Syncope Unveiling a Diagnosis of Adult-Onset Leukoencephalomyelopathy: A case report

Syncope Unveiling a Diagnosis of Adult-Onset Leukoencephalomyelopathy: 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 Research Article Syncope Unveiling a Diagnosis of Adult-Onset Leukoencephalomyelopathy: A case report Arp-Arpa Kasemsantitham, Nithit Singtokum, Chamaiporn Taychargumpoo, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7445286/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 We present a patient with orthostatic hypotension and presyncope, who, after autonomic testing and neuroimaging, was diagnosed with adult-onset leukoencephalopathy, highlighting the complexity of diagnosing this condition. syncope orthostatic hypotension leukodystrophy leukoencephalomyelopathy Figures Figure 1 Why this case fits the journal and adds value? Autonomic focus with clear physiology: The patient exhibited generalized autonomic failure with impaired adrenergic responses and markedly reduced sudomotor activity, while heart‑rate variability during breathing remained preserved—an instructive pattern for differentiating central from peripheral causes of nOH. Neuroimaging that maps to the central autonomic network: Brainstem and cerebellar white‑matter involvement (including regions encompassing pathways between the nucleus tractus solitarius and rostral ventrolateral medulla) aligns with the clinical phenotype and provides readers with concrete imaging correlates of autonomic dysfunction. Genetics‑aware, phenotype‑first approach: A broad, 728‑gene targeted panel was negative for known adult‑onset leukodystrophy/leukoencephalopathy variants (including LMNB1 alterations), highlighting the ongoing need for phenotype‑driven evaluation and the possibility of yet‑unresolved genetic etiologies in adults with nOH and leukoencephalomyelopathy. Management and longitudinal data: We report real‑world therapy (fludrocortisone, midodrine, bladder management) and 5‑year follow‑up, including ABPM that revealed prominent nocturnal hypertension—information directly relevant to the daily practice of autonomic medicine. Introduction Syncope remains a diagnostic challenge, with many patients discharged without a definitive diagnosis from outpatient settings despite thorough evaluations[1]. Neurogenic orthostatic hypotension (nOH), responsible for one-quarter of cases, is an atypical cause often missed in standard assessments [1, 2]. Its diagnosis, reflecting underlying disorders that impair the autonomic nervous networks, usually involves prolonged investigations and referral to specialists [2-4]. Leukoencephalopathy, a group of white matter disorders, is a less recognized cause of syncope and associated autonomic dysfunction. Although autonomic manifestations of these conditions, such as ataxia, muscle weakness, and cognitive decline, are acknowledged, syncope is rarely reported at initial medical consultations[5, 6]. Leukodystrophies are challenging to diagnose, with patients often undergoing extensive testing before conclusive diagnoses are reached. Early recognition and prompt treatment can avoid irreversible damage of the autonomic nervous system. Atypical presentations, such as syncope, may lead to delay in diagnosis and treatment. Neuroimaging is central in identifying these disorders but is not routinely performed for patients presenting with syncope, even when nOH is suspected. We present a patient with orthostatic hypotension and presyncope, who, after autonomic testing and neuroimaging, was diagnosed with adult-onset leukoencephalopathy, highlighting the complexity of diagnosing this condition. Case Presentation A 41-year-old male presented to the outpatient department with a five-year history of recurrent syncopal episodes (Figure 1a). At a bus terminal, he became dizzy and lost consciousness for less than a minute after standing up from a seated position. This was followed with transient arm and leg weakness. During his initial evaluation, syncopal episodes had increased to three or four times weekly. Within a year, he developed urinary urgency with overflow incontinence, later alternating diarrhea, and constipation, as well as cerebellar dysfunction, including gait ataxia and imbalance. He reported declining abilities to ascend stairs and reduced exercise tolerance compared to five years earlier. Despite these physical challenges, his cognitive functions remained intact. His medical history included mild head trauma from a bicycle accident occurring several months before the onset of syncopal episodes, for which he did not receive medical attention. He also reported seven years of hand and thigh paresthesia and hyperhidrosis. On examination, the patient demonstrated reduced muscle strength (graded 4) in proximal left legs and hands, without spasticity, rigidity, ankle clonus, and hyperreflexia. Neurological assessment confirmed cerebellar ataxia, as evidenced by impaired tandem gait and dysdiadochokinesia, pointing towards a complex presentation that suggested an underlying multisystem involvement beyond simple orthostatic hypotension. Diagnostic Assessments With suspicion for nOH, standardized autonomic testing was performed and revealed pronounced abnormality in all domains. Head-up tilt caused a 40 mmHg progressive drop in systolic BP (Figure 1b). The Valsalva maneuver demonstrated a 25 mmHg fall in early phase II, with an absent late phase II and markedly prolonged blood pressure recovery time (PRT) of approximately 10 seconds (Figure 1c). Quantitative sudomotor axon reflex testing (QSART) showed reduced sweat output at the forearm, proximal leg, distal leg, and foot (Figure 1d). Heart rate variability during breathing (HRDB) was 20 bpm, within the normal range of above 15 bpm. Together, these findings indicated a diagnosis of generalized autonomic dysfunction and moderate autonomic failure. Other investigations, including blood chemistry and autoimmune screening, were unremarkable. Urinary tract ultrasound revealed mild bilateral hydronephrosis without discernible blockage, consistent with neurogenic bladder. Eye examination revealed pathologic myopia and retinoschisis in the left eye, suggesting involvement of systems beyond the autonomic nervous system. Despite diverse clinical manifestations, the patient's cognitive functions were found intact during initial assessments. Given reported symptoms of weakness and numbness, magnetic resonance imaging (MRI) of the brain was conducted during the initial clinic visit. T2-weighted images revealed symmetrical hyperintensities in the periventricular white matter of bilateral frontal and parietal lobes, bilateral posterior limb of the internal capsules, and splenium of the corpus callosum, while sparing the subcortical white matter (Figure 1e). Reduced volumes in both the brainstem and cerebellum were seen, with additional hyperintensities in specific areas of the brainstem, including the ventral and lateral portions of the pons, the pontine-trigeminal nerve roots, and the medial lemniscus, extending along the corticospinal tracts from the pons down to the spinal cord (Figure 1f). There was also enhancement of the superior and middle cerebellar peduncles. T1-weighted images showed slight hypointensity, while diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping revealed no restricted diffusion. Follow-up MRI two years later did not demonstrate substantial change. Magnetic resonance spectroscopy (MRS) indicated reduction in N-acetylaspartate (NAA) levels within the confluent white matter lesions, without lactate peak. Whole spine MRI showed central cord enhancement, diffused spinal cord and conus medullaris atrophy, and faint intramedullary T2 hyperintensity in both lateral columns, attributing to the suspected underlying leukoencephalomyelopathy. In light of these findings, a commercial targeted gene panel sequencing test was conducted to identify any genetic mutations. The test results did not reveal any pathogenic variants in genes commonly associated with adult-onset leukodystrophy or leukoencephalopathy. Follow-Ups and Outcomes The patient was initially treated with both symptomatic and supportive measures. Fludrocortisone and Midodrine were prescribed to raise blood pressure, while Oxybutynin with intermittent catheterization was used to manage neurogenic bladder symptoms. However, at 5-year follow-up, the patient reported a decline in physical activity and persistent presyncope. After a motorcycle accident later that year, the patient observed muscle weakness that had been limited to the left side and had now progressed to all four extremities, with increased numbness on the right side of his body. Presyncopal symptoms became more pronounced and were accompanied by heightened tiredness, palpitations, and new-onset cognitive concerns. Ambulatory Blood Pressure Monitoring (ABPM) revealed a concerning nocturnal blood pressure pattern, with hypertensive averages of 165/117 mmHg indicative of significant autonomic dysregulation. These abnormalities reveal the complexity and progression of his underlying condition. Discussions Evaluation of syncope begins with comprehensive history, physical examination, and echocardiography. Recurrent, unexplained episodes raise concern for the presence of serious underlying conditions[4, 7]. In our case, the patient sought care for syncope accompanied by progressive autonomic symptoms lasting over five years. The emergence of symptoms of autonomic dysfunction and motor difficulties necessitated an investigation that extended beyond preliminary examination of orthostatic hypotension, leading to a suspicion of a neurological origin. Autonomic testing subsequently confirmed generalized dysfunction with impaired adrenergic response, and markedly reduced sudomotor activity, while neuroimaging established the diagnosis of leukoencephalomyelopathy. In the diagnostic process, non-neurogenic causes of orthostatic hypotension (OH), such as medication effects and volume depletion, must initially be excluded [8]. Once neurogenic orthostatic hypotension (nOH) is suspected, autonomic function testing confirms the diagnosis[9]. Distinguishing central from peripheral causes of nOH is important: central autonomic pathways dysfunction indicates chronic and progressive autonomic dysfunction, while peripheral involvement implicates noradrenergic fibers[4]. Central nervous system (CNS) pathologies, including alpha-synucleinopathies, neurodegenerative diseases, and disruptions within the central autonomic network, are common etiologies where MRI plays an essential role in evaluation[10]. The central autonomic network encompasses the insula, amygdala, hypothalamus, periaqueductal gray, nucleus of the solitary tract, and the ventrolateral medulla [11]. These regions, through interconnected white matter tracts, contribute to specific autonomic functions. Orthostatic hypotension is often linked to damage or demyelination of nerve fibers projecting from the nucleus tractus solitarius to the rostral ventrolateral medulla (RVLM) [12]. Consistent with the above case, MRI findings for our patient showed hyperintensity in the brainstem, including the RVLM, and abnormalities in the supraspinal anterior portion of the lateral columns. The disease progression in the absence of external triggers suggests a hereditary cause. The clinical presentation and neuroimaging findings align with adult-onset leukodystrophy, comprising a spectrum of hereditary neurodegenerative white matter disorders with variable phenotypes, age onset, and genetic mutations [5, 13]. Although diverse neurological symptoms can occur, autonomic dysfunction prominently features in only a select few leukoencephalomyelopathies, primarily adult-onset leukodystrophy (ADLD) and adult polyglucosan body disease (APBD) [13, 14]. Moreover, MRI findings, showing increased signal intensity in the frontoparietal deep cortex, cerebellar white matter, brainstem, and spinal cord, coincide with documented cases of ADLD with autonomic symptoms [15]. Nevertheless, genetic analysis did not identify LMNB1 duplication nor a heterozygous deletion in the LMNB1 promoter, underscoring the need for further genetic exploration to pinpoint the precise etiology of the patient's condition. Conclusions This case highlights the diagnostic complexity of syncope with autonomic dysfunction, leading to a diagnosis of adult-onset leukoencephalomyelopathy. Therefore, attention must not only be placed on history and physical examination, but also on appropriate investigations for evaluating syncope, especially when presented with autonomic involvement and other neurologic manifestations. This will steer physicians to the correct cause beyond one’s assumptions and initial diagnoses. Abbreviations nOH; neurogenic orthostatic hypotension ADLD; adult onset leukodystrophy APBD; Adult polyglucosan body disease CNS; Central Nervous System EKG; Electrocardiography MRI; magnetic resonance imaging RVLM; rostral ventral lateral medulla QSART; Quantitative sudomotor axon reflex testing Declarations Ethics & consent: Written informed consent for publication was obtained from the patient. The study was approved by the Institutional Review Board, Faculty of Medicine, Chulalongkorn University (IRB no. 0917/66; COE no. 022/2024). Authorship and transparency: All authors meet ICMJE authorship criteria, have approved the final manuscript, and agree to be accountable for all aspects of the work. The work is original, has not been published previously, and is not under consideration elsewhere. ORCID iDs and author emails are provided on the title page/manuscript metadata. Informed Consent Written informed consent was obtained from the patient for publication of this case report. Ethical approval for reporting this case report was obtained from the institutional review board of the Faculty of Medicine, Chulalongkorn University, Thailand (IRB no. 0917/66 and COE no. 022/2024) Author Contributions A.K. Conceptualization, Data Collection, Writing – Original Draft N.S. Conceptualization, Data Collection, Writing – Original Draft C.T. Data Collection, Writing – Review & Editing J.A. Conceptualization, Data Collection, Writing – Review & Editing, Supervision R.C. Data Collection, Writing – Review & Editing, Supervision K.J. Data Collection, Writing – Review & Editing, Supervision Ethical Approval This study has been reviewed and approved by the Institutional Review Board (IRB) of the Faculty of Medicine at Chulalongkorn University, Bangkok, Thailand. The approval was granted under the IRB No 0917/66 Funding J.A. has received funding from Chulalongkorn University for English editing and Article Processing Charges (APC) related to the publication of this study. However, this financial support does not influence the research, findings, or conclusions presented in this paper. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Acknowledgments We extend our heartfelt gratitude to our patient and his family for generously providing the necessary information and granting consent for the publication of this case report. References Brignole, M., et al., Guidelines on management (diagnosis and treatment) of syncope. European heart journal, 2001. 22(15): p. 1256-1306. Kalra, D.K., A. Raina, and S. Sohal, Neurogenic orthostatic hypotension: state of the art and therapeutic strategies. Clinical Medicine Insights: Cardiology, 2020. 14: p. 1179546820953415. https://doi.org/10.1177/1179546820953415 Bradley, J.G. and K.A. Davis, Orthostatic hypotension. American family physician, 2003. 68(12): p. 2393-2399. Metzler, M., et al., Neurogenic orthostatic hypotension: pathophysiology, evaluation, and management. Journal of neurology, 2013. 260(9): p. 2212-2219. https://doi.org/10.1007/s00415-012-6736-7 van der Knaap, M.S., et al., Diagnosis, prognosis, and treatment of leukodystrophies. The Lancet Neurology, 2019. 18(10): p. 962-972. https://doi.org/10.1016/S1474-4422(19)30143-7 Lynch, D.S., et al., Clinical and genetic characterization of leukoencephalopathies in adults. Brain, 2017. 140(5): p. 1204-1211. https://doi.org/10.1093/brain/awx045 Bennett, M.T., N. Leader, and A.D. Krahn, Recurrent syncope: differential diagnosis and management. Heart, 2015. 101(19): p. 1591-1599. https://doi.org/10.1136/heartjnl-2014-306627 Freeman, R., Neurogenic orthostatic hypotension. New England Journal of Medicine, 2008. 358(6): p. 615-624. https://doi.org/10.1056/nejmcp074189 Palma, J.A. and H. Kaufmann, Epidemiology, diagnosis, and management of neurogenic orthostatic hypotension. Movement disorders clinical practice, 2017. 4(3): p. 298-308. https://doi.org/10.1002/mdc3.12478 Sklerov, M., E. Dayan, and N. Browner, Functional neuroimaging of the central autonomic network: recent developments and clinical implications. Clinical autonomic research, 2019. 29(6): p. 555-566. https://doi.org/10.1007/s10286-018-0577-0 Cersosimo, M.G. and E.E. Benarroch, Central control of autonomic function and involvement in neurodegenerative disorders. Handbook of clinical neurology, 2013. 117: p. 45-57. https://doi.org/10.1016/B978-0-444-53491-0.00005-5 Chokroverty, S. and S. Bhat, Functional neuroanatomy of the peripheral autonomic nervous system , in Autonomic Nervous System and Sleep: Order and Disorder . 2021, Springer. p. 19-28. https://doi.org/10.1007/978-3-030-62263-3_3 Lynch, D.S., et al., Practical approach to the diagnosis of adult-onset leukodystrophies: an updated guide in the genomic era. Journal of Neurology, Neurosurgery & Psychiatry, 2019. 90(5): p. 543-555. https://doi.org/10.1136/jnnp-2018-319481 Köhler, W., J. Curiel, and A. Vanderver, Adulthood leukodystrophies. Nature Reviews Neurology, 2018. 14(2): p. 94-105. https://doi.org/10.1038/nrneurol.2017.175 Sundblom, J., et al., MR imaging characteristics and neuropathology of the spinal cord in adult-onset autosomal dominant leukodystrophy with autonomic symptoms. American journal of neuroradiology, 2009. 30(2): p. 328-335. https://doi.org/10.3174/ajnr.A1354 Supplementary Files Supplementary.pdf 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. 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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-7445286","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":517234357,"identity":"e4fa8ca5-cc34-4264-9b83-3e3cabbe2093","order_by":0,"name":"Arp-Arpa Kasemsantitham","email":"","orcid":"","institution":"Chulalongkorn University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Arp-Arpa","middleName":"","lastName":"Kasemsantitham","suffix":""},{"id":517234358,"identity":"04b5cbdf-58ad-4b5e-beed-8947e9c8fb4d","order_by":1,"name":"Nithit 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Timeline of signs and symptoms. \u003cstrong\u003eb. \u003c/strong\u003eTilt table test, heart rate, and blood pressure were monitored. The systolic pressure decreased by 20-25 mmHg within the first 3 minutes. At approximately 5 minutes, the systolic pressure fell below 90 mmHg, representing a total drop of 40 mmHg, accompanied by near-syncope symptoms, prompting termination of the test. \u003cstrong\u003ec. \u003c/strong\u003eValsalva maneuver, the graph revealed decreased mean BP of approximately 25 mmHg in the early phase II, with an absence of late phase II and prolonged PRT of approximately 10 seconds. \u003cstrong\u003ed. \u003c/strong\u003eQSART, the graph demonstrated reduced sweat output at the forearm, proximal leg, distal leg, and foot (0.308, 0.148, 0.114, and 0.114 µL/cm², respectively), all \u0026lt;50% of the 5th percentile of the normal population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ee.\u003c/strong\u003e Bilateral symmetrical hypersignal abnormality on axial FLAIR T2-weight image (I) in bilateral cerebral periventricular and deep white matter, posterior limb of bilateral internal capsules, and splenium of corpus callosum with relatively subcortical sparing. (II) Axial gadolinium-enhanced T1-weighted image reveals no enhancement. (III) and (IV) No restricted diffusion is observed on DWI and ADC. \u003cstrong\u003ef.\u003c/strong\u003e (I) and (II) Symmetrical FLAIR hypersignal intensity is demonstrated in both sides of the brain stem involving corticospinal tracts, medial lemniscus, pontine trigeminal nerve roots, and superior and middle cerebellar peduncles. (III) Sagittal and (IV) axial T2-weighted images of the cervical spine reveal a reduction in spinal cord volume with symmetrical hyperintensity in bilateral lateral columns.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7445286/v1/e288e3fb281af38aa82efcf6.png"},{"id":101753914,"identity":"9045acca-a493-423e-895d-5d72a3021811","added_by":"auto","created_at":"2026-02-03 10:41:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":770214,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7445286/v1/e42effb5-ea96-40b1-abe1-f84f9fe2cf8b.pdf"},{"id":91830519,"identity":"01b70412-14af-4532-b328-d41c86984dfb","added_by":"auto","created_at":"2025-09-22 09:04:01","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":223485,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7445286/v1/a5303697f8d6499dc2ba941b.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eSyncope Unveiling a Diagnosis of Adult-Onset Leukoencephalomyelopathy: A case report\u003c/p\u003e","fulltext":[{"header":"Why this case fits the journal and adds value?","content":"\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eAutonomic focus with clear physiology:\u003c/strong\u003e The patient exhibited generalized autonomic failure with impaired adrenergic responses and markedly reduced sudomotor activity, while heart‑rate variability during breathing remained preserved\u0026mdash;an instructive pattern for differentiating central from peripheral causes of nOH.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eNeuroimaging that maps to the central autonomic network:\u003c/strong\u003e Brainstem and cerebellar white‑matter involvement (including regions encompassing pathways between the nucleus tractus solitarius and rostral ventrolateral medulla) aligns with the clinical phenotype and provides readers with concrete imaging correlates of autonomic dysfunction.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eGenetics‑aware, phenotype‑first approach:\u003c/strong\u003e A broad, 728‑gene targeted panel was negative for known adult‑onset leukodystrophy/leukoencephalopathy variants (including \u003cem\u003eLMNB1\u003c/em\u003e alterations), highlighting the ongoing need for phenotype‑driven evaluation and the possibility of yet‑unresolved genetic etiologies in adults with nOH and leukoencephalomyelopathy.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eManagement and longitudinal data:\u003c/strong\u003e We report real‑world therapy (fludrocortisone, midodrine, bladder management) and 5‑year follow‑up, including ABPM that revealed prominent nocturnal hypertension\u0026mdash;information directly relevant to the daily practice of autonomic medicine.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eSyncope remains a diagnostic challenge, with many patients discharged without a definitive diagnosis from outpatient settings despite thorough evaluations[1]. Neurogenic orthostatic hypotension (nOH), responsible for one-quarter of cases, is an atypical cause often missed in standard assessments [1, 2]. Its diagnosis, reflecting underlying disorders that impair the autonomic nervous networks, usually involves prolonged investigations and referral to specialists\u0026nbsp;[2-4].\u003c/p\u003e\n\u003cp\u003eLeukoencephalopathy, a group of white matter disorders, is a less recognized cause of syncope and associated autonomic dysfunction. Although autonomic manifestations of these conditions, such as ataxia, muscle weakness, and cognitive decline, are acknowledged, syncope is rarely reported at initial medical consultations[5, 6]. Leukodystrophies are challenging to diagnose, with patients often undergoing extensive testing before conclusive diagnoses are reached. Early recognition and prompt treatment can avoid irreversible damage of the autonomic nervous system. Atypical presentations, such as syncope, may lead to delay in diagnosis and treatment. Neuroimaging is central in identifying these disorders but is not routinely performed for patients presenting with syncope, even when nOH is suspected.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe present a patient with orthostatic hypotension and presyncope, who, after autonomic testing and neuroimaging, was diagnosed with adult-onset leukoencephalopathy, highlighting the complexity of diagnosing this condition.\u003c/p\u003e"},{"header":"Case Presentation ","content":"\u003cp\u003eA 41-year-old male presented to the outpatient department with a five-year history of recurrent syncopal episodes (Figure 1a). At a bus terminal, he became dizzy and lost consciousness for less than a minute after standing up from a seated position. This was followed with transient arm and leg weakness. During his initial evaluation, syncopal episodes had increased to three or four times weekly.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWithin a year, he developed urinary urgency with overflow incontinence, later alternating diarrhea, and constipation, as well as cerebellar dysfunction, including gait ataxia and imbalance. He reported declining abilities to ascend stairs and reduced exercise tolerance compared to five years earlier. Despite these physical challenges, his cognitive functions remained intact.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHis medical history included mild head trauma from a bicycle accident occurring several months before the onset of syncopal episodes, for which he did not receive medical attention. He also reported seven years of hand and thigh paresthesia and hyperhidrosis.\u003c/p\u003e\n\u003cp\u003eOn examination, the patient demonstrated reduced muscle strength (graded 4) in proximal left legs and hands, without spasticity, rigidity, ankle clonus, and hyperreflexia. Neurological assessment confirmed cerebellar ataxia, as evidenced by impaired tandem gait and dysdiadochokinesia, pointing towards a complex presentation that suggested an underlying multisystem involvement beyond simple orthostatic hypotension.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eDiagnostic Assessments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWith suspicion for nOH, standardized autonomic testing was performed and revealed pronounced abnormality in all domains. Head-up tilt caused a 40 mmHg progressive drop in systolic BP (Figure 1b). The Valsalva maneuver demonstrated a 25 mmHg fall in early phase II, with an absent late phase II and markedly prolonged blood pressure recovery time (PRT) of approximately 10 seconds (Figure 1c). Quantitative sudomotor axon reflex testing (QSART) showed reduced sweat output at the forearm, proximal leg, distal leg, and foot (Figure 1d). Heart rate variability during breathing (HRDB) was 20 bpm, within the normal range of above 15 bpm. Together, these findings indicated a diagnosis of generalized autonomic dysfunction and moderate autonomic failure. Other investigations, including blood chemistry and autoimmune screening, were unremarkable.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Urinary tract ultrasound revealed mild bilateral hydronephrosis without discernible blockage, consistent with neurogenic bladder. Eye examination revealed pathologic myopia and retinoschisis in the left eye, suggesting involvement of systems beyond the autonomic nervous system. Despite diverse clinical manifestations, the patient\u0026apos;s cognitive functions were found intact during initial assessments.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Given reported symptoms of weakness and numbness, magnetic resonance imaging (MRI) of the brain was conducted during the initial clinic visit. T2-weighted images revealed symmetrical hyperintensities in the periventricular white matter of bilateral frontal and parietal lobes, bilateral posterior limb of the internal capsules, and splenium of the corpus callosum, while sparing the subcortical white matter (Figure 1e). Reduced volumes in both the brainstem and cerebellum were seen, with additional hyperintensities in specific areas of the brainstem, including the ventral and lateral portions of the pons, the pontine-trigeminal nerve roots, and the medial lemniscus, extending along the corticospinal tracts from the pons down to the spinal cord (Figure 1f). There was also enhancement of the superior and middle cerebellar peduncles. T1-weighted images showed slight hypointensity, while diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping revealed no restricted diffusion. Follow-up MRI two years later did not demonstrate substantial change. Magnetic resonance spectroscopy (MRS) indicated reduction in N-acetylaspartate (NAA) levels within the confluent white matter lesions, without lactate peak. Whole spine MRI showed central cord enhancement, diffused spinal cord and conus medullaris atrophy, and faint intramedullary T2 hyperintensity in both lateral columns, attributing to the suspected underlying leukoencephalomyelopathy.\u003c/p\u003e\n\u003cp\u003eIn light of these findings, a commercial targeted gene panel sequencing test was conducted to identify any genetic mutations. The test results did not reveal any pathogenic variants in genes commonly associated with adult-onset leukodystrophy or leukoencephalopathy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-Ups and Outcomes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient was initially treated with both symptomatic and supportive measures. Fludrocortisone and Midodrine were prescribed to raise blood pressure, while Oxybutynin with intermittent catheterization was used to manage neurogenic bladder symptoms. However, at 5-year follow-up, the patient reported a decline in physical activity and persistent presyncope. After a motorcycle accident later that year, the patient observed muscle weakness that had been limited to the left side and had now progressed to all four extremities, with increased numbness on the right side of his body. Presyncopal symptoms became more pronounced and were accompanied by heightened tiredness, palpitations, and new-onset cognitive concerns.\u003c/p\u003e\n\u003cp\u003eAmbulatory Blood Pressure Monitoring (ABPM) revealed a concerning nocturnal blood pressure pattern, with hypertensive averages of 165/117 mmHg indicative of significant autonomic dysregulation. These abnormalities reveal the complexity and progression of his underlying condition.\u003c/p\u003e"},{"header":"Discussions","content":"\u003cp\u003eEvaluation of syncope begins with comprehensive history, physical examination, and echocardiography. Recurrent, unexplained episodes raise concern for the presence of serious underlying conditions[4, 7]. In our case, the patient sought care for syncope accompanied by progressive autonomic symptoms lasting over five years. The emergence of symptoms of autonomic dysfunction and motor difficulties necessitated an investigation that extended beyond preliminary examination of orthostatic hypotension, leading to a suspicion of a neurological origin. Autonomic testing subsequently confirmed generalized dysfunction with impaired adrenergic response, and markedly reduced sudomotor activity, while neuroimaging established the diagnosis of leukoencephalomyelopathy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the diagnostic process, non-neurogenic causes of orthostatic hypotension (OH), such as medication effects and volume depletion, must initially be excluded [8]. Once neurogenic orthostatic hypotension (nOH) is suspected, autonomic function testing confirms the diagnosis[9]. Distinguishing central from peripheral causes of nOH is important: central autonomic pathways dysfunction indicates chronic and progressive autonomic dysfunction, while peripheral involvement implicates noradrenergic fibers[4]. Central nervous system (CNS) pathologies, including alpha-synucleinopathies, neurodegenerative diseases, and disruptions within the central autonomic network, are common etiologies where MRI plays an essential role in evaluation[10].\u003c/p\u003e\n\u003cp\u003eThe central autonomic network encompasses the insula, amygdala, hypothalamus, periaqueductal gray, nucleus of the solitary tract, and the ventrolateral medulla [11]. These regions, through interconnected white matter tracts, contribute to specific autonomic functions. Orthostatic hypotension\u0026nbsp;is often linked to damage or demyelination of nerve fibers projecting from the nucleus tractus solitarius to the rostral ventrolateral medulla (RVLM) [12]. Consistent with the above case, MRI findings for our patient showed hyperintensity in the brainstem, including the RVLM, and abnormalities in the supraspinal anterior portion of the lateral columns.\u003c/p\u003e\n\u003cp\u003eThe disease progression in the absence of external triggers suggests a hereditary cause. The clinical presentation and neuroimaging findings align with adult-onset leukodystrophy, comprising a spectrum of hereditary neurodegenerative white matter disorders with variable phenotypes, age onset, and genetic mutations [5, 13]. Although diverse neurological symptoms can occur, autonomic dysfunction prominently features in only a select few leukoencephalomyelopathies, primarily adult-onset leukodystrophy (ADLD) and adult polyglucosan body disease (APBD) [13, 14]. Moreover, MRI findings, showing increased signal intensity in the frontoparietal deep cortex, cerebellar white matter, brainstem, and spinal cord, coincide with documented cases of ADLD with autonomic symptoms [15]. Nevertheless, genetic analysis did not identify LMNB1 duplication nor a heterozygous deletion in the LMNB1 promoter, underscoring the need for further genetic exploration to pinpoint the precise etiology of the patient's condition.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis case highlights the diagnostic complexity of syncope with autonomic dysfunction, leading to a diagnosis of adult-onset leukoencephalomyelopathy. Therefore, attention must not only be placed on history and physical examination, but also on appropriate investigations for evaluating syncope, especially when presented with autonomic involvement and other neurologic manifestations. This will steer physicians to the correct cause beyond one\u0026rsquo;s assumptions and initial diagnoses.\u003c/p\u003e"},{"header":"Abbreviations ","content":"\u003cp\u003enOH; neurogenic orthostatic hypotension\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eADLD;\u0026nbsp;adult onset leukodystrophy\u003c/p\u003e\n\u003cp\u003eAPBD; Adult polyglucosan body disease\u003c/p\u003e\n\u003cp\u003eCNS; Central Nervous System\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEKG; Electrocardiography\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMRI; magnetic resonance imaging \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRVLM; rostral\u0026nbsp;ventral lateral medulla\u003c/p\u003e\n\u003cp\u003eQSART; Quantitative sudomotor axon reflex testing\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics \u0026amp; consent:\u003c/strong\u003e Written informed consent for publication was obtained from the patient. The study was approved by the Institutional Review Board, Faculty of Medicine, Chulalongkorn University (IRB no. 0917/66; COE no. 022/2024).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship and transparency:\u003c/strong\u003e All authors meet ICMJE authorship criteria, have approved the final manuscript, and agree to be accountable for all aspects of the work. The work is original, has not been published previously, and is not under consideration elsewhere. ORCID iDs and author emails are provided on the title page/manuscript metadata.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report. Ethical approval for reporting this case report was obtained from the institutional review board of the Faculty of Medicine, Chulalongkorn University, Thailand (IRB no. 0917/66 and COE no. 022/2024)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA.K. Conceptualization, Data Collection, Writing \u0026ndash; Original Draft\u003c/p\u003e\n\u003cp\u003eN.S. Conceptualization, Data Collection, Writing \u0026ndash; Original Draft\u003c/p\u003e\n\u003cp\u003eC.T. Data Collection, Writing \u0026ndash; Review \u0026amp; Editing\u003c/p\u003e\n\u003cp\u003eJ.A. Conceptualization, Data Collection, Writing \u0026ndash; Review \u0026amp; Editing, Supervision\u003c/p\u003e\n\u003cp\u003eR.C. Data Collection, Writing \u0026ndash; Review \u0026amp; Editing, Supervision\u003c/p\u003e\n\u003cp\u003eK.J. Data Collection, Writing \u0026ndash; Review \u0026amp; Editing, Supervision\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has been reviewed and approved by the Institutional Review Board (IRB) of the Faculty of Medicine at Chulalongkorn University, Bangkok, Thailand. The approval was granted under the IRB No 0917/66\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJ.A. has received funding from Chulalongkorn University for English editing and Article Processing Charges (APC) related to the publication of this study. However, this financial support does not influence the research, findings, or conclusions presented in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe extend our heartfelt gratitude to our patient and his family for generously providing the necessary information and granting consent for the publication of this case report.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eBrignole, M., et al., \u003cem\u003eGuidelines on management (diagnosis and treatment) of syncope.\u003c/em\u003e European heart journal, 2001. 22(15): p. 1256-1306.\u003c/li\u003e\n \u003cli\u003eKalra, D.K., A. Raina, and S. Sohal, \u003cem\u003eNeurogenic orthostatic hypotension: state of the art and therapeutic strategies.\u003c/em\u003e Clinical Medicine Insights: Cardiology, 2020. 14: p. 1179546820953415. https://doi.org/10.1177/1179546820953415\u003c/li\u003e\n \u003cli\u003eBradley, J.G. and K.A. Davis, \u003cem\u003eOrthostatic hypotension.\u003c/em\u003e American family physician, 2003. 68(12): p. 2393-2399.\u003c/li\u003e\n \u003cli\u003eMetzler, M., et al., \u003cem\u003eNeurogenic orthostatic hypotension: pathophysiology, evaluation, and management.\u003c/em\u003e Journal of neurology, 2013. 260(9): p. 2212-2219. https://doi.org/10.1007/s00415-012-6736-7\u003c/li\u003e\n \u003cli\u003evan der Knaap, M.S., et al., \u003cem\u003eDiagnosis, prognosis, and treatment of leukodystrophies.\u003c/em\u003e The Lancet Neurology, 2019. 18(10): p. 962-972. https://doi.org/10.1016/S1474-4422(19)30143-7\u003c/li\u003e\n \u003cli\u003eLynch, D.S., et al., \u003cem\u003eClinical and genetic characterization of leukoencephalopathies in adults.\u003c/em\u003e Brain, 2017. 140(5): p. 1204-1211. https://doi.org/10.1093/brain/awx045\u003c/li\u003e\n \u003cli\u003eBennett, M.T., N. Leader, and A.D. Krahn, \u003cem\u003eRecurrent syncope: differential diagnosis and management.\u003c/em\u003e Heart, 2015. 101(19): p. 1591-1599. https://doi.org/10.1136/heartjnl-2014-306627\u003c/li\u003e\n \u003cli\u003eFreeman, R., \u003cem\u003eNeurogenic orthostatic hypotension.\u003c/em\u003e New England Journal of Medicine, 2008. 358(6): p. 615-624. https://doi.org/10.1056/nejmcp074189\u003c/li\u003e\n \u003cli\u003ePalma, J.A. and H. Kaufmann, \u003cem\u003eEpidemiology, diagnosis, and management of neurogenic orthostatic hypotension.\u003c/em\u003e Movement disorders clinical practice, 2017. 4(3): p. 298-308. https://doi.org/10.1002/mdc3.12478\u003c/li\u003e\n \u003cli\u003eSklerov, M., E. Dayan, and N. Browner, \u003cem\u003eFunctional neuroimaging of the central autonomic network: recent developments and clinical implications.\u003c/em\u003e Clinical autonomic research, 2019. 29(6): p. 555-566. https://doi.org/10.1007/s10286-018-0577-0\u003c/li\u003e\n \u003cli\u003eCersosimo, M.G. and E.E. Benarroch, \u003cem\u003eCentral control of autonomic function and involvement in neurodegenerative disorders.\u003c/em\u003e Handbook of clinical neurology, 2013. 117: p. 45-57. https://doi.org/10.1016/B978-0-444-53491-0.00005-5\u003c/li\u003e\n \u003cli\u003eChokroverty, S. and S. Bhat, \u003cem\u003eFunctional neuroanatomy of the peripheral autonomic nervous system\u003c/em\u003e, in \u003cem\u003eAutonomic Nervous System and Sleep: Order and Disorder\u003c/em\u003e. 2021, Springer. p. 19-28. https://doi.org/10.1007/978-3-030-62263-3_3\u003c/li\u003e\n \u003cli\u003eLynch, D.S., et al., \u003cem\u003ePractical approach to the diagnosis of adult-onset leukodystrophies: an updated guide in the genomic era.\u003c/em\u003e Journal of Neurology, Neurosurgery \u0026amp; Psychiatry, 2019. 90(5): p. 543-555. https://doi.org/10.1136/jnnp-2018-319481\u003c/li\u003e\n \u003cli\u003eK\u0026ouml;hler, W., J. Curiel, and A. Vanderver, \u003cem\u003eAdulthood leukodystrophies.\u003c/em\u003e Nature Reviews Neurology, 2018. 14(2): p. 94-105. https://doi.org/10.1038/nrneurol.2017.175\u003c/li\u003e\n \u003cli\u003eSundblom, J., et al., \u003cem\u003eMR imaging characteristics and neuropathology of the spinal cord in adult-onset autosomal dominant leukodystrophy with autonomic symptoms.\u003c/em\u003e American journal of neuroradiology, 2009. 30(2): p. 328-335. https://doi.org/10.3174/ajnr.A1354\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"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":"syncope, orthostatic hypotension, leukodystrophy, leukoencephalomyelopathy","lastPublishedDoi":"10.21203/rs.3.rs-7445286/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7445286/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWe present a patient with orthostatic hypotension and presyncope, who, after autonomic testing and neuroimaging, was diagnosed with adult-onset leukoencephalopathy, highlighting the complexity of diagnosing this condition.\u003c/p\u003e","manuscriptTitle":"Syncope Unveiling a Diagnosis of Adult-Onset Leukoencephalomyelopathy: A case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-22 08:55:56","doi":"10.21203/rs.3.rs-7445286/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":"2c1ada4f-f3c8-4087-b0d1-80b601046eb0","owner":[],"postedDate":"September 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-03T02:21:52+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-22 08:55:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7445286","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7445286","identity":"rs-7445286","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}