Atypical Cortical Presentation of Anti-Ri Paraneoplastic Encephalitis Mimicking Tumor

Atypical Cortical Presentation of Anti-Ri Paraneoplastic Encephalitis Mimicking Tumor | 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 Atypical Cortical Presentation of Anti-Ri Paraneoplastic Encephalitis Mimicking Tumor Seolah Lee This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7360882/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Purpose Anti-Ri paraneoplastic neurological syndrome (PNS) typically manifests as brainstem or cerebellar dysfunction and is most commonly associated with breast cancer. Methods and Results We report the case of a 54-year-old woman who presented with transient executive dysfunction, confusion, and headache. Brain MRI revealed a tumor-like lesion in the right frontal cortex. Stereotactic brain biopsy showed inflammatory changes without evidence of malignancy. Serum testing was strongly positive for anti-Ri antibodies, and systemic workup identified right breast cancer with axillary lymph node metastasis. The patient received breast cancer treatment alongside high-dose steroid pulse therapy and four weekly doses of rituximab, resulting in marked resolution of the cortical lesion and neurological symptoms. Conclusion To our knowledge, this is the first reported case of anti-Ri PNS involving the frontal cortex. While current PNS-Care diagnostic criteria enabled a definitive diagnosis, further investigation is warranted to elucidate the underlying pathomechanism of cortical involvement in anti-Ri PNS. Anti-Ri antibody Paraneoplastic neurological syndrome (PNS) #neocortical encephalitis breast cancer rituximab Figures Figure 1 Figure 2 Introduction The diagnostic criteria of paraneoplastic neurological syndrome (PNS) —referring to immune-mediated neurological disorders triggered by a systemic cancer, but not by direct invasion or metastasis—had evolved to address symptoms that has true association with cancer rather than coincidental [1, 2]. This association is often supported by epidemiological evidence or the presence of mediating antibodies. However, the precise mechanisms by which these antibodies contribute to neurological disorder remain incompletely understood [2]. Anti-Ri antibody is a well-characterized onconeural antibody typically associated with cerebellar and brainstem involvement. However, a recent systematic review suggests much heterogeneous clinical manifestations and involvement of multiple systems [3]. Here, we report a case of anti-Ri-positive paraneoplastic syndrome with predominant frontal lobe involvement, which has not been previously reported to our knowledge. A 54-year-old female with no prior medical history experienced a brief episode of motor aphasia in December 2024, which resolved spontaneously. From April 2025, she developed intermittent headaches and experienced difficulty executing familiar tasks - such as frying egg on the pan without removing the shell, froze during a payment transaction, or forgot how to hail a taxi. Each episode lasted less than five minutes. These symptoms gradually became more frequent, prompting medical evaluation. On presentation to the emergency department, she was neurologically intact. However, brain MRI revealed a tumefactive lesion in the left frontal cortex, showing high signal intensity on diffusion weighted image, T2/ FLAIR sequences, but no contrast enhancement (Fig. 1A, 1B, 1C). Brain spectroscopy showed borderline increment of Cho/Cr ratio (~1.92) raising the possibility of a tumorous lesion such as glioma. She was admitted for brain biopsy, during which the intraoperative frozen section showed no evidence of malignancy. She was subsequently referred to the Neurology Department for further evaluation. Cerebrospinal fluid analysis showed 10 white blood cells with normal protein levels and negative for malignancy. Multiplex PCR for infectious pathogens was also negative. Paraneoplastic antibody screening of serum revealed a strongly positive anti-Ri antibody. Systemic malignancy screening, including chest and abdominal CT, breast MRI and FDG-PET/CT revealed a BI-RADS category 5 lesion in the right breast and axilla (Fig. 2B, 2C). By the time she finished high-dose methylprednisolone (1 g/day for 5 days), the final brain pathology demonstrated perivascular lymphoid infiltration, with no evidence of neoplasm. With no alternative diagnosis explaining the cortical lesion, she was diagnosed with anti-Ri-associated paraneoplastic encephalitis and started on rituximab. Meanwhile, core needle biopsy of the breast confirmed a ER/PR-positive, HER2/neu-negative, EGFR-negative carcinoma with lymph node metastasis. The patient underwent total mastectomy with sentinel lymph node biopsy, followed by adjuvant chemotherapy. Follow-up brain MRI after four weekly doses of rituximab showed complete resolution of the previously noted FLAIR hyperintensity (Fig. 1D,1E, 1F). Neurologically, she remained asymptomatic. According to the PNS-Care diagnostic criteria, the diagnosis of PNS is based on a scoring system across three weighted axes—clinical phenotype, antibody profile, and associated cancer—with the total score determining the level of diagnostic certainty [2]. However, these axes are not fully independent. While high-risk phenotypes are explicitly defined in the criteria, intermediate-risk phenotypes are determined based on the type of antibody and its known epidemiologic associations. For example, extra-limbic autoimmune encephalitis qualifies as intermediate phenotype when it has high or intermediate-risk antibody. Our patient fulfilled the criteria for probable PNS based solely on the presence of a high-risk antibody (3 points) and an associated malignancy (4 points), even without taking the clinical phenotype into account. This means that the diagnosis of probable PNS would have been justified even if her neurological presentation had been entirely novel or previously unreported. In fact, she had cortical encephalitis—a recognized intermediate-risk phenotype in conjunction with a high-risk antibody—allowing classification as definite PNS . The lack of a clearly defined set of intermediate phenotypes expands the possible clinical spectrum of PNS. However, it also introduces ambiguity, making it challenging to definitively rule out PNS in atypical presentation. In a large cohort study by Francesc et al., a broad spectrum of clinical presentations associated with anti-Ri antibodies was reported, including parkinsonism, stiff-person syndrome, and even confusional states, as seen in our patient [3]. The lesions were predominantly located in the brainstem, but also involved the caudate nucleus, spinal cord, thalamus, and medial temporal lobes. In other case reports, patients presented with cortical symptoms, such as seizures or confusion, with corresponding lesions in the insular or medial temporal cortex concurrent with anti Ri antibody [4-6]. The targets of anti-Ri antibodies are NOVA1 and NOVA2, neuron-specific RNA-binding proteins that regulate the alternative splicing of synaptic genes [7]. NOVA1 is primarily localized to the developing ventral brainstem, cerebellum, and spinal cord, whereas NOVA2 is more broadly expressed in the cortex and hippocampus . This distribution suggests that cortical involvement in anti-Ri encephalitis may be biologically plausible, particularly if NOVA2 is the predominant antigenic target. However, to definitively establish this mechanism, direct demonstration of anti-Ri IgG binding within the affected cortical tissue—such as through brain biopsy—would be necessary. Although both NOVA proteins serve as antigenic targets of anti-Ri antibodies, the predominance of clinical involvement in regions corresponding to NOVA1 expression, such as the brainstem and cerebellum, remains poorly understood and warrants further investigation. One possible explanation is that NOVA1 may be more densely expressed or that anti-Ri antibodies have differing affinities for NOVA1 and NOVA2, though this remains speculative. To our knowledge, this is the first reported case of anti-Ri-associated paraneoplastic syndrome with primary involvement of the frontal neocortex. This case expands the known clinical and radiological spectrum of anti-Ri PNS and highlights the need for more nuanced understanding of phenotype-antibody-cancer relationships within the existing diagnostic criteria. Declarations This research received no external funding. The authors declare no conflict of interest. Ethics Statement This case report was conducted in accordance with the principles outlined in the Declaration of Helsinki. Informed consent was obtained from the patient for the participation in the study and publication of this case report and any accompanying images. References Graus, F., et al., Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry, 2004. 75 (8): p. 1135-40. Graus, F., et al., Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes. Neurol Neuroimmunol Neuroinflamm, 2021. 8 (4). Simard, C., et al., Clinical spectrum and diagnostic pitfalls of neurologic syndromes with Ri antibodies. Neurol Neuroimmunol Neuroinflamm, 2020. 7 (3). Pittock, S.J., C.F. Lucchinetti, and V.A. Lennon, Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann Neurol, 2003. 53 (5): p. 580-7. Freydl, E., et al., Anti-Ri paraneoplastic neurological syndrome presenting with bilateral cranial nerve VI palsy and jaw dystonia-a distinctive syndrome within the anti-Ri spectrum? : Case report and literature review. Wien Med Wochenschr, 2024. 174 (1-2): p. 16-21. Novy, J., et al., Encephalitis with herpes simplex-2 in the cerebrospinal fluid and anti-RI (ANNA-2) antibodies: an infectious or a paraneoplastic syndrome? BMJ Case Rep, 2009. 2009 . Hormigo, A., et al., Immunological and pathological study of anti-Ri-associated encephalopathy. Ann Neurol, 1994. 36 (6): p. 896-902. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 28 Oct, 2025 Reviews received at journal 23 Oct, 2025 Reviewers agreed at journal 22 Oct, 2025 Reviews received at journal 18 Oct, 2025 Reviewers agreed at journal 29 Sep, 2025 Reviewers invited by journal 29 Sep, 2025 Editor invited by journal 25 Sep, 2025 Editor assigned by journal 08 Sep, 2025 Submission checks completed at journal 05 Sep, 2025 First submitted to journal 05 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7360882","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":527048973,"identity":"c001eb0f-980f-471e-ace4-d66646dc5a2a","order_by":0,"name":"Seolah Lee","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIie3QsUoDMRjA8YTA3XKnazvovcInncQrDr5IDuFc2mfw5CBZqvN16it0Kh0TPtAlD1DI5K5w3apUaK6bg3fnJpj/EAjkR/KFEJ/vb0YVLdLzIJRK1W4bhD2MI/noNDKZrhrC+hHM5hUfYdRsu0giS6U+1kiXRnFMP1fJCSO03k5+JmCeuX40dwxeHhROn+yFYIQN56sWMpiAisVVAM0t05mljgQsbiHJ4g30l2ARbDjg5cxedxKyiQBjcTMYVo6Qnc06CZic45nIwX2yG6qwt4LRsnWWRKJ+fRfpvQgl1ru9HS9kqett28O+RcVxLfqeb9r/5rDP5/P9lw6d1V3WNedcTAAAAABJRU5ErkJggg==","orcid":"","institution":"Chung-ang University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Seolah","middleName":"","lastName":"Lee","suffix":""}],"badges":[],"createdAt":"2025-08-13 05:08:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7360882/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7360882/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":93337272,"identity":"97ef8223-dd77-4006-8b6e-2dd308d88767","added_by":"auto","created_at":"2025-10-12 14:08:38","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1124805,"visible":true,"origin":"","legend":"","description":"","filename":"finalfileAntiRiencephalitis1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7360882/v1/aeea9ab1e7338b509cfa5b1f.docx"},{"id":93337322,"identity":"ebc14235-63df-40c2-8ffc-1ed523862559","added_by":"auto","created_at":"2025-10-12 14:08:41","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3008,"visible":true,"origin":"","legend":"","description":"","filename":"c7d57615eb9546b4acac43084ba9d485.json","url":"https://assets-eu.researchsquare.com/files/rs-7360882/v1/a036550285657a2c5d7648c7.json"},{"id":93337273,"identity":"72518877-c3e3-4a35-8593-42316945e5c1","added_by":"auto","created_at":"2025-10-12 14:08:38","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":21933,"visible":true,"origin":"","legend":"","description":"","filename":"c7d57615eb9546b4acac43084ba9d4851enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7360882/v1/bd0fc60d62d883a5bbed6ecc.xml"},{"id":93337270,"identity":"041fa8c5-67b9-4e5e-9b80-2249d5345732","added_by":"auto","created_at":"2025-10-12 14:08:37","extension":"jpeg","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":830203,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7360882/v1/38b61e79e7c808f04e5cb222.jpeg"},{"id":93337302,"identity":"35e2a62e-212f-416a-8b5e-53456b900734","added_by":"auto","created_at":"2025-10-12 14:08:40","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":179456,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7360882/v1/fef822bd9cdc96d90f66a8cb.png"},{"id":93337304,"identity":"3676ce87-2877-48ee-a2a6-b6fa91bb1f93","added_by":"auto","created_at":"2025-10-12 14:08:41","extension":"xml","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":21074,"visible":true,"origin":"","legend":"","description":"","filename":"c7d57615eb9546b4acac43084ba9d4851structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7360882/v1/736897277ab2ead895187d06.xml"},{"id":93337303,"identity":"81a00f2a-4faa-42a8-b214-8441bf3f506e","added_by":"auto","created_at":"2025-10-12 14:08:40","extension":"html","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":24676,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7360882/v1/16c5b9114ac0e5d76dbb353e.html"},{"id":93337301,"identity":"30449803-7af1-402b-85a7-fd2f3d0669a5","added_by":"auto","created_at":"2025-10-12 14:08:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":210947,"visible":true,"origin":"","legend":"\u003cp\u003eDWI, T2/FLAIR and T1/CE images of the patient at initial presentation show a tumor-like lesion in the right frontal cortex (A-C). Follow-up images after high-dose steroid pulse therapyand four weekly doses of rituximab demonstrate marked improvement (D-F).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7360882/v1/9997a03df6de87e19a741a70.png"},{"id":93337271,"identity":"2fd2ac9a-8252-47de-a195-bc518bac5935","added_by":"auto","created_at":"2025-10-12 14:08:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":66362,"visible":true,"origin":"","legend":"\u003cp\u003eWhole-body PET scan revealed decreased FDG uptake in the cortical lesion (A), with FDG-avid lesions observed in the right breast (B) and right axilla (C).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7360882/v1/8244de81967fe231724b6a47.png"},{"id":93337357,"identity":"5740e91f-19a3-4b83-855b-9be4ffaa6f31","added_by":"auto","created_at":"2025-10-12 14:08:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":509616,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7360882/v1/48a968da-5abb-4b97-b6f5-8f6cd6adbcdc.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Atypical Cortical Presentation of Anti-Ri Paraneoplastic Encephalitis Mimicking Tumor","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe diagnostic criteria of \u003cem\u003eparaneoplastic neurological syndrome (PNS)\u003c/em\u003e—referring to immune-mediated neurological disorders triggered by a systemic cancer, but not by direct invasion or metastasis—had evolved to address symptoms that has true association with cancer rather than coincidental [1, 2]. This association is often supported by epidemiological evidence or the presence of mediating antibodies. However, the precise mechanisms by which these antibodies contribute to neurological disorder remain incompletely understood [2].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnti-Ri antibody is a well-characterized onconeural antibody typically associated with cerebellar and brainstem involvement. However, a recent systematic review suggests much heterogeneous clinical manifestations and involvement of multiple systems [3]. Here, we report a case of \u003cem\u003eanti-Ri-positive\u003c/em\u003e paraneoplastic syndrome with predominant frontal lobe involvement, which has not been previously reported to our knowledge.\u003c/p\u003e\n\u003cp\u003eA 54-year-old\u0026nbsp;female with no prior medical history experienced a brief episode of motor aphasia in December 2024, which resolved spontaneously. From April 2025, she developed intermittent headaches and experienced difficulty executing familiar tasks - such as frying egg on the pan without removing the shell, froze during a payment transaction, or forgot how to hail a taxi. Each episode lasted less than five minutes. These symptoms gradually became more frequent, prompting medical evaluation.\u003c/p\u003e\n\u003cp\u003eOn presentation to the emergency department, she was neurologically intact. However, brain MRI revealed a tumefactive lesion in the left frontal cortex, showing high signal intensity on diffusion weighted image, T2/ FLAIR sequences, but no contrast enhancement (Fig. 1A, 1B, 1C). Brain spectroscopy showed borderline increment of Cho/Cr ratio (~1.92) raising the possibility of a tumorous lesion such as glioma. She was admitted for brain biopsy, during which the intraoperative frozen section showed no evidence of malignancy. She was subsequently referred to the Neurology Department for further evaluation.\u003c/p\u003e\n\u003cp\u003eCerebrospinal fluid analysis showed 10 white blood cells with normal protein levels and negative for malignancy. Multiplex PCR for infectious pathogens was also negative. Paraneoplastic antibody screening of serum revealed a strongly positive anti-Ri antibody. Systemic malignancy screening, including chest and abdominal CT, breast MRI and FDG-PET/CT revealed a BI-RADS category 5 lesion in the right breast and axilla (Fig. 2B, 2C).\u003c/p\u003e\n\u003cp\u003eBy the time she finished high-dose methylprednisolone (1 g/day for 5 days), the final brain pathology demonstrated perivascular lymphoid infiltration, with no evidence of neoplasm. With no alternative diagnosis explaining the cortical lesion, she was diagnosed with anti-Ri-associated paraneoplastic encephalitis and started on rituximab.\u003c/p\u003e\n\u003cp\u003eMeanwhile, core needle biopsy of the breast confirmed a ER/PR-positive, HER2/neu-negative, EGFR-negative carcinoma with lymph node metastasis. The patient underwent total mastectomy with sentinel lymph node biopsy, followed by adjuvant chemotherapy. Follow-up brain MRI after four weekly doses of rituximab showed complete resolution of the previously noted FLAIR hyperintensity (Fig. 1D,1E, 1F). Neurologically, she remained asymptomatic.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAccording to the PNS-Care diagnostic criteria, the diagnosis of PNS is based on a scoring system across three weighted axes—clinical phenotype, antibody profile, and associated cancer—with the total score determining the level of diagnostic certainty [2]. However, these axes are not fully independent. While high-risk phenotypes are explicitly defined in the criteria, intermediate-risk phenotypes are determined based on the type of antibody and its known epidemiologic associations. For example, extra-limbic autoimmune encephalitis qualifies as intermediate phenotype when it has high or intermediate-risk antibody.\u003c/p\u003e\n\u003cp\u003eOur patient fulfilled the criteria for \u003cstrong\u003eprobable PNS\u003c/strong\u003e based solely on the presence of a high-risk antibody (3 points) and an associated malignancy (4 points), even without taking the clinical phenotype into account. This means that the diagnosis of probable PNS would have been justified even if her neurological presentation had been entirely novel or previously unreported. In fact, she had cortical encephalitis—a recognized intermediate-risk phenotype in conjunction with a high-risk antibody—allowing classification as \u003cstrong\u003edefinite PNS\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe lack of a clearly defined set of intermediate phenotypes expands the possible clinical spectrum of PNS. However, it also introduces ambiguity, making it challenging to definitively rule out PNS in atypical presentation. In a large cohort study by Francesc et al., a broad spectrum of clinical presentations associated with anti-Ri antibodies was reported, including parkinsonism, stiff-person syndrome, and even confusional states, as seen in our patient [3]. The lesions were predominantly located in the brainstem, but also involved the caudate nucleus, spinal cord, thalamus, and medial temporal lobes. In other case reports, patients presented with cortical symptoms, such as seizures or confusion, with corresponding lesions in the insular or medial temporal cortex concurrent with anti Ri antibody [4-6].\u003c/p\u003e\n\u003cp\u003eThe targets of anti-Ri antibodies are NOVA1 and NOVA2, neuron-specific RNA-binding proteins that regulate the alternative splicing of synaptic genes [7]. NOVA1 is primarily localized to the developing ventral brainstem, cerebellum, and spinal cord, whereas NOVA2 is more broadly expressed in the cortex and hippocampus . This distribution suggests that cortical involvement in anti-Ri encephalitis may be biologically plausible, particularly if NOVA2 is the predominant antigenic target. However, to definitively establish this mechanism, direct demonstration of anti-Ri IgG binding within the affected cortical tissue—such as through brain biopsy—would be necessary.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough both NOVA proteins serve as antigenic targets of anti-Ri antibodies, the predominance of clinical involvement in regions corresponding to NOVA1 expression, such as the brainstem and cerebellum, remains poorly understood and warrants further investigation. One possible explanation is that NOVA1 may be more densely expressed or that anti-Ri antibodies have differing affinities for NOVA1 and NOVA2, though this remains speculative.\u003c/p\u003e\n\u003cp\u003eTo our knowledge, this is the first reported case of anti-Ri-associated paraneoplastic syndrome with primary involvement of the frontal neocortex. This case expands the known clinical and radiological spectrum of anti-Ri PNS and highlights the need for more nuanced understanding of phenotype-antibody-cancer relationships within the existing diagnostic criteria.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case report was conducted in accordance with the principles outlined in the Declaration of Helsinki. Informed consent was obtained from the patient for the participation in the study and publication of this case report and any accompanying images.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGraus, F., et al., \u003cem\u003eRecommended diagnostic criteria for paraneoplastic neurological syndromes.\u003c/em\u003e J Neurol Neurosurg Psychiatry, 2004. \u003cstrong\u003e75\u003c/strong\u003e(8): p. 1135-40.\u003c/li\u003e\n\u003cli\u003eGraus, F., et al., \u003cem\u003eUpdated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes.\u003c/em\u003e Neurol Neuroimmunol Neuroinflamm, 2021. \u003cstrong\u003e8\u003c/strong\u003e(4).\u003c/li\u003e\n\u003cli\u003eSimard, C., et al., \u003cem\u003eClinical spectrum and diagnostic pitfalls of neurologic syndromes with Ri antibodies.\u003c/em\u003e Neurol Neuroimmunol Neuroinflamm, 2020. \u003cstrong\u003e7\u003c/strong\u003e(3).\u003c/li\u003e\n\u003cli\u003ePittock, S.J., C.F. Lucchinetti, and V.A. Lennon, \u003cem\u003eAnti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments.\u003c/em\u003e Ann Neurol, 2003. \u003cstrong\u003e53\u003c/strong\u003e(5): p. 580-7.\u003c/li\u003e\n\u003cli\u003eFreydl, E., et al., \u003cem\u003eAnti-Ri paraneoplastic neurological syndrome presenting with bilateral cranial nerve VI palsy and jaw dystonia-a distinctive syndrome within the anti-Ri spectrum? : Case report and literature review.\u003c/em\u003e Wien Med Wochenschr, 2024. \u003cstrong\u003e174\u003c/strong\u003e(1-2): p. 16-21.\u003c/li\u003e\n\u003cli\u003eNovy, J., et al., \u003cem\u003eEncephalitis with herpes simplex-2 in the cerebrospinal fluid and anti-RI (ANNA-2) antibodies: an infectious or a paraneoplastic syndrome?\u003c/em\u003e BMJ Case Rep, 2009. \u003cstrong\u003e2009\u003c/strong\u003e.\u003c/li\u003e\n\u003cli\u003eHormigo, A., et al., \u003cem\u003eImmunological and pathological study of anti-Ri-associated encephalopathy.\u003c/em\u003e Ann Neurol, 1994. \u003cstrong\u003e36\u003c/strong\u003e(6): p. 896-902.\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":"discover-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dion","sideBox":"Learn more about [Discover Oncology](https://www.springer.com/12672)","snPcode":"","submissionUrl":"","title":"Discover Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Anti-Ri antibody, Paraneoplastic neurological syndrome (PNS) #neocortical encephalitis, breast cancer, rituximab","lastPublishedDoi":"10.21203/rs.3.rs-7360882/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7360882/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePurpose\u003c/p\u003e\n\u003cp\u003eAnti-Ri paraneoplastic neurological syndrome (PNS) typically manifests as brainstem or cerebellar dysfunction and is most commonly associated with breast cancer.\u003c/p\u003e\n\u003cp\u003eMethods and Results\u003c/p\u003e\n\u003cp\u003eWe report the case of a 54-year-old woman who presented with transient executive dysfunction, confusion, and headache. Brain MRI revealed a tumor-like lesion in the right frontal cortex. Stereotactic brain biopsy showed inflammatory changes without evidence of malignancy. Serum testing was strongly positive for anti-Ri antibodies, and systemic workup identified right breast cancer with axillary lymph node metastasis. The patient received breast cancer treatment alongside high-dose steroid pulse therapy and four weekly doses of rituximab, resulting in marked resolution of the cortical lesion and neurological symptoms.\u003c/p\u003e\n\u003cp\u003eConclusion\u003c/p\u003e\n\u003cp\u003eTo our knowledge, this is the first reported case of anti-Ri PNS involving the frontal cortex. While current PNS-Care diagnostic criteria enabled a definitive diagnosis, further investigation is warranted to elucidate the underlying pathomechanism of cortical involvement in anti-Ri PNS.\u003c/p\u003e","manuscriptTitle":"Atypical Cortical Presentation of Anti-Ri Paraneoplastic Encephalitis Mimicking Tumor","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-12 14:08:21","doi":"10.21203/rs.3.rs-7360882/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-28T05:38:35+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-23T14:45:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"289164860599194313993528383903481699868","date":"2025-10-22T16:38:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-18T14:34:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"225540799796998300317344184841455220720","date":"2025-09-29T12:42:56+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-29T10:36:51+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-25T07:11:30+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-08T12:18:39+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-05T08:26:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Discover Oncology","date":"2025-09-05T08:24:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"discover-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dion","sideBox":"Learn more about [Discover Oncology](https://www.springer.com/12672)","snPcode":"","submissionUrl":"","title":"Discover Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d0f636f6-b081-45cf-ba9d-e3172a364c48","owner":[],"postedDate":"October 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-27T07:26:00+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-12 14:08:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7360882","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7360882","identity":"rs-7360882","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}