A Case of Neuronal Intranuclear Inclusion Disease Presenting with Episodic Visual Blurring: A Case Report

A Case of Neuronal Intranuclear Inclusion Disease Presenting with Episodic Visual Blurring: A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report A Case of Neuronal Intranuclear Inclusion Disease Presenting with Episodic Visual Blurring: A Case Report Xin Shi, Longwei Qi, Liwen Tai, Guofeng Yang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7961766/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background: Neuronal intranuclear inclusion disease (NIID) is a rare, progressive neurodegenerative disorder characterized by the presence of eosinophilic hyaline intranuclear inclusions in both the nervous system and visceral organs. Clinical presentation is highly heterogeneous, often including cognitive impairment, movement disorders, autonomic dysfunction, and episodic encephalopathy. Episodic visual blurring as a sole or predominant initial symptom is exceedingly uncommon and poses a significant diagnostic challenge. Case Presentation: A 67-year-old male amateur cyclist presented with a 7-year history of recurrent episodes of bilateral visual blurring, consistently triggered by prolonged, strenuous exercise (e.g., cycling over 110 km). Symptoms resolved completely after several hours of rest. Initial ophthalmological and neurological workups were inconclusive. Over the years, serial brain diffusion-weighted imaging (DWI) revealed the characteristic corticomedullary "ribbon sign." A skin biopsy revealed intranuclear inclusions in sweat gland duct epithelial cells. Ultimately, genetic analysis confirmed a pathological GGC repeat expansion (approximately 114 repeats) in the NOTCH2NLC gene, diagnostic of NIID. Conclusion: This case underscores the diagnostic challenge of NIID, particularly when it presents with isolated episodic symptoms triggered by physical exertion. It highlights the importance of considering NIID in the differential diagnosis of transient neurological episodes and demonstrates the critical role of genetic testing for definitive diagnosis. Neuronal intranuclear inclusion disease (NIID) Visual symptoms Case report Figures Figure 1 Figure 2 Introduction Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative condition with a multisystem presentation. Its pathogenesis is linked to pathological GGC repeat expansions in the NOTCH2NLC gene[ 1 ]. The clinical spectrum of NIID is vast, encompassing dementia, cerebellar ataxia, parkinsonism, peripheral neuropathy, and autonomic dysfunction[ 2 ]. A notable feature in some patients is episodic encephalopathy, which can manifest as altered consciousness, seizures, or transient focal neurological deficits. These episodes are often misdiagnosed as transient ischemic attacks (TIAs). Genetic testing has now become the cornerstone for a definitive diagnosis[ 2 ]. The uniqueness of this case lies in its presentation of prolonged, exertion-induced episodic visual blurring as the predominant and long-standing symptom, illustrating a novel and diagnostically challenging phenotype of NIID. Case Presentation A 67-year-old retired male and avid amateur cyclist was admitted to our neurology department in June 2025 for evaluation of a 7-year history of episodic visual disturbances. The initial episode occurred in March 2018 after cycling approximately 110 kilometers. The patient gradually developed bilateral blurred vision, described as a "foggy sensation," which started predominantly in the peripheral visual fields and progressively extended toward the center, eventually involving the entire visual field. He denied associated headache, dizziness, fever, psychiatric symptoms, or incontinence. The symptoms resolved completely after 2–3 hours of rest. An evaluation at an ophthalmology hospital revealed normal visual acuity and visual fields. Intraocular pressure was 10 mmHg (right eye) and 9.3 mmHg (left eye). Ocular ultrasound showed mild vitreous opacity in both eyes. Optical coherence tomography (OCT) showed normal peripapillary retinal nerve fiber layer thickness bilaterally, with a central foveal thickness of 163 µm in the right eye and 158 µm in the left eye. Cranial CT scan showed only a lacunar infarct in the right corona radiata. Carotid ultrasound was unremarkable. Over the next several years, the patient experienced recurrent, stereotypical episodes of visual blurring exclusively triggered by long-distance cycling or mountain climbing. In June 2021, a routine check revealed mild anemia (hemoglobin 104 g/L, red blood cell count 3.42×10¹²/L). A brain MRI with diffusion-weighted imaging (DWI) showed multiple linear hyperintensities in the subcortical white matter of the bilateral frontal and parietal lobes, with no corresponding restricted diffusion on apparent diffusion coefficient (ADC) maps. By September 2023, he reported new subtle tremors in his left hand when holding heavy objects. An electromyogram was normal. In late 2024, he reported a single episode of forgetfulness. Cognitive screening showed a perfect Mini-Mental State Examination (MMSE) score of 30 but a mildly reduced Montreal Cognitive Assessment (MoCA) score of 26 (adjusted for high school education). A repeat brain MRI demonstrated bilateral frontotemporal subcortical white matter abnormalities and cerebral atrophy, raising suspicion for NIID. A skin biopsy from the left ankle revealed occasional suspicious intranuclear inclusions in sweat gland duct epithelial cells, supporting the suspected diagnosis. The patient's past medical history was otherwise unremarkable. He had a 30-year history of alcohol consumption (approximately 250 g/day) and tobacco use (2–3 cigarettes per day), both of which he discontinued 7 years prior to the current evaluation. The family history was notable only for an aunt with head tremor. No other family members were known to have neurological disorders. General physical examination was unremarkable. Neurological examination revealed a fully alert and oriented patient. Cranial nerve examination, including visual fields to confrontation, was normal. Motor examination showed normal strength, tone, and bulk. Coordination was intact (finger-nose test was steady, Romberg sign was negative). Gait was normal. Sensory examination and deep tendon reflexes (2+) were symmetric throughout. Plantar responses were flexor. No signs of autonomic dysfunction were present. Admission laboratory tests, including complete blood count, urinalysis, stool routine, coagulation profile, and comprehensive metabolic panel (liver and renal function, electrolytes, glucose, lipids), were all within normal limits. A routine electrocardiogram showed sinus bradycardia. Head-up tilt table testing was normal. Video electroencephalogram (EEG) showed an abnormal background with intermittent bursts of medium-amplitude slow waves(Fig. 1 ). A repeat brain MRI confirmed extensive bilateral white matter hyperintensities in the frontotemporal subcortical regions, Fazekas grade 2, cerebral atrophy, and a characteristic "cortical ribbon sign" (high signal on DWI at the corticomedullary junction). Magnetic resonance angiography (MRA) suggested cerebral arteriosclerosis (Fig. 1 ). The definitive diagnosis was confirmed by genetic testing, which identified an abnormal GGC repeat expansion in the NOTCH2NLC gene. The patient had one allele with approximately 19 repeats (normal) and another with approximately 114 repeats (pathological; normal ≤ 40, pathogenic typically > 60) (Fig. 2 ). The patient remained asymptomatic during hospitalization. He was discharged with recommendations for supportive care and outpatient follow-up. At subsequent clinic visits, he reported no further episodes of visual blurring or other neurological symptoms. Discussion This case presents an unusual and instructive presentation of NIID, dominated by prolonged, exertion-induced episodes of visual blurring. This highly atypical presentation is readily misattributed to more common conditions such as migraine aura, retinal vasospasm, or transient ischemic attacks (TIAs), highlighting the diagnostic challenge posed by the remarkable clinical heterogeneity of NIID. The Chinese NIID Consortium Research Alliance has classified NIID into five major clinical subtypes based on the dominant manifestation: episodic neurological symptom-dominant, cognitive impairment-dominant, movement disorder-dominant, autonomic dysfunction-dominant, and neuromuscular disease-dominant, with significant overlap noted among them[ 3 ]. While cases presenting with impaired consciousness, visual decline, limb tremor, or parkinsonism have been well-documented[ 4 , 5 ], strenuous physical exertion is not commonly reported as a primary trigger. The pathophysiological mechanism underlying exertion-triggered episodes remains speculative but may involve impaired cerebral autoregulation and neuronal energy metabolism due to the presence of intranuclear inclusions. Strenuous exercise could potentially induce a state of metabolic stress, precipitating transient dysfunction in the visually associated cortical areas. The temporal evolution of neuroimaging findings in this patient provides a valuable radiological roadmap for NIID. While the initial CT and early MRI scans were non-specific, a critical turning point was the 2021 DWI sequence, which revealed subcortical white matter hyperintensities without restricted diffusion—a recognized hallmark of NIID that distinguishes it from acute cerebral ischemia characterized by reduced ADC values. The subsequent development of extensive white matter lesions, cerebral atrophy, and the classic DWI "cortical ribbon sign" further consolidated the radiological suspicion. This sign, manifesting as hyperintensity at the corticomedullary junction, is a highly characteristic feature observed in nearly all sporadic NIID cases as the disease progresses [ 4 ]. It is known to persist for extended periods or may occasionally resolve after several years[ 6 , 7 ]. In our case, the MRI demonstrated this typical corticomedullary junction hyperintensity in the frontal, temporal, and occipital lobes, providing strong imaging evidence supporting the diagnosis of NIID. The skin biopsy results in this case were described as "suspicious," which, while suggestive, were not diagnostic, reflecting the known focal distribution of inclusions. Consequently, genetic analysis for a GGC repeat expansion in the NOTCH2NLC gene became the diagnostic cornerstone, providing a conclusive result. It is noteworthy that pathological NOTCH2NLC expansions have also been detected in a minority of patients with other neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, and essential tremor[ 8 – 10 ]. This evidence has led to the conceptualization of 'NIID-related diseases (NIIDRD)' for neurodegenerative disorders caused by this repeat expansion, thereby broadening the disease spectrum associated with this genetic defect [12]. Currently, there is no disease-modifying therapy available for NIID, and no intervention has been proven to eliminate the characteristic intranuclear inclusions or restore neurological function. Treatment remains primarily supportive and focuses on symptomatic management, which may help alleviate certain clinical manifestations such as seizures, cognitive decline, and parkinsonism. Conclusion Neuronal intranuclear inclusion disease (NIID) is an increasingly recognized, rare, and highly heterogeneous neurodegenerative disorder. The pathognomonic radiological finding of a corticomedullary 'ribbon sign' on DWI serves as a key indicator, warranting confirmation through skin biopsy and genetic analysis. Abbreviations NIID Neuronal intranuclear inclusion disease MRI Magnetic resonance imaging DWI Diffusion-weighted imaging MMSE Mini-Mental State Examination MoCA Montreal Cognitive Assessment MRA Magnetic Resonance Angiography TIAs Transient ischemic attacks OCT Optical coherence tomography ADC Diffusion coefficient EEG Video electroencephalogram MRA Magnetic resonance angiography. Declarations Ethics approval and consent to participate This study was conducted in accordance with the Declaration of Helsinki. The study involving human participants was reviewed and approved by the Clinical Research Ethics Committee of the First Hospital of Hebei Medical University. The participants provided written informed consent. Consent for publication Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent form is available for review by the editor of this journal. Conflict of interest All the authors declare that they have no competing interests. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Author Contribution X.S. wrote the main manuscript text. L.Q. prepared Figures 1-2. L.T. and G.Y. revised the data for the intellectual content. All authors reviewed and approved the final manuscript. Acknowledgement We thank the patient for kindly providing a detailed history and complete medical records from seven years of follow-up, and for consenting to share this case for educational purposes. Data availability References Zeng T, Chen Y, Huang H, Li S, Huang J, Xie H, Lin S, Chen S, Chen G, Yang D. Neuronal Intranuclear Inclusion Disease with NOTCH2NLC GGC Repeat Expansion: A Systematic Review and Challenges of Phenotypic Characterization. Aging Dis. 2024;16(1):578–97. Zhang T, Bao L, Chen H. Review of Phenotypic Heterogeneity of Neuronal Intranuclear Inclusion Disease and NOTCH2NLC-Related GGC Repeat Expansion Disorders. Neurol Genet. 2024;10(2):e200132. Tai H, Wang A, Zhang Y, Liu S, Pan Y, Li K, Zhao G, Wang M, Wu G, Niu S, et al. Clinical Features and Classification of Neuronal Intranuclear Inclusion Disease. Neurol Genet. 2023;9(2):e200057. Sone J, Mori K, Inagaki T, Katsumata R, Takagi S, Yokoi S, Araki K, Kato T, Nakamura T, Koike H, et al. Clinicopathological features of adult-onset neuronal intranuclear inclusion disease. Brain. 2016;139(Pt 12):3170–86. Chen H, Lu L, Wang B, Cui G, Wang X, Wang Y, Raza HK, Min Y, Li K, Cui Y, et al. Re-defining the clinicopathological spectrum of neuronal intranuclear inclusion disease. Ann Clin Transl Neurol. 2020;7(10):1930–41. Chen L, Wu L, Li S, Huang Q, Xiong J, Hong D, Zeng X. A long time radiological follow-up of neuronal intranuclear inclusion disease: Two case reports. Med (Baltim). 2018;97(49):e13544. Kawarabayashi T, Nakamura T, Seino Y, Hirohata M, Mori F, Wakabayashi K, Ono S, Harigaya Y, Shoji M. Disappearance of MRI imaging signals in a patient with neuronal intranuclear inclusion disease. J Neurol Sci. 2018;388:1–3. Tian Y, Wang JL, Huang W, Zeng S, Jiao B, Liu Z, Chen Z, Li Y, Wang Y, Min HX, et al. Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders. Am J Hum Genet. 2019;105(1):166–76. Ma D, Tan YJ, Ng ASL, Ong HL, Sim W, Lim WK, Teo JX, Ng EYL, Lim EC, Lim EW, et al. Association of NOTCH2NLC Repeat Expansions With Parkinson Disease. JAMA Neurol. 2020;77(12):1559–63. Sun QY, Xu Q, Tian Y, Hu ZM, Qin LX, Yang JX, Huang W, Xue J, Li JC, Zeng S, et al. Expansion of GGC repeat in the human-specific NOTCH2NLC gene is associated with essential tremor. Brain. 2020;143(1):222–33. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 18 Mar, 2026 Reviews received at journal 23 Dec, 2025 Reviewers agreed at journal 20 Dec, 2025 Reviewers agreed at journal 20 Dec, 2025 Reviewers agreed at journal 17 Dec, 2025 Reviewers agreed at journal 15 Dec, 2025 Reviewers invited by journal 24 Nov, 2025 Editor invited by journal 24 Nov, 2025 Editor assigned by journal 10 Nov, 2025 Submission checks completed at journal 10 Nov, 2025 First submitted to journal 27 Oct, 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-7961766","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":551757298,"identity":"d557d6c5-3d9f-41e4-b9ca-9009850c8b84","order_by":0,"name":"Xin 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10:07:58","extension":"html","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":44722,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7961766/v1/c70f86b7f9cdd26831d1ff18.html"},{"id":97127019,"identity":"48084515-fcdf-4d0c-b854-3915ab804685","added_by":"auto","created_at":"2025-12-01 08:26:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":433003,"visible":true,"origin":"","legend":"\u003cp\u003eBrain MRI findings in a patient with NIID. DWI showed bilateral frontal and temporoparietal corticomedullary junction hyperintensity, with no corresponding restricted diffusion on ADC maps. NIID = neuronal intranuclear inclusion disease.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7961766/v1/bafe4925d902966bc51c1489.png"},{"id":97142460,"identity":"8dd0a535-3536-4b69-9313-a3c0f108f872","added_by":"auto","created_at":"2025-12-01 10:07:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":118674,"visible":true,"origin":"","legend":"\u003cp\u003eGenetic analysis results. Genetic analysis demonstrated an abnormal expansion of 114 GGC repeats in the NOTCH2NLC gene\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7961766/v1/26b21ff45637540f63e0d2e4.png"},{"id":97145311,"identity":"cb7afe1c-610d-433d-a1d7-703dbd7fa805","added_by":"auto","created_at":"2025-12-01 10:13:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":967462,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7961766/v1/edb31705-7a2a-4faf-93c1-0a6dc6b3e7d2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Case of Neuronal Intranuclear Inclusion Disease Presenting with Episodic Visual Blurring: A Case Report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNeuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative condition with a multisystem presentation. Its pathogenesis is linked to pathological GGC repeat expansions in the NOTCH2NLC gene[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The clinical spectrum of NIID is vast, encompassing dementia, cerebellar ataxia, parkinsonism, peripheral neuropathy, and autonomic dysfunction[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. A notable feature in some patients is episodic encephalopathy, which can manifest as altered consciousness, seizures, or transient focal neurological deficits. These episodes are often misdiagnosed as transient ischemic attacks (TIAs). Genetic testing has now become the cornerstone for a definitive diagnosis[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The uniqueness of this case lies in its presentation of prolonged, exertion-induced episodic visual blurring as the predominant and long-standing symptom, illustrating a novel and diagnostically challenging phenotype of NIID.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 67-year-old retired male and avid amateur cyclist was admitted to our neurology department in June 2025 for evaluation of a 7-year history of episodic visual disturbances.\u003c/p\u003e\u003cp\u003eThe initial episode occurred in March 2018 after cycling approximately 110 kilometers. The patient gradually developed bilateral blurred vision, described as a \"foggy sensation,\" which started predominantly in the peripheral visual fields and progressively extended toward the center, eventually involving the entire visual field. He denied associated headache, dizziness, fever, psychiatric symptoms, or incontinence. The symptoms resolved completely after 2\u0026ndash;3 hours of rest. An evaluation at an ophthalmology hospital revealed normal visual acuity and visual fields. Intraocular pressure was 10 mmHg (right eye) and 9.3 mmHg (left eye). Ocular ultrasound showed mild vitreous opacity in both eyes. Optical coherence tomography (OCT) showed normal peripapillary retinal nerve fiber layer thickness bilaterally, with a central foveal thickness of 163 \u0026micro;m in the right eye and 158 \u0026micro;m in the left eye. Cranial CT scan showed only a lacunar infarct in the right corona radiata. Carotid ultrasound was unremarkable.\u003c/p\u003e\u003cp\u003eOver the next several years, the patient experienced recurrent, stereotypical episodes of visual blurring exclusively triggered by long-distance cycling or mountain climbing. In June 2021, a routine check revealed mild anemia (hemoglobin 104 g/L, red blood cell count 3.42\u0026times;10\u0026sup1;\u0026sup2;/L). A brain MRI with diffusion-weighted imaging (DWI) showed multiple linear hyperintensities in the subcortical white matter of the bilateral frontal and parietal lobes, with no corresponding restricted diffusion on apparent diffusion coefficient (ADC) maps. By September 2023, he reported new subtle tremors in his left hand when holding heavy objects. An electromyogram was normal. In late 2024, he reported a single episode of forgetfulness. Cognitive screening showed a perfect Mini-Mental State Examination (MMSE) score of 30 but a mildly reduced Montreal Cognitive Assessment (MoCA) score of 26 (adjusted for high school education). A repeat brain MRI demonstrated bilateral frontotemporal subcortical white matter abnormalities and cerebral atrophy, raising suspicion for NIID. A skin biopsy from the left ankle revealed occasional suspicious intranuclear inclusions in sweat gland duct epithelial cells, supporting the suspected diagnosis.\u003c/p\u003e\u003cp\u003eThe patient's past medical history was otherwise unremarkable. He had a 30-year history of alcohol consumption (approximately 250 g/day) and tobacco use (2\u0026ndash;3 cigarettes per day), both of which he discontinued 7 years prior to the current evaluation. The family history was notable only for an aunt with head tremor. No other family members were known to have neurological disorders.\u003c/p\u003e\u003cp\u003eGeneral physical examination was unremarkable. Neurological examination revealed a fully alert and oriented patient. Cranial nerve examination, including visual fields to confrontation, was normal. Motor examination showed normal strength, tone, and bulk. Coordination was intact (finger-nose test was steady, Romberg sign was negative). Gait was normal. Sensory examination and deep tendon reflexes (2+) were symmetric throughout. Plantar responses were flexor. No signs of autonomic dysfunction were present.\u003c/p\u003e\u003cp\u003eAdmission laboratory tests, including complete blood count, urinalysis, stool routine, coagulation profile, and comprehensive metabolic panel (liver and renal function, electrolytes, glucose, lipids), were all within normal limits. A routine electrocardiogram showed sinus bradycardia. Head-up tilt table testing was normal. Video electroencephalogram (EEG) showed an abnormal background with intermittent bursts of medium-amplitude slow waves(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). A repeat brain MRI confirmed extensive bilateral white matter hyperintensities in the frontotemporal subcortical regions, Fazekas grade 2, cerebral atrophy, and a characteristic \"cortical ribbon sign\" (high signal on DWI at the corticomedullary junction). Magnetic resonance angiography (MRA) suggested cerebral arteriosclerosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe definitive diagnosis was confirmed by genetic testing, which identified an abnormal GGC repeat expansion in the NOTCH2NLC gene. The patient had one allele with approximately 19 repeats (normal) and another with approximately 114 repeats (pathological; normal\u0026thinsp;\u0026le;\u0026thinsp;40, pathogenic typically\u0026thinsp;\u0026gt;\u0026thinsp;60) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe patient remained asymptomatic during hospitalization. He was discharged with recommendations for supportive care and outpatient follow-up. At subsequent clinic visits, he reported no further episodes of visual blurring or other neurological symptoms.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case presents an unusual and instructive presentation of NIID, dominated by prolonged, exertion-induced episodes of visual blurring. This highly atypical presentation is readily misattributed to more common conditions such as migraine aura, retinal vasospasm, or transient ischemic attacks (TIAs), highlighting the diagnostic challenge posed by the remarkable clinical heterogeneity of NIID.\u003c/p\u003e\u003cp\u003eThe Chinese NIID Consortium Research Alliance has classified NIID into five major clinical subtypes based on the dominant manifestation: episodic neurological symptom-dominant, cognitive impairment-dominant, movement disorder-dominant, autonomic dysfunction-dominant, and neuromuscular disease-dominant, with significant overlap noted among them[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. While cases presenting with impaired consciousness, visual decline, limb tremor, or parkinsonism have been well-documented[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], strenuous physical exertion is not commonly reported as a primary trigger. The pathophysiological mechanism underlying exertion-triggered episodes remains speculative but may involve impaired cerebral autoregulation and neuronal energy metabolism due to the presence of intranuclear inclusions. Strenuous exercise could potentially induce a state of metabolic stress, precipitating transient dysfunction in the visually associated cortical areas.\u003c/p\u003e\u003cp\u003eThe temporal evolution of neuroimaging findings in this patient provides a valuable radiological roadmap for NIID. While the initial CT and early MRI scans were non-specific, a critical turning point was the 2021 DWI sequence, which revealed subcortical white matter hyperintensities without restricted diffusion\u0026mdash;a recognized hallmark of NIID that distinguishes it from acute cerebral ischemia characterized by reduced ADC values. The subsequent development of extensive white matter lesions, cerebral atrophy, and the classic DWI \"cortical ribbon sign\" further consolidated the radiological suspicion. This sign, manifesting as hyperintensity at the corticomedullary junction, is a highly characteristic feature observed in nearly all sporadic NIID cases as the disease progresses [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. It is known to persist for extended periods or may occasionally resolve after several years[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In our case, the MRI demonstrated this typical corticomedullary junction hyperintensity in the frontal, temporal, and occipital lobes, providing strong imaging evidence supporting the diagnosis of NIID.\u003c/p\u003e\u003cp\u003eThe skin biopsy results in this case were described as \"suspicious,\" which, while suggestive, were not diagnostic, reflecting the known focal distribution of inclusions. Consequently, genetic analysis for a GGC repeat expansion in the NOTCH2NLC gene became the diagnostic cornerstone, providing a conclusive result. It is noteworthy that pathological NOTCH2NLC expansions have also been detected in a minority of patients with other neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, and essential tremor[\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This evidence has led to the conceptualization of 'NIID-related diseases (NIIDRD)' for neurodegenerative disorders caused by this repeat expansion, thereby broadening the disease spectrum associated with this genetic defect [12].\u003c/p\u003e\u003cp\u003eCurrently, there is no disease-modifying therapy available for NIID, and no intervention has been proven to eliminate the characteristic intranuclear inclusions or restore neurological function. Treatment remains primarily supportive and focuses on symptomatic management, which may help alleviate certain clinical manifestations such as seizures, cognitive decline, and parkinsonism.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eNeuronal intranuclear inclusion disease (NIID) is an increasingly recognized, rare, and highly heterogeneous neurodegenerative disorder. The pathognomonic radiological finding of a corticomedullary 'ribbon sign' on DWI serves as a key indicator, warranting confirmation through skin biopsy and genetic analysis.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNIID\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNeuronal intranuclear inclusion disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMagnetic resonance imaging\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDWI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDiffusion-weighted imaging\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMMSE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMini-Mental State Examination\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMoCA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMontreal Cognitive Assessment\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMRA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMagnetic Resonance Angiography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTIAs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTransient ischemic attacks\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOCT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eOptical coherence tomography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eADC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDiffusion coefficient\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEEG\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eVideo electroencephalogram\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMRA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMagnetic resonance angiography.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki. The study involving human participants was reviewed and approved by the Clinical Research Ethics Committee of the First Hospital of Hebei Medical University. The participants provided written informed consent.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent form is available for review by the editor of this journal.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003cp\u003eAll the authors declare that they have no competing interests.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eX.S. wrote the main manuscript text. L.Q. prepared Figures 1-2. L.T. and G.Y. revised the data for the intellectual content. All authors reviewed and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe thank the patient for kindly providing a detailed history and complete medical records from seven years of follow-up, and for consenting to share this case for educational purposes.\u003c/p\u003e\u003ch2\u003eData availability\u003c/h2\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eZeng T, Chen Y, Huang H, Li S, Huang J, Xie H, Lin S, Chen S, Chen G, Yang D. Neuronal Intranuclear Inclusion Disease with NOTCH2NLC GGC Repeat Expansion: A Systematic Review and Challenges of Phenotypic Characterization. Aging Dis. 2024;16(1):578\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhang T, Bao L, Chen H. Review of Phenotypic Heterogeneity of Neuronal Intranuclear Inclusion Disease and NOTCH2NLC-Related GGC Repeat Expansion Disorders. Neurol Genet. 2024;10(2):e200132.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTai H, Wang A, Zhang Y, Liu S, Pan Y, Li K, Zhao G, Wang M, Wu G, Niu S, et al. Clinical Features and Classification of Neuronal Intranuclear Inclusion Disease. Neurol Genet. 2023;9(2):e200057.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSone J, Mori K, Inagaki T, Katsumata R, Takagi S, Yokoi S, Araki K, Kato T, Nakamura T, Koike H, et al. Clinicopathological features of adult-onset neuronal intranuclear inclusion disease. Brain. 2016;139(Pt 12):3170\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen H, Lu L, Wang B, Cui G, Wang X, Wang Y, Raza HK, Min Y, Li K, Cui Y, et al. Re-defining the clinicopathological spectrum of neuronal intranuclear inclusion disease. Ann Clin Transl Neurol. 2020;7(10):1930\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen L, Wu L, Li S, Huang Q, Xiong J, Hong D, Zeng X. A long time radiological follow-up of neuronal intranuclear inclusion disease: Two case reports. Med (Baltim). 2018;97(49):e13544.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKawarabayashi T, Nakamura T, Seino Y, Hirohata M, Mori F, Wakabayashi K, Ono S, Harigaya Y, Shoji M. Disappearance of MRI imaging signals in a patient with neuronal intranuclear inclusion disease. J Neurol Sci. 2018;388:1\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTian Y, Wang JL, Huang W, Zeng S, Jiao B, Liu Z, Chen Z, Li Y, Wang Y, Min HX, et al. Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders. Am J Hum Genet. 2019;105(1):166\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMa D, Tan YJ, Ng ASL, Ong HL, Sim W, Lim WK, Teo JX, Ng EYL, Lim EC, Lim EW, et al. Association of NOTCH2NLC Repeat Expansions With Parkinson Disease. JAMA Neurol. 2020;77(12):1559\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSun QY, Xu Q, Tian Y, Hu ZM, Qin LX, Yang JX, Huang W, Xue J, Li JC, Zeng S, et al. Expansion of GGC repeat in the human-specific NOTCH2NLC gene is associated with essential tremor. Brain. 2020;143(1):222\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Neuronal intranuclear inclusion disease (NIID), Visual symptoms, Case report","lastPublishedDoi":"10.21203/rs.3.rs-7961766/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7961766/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Neuronal intranuclear inclusion disease (NIID) is a rare, progressive neurodegenerative disorder characterized by the presence of eosinophilic hyaline intranuclear inclusions in both the nervous system and visceral organs. Clinical presentation is highly heterogeneous, often including cognitive impairment, movement disorders, autonomic dysfunction, and episodic encephalopathy. Episodic visual blurring as a sole or predominant initial symptom is exceedingly uncommon and poses a significant diagnostic challenge.\u003c/p\u003e\n\u003cp\u003eCase Presentation: A 67-year-old male amateur cyclist presented with a 7-year history of recurrent episodes of bilateral visual blurring, consistently triggered by prolonged, strenuous exercise (e.g., cycling over 110 km). Symptoms resolved completely after several hours of rest. Initial ophthalmological and neurological workups were inconclusive. Over the years, serial brain diffusion-weighted imaging (DWI) revealed the characteristic corticomedullary \"ribbon sign.\" A skin biopsy revealed intranuclear inclusions in sweat gland duct epithelial cells. Ultimately, genetic analysis confirmed a pathological GGC repeat expansion (approximately 114 repeats) in the NOTCH2NLC gene, diagnostic of NIID.\u003c/p\u003e\n\u003cp\u003eConclusion: This case underscores the diagnostic challenge of NIID, particularly when it presents with isolated episodic symptoms triggered by physical exertion. It highlights the importance of considering NIID in the differential diagnosis of transient neurological episodes and demonstrates the critical role of genetic testing for definitive diagnosis.\u003c/p\u003e","manuscriptTitle":"A Case of Neuronal Intranuclear Inclusion Disease Presenting with Episodic Visual Blurring: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-01 08:26:06","doi":"10.21203/rs.3.rs-7961766/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-03-18T16:07:38+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-23T13:02:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"199789420738924493388001722603968746668","date":"2025-12-20T13:06:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"274116050542568002864216803941146246382","date":"2025-12-20T10:42:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"324185907217342752176996879069366523141","date":"2025-12-17T07:01:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"187099818327927618844888291574136643138","date":"2025-12-15T17:28:48+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-24T23:09:03+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-11-24T08:46:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-10T09:57:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-10T09:56:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2025-10-27T14:59:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"11fa3d37-94ac-4a47-8119-b3618c724e65","owner":[],"postedDate":"December 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-12-01T08:26:06+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-01 08:26:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7961766","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7961766","identity":"rs-7961766","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}