Tolosa-Hunt Syndrome with Highly Elevated Interleukin 6 Levels: Case Report

Tolosa-Hunt Syndrome with Highly Elevated Interleukin 6 Levels: Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Tolosa-Hunt Syndrome with Highly Elevated Interleukin 6 Levels: Case Report Robert Fekete This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6341031/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Ophthalmoplegic migraine was first defined by Charcot as "a condition associated with migraine in which there is a palsy of an ocular nerve, usually the third, temporary at first and later becoming permanent." Under current International Classification of Headache Disorders (ICHD) third edition criteria, ophthalmoplegic migraine requires absence of a mass lesions, whereas a granulomatous periorbital lesion is required for the diagnosis of Tolosa-Hunt syndrome which is considered to be idiopathic orbital inflammation and causes orbital pain with ipsilateral cranial nerve palsy. Most cases improve with steroids. Case report The patient is a 42-year-old Hispanic female with Peruvian ancestry who presented with episodes of diplopia, proptosis, and eye pain. She had a severe episode 10 years ago which led to horizontal diplopia as well as another episode 4 years ago. Both episodes resolved with about five weeks of oral methylprednisolone dosing. There is complete relief of diplopia between these episodes. She is maintained on oral methylprednisolone 6-day dose pack about twice yearly for orbital pain. At the time of the diplopia 4 years ago, Magnetic Resonance Imaging showed a left cavernous sinus mass, which resolved on subsequent imaging. Her Interleukin 6 (IL-6) serum level done outside of the episodes was highly elevated at 90.5 pg/ml (normal <5 pg/ml). Discussion The pathology of the original case of Dr. Eduardo Tolosa was reviewed by Hunt et al. in 1961. While the pathology of Tolosa-Hunt syndrome is generally described as granulomatous, the slides showed a lymphocyte and plasma cell infiltrate, scarcity of blood vessels, and proliferation of fibroblasts leading to fibrosis. It is possible that prolonged IL-6 stimulation leads to inappropriate B and T-cell terminal differentiation which supports the lymphoplasmacytic lesion in Dr. Tolosa’s case. The possibility of fibrosis means that early treatment with steroids is important in preventing cumulative damage. Neurology Tolosa-Hunt Syndrome Interleukin-6 IL-6 ophthalmoplegic migraine cavernous sinus Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Charcot initially defined ophthalmoplegic migraine as "a condition associated with migraine in which there is a palsy of an ocular nerve, usually the third, temporary at first and later becoming permanent" [1]. Hunt in 1961 discussed painful ophthalmoplegia as being associated with low grade inflammation of the carotid sinus and having pain that is described as “boring or gnawing” as opposed to throbbing pain of classical migraine [2]. Under International Classification of Headache Disorders (ICHD) (second edition) the syndrome was reclassified under cranial neuropathies but still retained the migraine name [3]. In the third edition of ICHD, it is called Recurrent Painful Ophthalmoplegic Cranial Neuropathy (RPON) and requires absence of mass lesion [4]. On the other hand, Tolosa-Hunt syndrome is defined as unilateral pain associated with cranial nerve paresis caused by granulomatous inflammation in the cavernous sinus [4]. Case report The patient is a 42-year-old Hispanic female with Peruvian ancestry who presented with episodes of diplopia, proptosis, and eye pain. Ten years ago, she had an episode of severe left trigeminal V1 distribution and retro orbital pain, proptosis and diplopia horizontally with 6th nerve palsy. There was no otitis media to form the triad of Gradenigo syndrome. There was no contributory family history. Initial non-contrast Magnetic Resonance Imaging (MRI) brain was normal on coronal T2 fat-saturated coronal (Supplementary File 1) and Spectral Attenuated Inversion Recovery (SPAIR) images (Supplementary File 2). She was diagnosed with ophthalmoplegic migraine [4,5]. The associated headaches were migraine - like with 8/10 sharp pain, photophobia, phonophobia, and nausea with diplopia occurring at same time as headache. Headache and diplopia would last for about a week. Headache would improve when she stopped activity and went to a dark room. Her examination was significant for proptosis of the left eye and partial left sixth nerve palsy. The second severe episode with the same symptoms happened four years ago. This was treated with methylprednisolone 4 mg twice a day for a month and one methylprednisolone 4 mg, 6 day, 21 tablet dose pack with full resolution of symptoms. The first episode also resolved after the introduction of methylprednisolone 4 mg twice daily for a month. Given Magnetic Resonance Imaging (MRI) finding of left cavernous sinus mass, she was diagnosed with Tolosa-Hunt Syndrome in accordance with International Classification of Headache Disorders (ICHD)-II criteria for the Tolosa-Hunt syndrome [4,6]. Subsequently, she would experience up to 3 episodes per year of left retroorbital pain without proptosis or diplopia, treated with just one 21 tablet methylprednisolone dose pack at a time with resolution. MRI brain performed 4 years ago demonstrated mass like enlargement of the left cavernous sinus on a type of 3D Fluid-Attenuated Inversion Recovery (FLAIR) MRI sequence that used compressed sensing (SHC) and spatial sensitivity encoding (SENSE) technique in the postcontrast axial (Figure 1) and coronal (Figure 2) views. The region of enhancement was defined as 18 mm by 5 mm by 17 mm in size. Follow up MRI brain performed 8 months later showed a decreased size of the left cavernous sinus on axial T2 weighted Spectral Presaturation with Inversion Recovery (SPIR) sequence (Figure 3). T2 SPIR coronal imaging two years ago showed resolution of the left cavernous sinus mass (Figure 4). A year ago, she had normal inflammatory markers including erythrocyte sedimentation rate of 2 (0-20 normal range), C-reactive protein of <0.1 mg/dl (normal less than 0.10 mg/dl), angiotensin converting enzyme level was 23 U/L (normal 9-67), C1q at 6.0 mg/dl (normal 5-8.6 mg/dl) normal anti-neutrophil cytoplasmic antibodies (ANCA) (normal <20), and normal anti-Double-Stranded DNA (dsDNA) antibody (<12.3 International Units per ml). Given a positive anti-nuclear antibody at 1:80, speckled appearance, and low C3 at 65 mg/dl (normal 83-180 mg/dl) and C4 at 8 mg/dl (normal 18-45 mg/dl), she was referred to rheumatology and was deemed to not have systemic lupus erythematosus given normal anti-dsDNA antibody. Her cytokines were significant for Interleukin 10 (IL-10) elevated to 5.0 pg/mL (normal <=2.8). Interleukin 6 (IL-6) was elevated to 90.5 pg/mL (normal <=2.0). Other cytokines, IgG subtypes, and IgA subtypes were normal (Supplementary file 3). She is currently asymptomatic except for occasional mild headaches. She takes the 21-tablet methylprednisolone dose pack twice a year on average as needed for headaches that become moderate in intensity. Discussion Tolosa Hunt syndrome is considered to be a syndrome of idiopathic orbital inflammation. A granulomatous lesion either by biopsy or MRI visualization is required for the diagnosis [4]. Most cases of Tolosa Hunt syndrome improve with steroids. This patient had extremely elevated IL-6 during clinical remission. One of the prior names of IL-6 was B cell stimulatory factor – 2 (BSF-2), given its ability to trigger differentiation of activated B cells into antibody producing plasma cells [7]. IL-6 can also activate T-cells. In systemic lupus erythematosus (SLE), this process leads to autoantibody production. Elevated systemic IL-6 has been shown in SLE [8]. Perhaps a similar process involving B-cell and T-cell activation is occurring in Tolosa-Hunt syndrome via IL-6. The pathology of the original case of Dr. Eduardo Tolosa was reviewed by Hunt et al. in 1961 [2]. The slides show a lymphocyte and plasma cell infiltrate, scarcity of blood vessels, and proliferation of fibroblasts leading to fibrosis. There was constriction of the internal carotid artery. This pathological finding bears striking similarity to the IgG4-related disease (IgG4-RD) diagnostic criteria, except that the layering of fibrosis is linear as opposed to the spoke wheel type of fibrosis in IgG4-RD [9]. Unlike in most cases of IgG4-RD, the IgG subsets are normal, soluble interleukin-2 receptor subunit alpha and transforming growth factor beta-1 are also normal in this patient. Magnetic resonance angiography (MRA) of the head and neck was normal in this patient. While Tolosa-Hunt syndrome does resolve clinically and radiologically after oral steroid administration, the presence of fibrosis on Dr. Tolosa’s case raises the possibility of cumulative pathology. Prompt administration of steroids would be helpful in reducing the risk of fibrosis. Screening MRA given constriction of the internal carotid artery in Dr. Tolosa’s case report may be considered. Declarations Patient perspective The patient appreciates the opportunity to share information the diagnosis and treatment of her rare disorder. Acknowledgements None. Declarations Ethics approval and consent to participate Written informed consent was obtained from the patient for participation in this case report however, no ethical approval was needed. "The institution’s policy, therefore, is that a case report is not research that must be approved by the IRB." New York Medical College Policies and Procedures for the Conduct of Research Involving Human Subjects. [https://www.nymc.edu/media/schools-andcolleges/nymc/pdf/human-subjects-research/IRBmanual.pdf] Accessed on 3/24/2025. Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Availability of data All supporting data were included in this manuscript. Patient clinical data is protected by the United States Health Insurance Portability and Accountability Act (HIPAA) of 1996. Competing interests The author declares that he does not have any competing interests Funding None. Author contributions RF: conception, data acquisition, writing, and revising References Harrington DO, Flocks M. Ophthalmoplegic migraine. AMA Arch Ophthalmol. 1953;49(6):643-655. doi:10.1001/archopht.1953.00920020656005 Hunt WE, Meagher JH, LeFever HE, Zeman W. Painful ophthalmoplegia: Its relation to indolent inflammation of the cavernous sinus. Neurology. 11(1):56 https://doi.org/10.1212/WNL.11.1.56 Gelfand AA, Gelfand JM, Prabakhar P, Goadsby PJ. Ophthalmoplegic “Migraine” or Recurrent Ophthalmoplegic Cranial Neuropathy: New Cases and a Systematic Review. J Child Neurol. 2012 Jan 12;27(6):759–766. doi: 10.1177/0883073811426502 No authors listed. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018 Jan;38(1):1-211. doi: 10.1177/0333102417738202. Chakravarty A, Mukherjee A. Ophthalmoplegic migraine: A critical analysis and a new proposal. Ann Indian Acad Neurol. 2012 Aug;15(Suppl 1):S2–S6. doi: 10.4103/0972-2327.99985 PMCID: PMC3444213 PMID: 23024560 Colnaghi S, Versino M, Marchioni E, et al. ICHD-II diagnostic criteria for Tolosa-Hunt syndrome in idiopathic inflammatory syndromes of the orbit and/or the cavernous sinus. Cephalalgia. 2008 Jun;28(6):577-84. doi: 10.1111/j.1468-2982.2008.01569.x. Epub 2008 Mar 31. Tanaka T, Masahashi N, Kishimoto T. IL-6 in Inflammation, Immunity, and Disease. Cold Spring Harb Perspect Biol. 2014 Oct;6(10):a016295. doi: 10.1101/cshperspect.a016295 Ding J, Su S, You T, et al. Serum interleukin-6 level is correlated with the disease activity of systemic lupus erythematosus: a meta-analysis. Clinics (Sao Paulo). 2020 Oct 5;75:e1801. doi: 10.6061/clinics/2020/e1801 PMCID: PMC7536892 PMID: 33084768 Deshpande V, Zen Y, Chan JKC, et al. Consensus statement on the pathology of IgG4-related disease. Modern Pathology. 25(9):1181-92. https://doi.org/10.1038/modpathol.2012.72 Additional Declarations The authors declare no competing interests. Supplementary Files supplementaryfile1.png Supplementary File 1: Initial normal non-contrast MRI brain coronal T2 fat-saturated coronal image obtained 10 years ago. supplementaryfile2.png Supplementary File 2: Initial normal non-contrast coronal MRI Spectral Attenuated Inversion Recovery (SPAIR) image obtained 10 years ago SupplementaryFile3.docx Supplementary File 3: Laboratory results Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6341031","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":436066932,"identity":"a834790a-ff3d-49c4-8c7b-788f7f11853d","order_by":0,"name":"Robert Fekete","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYFACHhAhxyABoj42gEjGxgOEtSQYA7UwMzDObABpZWwgXgszbwPENrxazNt7Dz6u/GEgJ9nef/Cx7Q6bOt32w0BbamyicWmROXMu2fBMgoGxNM9hZuPcM2kSZmcSgVqOpeU24NAiIZFjJtmQ8CdxnkQym3Ru22EJswNALYwNh/FpMf/ZkGBQP0/+MftvS5CW8w8JajFjBGpJkJZgZmNmBGm5QcgWnnPJkg1pBoYze5KNJXvb0iS33QDakoDPL+y9Bz822BjISxw/+PDDzzYbfrPz6Q8ffKixwakFB0ggTfkoGAWjYBSMAjQAAO/dXF4eaCYtAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-0627-8340","institution":"New York Medical College","correspondingAuthor":true,"prefix":"","firstName":"Robert","middleName":"","lastName":"Fekete","suffix":""}],"badges":[],"createdAt":"2025-03-31 02:41:09","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":true,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6341031/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6341031/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":79673904,"identity":"5aa6c9ad-a5b7-414d-a381-1348d9c3a705","added_by":"auto","created_at":"2025-04-01 11:51:21","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1072696,"visible":true,"origin":"","legend":"\u003cp\u003ePost-contrast axial Magnetic Resonance Imaging (MRI) image obtained 4 years ago with arrow showing left cavernous sinus mass\u003c/p\u003e","description":"","filename":"figure1apngdonearrow.png","url":"https://assets-eu.researchsquare.com/files/rs-6341031/v1/96a17ea2e3311457ba952498.png"},{"id":79673907,"identity":"1022a7a9-709a-4e84-92f4-6d391dccf10e","added_by":"auto","created_at":"2025-04-01 11:51:21","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1131716,"visible":true,"origin":"","legend":"\u003cp\u003ePost-contrast coronal MRI image obtained 4 years ago with arrow showing left cavernous sinus mass\u003c/p\u003e","description":"","filename":"figure2apngdonearrow.png","url":"https://assets-eu.researchsquare.com/files/rs-6341031/v1/b8c376d6ae42942ba1e16ace.png"},{"id":79673919,"identity":"ed57edf7-3349-4e83-965d-1ba021cd1265","added_by":"auto","created_at":"2025-04-01 11:51:21","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":750453,"visible":true,"origin":"","legend":"\u003cp\u003eFollow-up MRI brain showing a decreased size of the left cavernous sinus on axial T2 weighted Spectral Presaturation with Inversion Recovery (SPIR) sequence\u003c/p\u003e","description":"","filename":"figure3axialpngdone.png","url":"https://assets-eu.researchsquare.com/files/rs-6341031/v1/b61372ca8a2bdd44f10f79f2.png"},{"id":79674994,"identity":"f1d8a63f-88ef-4794-a83e-30fcb3c03bd6","added_by":"auto","created_at":"2025-04-01 11:59:21","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":514459,"visible":true,"origin":"","legend":"\u003cp\u003eT2 SPIR MRI coronal image obtained two years ago showing resolution of the left cavernous sinus mass\u003c/p\u003e","description":"","filename":"figure4pngdone.png","url":"https://assets-eu.researchsquare.com/files/rs-6341031/v1/e7d035c46535dca97461f3ed.png"},{"id":79675602,"identity":"040530e4-8b96-47e5-a283-bd5557bbf322","added_by":"auto","created_at":"2025-04-01 12:07:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3349004,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6341031/v1/8c5e5de9-b579-4b38-b26e-d9184a886904.pdf"},{"id":79673903,"identity":"516acc63-2c24-4708-9a1a-7821477ab17e","added_by":"auto","created_at":"2025-04-01 11:51:21","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1306271,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary File 1: Initial normal non-contrast MRI brain coronal T2 fat-saturated coronal image obtained 10 years ago.\u003c/p\u003e","description":"","filename":"supplementaryfile1.png","url":"https://assets-eu.researchsquare.com/files/rs-6341031/v1/61324db57cfd0f87ae396ca0.png"},{"id":79674992,"identity":"c2af8230-caa1-4712-9282-c7e2c23a4ceb","added_by":"auto","created_at":"2025-04-01 11:59:21","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1508128,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary File 2: Initial normal non-contrast coronal MRI Spectral Attenuated Inversion Recovery (SPAIR) image obtained 10 years ago\u003c/p\u003e","description":"","filename":"supplementaryfile2.png","url":"https://assets-eu.researchsquare.com/files/rs-6341031/v1/3485212789604d5692dafb22.png"},{"id":79673918,"identity":"40b4385e-c9b1-418f-a557-bed65b9dfd10","added_by":"auto","created_at":"2025-04-01 11:51:21","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":15536,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary File 3: Laboratory results\u003c/p\u003e","description":"","filename":"SupplementaryFile3.docx","url":"https://assets-eu.researchsquare.com/files/rs-6341031/v1/e8af0caed10f7a85d49cf554.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eTolosa-Hunt Syndrome with Highly Elevated Interleukin 6 Levels: Case Report\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eCharcot initially defined ophthalmoplegic migraine as \"a condition associated with migraine in which there is a palsy of an ocular nerve, usually the third, temporary at first and later becoming permanent\" [1]. Hunt in 1961 discussed painful ophthalmoplegia as being associated with low grade inflammation of the carotid sinus and having pain that is described as “boring or gnawing” as opposed to throbbing pain of classical migraine [2]. Under International Classification of Headache Disorders (ICHD) (second edition) the syndrome was reclassified under cranial neuropathies but still retained the migraine name [3]. In the third edition of ICHD, it is called Recurrent Painful Ophthalmoplegic Cranial Neuropathy (RPON) and requires absence of mass lesion [4]. On the other hand, Tolosa-Hunt syndrome is defined as unilateral pain associated with cranial nerve paresis caused by granulomatous inflammation in the cavernous sinus [4].\u003c/p\u003e"},{"header":"Case report","content":"\u003cp\u003eThe patient is a 42-year-old Hispanic female with Peruvian ancestry who presented with episodes of diplopia, proptosis, and eye pain.\u003c/p\u003e\n\u003cp\u003eTen years ago, she had an episode of severe left trigeminal V1 distribution and retro orbital pain, proptosis and diplopia horizontally with 6th nerve palsy. There was no otitis media to form the triad of Gradenigo syndrome. \u0026nbsp;There was no contributory family history. Initial non-contrast Magnetic Resonance Imaging (MRI) brain was normal on coronal T2 fat-saturated coronal (Supplementary File 1) and Spectral Attenuated Inversion Recovery (SPAIR) images (Supplementary File 2). She was diagnosed with ophthalmoplegic migraine [4,5]. \u0026nbsp;The associated headaches were migraine - like with 8/10 sharp pain, photophobia, phonophobia, and nausea with diplopia occurring at same time as headache. Headache and diplopia would last for about a week. Headache would improve when she stopped activity and went to a dark room. \u0026nbsp;Her examination was significant for proptosis of the left eye and partial left sixth nerve palsy.\u003c/p\u003e\n\u003cp\u003eThe second severe episode with the same symptoms happened four years ago. This was treated with methylprednisolone 4 mg twice a day for a month and one methylprednisolone 4 mg, 6 day, 21 tablet dose pack with full resolution of symptoms. The first episode also resolved after the introduction of methylprednisolone 4 mg twice daily for a month. \u0026nbsp;Given Magnetic Resonance Imaging (MRI) finding of left cavernous sinus mass, she was diagnosed with Tolosa-Hunt Syndrome in accordance with International Classification of Headache Disorders (ICHD)-II criteria for the Tolosa-Hunt syndrome [4,6].\u003c/p\u003e\n\u003cp\u003eSubsequently, she would experience up to 3 episodes per year of left retroorbital pain without proptosis or diplopia, treated with just one 21 tablet methylprednisolone dose pack at a time with resolution.\u003c/p\u003e\n\u003cp\u003eMRI brain performed 4 years ago demonstrated mass like enlargement of the left cavernous sinus on a type of 3D Fluid-Attenuated Inversion Recovery (FLAIR) MRI sequence that used compressed sensing (SHC) and spatial sensitivity encoding (SENSE) technique in the postcontrast axial (Figure 1) and coronal (Figure 2) views. \u0026nbsp;The region of enhancement was defined as 18 mm by 5 mm by 17 mm in size. Follow up MRI brain performed 8 months later showed a decreased size of the left cavernous sinus on axial T2 weighted Spectral Presaturation with Inversion Recovery (SPIR) sequence (Figure 3). T2 SPIR coronal imaging two years ago showed resolution of the left cavernous sinus mass (Figure 4).\u003c/p\u003e\n\u003cp\u003eA year ago, she had normal inflammatory markers including erythrocyte sedimentation rate of 2 (0-20 normal range), C-reactive protein of \u0026lt;0.1 mg/dl (normal less than 0.10 mg/dl), angiotensin converting enzyme level was 23 U/L (normal 9-67), C1q at 6.0 mg/dl (normal 5-8.6 mg/dl) normal anti-neutrophil cytoplasmic antibodies (ANCA) (normal \u0026lt;20), and normal anti-Double-Stranded DNA (dsDNA) antibody (\u0026lt;12.3 International Units per ml). Given a positive anti-nuclear antibody at 1:80, speckled appearance, and low C3 at 65 mg/dl (normal 83-180 mg/dl) and C4 at 8 mg/dl (normal 18-45 mg/dl), she was referred to rheumatology and was deemed to not have systemic lupus erythematosus given normal anti-dsDNA antibody. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHer cytokines were significant for Interleukin 10 (IL-10) elevated to 5.0 pg/mL (normal \u0026lt;=2.8). \u0026nbsp; Interleukin 6 (IL-6) was elevated to 90.5 pg/mL (normal \u0026lt;=2.0). Other cytokines, IgG subtypes, and IgA subtypes were normal (Supplementary file 3).\u003c/p\u003e\n\u003cp\u003eShe is currently asymptomatic except for occasional mild headaches. She takes the 21-tablet methylprednisolone dose pack twice a year on average as needed for headaches that become moderate in intensity.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTolosa Hunt syndrome is considered to be a syndrome of idiopathic orbital inflammation. A granulomatous lesion either by biopsy or MRI visualization is required for the diagnosis [4]. Most cases of Tolosa Hunt syndrome improve with steroids.\u003c/p\u003e\n\u003cp\u003eThis patient had extremely elevated IL-6 during clinical remission. One of the prior names of IL-6 was B cell stimulatory factor – 2 (BSF-2), given its ability to trigger differentiation of activated B cells into antibody producing plasma cells [7]. IL-6 can also activate T-cells. In systemic lupus erythematosus (SLE), this process leads to autoantibody production. Elevated systemic IL-6 has been shown in SLE [8]. Perhaps a similar process involving B-cell and T-cell activation is occurring in Tolosa-Hunt syndrome via IL-6.\u003c/p\u003e\n\u003cp\u003eThe pathology of the original case of Dr. Eduardo Tolosa was reviewed by Hunt et al. in 1961 [2]. The slides show a lymphocyte and plasma cell infiltrate, scarcity of blood vessels, and proliferation of fibroblasts leading to fibrosis. There was constriction of the internal carotid artery. This pathological finding bears striking similarity to the IgG4-related disease (IgG4-RD) diagnostic criteria, except that the layering of fibrosis is linear as opposed to the spoke wheel type of fibrosis in IgG4-RD [9]. Unlike in most cases of IgG4-RD, the IgG subsets are normal, soluble interleukin-2 receptor subunit alpha and transforming growth factor beta-1 are also normal in this patient. \u0026nbsp; Magnetic resonance angiography (MRA) of the head and neck was normal in this patient.\u003c/p\u003e\n\u003cp\u003eWhile Tolosa-Hunt syndrome does resolve clinically and radiologically after oral steroid administration, the presence of fibrosis on Dr. Tolosa’s case raises the possibility of cumulative pathology. Prompt administration of steroids would be helpful in reducing the risk of fibrosis. Screening MRA given constriction of the internal carotid artery in Dr. Tolosa’s case report may be considered.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003ePatient perspective\u003c/p\u003e\n\u003cp\u003eThe patient appreciates the opportunity to share information the diagnosis and treatment of her rare disorder.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003eDeclarations\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for participation in this case\u003c/p\u003e\n\u003cp\u003ereport however, no ethical approval was needed.\u003c/p\u003e\n\u003cp\u003e\"The institution’s policy, therefore, is that a case report is not research that must be\u003c/p\u003e\n\u003cp\u003eapproved by the IRB.\"\u003c/p\u003e\n\u003cp\u003eNew York Medical College Policies and Procedures for the Conduct of Research\u003c/p\u003e\n\u003cp\u003eInvolving Human Subjects. [https://www.nymc.edu/media/schools-andcolleges/nymc/pdf/human-subjects-research/IRBmanual.pdf] Accessed on 3/24/2025.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of\u003c/p\u003e\n\u003cp\u003ethis case report and any accompanying images. A copy of the written consent\u003c/p\u003e\n\u003cp\u003eis available for review by the Editor-in-Chief of this journal.\u003c/p\u003e\n\u003cp\u003eAvailability of data\u003c/p\u003e\n\u003cp\u003eAll supporting data were included in this manuscript. Patient clinical data is protected by\u003c/p\u003e\n\u003cp\u003ethe United States Health Insurance Portability and Accountability Act (HIPAA) of 1996.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe author declares that he does not have any competing interests\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eRF: conception, data acquisition, writing, and revising\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eHarrington DO, Flocks M. Ophthalmoplegic migraine. AMA Arch Ophthalmol. 1953;49(6):643-655. doi:10.1001/archopht.1953.00920020656005\u003c/li\u003e\n \u003cli\u003eHunt WE, Meagher JH, LeFever HE, Zeman W. Painful ophthalmoplegia: Its relation to indolent inflammation of the cavernous sinus. Neurology. 11(1):56 https://doi.org/10.1212/WNL.11.1.56\u003c/li\u003e\n \u003cli\u003eGelfand AA, Gelfand JM, Prabakhar P, Goadsby PJ. Ophthalmoplegic \u0026ldquo;Migraine\u0026rdquo; or Recurrent Ophthalmoplegic Cranial Neuropathy: New Cases and a Systematic Review. J Child Neurol. 2012 Jan 12;27(6):759\u0026ndash;766. doi: 10.1177/0883073811426502\u003c/li\u003e\n \u003cli\u003eNo authors listed. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia.\u0026nbsp;2018 Jan;38(1):1-211. doi: 10.1177/0333102417738202.\u003c/li\u003e\n \u003cli\u003eChakravarty A, Mukherjee A. \u0026nbsp;Ophthalmoplegic migraine: A critical analysis and a new proposal. Ann Indian Acad Neurol. 2012 Aug;15(Suppl 1):S2\u0026ndash;S6. doi: 10.4103/0972-2327.99985 PMCID: PMC3444213 PMID: 23024560\u003c/li\u003e\n \u003cli\u003eColnaghi S, Versino M, Marchioni E, et al. ICHD-II diagnostic criteria for Tolosa-Hunt syndrome in idiopathic inflammatory syndromes of the orbit and/or the cavernous sinus. Cephalalgia. 2008 Jun;28(6):577-84. doi: 10.1111/j.1468-2982.2008.01569.x. Epub 2008 Mar 31.\u003c/li\u003e\n \u003cli\u003eTanaka T, Masahashi N, Kishimoto T. IL-6 in Inflammation, Immunity, and Disease. Cold Spring Harb Perspect Biol. 2014 Oct;6(10):a016295. doi: 10.1101/cshperspect.a016295\u003c/li\u003e\n \u003cli\u003eDing J, Su S, You T, et al. \u0026nbsp;Serum interleukin-6 level is correlated with the disease activity of systemic lupus erythematosus: a meta-analysis. Clinics (Sao Paulo). 2020 Oct 5;75:e1801. doi: 10.6061/clinics/2020/e1801 PMCID: PMC7536892 PMID: 33084768\u003c/li\u003e\n \u003cli\u003eDeshpande V, Zen Y, Chan JKC, et al. Consensus statement on the pathology of IgG4-related disease. Modern Pathology. \u0026nbsp;25(9):1181-92. https://doi.org/10.1038/modpathol.2012.72\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"New York Medical College","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Tolosa-Hunt Syndrome, Interleukin-6, IL-6, ophthalmoplegic migraine, cavernous sinus","lastPublishedDoi":"10.21203/rs.3.rs-6341031/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6341031/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\n\u003cp\u003eOphthalmoplegic migraine was first defined by Charcot as \"a condition associated with migraine in which there is a palsy of an ocular nerve, usually the third, temporary at first and later becoming permanent.\" Under current International Classification of Headache Disorders (ICHD) third edition criteria, ophthalmoplegic migraine requires absence of a mass lesions, whereas a granulomatous periorbital lesion is required for the diagnosis of Tolosa-Hunt syndrome which is considered to be idiopathic orbital inflammation and causes orbital pain with ipsilateral cranial nerve palsy. Most cases improve with steroids.\u003c/p\u003e\n\u003cp\u003eCase report\u003c/p\u003e\n\u003cp\u003eThe patient is a 42-year-old Hispanic female with Peruvian ancestry who presented with episodes of diplopia, proptosis, and eye pain. She had a severe episode 10 years ago which led to horizontal diplopia as well as another episode 4 years ago. Both episodes resolved with about five weeks of oral methylprednisolone dosing. There is complete relief of diplopia between these episodes. She is maintained on oral methylprednisolone 6-day dose pack about twice yearly for orbital pain. At the time of the diplopia 4 years ago, Magnetic Resonance Imaging showed a left cavernous sinus mass, which resolved on subsequent imaging. Her Interleukin 6 (IL-6) serum level done outside of the episodes was highly elevated at 90.5 pg/ml (normal \u0026lt;5 pg/ml).\u003c/p\u003e\n\u003cp\u003eDiscussion\u003c/p\u003e\n\u003cp\u003eThe pathology of the original case of Dr. Eduardo Tolosa was reviewed by Hunt et al. in 1961. While the pathology of Tolosa-Hunt syndrome is generally described as granulomatous, the slides showed a lymphocyte and plasma cell infiltrate, scarcity of blood vessels, and proliferation of fibroblasts leading to fibrosis. It is possible that prolonged IL-6 stimulation leads to inappropriate B and T-cell terminal differentiation which supports the lymphoplasmacytic lesion in Dr. Tolosa’s case. The possibility of fibrosis means that early treatment with steroids is important in preventing cumulative damage.\u003c/p\u003e","manuscriptTitle":"Tolosa-Hunt Syndrome with Highly Elevated Interleukin 6 Levels: Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-01 11:51:17","doi":"10.21203/rs.3.rs-6341031/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"73756a78-b3e4-4fac-b1e5-f4625bc80cdf","owner":[],"postedDate":"April 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":46424709,"name":"Neurology"}],"tags":[],"updatedAt":"2025-04-01T11:51:17+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-01 11:51:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6341031","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6341031","identity":"rs-6341031","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}