Progressive Supranuclear Palsy with Post-Traumatic Frontal Lobe Damage Mimicking Anti-IgLON5 Antibody Disease

Progressive Supranuclear Palsy with Post-Traumatic Frontal Lobe Damage Mimicking Anti-IgLON5 Antibody Disease | 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 Progressive Supranuclear Palsy with Post-Traumatic Frontal Lobe Damage Mimicking Anti-IgLON5 Antibody Disease Damla Ates-Gulkok, Aiswarya Raj, Yakira Mishan, Brittany Zaita, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7794938/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Phenotypic overlap between autoimmune encephalitis and movement disorders may rarely occur. Anti-IgLON5 antibody mediated disease and progressive supranuclear palsy (PSP) may clinically mimic each other. PSP is one of the tauopathies and a clinicopathologic entity marked by vertical supranuclear gaze palsy, pseudobulbar palsy, symmetric bradykinesia, frontal-subcortical cognitive dysfunction, gait impairment, and postural instability. Anti-IgLON5 antibody mediated disease may also have vertical supranuclear gaze palsy, combined non-REM/REM parasomnias,, bulbar dysfunction (dysarthria, dysphagia, vocal-fold paresis, episodic respiratory failure), gait disturbance, and movement disorder. We present a patient with progressive gait disturbance, vertical supranuclear gaze palsy, cognitive decline, as well as extremity chorea, highlighting the phenotypic overlap between PSP and anti-IgLON5 disease. His workup was negative for the antibody both in serum and cerebrospinal fluid. Fall leading to subdural hemorrhage and bilateral post-traumatic frontal lobe changes likely led to his bilateral upper and lower extremity involuntary movements. His mental status improved after lumbar puncture. His condition further improved on treatment with carbidopa levodopa 25/100 mg three times a day. While the presentation of this case was consistent with anti-IGLON5 antibody mediated disease, the involuntary movements were due to frontal lobe damage. Neurology chorea involuntary limb movement progressive supranuclear palsy psp frontal lobe injury Figures Figure 1 Figure 2 Figure 3 Introduction Phenotypic overlap between autoimmune encephalitis and movement disorders may rarely occur. Anti-IgLON5 antibody-mediated disease and progressive supranuclear palsy (PSP) may clinically mimic each other [ 1 ]. PSP is one of the tauopathies and a clinicopathologic entity marked by vertical supranuclear gaze palsy, pseudobulbar palsy, symmetric bradykinesia, frontal-subcortical cognitive dysfunction, gait impairment, and postural instability. In contrast, anti-IgLON5 disease, associated with antibodies against IgLON5, a neuronal cell-adhesion protein, typically presents with combined non-REM/REM parasomnias (stridor and obstructive sleep apnea), bulbar dysfunction (dysarthria, dysphagia, vocal-fold paresis, or episodic respiratory failure), and gait disturbance. Notably, both conditions feature prominent gait and movement abnormalities, which can often confound the differential diagnosis. We present a patient with progressive gait disturbance, vertical supranuclear gaze palsy, and cognitive decline, as well as extremity chorea, highlighting the phenotypic overlap between PSP and anti-IgLON5 disease Case Presentation The patient is a 76 year old Hispanic male who was transferred to our hospital for evaluation for normal pressure hydrocephalus. There is no past medical history. There is no family history of neurological disorders. He was in his usual state of good health until about six months prior to his presentation at which time he developed subacute, progressive memory loss, and gait disturbance with imbalance. The imbalance led to a fall on the stairs in which he hit his occiput and had a contrecoup contusion and hemorrhage of the bilateral frontal lobes one month prior to his presentation. Imaging at this time was significant for T2 Fluid Attenuation Inversion Recovery (FLAIR) hyperintensities in bilateral frontal lobes as well as 2.42 mm right convexity subdural hemorrhage are seen on MRI in Fig. 1 . Following an admission for his traumatic brain injury he went to inpatient rehabilitation. His rehabilitation course was complicated by progressive drowsiness. Lumbar puncture was performed, which his family reports resulted in him becoming more awake and cooperative. Hence, post traumatic hydrocephalus was considered and he was transferred to our hospital for higher level of care. At the time of transfer to our hospital he had waxing and waning mental status with about five minute episodes of depressed mental status with closed eyes, not following verbal commands, but withdrawing to noxious stimuli and increased tone in the upper extremities bilaterally, which was bordering on catatonic. He did not have any verbal output and did not follow verbal commands during these episodes. Lifting of either extremity by the examiner led to him holding up that extremity for about three seconds before slowly dropping it back down. He was previously evaluated by the psychiatry department at the sending institution and catatonia was considered. He was given a benzodiazepine trial (Valium 5 mg single dose) with the family reporting absence of improvement. He was also noted to have chorea of both hands and feet which was moderate continuous. He subsequently had five minute episodes of clearer mental status during which he had open eyes and he could intermittently follow one step commands such as to perform finger taps and finger to nose testing. He was also oriented to self and hospital. He was able to provide brief, up to two word, answers to verbal questions. There was paucity of spontaneous speech. For the frontal release signs; the glabellar sign was positive, palmomental sign was negative bilaterally, and orbicularis oris (snout) reflex was negative. The rest of the examination was the same. On cranial nerve examination, during the depressed mental status episodes he did not have horizontal or vertical pursuit but he did have normal oculocephalic response horizontally and vertically. During improved mental status episodes as well as after repeat lumbar puncture at our hospital, he had apraxia of horizontal gaze on verbal command but he could perform horizontal pursuit towards the right and left. He also would spontaneously have slow saccadic movements horizontally to a vertically moving stimulus. He could not perform vertical gaze movements on command. There was no vertical upward gaze on pursuit. There was severely diminished downward gaze on pursuit. He was also noted to have a decreased blink rate and at times an eyelid -opening apraxia. During all levels of mental status, he had diminished, but still present horizontal optokinetic kinetic nystagmus (OKN). There was an absence of upward and downward OKN. There was horizontal nystagmus while the patient was provided upward and downward moving stripe stimulus during vertical OKN testing. There was normal oculocephalic response with vertical and horizontal head tilt in all directions (Video 1). He received a lumbar puncture with opening pressure of 10 CM H2O, glucose normal at 51 mg/dL, 4 white blood cells per mm3, 2 red blood cells per mm3 and mild elevation in protein to 46 mg/dL (normal 15–45 mg/dL). Cerebrospinal fluid (CSF) lactate dehydrogenase was normal at 24 units / L. CSF analysis showed a normal proportion of 89% lymphocytes as well as 0% lymphocytes and low monocytes at 11% (normal 16–56%). CSF Gram stain and bacterial cultures were negative. He underwent further extensive workup for his decline in mental status. Copper level was normal at 120 mcg/dL and ferritin level was normal at 356.1 micrograms/L. Total iron was low at 38 mcg/dL (normal 60–160 mcg/dL), total iron binding capacity was low at 160 mcg/dL (normal 275–365 mcg/dL), and UIBC was low at 122 mcg/dL (normal 136–286 mcg/dL). Iron percent saturation was normal at 24%. Serum IgG4 level was normal at 14.1 mg/dL. Serum carcinoembryogenic antigen was normal at 1.5 ng/mL. Serum red blood cell morphology was normal. MRI brain showed eye of the tiger sign (Fig. 2 ) and midbrain atrophy (Fig. 3 ) [ 3 ]. After this lumbar puncture, he remained in the clearer mental state continuously. He was alert and oriented to person and place with paucity of verbal output. Three word responses to verbal questions were present and he was following one step commands with eyes mostly open, but intermittently manifesting apraxia of eyelid opening and horizontal gaze apraxia. At this time, the patient could perform only the first step of the Luria sequence with the right hand. He could not perform any steps of the Luria sequence with the left hand. He had continuous stereotypic hand wringing movements bilaterally and continuous chorea of the feet. The patient was more attentive and engaging, however chorea remained present at a moderate level after the administration of Carbidopa levodopa 25/ 100 mg tablets three times a day. He had improvement of upper extremity rigidity from moderate to mild post carbidopa / levodopa initiation. Discussion IgLON plays an important role in the process of neuronal adhesion, neurogenesis and neuroplasticity and may play a role in maintaining the blood-brain barrier [ 4 ]. Anti-IgLON5 disease can present with nonspecific symptoms such as shortness of breath during sleep, cognitive decline, gait disturbance and autonomic nervous system dysregulation [ 4 ]. Anti-IgLON5 disease does not only have the antibodies against the IgLON5 protein but also shows a deposition of hyperphosphorylated tau in the tegmentum of the brainstem and hypothalamus leading to progressive neuro-degeneration similar to other tauopathies such as PSP [ 2 ]. Patients with gaze palsy and postural instability diagnosed with PSP can develop these symptoms as a result of anti-IgLON5 [ 4 , 5 ]. IgLON5 has a variable presentation with sleep disorder, bulbar symptoms, gait abnormalities and cognitive dysfunction being the most prevalent. Other common representations include occulomotor abnormalities with vertical or horizontal gaze palsy, nystagmus and ptosis. Some patients have been reported to have dysautonomia, cerebellar signs and muscle weakness. Almost any movement disorder has been reported ranging from hyperkinetic to hypokinetic. In fact some studies have identified a few clinical phenotypes which feature sleep disorder predominance, bulbar symptoms, progressive supranuclear palsy-like syndrome, cognitive disorders with or without chorea. Of interest the case we have presented has symptoms of multiple phenotypes. While the oculomotor features of PSP and IgLON5 disease show great overlap, a lack of saccadic intrusions and square wave jerks have been found to be more common in anti-IgLON 5 than PSP which may be as a result of the involvement of the cerebellum in PSP but not in IgLON5 disease. In contrast supranuclear gaze palsy has been found to be more common in PSP than Anti-IgLON5. This patient presented with a complex combination of symptoms as he had a 6 month history of memory disorder and gait imbalance in keeping with the PSP phenotype seen on examination. This ultimately resulted in his fall and traumatic brain injury. The patient’s frontal lobe injury as seen in Fig. 1 and possible post traumatic hydrocephalus led to akinetic mutism with closed eyes and no verbal output. Repeat lumbar puncture improved his mental status. Absent vertical OKN with normal oculocephalic reflex is consistent with supranuclear gaze palsy. Eye of the tiger sign and midbrain atrophy are classic findings in PSP. However, the chorea of his lower limbs is atypical for PSP and raised concern for anti-IgLON 5 disease. Conclusion The combination of PSP clinical features including rigidity, gait disturbance, and classic absence of vertical OKN, together with extremity chorea is an unusual presentation of anti-IgLON5 antibody disease. Midbrain atrophy is a feature of either anti-IGLON5 antibody disease or PSP [ 2 ]. There are case reports of the eye of the tiger sign in PSP [ 3 ], but the sign has not been demonstrated in anti-IgLON5 antibody disease. Declarations Study approval statement : This retrospective review of patient data did not require ethical approval in accordance with local / national guidelines. Consent to publish statement : Written informed consent was obtained from the patient's next of kin for publication of the details of their medical case and any accompanying images. Conflict of Interest Statement The authors have no conflicts of interest to declare. Funding Sources This study was not supported by any sponsor or funder. References Graus F, Sabater L, Gaig C et al (2025) Anti-IgLON5 Disease 10 Years Later: What We Know and What We Do Not Know. Neurol Neuroimmunol Neuroinflamm 12(1):e200353. 10.1212/NXI.0000000000200353 Gelpi E, Reinecke R, Gaig C et al (2024) Neuropathological spectrum of anti-IgLON5 disease and stages of brainstem tau pathology: updated neuropathological research criteria of the disease-related tauopathy. Acta Neuropathol 148(1):53. 10.1007/s00401-024-02805-y Genç H, Öksüz N, Doğu O (2024) The Eye of the tiger sign in Progressive Supranuclear Palsy: Is it a coincidence or not? Exp Appl Med Sci 4(4):595–600. 10.46871/eams.1322881 Madetko N, Marzec W, Kowalska A, Przewodowska D, Alster P, Koziorowski D Anti-IgLON5 Disease - The Current State Knowledge and Further Perspectives. Front Immunol. 20221, 13:852215. 10.3389/fimmu.2022.852215 Macher S, Milenkovic I, Zrzavy T et al (2021) Ocular Motor Abnormalities in Anti-IgLON5 Disease. Front Immunol 30:75356. 10.3389/fimmu.2021.753856 Additional Declarations The authors declare no competing interests. Supplementary Files Video1Eyemovementsandextremitysterotypies.mp4 Video 1. Patient demonstrates horizontal nystagmus upon presentation of vertically moving simulated optimistic tape, with absence of vertical eye movements on verbal command. Upgaze can be achieved via head tilt. Bilateral hand and foot stereotypic movements are present. Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions 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-7794938","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":528349506,"identity":"a8f9df24-182c-476e-99fc-76e07190332e","order_by":0,"name":"Damla Ates-Gulkok","email":"","orcid":"","institution":"New York Medical College","correspondingAuthor":false,"prefix":"","firstName":"Damla","middleName":"","lastName":"Ates-Gulkok","suffix":""},{"id":528349507,"identity":"c4804fb9-2496-4294-a21d-2692ce877aa4","order_by":1,"name":"Aiswarya Raj","email":"","orcid":"","institution":"New York Medical College","correspondingAuthor":false,"prefix":"","firstName":"Aiswarya","middleName":"","lastName":"Raj","suffix":""},{"id":528349508,"identity":"9c62a8d6-4e37-47ae-b630-97027efb2d84","order_by":2,"name":"Yakira Mishan","email":"","orcid":"","institution":"New York Medical College","correspondingAuthor":false,"prefix":"","firstName":"Yakira","middleName":"","lastName":"Mishan","suffix":""},{"id":528349509,"identity":"cc5ad25e-d842-4df4-ac86-0141837fba3b","order_by":3,"name":"Brittany Zaita","email":"","orcid":"","institution":"New York Medical College","correspondingAuthor":false,"prefix":"","firstName":"Brittany","middleName":"","lastName":"Zaita","suffix":""},{"id":528349510,"identity":"c3c2927a-3c33-4bd1-b71d-38333217864f","order_by":4,"name":"Jessica Bloom","email":"","orcid":"","institution":"New York Medical College","correspondingAuthor":false,"prefix":"","firstName":"Jessica","middleName":"","lastName":"Bloom","suffix":""},{"id":528349511,"identity":"99f6d697-56d8-4d70-980b-1c07b163c2b6","order_by":5,"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":"2025-10-07 01:45:09","currentVersionCode":2,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":true,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7794938/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-7794938/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":99734579,"identity":"3555ddc9-35d6-4184-824f-ae7eafc72c14","added_by":"auto","created_at":"2026-01-07 19:01:11","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":21778,"visible":true,"origin":"","legend":"","description":"","filename":"ProgressiveSupranuclearPalsywithPost2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7794938/v2/ccbccf6990b898b1f9510d7c.docx"},{"id":99798042,"identity":"4fc00407-e0df-4a48-aada-6fcd923f64e1","added_by":"auto","created_at":"2026-01-08 13:47:08","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":342,"visible":true,"origin":"","legend":"","description":"","filename":"rs7794938.json","url":"https://assets-eu.researchsquare.com/files/rs-7794938/v2/97ccb535ab09dc726c380982.json"},{"id":99734584,"identity":"0f3f3bae-0007-4f1d-af31-b3bab48dba61","added_by":"auto","created_at":"2026-01-07 19:01:11","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":27256,"visible":true,"origin":"","legend":"","description":"","filename":"rs77949380enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7794938/v2/6a17f426cbfcc86dd7e1ef2b.xml"},{"id":99734585,"identity":"393af674-b60b-4544-a91a-271f64686e22","added_by":"auto","created_at":"2026-01-07 19:01:11","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":25799,"visible":true,"origin":"","legend":"","description":"","filename":"rs77949380structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7794938/v2/707efe8fcf259900aec0cfdf.xml"},{"id":99734586,"identity":"77ffc0e9-6941-43dc-b8cb-b7ea91e35594","added_by":"auto","created_at":"2026-01-07 19:01:11","extension":"html","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":30915,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7794938/v2/9fa39caeeb6b54aeec673c45.html"},{"id":99797298,"identity":"5dedbca7-1ace-44dc-a2ee-5f3f06036208","added_by":"auto","created_at":"2026-01-08 13:45:33","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":212546,"visible":true,"origin":"","legend":"\u003cp\u003eMRI T2 Fluid Attenuation Inversion Recovery (FLAIR) hyperintensities in bilateral frontal lobes as well as 2.42 mm right convexity subdural hemorrhage\u003c/p\u003e","description":"","filename":"figure1T2FLAIRhyperintensitiesfrontallobes.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7794938/v2/89e5ffdb9c7a14cd51ea526f.jpg"},{"id":99734580,"identity":"8d49d054-00b6-4a4c-a9ec-8376692c1937","added_by":"auto","created_at":"2026-01-07 19:01:11","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":44228,"visible":true,"origin":"","legend":"\u003cp\u003eCoronal MRI T2 FLAIR image demonstrating eye of the tiger sign\u003c/p\u003e","description":"","filename":"Figure2eyeofthetigersign1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7794938/v2/55d1c0f50e1135fe4ad9407a.jpeg"},{"id":99734582,"identity":"29df113e-62e4-4bfd-9675-0dc52da96ce9","added_by":"auto","created_at":"2026-01-07 19:01:11","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":60668,"visible":true,"origin":"","legend":"\u003cp\u003eT2 weighted Turbo Spin Echo (TSE) axial MRI brain image showing midbrain atrophy\u003c/p\u003e","description":"","filename":"Figure3axialT2TSEmidbrainatrophy.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7794938/v2/e714991b73211bf82a9fd9ad.jpeg"},{"id":99805413,"identity":"59c3a79a-a80d-4ebb-bfbf-ea0ddba5b1d2","added_by":"auto","created_at":"2026-01-08 14:16:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":610570,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7794938/v2/f76def80-2017-4e7e-99e7-08f18d39e165.pdf"},{"id":99734587,"identity":"3ced7a30-7fdf-4b7b-8e0d-812f9c7473f9","added_by":"auto","created_at":"2026-01-07 19:01:11","extension":"mp4","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":8091536,"visible":true,"origin":"","legend":"\u003cp\u003eVideo 1. Patient demonstrates horizontal nystagmus upon presentation of vertically moving simulated optimistic tape, with absence of vertical eye movements on verbal command. Upgaze can be achieved via head tilt. Bilateral hand and foot stereotypic movements are present.\u003c/p\u003e","description":"","filename":"Video1Eyemovementsandextremitysterotypies.mp4","url":"https://assets-eu.researchsquare.com/files/rs-7794938/v2/63ab8fec05a8cac8ebeed993.mp4"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"Progressive Supranuclear Palsy with Post-Traumatic Frontal Lobe Damage Mimicking Anti-IgLON5 Antibody Disease","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePhenotypic overlap between autoimmune encephalitis and movement disorders may rarely occur. Anti-IgLON5 antibody-mediated disease and progressive supranuclear palsy (PSP) may clinically mimic each other [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePSP is one of the tauopathies and a clinicopathologic entity marked by vertical supranuclear gaze palsy, pseudobulbar palsy, symmetric bradykinesia, frontal-subcortical cognitive dysfunction, gait impairment, and postural instability. In contrast, anti-IgLON5 disease, associated with antibodies against IgLON5, a neuronal cell-adhesion protein, typically presents with combined non-REM/REM parasomnias (stridor and obstructive sleep apnea), bulbar dysfunction (dysarthria, dysphagia, vocal-fold paresis, or episodic respiratory failure), and gait disturbance. Notably, both conditions feature prominent gait and movement abnormalities, which can often confound the differential diagnosis.\u003c/p\u003e\u003cp\u003eWe present a patient with progressive gait disturbance, vertical supranuclear gaze palsy, and cognitive decline, as well as extremity chorea, highlighting the phenotypic overlap between PSP and anti-IgLON5 disease\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eThe patient is a 76 year old Hispanic male who was transferred to our hospital for evaluation for normal pressure hydrocephalus. There is no past medical history. There is no family history of neurological disorders.\u003c/p\u003e\u003cp\u003eHe was in his usual state of good health until about six months prior to his presentation at which time he developed subacute, progressive memory loss, and gait disturbance with imbalance. The imbalance led to a fall on the stairs in which he hit his occiput and had a contrecoup contusion and hemorrhage of the bilateral frontal lobes one month prior to his presentation. Imaging at this time was significant for T2 Fluid Attenuation Inversion Recovery (FLAIR) hyperintensities in bilateral frontal lobes as well as 2.42 mm right convexity subdural hemorrhage are seen on MRI in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Following an admission for his traumatic brain injury he went to inpatient rehabilitation. His rehabilitation course was complicated by progressive drowsiness. Lumbar puncture was performed, which his family reports resulted in him becoming more awake and cooperative. Hence, post traumatic hydrocephalus was considered and he was transferred to our hospital for higher level of care.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAt the time of transfer to our hospital he had waxing and waning mental status with about five minute episodes of depressed mental status with closed eyes, not following verbal commands, but withdrawing to noxious stimuli and increased tone in the upper extremities bilaterally, which was bordering on catatonic. He did not have any verbal output and did not follow verbal commands during these episodes. Lifting of either extremity by the examiner led to him holding up that extremity for about three seconds before slowly dropping it back down. He was previously evaluated by the psychiatry department at the sending institution and catatonia was considered. He was given a benzodiazepine trial (Valium 5 mg single dose) with the family reporting absence of improvement. He was also noted to have chorea of both hands and feet which was moderate continuous.\u003c/p\u003e\u003cp\u003eHe subsequently had five minute episodes of clearer mental status during which he had open eyes and he could intermittently follow one step commands such as to perform finger taps and finger to nose testing. He was also oriented to self and hospital. He was able to provide brief, up to two word, answers to verbal questions. There was paucity of spontaneous speech.\u003c/p\u003e\u003cp\u003eFor the frontal release signs; the glabellar sign was positive, palmomental sign was negative bilaterally, and orbicularis oris (snout) reflex was negative. The rest of the examination was the same.\u003c/p\u003e\u003cp\u003eOn cranial nerve examination, during the depressed mental status episodes he did not have horizontal or vertical pursuit but he did have normal oculocephalic response horizontally and vertically. During improved mental status episodes as well as after repeat lumbar puncture at our hospital, he had apraxia of horizontal gaze on verbal command but he could perform horizontal pursuit towards the right and left. He also would spontaneously have slow saccadic movements horizontally to a vertically moving stimulus. He could not perform vertical gaze movements on command. There was no vertical upward gaze on pursuit. There was severely diminished downward gaze on pursuit. He was also noted to have a decreased blink rate and at times an eyelid -opening apraxia.\u003c/p\u003e\u003cp\u003eDuring all levels of mental status, he had diminished, but still present horizontal optokinetic kinetic nystagmus (OKN). There was an absence of upward and downward OKN. There was horizontal nystagmus while the patient was provided upward and downward moving stripe stimulus during vertical OKN testing. There was normal oculocephalic response with vertical and horizontal head tilt in all directions (Video 1).\u003c/p\u003e\u003cp\u003eHe received a lumbar puncture with opening pressure of 10 CM H2O, glucose normal at 51 mg/dL, 4 white blood cells per mm3, 2 red blood cells per mm3 and mild elevation in protein to 46 mg/dL (normal 15\u0026ndash;45 mg/dL). Cerebrospinal fluid (CSF) lactate dehydrogenase was normal at 24 units / L. CSF analysis showed a normal proportion of 89% lymphocytes as well as 0% lymphocytes and low monocytes at 11% (normal 16\u0026ndash;56%). CSF Gram stain and bacterial cultures were negative.\u003c/p\u003e\u003cp\u003eHe underwent further extensive workup for his decline in mental status.\u003c/p\u003e\u003cp\u003eCopper level was normal at 120 mcg/dL and ferritin level was normal at 356.1 micrograms/L. Total iron was low at 38 mcg/dL (normal 60\u0026ndash;160 mcg/dL), total iron binding capacity was low at 160 mcg/dL (normal 275\u0026ndash;365 mcg/dL), and UIBC was low at 122 mcg/dL (normal 136\u0026ndash;286 mcg/dL). Iron percent saturation was normal at 24%.\u003c/p\u003e\u003cp\u003eSerum IgG4 level was normal at 14.1 mg/dL. Serum carcinoembryogenic antigen was normal at 1.5 ng/mL. Serum red blood cell morphology was normal. MRI brain showed eye of the tiger sign (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) and midbrain atrophy (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAfter this lumbar puncture, he remained in the clearer mental state continuously. He was alert and oriented to person and place with paucity of verbal output. Three word responses to verbal questions were present and he was following one step commands with eyes mostly open, but intermittently manifesting apraxia of eyelid opening and horizontal gaze apraxia.\u003c/p\u003e\u003cp\u003eAt this time, the patient could perform only the first step of the Luria sequence with the right hand. He could not perform any steps of the Luria sequence with the left hand. He had continuous stereotypic hand wringing movements bilaterally and continuous chorea of the feet. The patient was more attentive and engaging, however chorea remained present at a moderate level after the administration of Carbidopa levodopa 25/ 100 mg tablets three times a day. He had improvement of upper extremity rigidity from moderate to mild post carbidopa / levodopa initiation.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIgLON plays an important role in the process of neuronal adhesion, neurogenesis and neuroplasticity and may play a role in maintaining the blood-brain barrier [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Anti-IgLON5 disease can present with nonspecific symptoms such as shortness of breath during sleep, cognitive decline, gait disturbance and autonomic nervous system dysregulation [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Anti-IgLON5 disease does not only have the antibodies against the IgLON5 protein but also shows a deposition of hyperphosphorylated tau in the tegmentum of the brainstem and hypothalamus leading to progressive neuro-degeneration similar to other tauopathies such as PSP [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Patients with gaze palsy and postural instability diagnosed with PSP can develop these symptoms as a result of anti-IgLON5 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIgLON5 has a variable presentation with sleep disorder, bulbar symptoms, gait abnormalities and cognitive dysfunction being the most prevalent. Other common representations include occulomotor abnormalities with vertical or horizontal gaze palsy, nystagmus and ptosis. Some patients have been reported to have dysautonomia, cerebellar signs and muscle weakness. Almost any movement disorder has been reported ranging from hyperkinetic to hypokinetic. In fact some studies have identified a few clinical phenotypes which feature sleep disorder predominance, bulbar symptoms, progressive supranuclear palsy-like syndrome, cognitive disorders with or without chorea. Of interest the case we have presented has symptoms of multiple phenotypes.\u003c/p\u003e\u003cp\u003eWhile the oculomotor features of PSP and IgLON5 disease show great overlap, a lack of saccadic intrusions and square wave jerks have been found to be more common in anti-IgLON 5 than PSP which may be as a result of the involvement of the cerebellum in PSP but not in IgLON5 disease. In contrast supranuclear gaze palsy has been found to be more common in PSP than Anti-IgLON5.\u003c/p\u003e\u003cp\u003eThis patient presented with a complex combination of symptoms as he had a 6 month history of memory disorder and gait imbalance in keeping with the PSP phenotype seen on examination. This ultimately resulted in his fall and traumatic brain injury.\u003c/p\u003e\u003cp\u003eThe patient\u0026rsquo;s frontal lobe injury as seen in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and possible post traumatic hydrocephalus led to akinetic mutism with closed eyes and no verbal output. Repeat lumbar puncture improved his mental status. Absent vertical OKN with normal oculocephalic reflex is consistent with supranuclear gaze palsy. Eye of the tiger sign and midbrain atrophy are classic findings in PSP. However, the chorea of his lower limbs is atypical for PSP and raised concern for anti-IgLON 5 disease.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe combination of PSP clinical features including rigidity, gait disturbance, and classic absence of vertical OKN, together with extremity chorea is an unusual presentation of anti-IgLON5 antibody disease. Midbrain atrophy is a feature of either anti-IGLON5 antibody disease or PSP [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. There are case reports of the eye of the tiger sign in PSP [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], but the sign has not been demonstrated in anti-IgLON5 antibody disease.\u003c/p\u003e"},{"header":"Declarations","content":"\n\u003cp\u003e\u003cu\u003eStudy approval statement\u003c/u\u003e:\u003c/p\u003e\n\u003cp\u003eThis retrospective review of patient data did not require ethical approval in accordance with local / national guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConsent to publish statement\u003c/u\u003e:\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient's next of kin for publication of the details of their medical case and any accompanying images.\u003c/p\u003e\n\u003cp\u003eConflict of Interest Statement\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was not supported by any sponsor or funder.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGraus F, Sabater L, Gaig C et al (2025) Anti-IgLON5 Disease 10 Years Later: What We Know and What We Do Not Know. Neurol Neuroimmunol Neuroinflamm 12(1):e200353. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1212/NXI.0000000000200353\u003c/span\u003e\u003cspan address=\"10.1212/NXI.0000000000200353\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGelpi E, Reinecke R, Gaig C et al (2024) Neuropathological spectrum of anti-IgLON5 disease and stages of brainstem tau pathology: updated neuropathological research criteria of the disease-related tauopathy. Acta Neuropathol 148(1):53. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00401-024-02805-y\u003c/span\u003e\u003cspan address=\"10.1007/s00401-024-02805-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGen\u0026ccedil; H, \u0026Ouml;ks\u0026uuml;z N, Doğu O (2024) The Eye of the tiger sign in Progressive Supranuclear Palsy: Is it a coincidence or not? Exp Appl Med Sci 4(4):595\u0026ndash;600. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.46871/eams.1322881\u003c/span\u003e\u003cspan address=\"10.46871/eams.1322881\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMadetko N, Marzec W, Kowalska A, Przewodowska D, Alster P, Koziorowski D Anti-IgLON5 Disease - The Current State Knowledge and Further Perspectives. Front Immunol. 20221, 13:852215. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fimmu.2022.852215\u003c/span\u003e\u003cspan address=\"10.3389/fimmu.2022.852215\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMacher S, Milenkovic I, Zrzavy T et al (2021) Ocular Motor Abnormalities in Anti-IgLON5 Disease. Front Immunol 30:75356. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fimmu.2021.753856\u003c/span\u003e\u003cspan address=\"10.3389/fimmu.2021.753856\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":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":"chorea, involuntary limb movement, progressive supranuclear palsy, psp, frontal lobe injury","lastPublishedDoi":"10.21203/rs.3.rs-7794938/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7794938/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePhenotypic overlap between autoimmune encephalitis and movement disorders may rarely occur. Anti-IgLON5 antibody mediated disease and progressive supranuclear palsy (PSP) may clinically mimic each other. PSP is one of the tauopathies and a clinicopathologic entity marked by vertical supranuclear gaze palsy, pseudobulbar palsy, symmetric bradykinesia, frontal-subcortical cognitive dysfunction, gait impairment, and postural instability. Anti-IgLON5 antibody mediated disease may also have vertical supranuclear gaze palsy, combined non-REM/REM parasomnias,, bulbar dysfunction (dysarthria, dysphagia, vocal-fold paresis, episodic respiratory failure), gait disturbance, and movement disorder.\u003c/p\u003e\u003cp\u003eWe present a patient with progressive gait disturbance, vertical supranuclear gaze palsy, cognitive decline, as well as extremity chorea, highlighting the phenotypic overlap between PSP and anti-IgLON5 disease. His workup was negative for the antibody both in serum and cerebrospinal fluid. Fall leading to subdural hemorrhage and bilateral post-traumatic frontal lobe changes likely led to his bilateral upper and lower extremity involuntary movements. His mental status improved after lumbar puncture. His condition further improved on treatment with carbidopa levodopa 25/100 mg three times a day.\u003c/p\u003e\u003cp\u003eWhile the presentation of this case was consistent with anti-IGLON5 antibody mediated disease, the involuntary movements were due to frontal lobe damage.\u003c/p\u003e","manuscriptTitle":"Progressive Supranuclear Palsy with Post-Traumatic Frontal Lobe Damage Mimicking Anti-IgLON5 Antibody Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2026-01-07 19:00:57","doi":"10.21203/rs.3.rs-7794938/v2","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}},{"code":1,"date":"2025-10-12 14:31:54","doi":"10.21203/rs.3.rs-7794938/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":"January 7th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":56155672,"name":"Neurology"}],"tags":[],"updatedAt":"2025-10-12T14:31:54+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-07 19:00:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-7794938","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7794938","identity":"rs-7794938","version":["v2"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}