotone speech with suspected explosive language. Small horizontal nystagmus could be detected in both eyes and the sign of difficulty in standing with eyes closed (+). A lumbar puncture was performed with the patient's informed consent. Cerebrospinal fluid and serum tissue-based assay (TBA) screening showed positive fluorescence in the membrane of neurons in the cerebellum, hippocampus, and cortex, suggesting that there may be some positive autoimmune brain antibodies, and the specific antibodies are unknown. However, cytometric bead array (CBA) screening for common autoimmune encephalitis-related antibodies and paraneoplastic-related antibodies were negative. After cochlear implantation, the patient could not undergo an MRI of the head, but the results of the CT of the head were normal. The admission diagnosis was considered bilateral hearing loss of unknown origin and suspected autoimmune encephalitis. Intravenous immunoglobulins (IVIG) and methylprednisolon treatment, patients were dizziness improved. Three months later, breast ultrasound examination showed a deep hypoechoic nodule with calcification in the right breast nipple (BI-RADS class 4a). Chest CT examination showed multiple enlarged lymph nodes in the right axilla, and pathological examination showed poorly differentiated adenocarcinoma. Right axillary lymph node biopsy (HE staining, 40 x) lymphoid tissue and fibrous tissue background visible in poorly differentiated adenocarcinoma (Fig. 2 ). Immunohistochemical staining showed approximately 100% ER (+), Her-2 2+, CK (+), CK7 (+), CATA-3 (+), while CgA (-), Syn (-), CD56 (-), P40 (-), SOX-2 (-), GCDFP-15 (-), PAX-8 (-), which were consistent with the mammary origin. PET/CT revealed "metastatic adenocarcinoma in the right axillary lymph node". Finally, it was considered as occult breast cancer with lymph node metastasis adenocarcinoma. The patient refused surgical treatment and received endocrine therapy temporarily. In conclusion, the diagnosis of PCWP was considered. One year later, the patient was still receiving endocrine conservative treatment for breast cancer, and regular chest CT showed that the right axillary lymph nodes had become smaller (Fig. 3 ). Unfortunately, it is not possible to monitor the patient's hearing prognosis after cochlear implantation. Patient #2 A 54-year-old woman was admitted to Tianjin Huanhu Hospital due to vertigo for 1 day. Physical examination showed bilateral horizontal micronystagmus, normal upper limb coordination, and difficulty standing with eyes closed (+). The patient had a 10-year history of autoimmune thyroid disease and had unprovoked hearing loss in both ears 8 months before admission. Pure tone audiometry showed an air-conducted PTA of 50 dB in the left ear and 50 dB in the right ear, with an A-frame in both ears, suggesting binaural sensorineural hearing loss. A one-month course of IVIG for hearing loss was also ineffective (Fig. 1 ). BAEP and cochleogram were normal, and otoacoustic emission showed cochlear dysfunction in both ears. Temporal bone CT and cranial MRI showed no obvious abnormalities. The common autoimmune encephalitis-related antibodies and paraneoplastic-related antibodies (TBA + CBA) in cerebrospinal fluid and serum were negative. The whole body PET/CT showed breast cancer (pathology: invasive ductal carcinoma), and surgical resection was performed immediately. In summary, the diagnosis was a paraneoplastic cochleo-vestibular lesion. After One year of follow-up, the patient's vertigo was improved, but her hearing was not significantly improved, and she now wears hearing AIDS. Discussion PCVP is clinically rare and difficult to diagnose clinically because the onset of neurologic symptoms often precedes the diagnosis of malignancy. Direct neurologic involvement by the cancer, as well as indirect effects due to treatment-related neurotoxicity, metabolism, or infection, also need to be carefully excluded. Pathogenesis The pathogenesis of PCVP remains unclear. Early Chen et al.( 5 ) proposed that antigen-induced interleukin production, especially the increase in the amount of interleukin-2, leads to cellular damage in the auditory and vestibular systems, causing tinnitus, vertigo, and hearing loss, and in severe cases, cochlear fibrosis and ossification. However, crossing mechanism of immune response is now widely recognized( 6 ). One study showed that auditory-vestibular disorders are thought to result from cross-reactivity of the immune system, where antibodies produced in the body cross-react with melanoma cells and labyrinthine melanocytes, resulting in altered endolymphatic fluid homeostasis ( 7 , 8 ). Dubey et al. found that the pathological manifestations of paraneoplastic anti-KLHL-11-IGg encephalitis were T cell-dominated inflammation and non-necrotizing granulomas, suggesting that auditory-vestibular disorders may be related to T cell-mediated autoimmunity ( 9 ). In addition, the inner ear may be affected by tumor invasion of mesenchymal cells or neuroectoderm through the basement membrane or blood-brain barrier, activating the immune system and leading to paraneoplastic syndromes, while endolymphatic sac is involved in antigen processing and immune response ( 10 ). Clinical Manifestations The initial presentation of PCVP is usually rapidly progressive bilateral SNHL and vestibular dysfunction. However, these symptoms often occur simultaneously with or after brainstem/cerebellar manifestations. In the retrospective analysis by Greene et al., the median age of onset of SNHL was 42 years, there were more females (n = 9, 69%), malignant tumors were diagnosed 2 weeks or 2 years after the onset of SNHL, and tumors rarely appeared earlier than neurological symptoms ( 11 ). In contrast, Hammami et al. found that most patients were male (n = 23, 88%), KLHL11-IgG combined with seminoma was the most common, and the average age was 45 years ( 12 ). We summarized 46 patients considered for the diagnosis of PCVP from 5 publications, plus the 2 we provided, for a total of 48 cases( 11 – 15 ). The clinical manifestations were analyzed as in Table 1 . Of the 48 patients, 33 were male and 11 were female, with a median age of 45 years. With a variety of manifestations, mainly SNHL (46/48, 96%), ataxia (36/48, 75%), limb dysmetria (22/48, 46%), diplopia (21/48, 43%), tinnitus (19/48, 40%), nystagmus (18/48, 37%), dysarthria (14/48, 29%), vertigo (12/48, 25%), etc. Other symptoms such as altered mental status were less common. Only two patients presented with tinnitus ( 12 ), the possibility of PCVP could not be excluded when patients presented only with tinnitus without significant hearing loss. A graph of their hearing loss pattern was available for 24 (24/48) of these patients (Fig. 4 ), and the pattern of hearing loss was flat in the majority of the patients (n = 12/24, 50%), followed by high frequencies (n = 9/24, 37%) and low and medium frequencies (n = 3/24, 13%). Meniere's disease mainly affects low-frequency hearing in one ear, and hearing loss is fluctuating, often accompanied by tinnitus. Therefore, in the presence of monaural low-frequency hearing loss, we need to differentiate it from peripheral diseases ( 16 , 17 ). Previous studies have shown that( 12 ) PCVP is accompanied by other conforms to the diamond encephalitis or encephalomyelitis central nervous system, including physical activity disorder, ataxia, dizziness, dysarthria, nystagmus, etc. The cerebellar and its associated fibers could be located in the ataxia, binocular horizontal nystagmus of patient #1 and patient #2, and the explosive speech of patient #1. Table 1 Literature Review of Patients with Paraneoplastic Cochleovestibulopathy Study or MD reporting case Number of cases Age/sex Frequency of hearing impairment Except the clinical manifestations of SNHL Prior history Cranial Imaging (MRI, CT) Paraneoplastic panel Latent malignant tumor Treat Outcome Fioretti et al( 14 ) 1 50/ female high frequency / both ears tinnitus, vertigo, ataxia, altered mental status ATD no abnormality seen unknown breast cancer mastectomy, chemotherapy not improved Kattah et al( 13 ) 1 45/ male high frequency / both ears vertigo, ataxia, nystagmus seminoma testis no abnormality seen KLHL11-IgG(+) testicular germ cell tumour PLEX, intravenous methylprednisolone, chemotherapy hearing loss worsened Renna et al( 15 ) 1 67/ female unknown / both ears limb dysmetria, ataxia, unknown abnormal signals in the auditory nerve Hu-IgG(+) SCLC unknown unknown Greene et al( 11 ) 17 median age 42/ 9 males, 4 females, 4 unknown 3 patients: Flat (n = 2, 67%), high frequency (n = 1, 33%) / both ears (n = 3, 100%); others unknown vertigo (n = 9, 53%), ataxia (n = 5, 29%), altered mental status (n = 3, 16%), limb dysmetria (n = 2, 12%), diplopia (n = 1, 5%) 1 with non-Hodgkin's lymphoma in remission, others unknown no abnormality in 2 patients, unknown in others Hu-IgG (n = 4, 21%), AChR-IgG union VGKC-IgG (n = 1, 5%), CAD65-IgG (n = 1, 5%), unknown (n = 5, 29%), negative (n = 6, 32%) thymoma (n = 5, 29%), SCLC (n = 3, 18%), lymphoma (n = 3, 18%), renal neoplasm (n = 2, 12%), serous adenocarcinoma (L ovary) (n = 1, 6%), neuroblastoma (n = 1, 6%), none detected (n = 1, 6%), clear cell carcinoma (n = 1, 6%) intravenous methylprednisolone (n = 4, 21%), IVIG (n = 4, 21%), surgery (n = 6, 46%), others unknown dead (n = 8, 21%), deaf (n = 9, 21%), others unknown Hammami et al( 12 ) 26 median age 45 / 23 males, 3 females 17 patients: flat (n = 10, 53%), high frequency (n = 4, 21%), low-mid frequency (n = 3, 16%)/ one ear (4/13, 31%), both ears (9/13, 69%); others unknown ataxia (n = 26, 100%), diplopia (n = 20, 77%), dysarthria (n = 14, 54%), limb dysmetria (n = 19, 73%), nystagmus (n = 15, 58%), tinnitus (n = 18, 69%) unknown 25 patients: IAC enhancement and/or T2 hyperintensity (n = 4, 16%), abnormal T2 hyperintensity of the inner ear structures on FLAIR images (n = 1, 4%), cerebellar atrop-hy (n = 11, 44%), normal (n = 7, 28%) KLHL11-IgG (n = 20, 77%), ANNA1-IgG (n = 3, 12%), amphiphysin-IgG (n = 2, 8%), LUZP4-IgG (n = 9, 4%), KLHL11-IgG union LUZP4-IgG (n = 8, 31%) 18 patients: testicular/extra-testicular germ cell tumour (n = 13, 50%), non-small cell lung cancer (n = 3, 12%) and breast adenocarcinoma (n = 2, 8%); None detect-ed (n = 8, 31%) intravenous methylprednisolone (n = 23, 89%), oral prednisone (n = 16, 62%), IVIG (n = 15, 58%), PLEX (n = 12, 46%) hearing loss worsened (n = 16, 73%), stabilized (n = 4, 18%) and improved (n = 2, 9%) / neurological function worsened (n = 16, 62%), stabilised (n = 8, 31%), improved (n = 2, 8%) Case 1 1 40/ female high frequency / both ears Nystagmus, vertigo, ataxia nonspecific no abnormality seen unknown antibody breast cancer endocrine therapy hearing loss worsened Case 2 1 54/ female high frequency / both ears nystagmus, ataxia ATD no abnormality seen (-) breast cancer mastectomy, chemotherapy hearing loss worsened sensorineural hearing loss=SNHL, autoimmune thyroid disease=ATD, plasma exchange=PLEX, small-cell lung cancer=SCLC, internal auditory canal=IAC, fluid-attenuated inversion recovery = FLAIR, intravenous immunoglobulins=IVIG Associated Antibodies and Tumors With the exception of 6 individuals for whom no paraneoplastic antibodies were detected, the most common antibody among the 42 (Fig. 4 ) was KLHL11-Ig G (n = 21, 44%), which was combined with LUZP4-IgG in 8 cases (n = 8, 17%)( 12 ), followed by Hu-Ig G (n = 5, 10%), ANNA1-IgG (n = 3, 6%), amphiphysin-IgG (n = 2, 4%), LUZP4-IgG ( n = 1, 2%), AChR-Ig G combined with VGKC-Ig G (n = 1, 2%), and GAD65-Ig G (n = 1, 2%), whereas paraneoplastic antibodies were not detected in 15% of patients( 11 – 15 ). It is important to note that because the paraneoplastic antibody pool is evolving, a negative paraneoplastic antibody test cannot be used to exclude the diagnosis of the disease, and the detection of the antibodies is important in suggesting subsequent tumorigenesis. Analysis of the reasons for non-detection of antibodies against paraneoplastic tumors may be due to low titer of antibodies and easy destruction, strong binding of antibodies to tissues preventing their solubilization in serum or cerebrospinal fluid, a paraneoplastic pathogenic process not mediated by humoral immunity, and changes of peptides on the cell surface due to paraneoplastic antibodies against intracellular antigens that are not easily detected by antibodies. Vertigo, SNHL, and tinnitus have been shown to be common and specific clinical symptoms in patients with paraneoplastic anti-KLHL11-IgG encephalitis ( 18 , 19 ), whose hearing loss first involves high-frequency hearing in both ears and is specific to men ( 9 , 19 ). We found that male patients presenting with progressive cochlear vestibular symptoms and progressive ataxia should be evaluated for paraneoplastic KLHL11-IgG and potential germ cell tumors, and that early recognition would have an impact on neurological and tumor prognosis, as aggressive immunosuppression could benefit patients ( 9 , 13 , 19 ). However, we summarized the cases and found testicular/extra-testicular germ cell tumor (n = 14, 29%), lung cancer (n = 7, 15%), breast cancer(n = 5, 11%) and thymoma (n = 5, 10%), female patients need to be vigilant for breast cancer. Treatment There are no large-sample randomized controlled studies on treatment options for PCVP due to the limited number of cases, and treatment of the underlying malignancy is a top priority. In a retrospective study of patients with paraneoplastic lesions, patients who had been treated for malignancy (radiotherapy, chemotherapy and/or surgery) were 1.5 times more likely to have improved neurological symptoms than those who had not been treated ( 20 ). However, Greene concluded that there are no effective means of treating PCVP, and he found that intravenous immunoglobulins, corticosteroids, and immunosuppressive agents did not significantly improve hearing loss in patients ( 11 ). Hammami found that after treatment with corticosteroids (CSs) hearing loss was found to worsen in 16 cases (73%) and improve in 2 cases (9%) ( 12 ). In our cases, patient #1 was treated aggressively after screening for breast cancer, and regular follow-up revealed a smaller right axillary lymph node than before and a hearing prognosis that could not be monitored. Patient #2 underwent surgical treatment for breast cancer with no significant improvement in hearing loss and eventually required hearing aid assistance. However, both of our patients had early detection of malignant tumors and were treated aggressively in time to curb further tumor invasion. Early recognition and timely treatment of cancer can be beneficial to patients, and limited research is currently available, with possible new results in future prospective studies ( 12 , 13 ). If PCVP is suspected, the first step should be to carefully inquire about past medical history, including history of tumor, autoimmune disease, etc., and studies have shown that autoimmune disease has an increased probability of secondary paraneoplastic neurological disease ( 14 ). Adjunctive examinations should include hearing tests, cochlea electrogram, otoacoustic emission, cranial imaging, etc. Occult tumor screening is necessary, and serum and cerebrospinal fluid paraneoplastic-associated antibody testing should be improved. Due to the low sensitivity of paraneoplastic antibodies and occult malignancies, detection of positive antibodies but negative tumor imaging suggests screening every 6 months for at least 2 to 3 years. Conclusion In summary, we report two patients with PCVP in middle-aged women with progressive hearing loss as the first symptom and detection of breast cancer. Hearing loss is localized to the cochlea, and progressive hearing loss is SNHL progresses slower than sudden deafness but faster than senile deafness, usually taking days to months. PCVP should be considered in middle-aged patients presenting with bilateral progressive hearing loss with/without vestibular dysfunction when steroid therapy is not effective after exclusion of organic pathology. Serum and cerebrospinal fluid antibodies to paraneoplastic tumors are helpful for early diagnosis. In addition, regular review of whole-body PET/CT is necessary, and attention should be paid to breast cancer in female patients and testicular/extra-testicular germ cell tumour and KLHL11-IgG in male patients. Through literature review, the clinical manifestations and pathogenesis of patients with paraneoplastic cochlear vestibulopathy were discussed in detail, and it was emphasized that screening for breast cancer should be considered for middle-aged female patients with progressive binaural hearing loss as the main manifestation of the clinical disease. Abbreviations PCVP Paraneoplastic cochleovestibulopathy SNHL Sensorineural hearing loss BAEP Brainstem auditory evoked potentials PTA Pure tone average PET/CT Positron emission tomography/computedtomography AIED Autoimmune inner ear disease PNS Paraneoplastic neurological syndromes CT Computed tomography MRI Magnetic resonance imaging TBA Tissue-based assay CBA Cytometric cead array IVIG Intravenous immunoglobulins ATD Autoimmune thyroid disease PLEX Plasma exchange SCLC Small-cell lung cancer IAC Internal auditory canal FLAIR Fluid-attenuated inversion recovery Declarations Acknowledgements We thank the husbands of both patients for their consent to share patients’ information. Author contributions L.Q.Y. and X.Q.L. were involved in the identification, selection, and management of the patient and manuscript review. W.X.L. and Y.N.H. performed the clinical follow-up of the patient. L.Q.Y. wrote the initial paper. T.Z., S.M.T. and X.L. revised the paper; W.Y. had primary responsibility for the final content. All authors read and approved the final manuscript. Funding This study was supported by Tianjin Key Medical Discipline (Specialty) Construction Project (No. TJYXZDXK-052B), Tianjin Health Commission Science and Technology Projects (TJWJ2021QN061 and ZC20134). Data availability statement The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author. Ethics approval and consent to participate This study has been granted an exemption from requiring ethics approval by Tianjin Huanhu Hospital of Tianjin Medical University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. Consent for publication Written informed consent was obtained from the patient to publish this Case report and any accompanying images. Conflict of interest The authors declare no competing interests. References McCabe BF. Autoimmune sensorineural hearing loss. The Annals of Otology, Rhinology, and Laryngology. 1979;88(5 Pt 1):585-9. Mijovic T, Zeitouni A, Colmegna I. Autoimmune sensorineural hearing loss: the otology-rheumatology interface. Rheumatology (Oxford). 2013;52(5):780-9. Graus F, Vogrig A, Muñiz-Castrillo S, Antoine J-CG, Desestret V, Dubey D, et al. Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes. Neurol Neuroimmunol Neuroinflamm. 2021;8(4). Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004;75(8):1135-40. Chen MC, Harris JP, Keithley EM. 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Cite Share Download PDF Status: Published Journal Publication published 12 Dec, 2025 Read the published version in BMC Neurology → Version 1 posted Editorial decision: Revision requested 18 Jun, 2025 Reviews received at journal 12 Jun, 2025 Reviewers agreed at journal 06 Jun, 2025 Reviews received at journal 22 Sep, 2024 Reviewers agreed at journal 22 Sep, 2024 Reviewers invited by journal 04 Sep, 2024 Editor invited by journal 02 Aug, 2024 Editor assigned by journal 17 Jul, 2024 Submission checks completed at journal 17 Jul, 2024 First submitted to journal 16 Jul, 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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Yue","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4UlEQVRIiWNgGAWjYBACAwkIzcPPzNj44IOBjR3xWiTbmw8bzihISyZaC4PBmWNp0jwfDjE2ENJiLt1jJvGxzUaG4UaOsbGNwQFmBvbDRzfg02I554yZ5My2NB7GGTmGj3MM7vAx8KSl3cDrsBs5ZtK82w7zMEsAbckxeMbMIMFjRljL323/edgkgAwLg8OMDURpYdx2gIeHB+h9BuK0pBVb9v5L5pFgBwZyj0FaMhthvyRvvPHjjJ29/WFgVP74Y2PHz374GF4tDAwcBqh8NvzKQYD9AWE1o2AUjIJRMLIBAL+bSljHxdqlAAAAAElFTkSuQmCC","orcid":"","institution":"Tianjin Medical University, Tianjin Huanhu Hospital","correspondingAuthor":true,"prefix":"","firstName":"Wei","middleName":"","lastName":"Yue","suffix":""}],"badges":[],"createdAt":"2024-07-16 16:14:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4751102/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4751102/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12883-025-04508-7","type":"published","date":"2025-12-12T15:58:32+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62654522,"identity":"8bf8806e-dd3e-4d21-ac8f-ce2820cea6d0","added_by":"auto","created_at":"2024-08-17 01:25:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":356081,"visible":true,"origin":"","legend":"\u003cp\u003eAudiograms of Patient #1 upon presentation (A) and 1 month later after treatment with oral prednisone (B), Patient #2 on initial presentation (C) and 1 month later after treatment with IVIG (D).\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-4751102/v1/ea3c5be60659520f35896ba3.png"},{"id":62654525,"identity":"ab34f4c2-9769-487d-b7d3-11670a285f55","added_by":"auto","created_at":"2024-08-17 01:25:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":770844,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemical staining showed approximately 100% ER (+), Her-2 2+, CK (+), CK7 (+), CATA-3 (+), while CgA (-), Syn (-), CD56 (-), P40 (-), SOX-2 (-), GCDFP-15 (-), PAX-8 (-), which were consistent with the mammary origin.\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-4751102/v1/a4b0b580228833c8503084cc.png"},{"id":62654524,"identity":"3fdabe7c-3bda-43bf-b37b-3b99ddf22b13","added_by":"auto","created_at":"2024-08-17 01:25:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1010428,"visible":true,"origin":"","legend":"\u003cp\u003eChest CT showed that the right axillary lymph nodes were smaller after 1 year (A) than after 3 months (B).\u003c/p\u003e","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-4751102/v1/7a3f81778af3d498bfcdc6b7.png"},{"id":62654523,"identity":"56ea6079-411d-4cd8-9280-6d2c93ad5588","added_by":"auto","created_at":"2024-08-17 01:25:37","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":218359,"visible":true,"origin":"","legend":"\u003cp\u003eClinical manifestations (A), frequency of hearing impairment (B), paraneoplastic panel (C), and latent malignant tumor (D) in 48 PCVP patients.\u003c/p\u003e","description":"","filename":"Fig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-4751102/v1/f4405854ec322cb2f80b59e6.png"},{"id":98243912,"identity":"bc3340fc-2713-42ec-b58b-f3e54a9498df","added_by":"auto","created_at":"2025-12-15 16:11:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3602249,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4751102/v1/d23f3cb7-bb6d-4fc3-98a6-de442b676c6e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Two Cases of Paraneoplastic Cochleovestibulopathy with Detection of Breast Cancer and Literature Review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMcCabe first linked hearing-vestibular disorders to autoimmunity in 1979, when he identified and named \u0026quot;autoimmune inner ear disease\u0026quot; (AIED), which is rare, accounting for \u0026lt;1% of all cases of hearing loss and dizziness\u0026nbsp;(1).\u0026nbsp;AIED is most common in female middle-aged patients, and most cases present with\u0026nbsp;SNHL\u0026nbsp;in both ears that advance rapidly or fluctuate over a period of months. Systemic autoimmune disease is present in 30% of cases\u0026nbsp;(2).\u0026nbsp;Autoimmune diseases and symptoms are sometimes included in paraneoplastic syndromes. Paraneoplastic syndromes combined with cochlear vestibular lesions should be considered in patients with tumors that present with auditory and vestibular dysfunction.\u0026nbsp;PCVP first proposed by Greene in 2014, is an atypical neurologic paraneoplastic syndrome presenting with\u0026nbsp;progressive\u0026nbsp;SNHL with or without vestibular dysfunction that is not responsive to high-dose oral or intratympanic Steroid therapy is ineffective, and antibodies to malignant tumors and paraneoplastic tumors are usually detected\u0026nbsp;(3).\u0026nbsp;Moreover, paraneoplastic neurological syndromes (PNS) are clinical syndromes of neurological and/or muscular damage secondary to a malignant tumor, caused by an autoimmune response in the absence of tumor metastasis, usually detected within 5 years of diagnosis of the tumor or associated antibodies\u0026nbsp;(3, 4).\u0026nbsp;Atypical PNS, however, is prone to misdiagnosis and mistreatment due to its atypical clinical symptoms.\u003c/p\u003e\n\u003cp\u003eSNHL occurs in lesions proximal to the oval window of the cochlea, locally including the cochlea, cochlear nerve, cerebellopontine Angle, or brainstem auditory nucleus. Patients with tumors associated with cochlear vestibular lesions are rarely reported due to the lack of audiologic testing, and mild hearing loss is often overlooked, especially in patients with bilateral hearing loss. In some cases, hearing loss demonstrated by PTA alone is insufficient to determine whether it is central or peripheral. PCVP is rare in clinical practice, and we have not found reports of breast cancer detection in China. Here, we report two cases of PCVP in China with SNHL and vertigo as the initial symptoms and concomitant breast cancer, and review the relevant literature with the aim of analyzing its clinical features and pathogenesis.\u003c/p\u003e"},{"header":"Case presentation","content":"\n\u003ch3\u003ePatient #1\u003c/h3\u003e\n\u003cp\u003eA 40-year-old female was hospitalized in Tianjin Huanhu Hospital 2 days before admission with a sudden onset of vertigo, accompanied by unsteady walking. Ten months prior to admission, the patient with a history of hearing loss in the left ear without any obvious cause, and then the right ear was involved. Oral prednisone was given and progressive hearing loss occurred in both ears one month later, with the right side being the most prominent (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Pure-tone audiograms showed that the hearing was impaired in both ears, and Brainstem Auditory Evoked Potentials (BAEP) and cochlea electrography were normal. Computed tomography (CT) of the temporal bone, magnetic resonance imaging (MRI) of the head, and magnetic resonance angiography (MRA) showed no abnormalities. She was diagnosed as \"SNHL\" and was treated with steroids and neurotrophic therapy, but the result was unsatisfactory. Therefore, she underwent cochlear implantation one month before he was admitted to the hospital. Physical examination revealed impulsive, monotone speech with suspected explosive language. Small horizontal nystagmus could be detected in both eyes and the sign of difficulty in standing with eyes closed (+). A lumbar puncture was performed with the patient's informed consent. Cerebrospinal fluid and serum tissue-based assay (TBA) screening showed positive fluorescence in the membrane of neurons in the cerebellum, hippocampus, and cortex, suggesting that there may be some positive autoimmune brain antibodies, and the specific antibodies are unknown. However, cytometric bead array (CBA) screening for common autoimmune encephalitis-related antibodies and paraneoplastic-related antibodies were negative. After cochlear implantation, the patient could not undergo an MRI of the head, but the results of the CT of the head were normal. The admission diagnosis was considered bilateral hearing loss of unknown origin and suspected autoimmune encephalitis. Intravenous immunoglobulins (IVIG) and methylprednisolon treatment, patients were dizziness improved.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThree months later, breast ultrasound examination showed a deep hypoechoic nodule with calcification in the right breast nipple (BI-RADS class 4a). Chest CT examination showed multiple enlarged lymph nodes in the right axilla, and pathological examination showed poorly differentiated adenocarcinoma. Right axillary lymph node biopsy (HE staining, 40 x) lymphoid tissue and fibrous tissue background visible in poorly differentiated adenocarcinoma (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Immunohistochemical staining showed approximately 100% ER (+), Her-2 2+, CK (+), CK7 (+), CATA-3 (+), while CgA (-), Syn (-), CD56 (-), P40 (-), SOX-2 (-), GCDFP-15 (-), PAX-8 (-), which were consistent with the mammary origin. PET/CT revealed \"metastatic adenocarcinoma in the right axillary lymph node\". Finally, it was considered as occult breast cancer with lymph node metastasis adenocarcinoma. The patient refused surgical treatment and received endocrine therapy temporarily.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn conclusion, the diagnosis of PCWP was considered. One year later, the patient was still receiving endocrine conservative treatment for breast cancer, and regular chest CT showed that the right axillary lymph nodes had become smaller (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Unfortunately, it is not possible to monitor the patient's hearing prognosis after cochlear implantation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003ePatient #2\u003c/h3\u003e\n\u003cp\u003eA 54-year-old woman was admitted to Tianjin Huanhu Hospital due to vertigo for 1 day. Physical examination showed bilateral horizontal micronystagmus, normal upper limb coordination, and difficulty standing with eyes closed (+). The patient had a 10-year history of autoimmune thyroid disease and had unprovoked hearing loss in both ears 8 months before admission. Pure tone audiometry showed an air-conducted PTA of 50 dB in the left ear and 50 dB in the right ear, with an A-frame in both ears, suggesting binaural sensorineural hearing loss. A one-month course of IVIG for hearing loss was also ineffective (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). BAEP and cochleogram were normal, and otoacoustic emission showed cochlear dysfunction in both ears. Temporal bone CT and cranial MRI showed no obvious abnormalities. The common autoimmune encephalitis-related antibodies and paraneoplastic-related antibodies (TBA\u0026thinsp;+\u0026thinsp;CBA) in cerebrospinal fluid and serum were negative. The whole body PET/CT showed breast cancer (pathology: invasive ductal carcinoma), and surgical resection was performed immediately. In summary, the diagnosis was a paraneoplastic cochleo-vestibular lesion. After One year of follow-up, the patient's vertigo was improved, but her hearing was not significantly improved, and she now wears hearing AIDS.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePCVP is clinically rare and difficult to diagnose clinically because the onset of neurologic symptoms often precedes the diagnosis of malignancy. Direct neurologic involvement by the cancer, as well as indirect effects due to treatment-related neurotoxicity, metabolism, or infection, also need to be carefully excluded.\u003c/p\u003e\n\u003ch3\u003ePathogenesis\u003c/h3\u003e\n\u003cp\u003eThe pathogenesis of PCVP remains unclear. Early Chen et al.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) proposed that antigen-induced interleukin production, especially the increase in the amount of interleukin-2, leads to cellular damage in the auditory and vestibular systems, causing tinnitus, vertigo, and hearing loss, and in severe cases, cochlear fibrosis and ossification. However, crossing mechanism of immune response is now widely recognized(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). One study showed that auditory-vestibular disorders are thought to result from cross-reactivity of the immune system, where antibodies produced in the body cross-react with melanoma cells and labyrinthine melanocytes, resulting in altered endolymphatic fluid homeostasis (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Dubey et al. found that the pathological manifestations of paraneoplastic anti-KLHL-11-IGg encephalitis were T cell-dominated inflammation and non-necrotizing granulomas, suggesting that auditory-vestibular disorders may be related to T cell-mediated autoimmunity (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In addition, the inner ear may be affected by tumor invasion of mesenchymal cells or neuroectoderm through the basement membrane or blood-brain barrier, activating the immune system and leading to paraneoplastic syndromes, while endolymphatic sac is involved in antigen processing and immune response (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eClinical Manifestations\u003c/h2\u003e \u003cp\u003eThe initial presentation of PCVP is usually rapidly progressive bilateral SNHL and vestibular dysfunction. However, these symptoms often occur simultaneously with or after brainstem/cerebellar manifestations. In the retrospective analysis by Greene et al., the median age of onset of SNHL was 42 years, there were more females (n\u0026thinsp;=\u0026thinsp;9, 69%), malignant tumors were diagnosed 2 weeks or 2 years after the onset of SNHL, and tumors rarely appeared earlier than neurological symptoms (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). In contrast, Hammami et al. found that most patients were male (n\u0026thinsp;=\u0026thinsp;23, 88%), KLHL11-IgG combined with seminoma was the most common, and the average age was 45 years (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe summarized 46 patients considered for the diagnosis of PCVP from 5 publications, plus the 2 we provided, for a total of 48 cases(\u003cspan additionalcitationids=\"CR12 CR13 CR14\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The clinical manifestations were analyzed as in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Of the 48 patients, 33 were male and 11 were female, with a median age of 45 years. With a variety of manifestations, mainly SNHL (46/48, 96%), ataxia (36/48, 75%), limb dysmetria (22/48, 46%), diplopia (21/48, 43%), tinnitus (19/48, 40%), nystagmus (18/48, 37%), dysarthria (14/48, 29%), vertigo (12/48, 25%), etc. Other symptoms such as altered mental status were less common. Only two patients presented with tinnitus (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), the possibility of PCVP could not be excluded when patients presented only with tinnitus without significant hearing loss. A graph of their hearing loss pattern was available for 24 (24/48) of these patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e), and the pattern of hearing loss was flat in the majority of the patients (n\u0026thinsp;=\u0026thinsp;12/24, 50%), followed by high frequencies (n\u0026thinsp;=\u0026thinsp;9/24, 37%) and low and medium frequencies (n\u0026thinsp;=\u0026thinsp;3/24, 13%). Meniere's disease mainly affects low-frequency hearing in one ear, and hearing loss is fluctuating, often accompanied by tinnitus. Therefore, in the presence of monaural low-frequency hearing loss, we need to differentiate it from peripheral diseases (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePrevious studies have shown that(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) PCVP is accompanied by other conforms to the diamond encephalitis or encephalomyelitis central nervous system, including physical activity disorder, ataxia, dizziness, dysarthria, nystagmus, etc. The cerebellar and its associated fibers could be located in the ataxia, binocular horizontal nystagmus of patient #1 and patient #2, and the explosive speech of patient #1.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLiterature Review of Patients with Paraneoplastic Cochleovestibulopathy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy or MD reporting case\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of cases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge/sex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFrequency of hearing impairment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eExcept the clinical manifestations of SNHL\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePrior history\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCranial Imaging (MRI, CT)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eParaneoplastic panel\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eLatent malignant tumor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eTreat\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFioretti et al(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50/ female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ehigh frequency / both ears\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003etinnitus, vertigo, ataxia, altered mental status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eno abnormality seen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eunknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ebreast cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003emastectomy, chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003enot improved\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKattah et al(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45/ male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ehigh frequency / both ears\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003evertigo, ataxia, nystagmus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eseminoma testis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eno abnormality seen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eKLHL11-IgG(+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003etesticular germ cell tumour\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003ePLEX, intravenous methylprednisolone, chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003ehearing loss worsened\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenna et al(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67/ female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eunknown / both ears\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003elimb dysmetria, ataxia,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eunknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eabnormal signals in the auditory nerve\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHu-IgG(+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSCLC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eunknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eunknown\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGreene et al(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003emedian age 42/ 9 males, 4 females, 4 unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 patients:\u003c/p\u003e \u003cp\u003eFlat (n\u0026thinsp;=\u0026thinsp;2, 67%), high frequency (n\u0026thinsp;=\u0026thinsp;1, 33%) / both ears (n\u0026thinsp;=\u0026thinsp;3, 100%); others unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003evertigo (n\u0026thinsp;=\u0026thinsp;9, 53%), ataxia (n\u0026thinsp;=\u0026thinsp;5, 29%), altered mental status (n\u0026thinsp;=\u0026thinsp;3, 16%), limb dysmetria (n\u0026thinsp;=\u0026thinsp;2, 12%), diplopia (n\u0026thinsp;=\u0026thinsp;1, 5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 with non-Hodgkin's lymphoma in remission, others unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eno abnormality in 2 patients, unknown in others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHu-IgG (n\u0026thinsp;=\u0026thinsp;4, 21%), AChR-IgG union VGKC-IgG (n\u0026thinsp;=\u0026thinsp;1, 5%), CAD65-IgG (n\u0026thinsp;=\u0026thinsp;1, 5%), unknown (n\u0026thinsp;=\u0026thinsp;5, 29%), negative (n\u0026thinsp;=\u0026thinsp;6, 32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ethymoma (n\u0026thinsp;=\u0026thinsp;5, 29%), SCLC (n\u0026thinsp;=\u0026thinsp;3, 18%), lymphoma (n\u0026thinsp;=\u0026thinsp;3, 18%), renal neoplasm (n\u0026thinsp;=\u0026thinsp;2, 12%), serous adenocarcinoma (L ovary) (n\u0026thinsp;=\u0026thinsp;1, 6%), neuroblastoma (n\u0026thinsp;=\u0026thinsp;1, 6%), none detected (n\u0026thinsp;=\u0026thinsp;1, 6%), clear cell carcinoma (n\u0026thinsp;=\u0026thinsp;1, 6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eintravenous methylprednisolone (n\u0026thinsp;=\u0026thinsp;4, 21%), IVIG (n\u0026thinsp;=\u0026thinsp;4, 21%), surgery (n\u0026thinsp;=\u0026thinsp;6, 46%), others unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003edead (n\u0026thinsp;=\u0026thinsp;8, 21%), deaf (n\u0026thinsp;=\u0026thinsp;9, 21%), others unknown\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHammami et al(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003emedian age 45 / 23 males, 3 females\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 patients: flat (n\u0026thinsp;=\u0026thinsp;10, 53%), high frequency (n\u0026thinsp;=\u0026thinsp;4, 21%), low-mid frequency (n\u0026thinsp;=\u0026thinsp;3, 16%)/ one ear (4/13, 31%), both ears (9/13, 69%); others unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eataxia (n\u0026thinsp;=\u0026thinsp;26, 100%), diplopia (n\u0026thinsp;=\u0026thinsp;20, 77%), dysarthria (n\u0026thinsp;=\u0026thinsp;14, 54%), limb dysmetria (n\u0026thinsp;=\u0026thinsp;19, 73%), nystagmus (n\u0026thinsp;=\u0026thinsp;15, 58%), tinnitus (n\u0026thinsp;=\u0026thinsp;18, 69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eunknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e25 patients: IAC enhancement and/or T2 hyperintensity (n\u0026thinsp;=\u0026thinsp;4, 16%), abnormal T2 hyperintensity of the inner ear structures on FLAIR images (n\u0026thinsp;=\u0026thinsp;1, 4%), cerebellar atrop-hy (n\u0026thinsp;=\u0026thinsp;11, 44%), normal (n\u0026thinsp;=\u0026thinsp;7, 28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eKLHL11-IgG\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;20, 77%), ANNA1-IgG (n\u0026thinsp;=\u0026thinsp;3, 12%), amphiphysin-IgG (n\u0026thinsp;=\u0026thinsp;2, 8%), LUZP4-IgG (n\u0026thinsp;=\u0026thinsp;9, 4%), KLHL11-IgG union LUZP4-IgG (n\u0026thinsp;=\u0026thinsp;8, 31%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e18 patients: testicular/extra-testicular germ cell tumour (n\u0026thinsp;=\u0026thinsp;13, 50%), non-small cell lung cancer (n\u0026thinsp;=\u0026thinsp;3, 12%) and breast adenocarcinoma (n\u0026thinsp;=\u0026thinsp;2, 8%); None detect-ed (n\u0026thinsp;=\u0026thinsp;8, 31%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eintravenous methylprednisolone (n\u0026thinsp;=\u0026thinsp;23, 89%), oral prednisone (n\u0026thinsp;=\u0026thinsp;16, 62%), IVIG (n\u0026thinsp;=\u0026thinsp;15, 58%), PLEX (n\u0026thinsp;=\u0026thinsp;12, 46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003ehearing loss worsened (n\u0026thinsp;=\u0026thinsp;16, 73%), stabilized (n\u0026thinsp;=\u0026thinsp;4, 18%) and\u003c/p\u003e \u003cp\u003eimproved (n\u0026thinsp;=\u0026thinsp;2, 9%) / neurological function worsened (n\u0026thinsp;=\u0026thinsp;16, 62%), stabilised (n\u0026thinsp;=\u0026thinsp;8, 31%), improved (n\u0026thinsp;=\u0026thinsp;2, 8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40/ female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ehigh frequency / both ears\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNystagmus, vertigo, ataxia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003enonspecific\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eno abnormality seen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eunknown antibody\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ebreast cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eendocrine therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003ehearing loss worsened\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54/ female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ehigh frequency / both ears\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003enystagmus, ataxia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eATD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eno abnormality seen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(-)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ebreast cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003emastectomy, chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003ehearing loss worsened\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\u003cp\u003esensorineural hearing loss=SNHL, autoimmune thyroid disease=ATD, plasma exchange=PLEX, small-cell lung cancer=SCLC, internal auditory canal=IAC, fluid-attenuated inversion recovery = FLAIR, intravenous immunoglobulins=IVIG\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eAssociated Antibodies and Tumors\u003c/h2\u003e \u003cp\u003eWith the exception of 6 individuals for whom no paraneoplastic antibodies were detected, the most common antibody among the 42 (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) was KLHL11-Ig G (n\u0026thinsp;=\u0026thinsp;21, 44%), which was combined with LUZP4-IgG in 8 cases (n\u0026thinsp;=\u0026thinsp;8, 17%)(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), followed by Hu-Ig G (n\u0026thinsp;=\u0026thinsp;5, 10%), ANNA1-IgG (n\u0026thinsp;=\u0026thinsp;3, 6%), amphiphysin-IgG (n\u0026thinsp;=\u0026thinsp;2, 4%), LUZP4-IgG ( n\u0026thinsp;=\u0026thinsp;1, 2%), AChR-Ig G combined with VGKC-Ig G (n\u0026thinsp;=\u0026thinsp;1, 2%), and GAD65-Ig G (n\u0026thinsp;=\u0026thinsp;1, 2%), whereas paraneoplastic antibodies were not detected in 15% of patients(\u003cspan additionalcitationids=\"CR12 CR13 CR14\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). It is important to note that because the paraneoplastic antibody pool is evolving, a negative paraneoplastic antibody test cannot be used to exclude the diagnosis of the disease, and the detection of the antibodies is important in suggesting subsequent tumorigenesis. Analysis of the reasons for non-detection of antibodies against paraneoplastic tumors may be due to low titer of antibodies and easy destruction, strong binding of antibodies to tissues preventing their solubilization in serum or cerebrospinal fluid, a paraneoplastic pathogenic process not mediated by humoral immunity, and changes of peptides on the cell surface due to paraneoplastic antibodies against intracellular antigens that are not easily detected by antibodies.\u003c/p\u003e \u003cp\u003eVertigo, SNHL, and tinnitus have been shown to be common and specific clinical symptoms in patients with paraneoplastic anti-KLHL11-IgG encephalitis (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), whose hearing loss first involves high-frequency hearing in both ears and is specific to men (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). We found that male patients presenting with progressive cochlear vestibular symptoms and progressive ataxia should be evaluated for paraneoplastic KLHL11-IgG and potential germ cell tumors, and that early recognition would have an impact on neurological and tumor prognosis, as aggressive immunosuppression could benefit patients (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). However, we summarized the cases and found testicular/extra-testicular germ cell tumor (n\u0026thinsp;=\u0026thinsp;14, 29%), lung cancer (n\u0026thinsp;=\u0026thinsp;7, 15%), breast cancer(n\u0026thinsp;=\u0026thinsp;5, 11%) and thymoma (n\u0026thinsp;=\u0026thinsp;5, 10%), female patients need to be vigilant for breast cancer.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTreatment\u003c/h3\u003e\n\u003cp\u003eThere are no large-sample randomized controlled studies on treatment options for PCVP due to the limited number of cases, and treatment of the underlying malignancy is a top priority. In a retrospective study of patients with paraneoplastic lesions, patients who had been treated for malignancy (radiotherapy, chemotherapy and/or surgery) were 1.5 times more likely to have improved neurological symptoms than those who had not been treated (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). However, Greene concluded that there are no effective means of treating PCVP, and he found that intravenous immunoglobulins, corticosteroids, and immunosuppressive agents did not significantly improve hearing loss in patients (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Hammami found that after treatment with corticosteroids (CSs) hearing loss was found to worsen in 16 cases (73%) and improve in 2 cases (9%) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn our cases, patient #1 was treated aggressively after screening for breast cancer, and regular follow-up revealed a smaller right axillary lymph node than before and a hearing prognosis that could not be monitored. Patient #2 underwent surgical treatment for breast cancer with no significant improvement in hearing loss and eventually required hearing aid assistance. However, both of our patients had early detection of malignant tumors and were treated aggressively in time to curb further tumor invasion. Early recognition and timely treatment of cancer can be beneficial to patients, and limited research is currently available, with possible new results in future prospective studies (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIf PCVP is suspected, the first step should be to carefully inquire about past medical history, including history of tumor, autoimmune disease, etc., and studies have shown that autoimmune disease has an increased probability of secondary paraneoplastic neurological disease (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Adjunctive examinations should include hearing tests, cochlea electrogram, otoacoustic emission, cranial imaging, etc. Occult tumor screening is necessary, and serum and cerebrospinal fluid paraneoplastic-associated antibody testing should be improved. Due to the low sensitivity of paraneoplastic antibodies and occult malignancies, detection of positive antibodies but negative tumor imaging suggests screening every 6 months for at least 2 to 3 years.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, we report two patients with PCVP in middle-aged women with progressive hearing loss as the first symptom and detection of breast cancer. Hearing loss is localized to the cochlea, and progressive hearing loss is SNHL progresses slower than sudden deafness but faster than senile deafness, usually taking days to months. PCVP should be considered in middle-aged patients presenting with bilateral progressive hearing loss with/without vestibular dysfunction when steroid therapy is not effective after exclusion of organic pathology. Serum and cerebrospinal fluid antibodies to paraneoplastic tumors are helpful for early diagnosis. In addition, regular review of whole-body PET/CT is necessary, and attention should be paid to breast cancer in female patients and testicular/extra-testicular germ cell tumour and KLHL11-IgG in male patients. Through literature review, the clinical manifestations and pathogenesis of patients with paraneoplastic cochlear vestibulopathy were discussed in detail, and it was emphasized that screening for breast cancer should be considered for middle-aged female patients with progressive binaural hearing loss as the main manifestation of the clinical disease.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003ePCVP \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Paraneoplastic cochleovestibulopathy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSNHL \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Sensorineural hearing loss\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBAEP \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Brainstem auditory evoked potentials\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePTA \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Pure tone average\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePET/CT \u0026nbsp; \u0026nbsp; Positron emission tomography/computedtomography\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAIED \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Autoimmune inner ear disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePNS \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Paraneoplastic neurological syndromes\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCT \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Computed tomography\u003c/p\u003e\n\u003cp\u003eMRI \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Magnetic resonance imaging\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTBA \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp;Tissue-based assay\u003c/p\u003e\n\u003cp\u003eCBA \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Cytometric cead array\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIVIG \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Intravenous immunoglobulins\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eATD \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Autoimmune thyroid disease\u003c/p\u003e\n\u003cp\u003ePLEX \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Plasma exchange\u003c/p\u003e\n\u003cp\u003eSCLC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Small-cell lung cancer\u003c/p\u003e\n\u003cp\u003eIAC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Internal auditory canal\u003c/p\u003e\n\u003cp\u003eFLAIR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Fluid-attenuated inversion recovery\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the husbands of both patients for their consent to share patients\u0026rsquo; information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eL.Q.Y. and X.Q.L. were involved in the identification, selection, and management of the patient and manuscript review. W.X.L. and Y.N.H. performed the clinical follow-up of the patient. L.Q.Y. wrote the initial paper. T.Z., S.M.T. and X.L. revised the paper; W.Y. had primary responsibility for the final content. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by Tianjin Key Medical Discipline (Specialty) Construction Project (No. TJYXZDXK-052B), Tianjin Health Commission Science and Technology Projects (TJWJ2021QN061 and ZC20134).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has been granted an exemption from requiring ethics approval by\u0026nbsp;Tianjin Huanhu Hospital\u0026nbsp;of\u0026nbsp;Tianjin Medical University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\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 to publish this Case report and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMcCabe BF. Autoimmune sensorineural hearing loss. The Annals of Otology, Rhinology, and Laryngology. 1979;88(5 Pt 1):585-9.\u003c/li\u003e\n\u003cli\u003eMijovic T, Zeitouni A, Colmegna I. 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Acta Otolaryngol. 1988;106(5-6):409-16.\u003c/li\u003e\n\u003cli\u003eGreene JJ, Keefe MW, Harris JP, Matsuoka AJ. Paraneoplastic syndrome: a masquerade of autoimmune inner ear disease. Otology \u0026amp; Neurotology : Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 2015;36(1):e3-10.\u003c/li\u003e\n\u003cli\u003eHammami MB, Eggers SDZ, Madhavan A, Montalvo MJ, Pittock SJ, Dubey D. Paraneoplastic cochleovestibulopathy: clinical presentations, oncological and serological associations. J Neurol Neurosurg Psychiatry. 2021;92(11):1181-5.\u003c/li\u003e\n\u003cli\u003eKattah JC, Eggers SD, Bach SE, Dubey D, McKeon AB. Paraneoplastic Progressive Downbeat Nystagmus, Ataxia and Sensorineural Hearing Loss due to the ANTI-Kelch-11 Protein Antibody. Journal of Neuro-ophthalmology : the Official Journal of the North American Neuro-Ophthalmology Society. 2021;41(2):261-5.\u003c/li\u003e\n\u003cli\u003eFioretti A, Di Rubbo V, Peri G, Vitti E, Cisternino S, Varakliotis T, et al. Cochlear Impairment and Autoimmune Ear Disorder in a Patient with Breast Cancer. Audiol Res. 2017;7(1):165.\u003c/li\u003e\n\u003cli\u003eRenna R, Plantone D, Batocchi AP. Teaching NeuroImages: a case of hearing loss in a paraneoplastic syndrome associated with anti-Hu antibody. Neurology. 2012;79(15):e134.\u003c/li\u003e\n\u003cli\u003eZhang S, Guo Z, Tian E, Liu D, Wang J, Kong W. Meniere disease subtyping: the direction of diagnosis and treatment in the future. Expert Rev Neurother. 2022;22(2):115-27.\u003c/li\u003e\n\u003cli\u003eLopez-Escamez JA, Carey J, Chung W-H, Goebel JA, Magnusson M, Mandal\u0026agrave; M, et al. Diagnostic criteria for Meni\u0026egrave;re\u0026apos;s disease. Journal of Vestibular Research : Equilibrium \u0026amp; Orientation. 2015;25(1):1-7.\u003c/li\u003e\n\u003cli\u003eLi J, Pan Y, Wang M, Meng X, Lin J, Li Z, et al. Predictive Role of hsCRP in Recurrent Stroke Differed According to Severity of Cerebrovascular Disease: Analysis from a Prospective Cohort Study. J Clin Med. 2023;12(4).\u003c/li\u003e\n\u003cli\u003eMandel-Brehm C, Dubey D, Kryzer TJ, O\u0026apos;Donovan BD, Tran B, Vazquez SE, et al. Kelch-like Protein 11 Antibodies in Seminoma-Associated Paraneoplastic Encephalitis. The New England Journal of Medicine. 2019;381(1):47-54.\u003c/li\u003e\n\u003cli\u003eCandler PM, Hart PE, Barnett M, Weil R, Rees JH. A follow up study of patients with paraneoplastic neurological disease in the United Kingdom. J Neurol Neurosurg Psychiatry. 2004;75(10):1411-5.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Paraneoplastic cochleovestibulopathy, Sensorineural hearing loss, Breast cancer, KLHL11-IgG, Neurological paraneoplastic syndrome, Case report","lastPublishedDoi":"10.21203/rs.3.rs-4751102/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4751102/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eParaneoplastic cochleovestibulopathy (PCVP) is an atypical neurological paraneoplastic syndrome characterized by rapidly progressive hearing loss with or without vestibular dysfunction, usually detectable malignancy, and paraneoplastic antibodies. PCVP is rare and easy to be misdiagnosed and mistreated. Previous studies have suggested that KLHL11-IgG and seminomas are associated with male patients. However, the tumors associated with female patients are not known.\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e \u003cp\u003eWe report two cases of middle-aged women with binaural sensorineural hearing loss (SNHL) as the first symptom. Pure tone audiograms showed binaural hearing impairment, brainstem auditory evoked potentials (BAEP) and cochlear electrograms were normal, and otoacoustic emissions showed binaural cochlear dysfunction. Intracranial organic lesions and vascular lesions were excluded by cranial imaging. After steroid treatment is invalid, the positron emission tomography/computedtomography (PET/CT) and pathologic examination, and breast cancer was screened. After treatment with endocrine therapy (patient \u003cb\u003e#\u003c/b\u003e1) and surgical excision (patient #2) for breast cancer, no significant improvement in pure tone average (PTA) was seen at the 1 year of follow-up.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003ePCVP should be considered in middle-aged patients presenting with progressive hearing loss in both ears without organic pathology, mostly with vestibular dysfunction and signs of cerebellar and brainstem pathology. Regular review of PET/CT is warranted. Female patients need to be concerned about breast cancer.\u003c/p\u003e","manuscriptTitle":"Two Cases of Paraneoplastic Cochleovestibulopathy with Detection of Breast Cancer and Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-17 01:25:32","doi":"10.21203/rs.3.rs-4751102/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-18T11:45:20+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-13T02:43:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"180587170332839588641944006782516036976","date":"2025-06-06T06:14:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-22T07:43:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"170836175264082137235972904490018921315","date":"2024-09-22T07:15:34+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-04T11:02:53+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-08-02T09:31:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-17T07:48:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-17T07:48:24+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2024-07-16T16:12:54+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":"a9f2a901-8e0f-41e1-8224-aa9942c87a26","owner":[],"postedDate":"August 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-15T16:03:49+00:00","versionOfRecord":{"articleIdentity":"rs-4751102","link":"https://doi.org/10.1186/s12883-025-04508-7","journal":{"identity":"bmc-neurology","isVorOnly":false,"title":"BMC Neurology"},"publishedOn":"2025-12-12 15:58:32","publishedOnDateReadable":"December 12th, 2025"},"versionCreatedAt":"2024-08-17 01:25:32","video":"","vorDoi":"10.1186/s12883-025-04508-7","vorDoiUrl":"https://doi.org/10.1186/s12883-025-04508-7","workflowStages":[]},"version":"v1","identity":"rs-4751102","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4751102","identity":"rs-4751102","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}